Clinical trial NCT02133924
Conditions: Acute Graft Versus Host Disease
Keywords: Graft vs Host Disease Graft vs Host Reaction allogeneic bone marrow transplantation allogeneic hematopoietic stem cell transplantation adverse effects
Sponsor: John Levine
Start date: 2016-08-01; Completion date: 2021-11-21
Enrollment: 76 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research trial is designed to study the safety and effectiveness of combining the study drug, Natalizumab (Tysabri®) with the standard treatment, the use of steroids, as a new treatment for acute graft versus host disease (acute GVHD). GVHD is the most common serious complication, after bone marrow transplant. GVHD occurs when the donor cells (the graft), treat the recipient's body as "foreign" and attack the cells in the recipient's body. During this immune system response, donor cells damage body tissues, such as the skin, liver, stomach, and/or intestines. Acute GVHD can be severe and if severe, potentially fatal to the transplant recipient. Acute GVHD usually happens within the first several months after transplant.

The goal of this research is to develop a safer and more effective treatment for acute GVHD, and particularly for acute GVHD that affects the gastrointestinal (or GI) tract, with the ultimate goal being safer and more effective transplant therapies for blood cancers such as leukemia, lymphoma, and multiple myeloma.

Detailed description:
The only proven effective treatment for patients with acute graft vs host disease is steroids. Patients not responding to steroid treatment are at high risk for death. Unfortunately, based on the early symptoms, it is not possible to tell whether a patient will respond to steroids, when GVHD is diagnosed and treatment with steroids, such as prednisone, is started.

This research trial is designed to study the safety and effectiveness of combining the study drug, Natalizumab (Tysabri®) with the use of steroids to treat acute GVHD in patients at the earliest stages of clinical symptoms, but, by using a proprietary method developed at the University of Michigan and the Icahn School of Medicine at Mount Sinai, are predicted to be at high risk for not responding to steroid therapy, the standard of care.

Investigators at Mount Sinai have developed a research method believed that it might make it possible to predict who is at high risk for not responding to steroids. This method, called Ann Arbor GVHD scoring, uses the levels of naturally occurring chemicals in the blood (called biomarkers) to determine a patient's GVHD score(1, 2, or 3).

A hypothesis is that many patients with Ann Arbor score 2 or 3 GVHD, will not respond well to steroid treatment and die within 6 months of their GVHD diagnosis. Most of the deaths are due to intestinal GVHD, which sometimes does not develop, until after standard steroid treatment has already begun.

Only patients with Ann Arbor score 2 or 3 GVHD, will be eligible for this study treatment. It is important to understand that Ann Arbor GVHD grading is not approved for clinical use. It can only be used as a test for research purposes. In this study, patients must have their blood tested to determine, if they qualify as Ann Arbor score 2 or 3 GVHD, and must start the study treatment within 3 days of starting systemic steroid treatment for acute GVHD.

The study will test whether the investigators can improve steroid response and prevent death from GVHD with the combination therapy, by blocking the donor cells from getting to the intestine and causing damage. Natalizumab (Tysabri®) is a drug that works by blocking the signals that cause immune cells like donor cells, to travel to organs like the intestine or brain.

Natalizumab is FDA-approved in adults, to treat Crohn's disease, a chronic condition where immune cells cause damage to the digestive system (such as the stomach, intestines). It is also used to treat multiple sclerosis where immune cells cause damage to the nervous system in the brain. Its intended use is for patients with disease that has not responded to the standard treatment, or cannot tolerate the side effects from standard treatments.

Natalizumab has never been used for treating GVHD. It is an experimental drug for this study, because the investigators are investigating a new use for the drug, as a GVHD treatment.

Arms: arm 1: For subjects whose GVHD assay is Ann Arbor score 2 or 3, the study treatment will consist of two drugs, prednisone (or methylprednisolone) and natalizumab.

Protocol treatment must start within 3 days of the subject's diagnosis of acute GVHD.
Interventions: intervention 1: natalizumab intervention 2: steroids
Intervention descriptions: intervention 1: Natalizumab 300mg on days 0 and 14. intervention 2: Prednisone 2mg/kg/d (or methyl-prednisolone IV equivalent)

Protocol documents:
Prot_SAP_000.pdf: 
Phase II Multicenter Study Of Natalizumab Plus Standard Steroid Treatment 
For High Risk Acute Graft-Versus-Host Disease
PI: John Levine, MD
NCT02133924
Document Date: May 11, 2020


 
 
PHASE II MULTICENTER STUDY OF NATALIZUMAB PLUS STANDARD STEROID TREATMENT FOR HIGH 
RISK ACUTE GRAFT-VERSUS-HOST DISEASE 
 
Co-Principal Investigators: 
John E. Levine, MD, MS 
Bone Marrow Transplantation Program 
The Tisch Cancer Institute 
Division of Hematology/Medical Oncology 
Icahn School of Medicine at Mount Sinai 
1 Gustave L. Levy Pl, Box 1410,  
New York, New York 10029 
Phone: 212-241-6021 
Fax: 212-241-8618 
john.levine@mountsinai.org  
James Ferrara, MD, DSc 
Ward-Coleman Chair in Cancer Medicine 
The Tisch Cancer Institute 
Division of Hematology/Medical Oncology 
Icahn School of Medicine at Mount Sinai  
1470 Madison Avenue, 
 
New York, New York 10029 
Phone: 212-824-9365 
Fax: 646-537-9576 
james.ferrara@mssm.edu  
 
Biostatistician:  
 
Umut Özbek, PhD 
 
 
 
 
The Tisch Cancer Institute 
 
 
 
 
Icahn School of Medicine at Mount Sinai 
 
 
 
 
Department of Population Health Science and Policy 
 
 
 
 
1 Gustave L. Levy Pl, Box 1077, 
 
 
 
 
New York, New York 10029 
 
 
 
 
Phone: 212-659-9633 
 
 
 
 
Fax: 212-241-2998 
 
 
 
 
umut.ozbek@mountsinai.org 
 
Study Drug: 
 
 
Natalizumab (Tysabri) 
US IND No.: 
 
 
122,555 
 
Participating Centers: 
 
Monzr M. Al Malki, MD 
City of Hope National Medical 
Center 
Phone: 626-256-4673 x62405 
Fax: 626-301-8116 
malmalki@coh.org   
 
Sunil Abhyankar, MD 
University of Kansas Cancer 
Center  
Phone: 913-588-6030 
Fax: 913-588-8279 
sabhyankar@kumc.edu 
William Hogan, M.B., B.Ch.  
Mayo Clinic 
Phone: 507-284-2017 
Fax: 507-266-2412 
 
hogan.william@mayo.edu 
Yvonne Efebera, MD 
The Ohio State University 
Phone: 614-293-2268 
Fax: 614-293-7526 
 
yvonne.efebera@osumc.edu 
Ran Reshef, MD  
Herbert Irving Comprehensive 
Cancer Center,  
Columbia University Medical 
Center 
Phone: 212-342-0530 
Fax: 212-342-0550 
rr3036@cumc.columbia.edu 
 
Gerhard Hildebrandt, MD 
University of Kentucky 
Phone: 859-218-4966 
Fax: 859-257-3531 
gerhard.hildebrandt@uky.edu 
Doris M. Ponce, MD 
Memorial Sloan-Kettering  
Cancer Center 
Phone: 212-639-4838 
Fax: 212-717-3500 
ponced@mskcc.org 
 
David Porter, MD  
University of Pennsylvania 
Phone: 215-662-2862 
Fax: 215-615-5888 
david.porter@uphs.upenn.edu 
Amelia Langston, MD 
Winship Cancer Institute,  
Emory University 
Phone: 404-778-5984 
Fax: 404-778-3110 
zalkadh@emory.edu   
Yi-Bin Chen, MD 
Massachusetts General Hospital  
Phone: 617-726-0187 
Fax: 617-643-5843 
ychen6@partners.org   
Kehinde Adekola, MD, MSc 
Robert H Lurie Comprehensive 
Cancer Center,  
Northwestern University 
Phone: 312-695-2597 
Fax: 312-695-6189 
kehinde-
adekola@northwestern.edu 
Carrie L. Kitko, MD 
Vanderbilt University 
Phone: 615-936-2088 
Fax : 615-936-1767 
carrie.l.kitko@vanderbilt.edu 
 
Initial version: 
 
Apr-10-2014   
Amended version:  
May-10-2014 v1.0 
Amended version:  
Sept-08-2015 v 2.0 
Amended version:  
Nov-13-2015 v 3.0 
Amended version:  
Mar-18-2016 v 4.0 
Amended version: 
Mar-27-2017 v 5.0 
Amended version: 
Sept-14-2017 v 6.0 
Amended version: 
Aug-14-2018 v7.0 
Amended version: 
May-11-2020 v8.0 
 


________________________________________________________________________ 
 
Page ii of iv 
 
 
TABLE OF CONTENTS 
ABBREVIATIONS ............................................................................................................1 
1.0 
BACKGROUND AND RATIONALE ...................................................................6 
1.1 
Acute GVHD .................................................................................................................... 6 
1.2 
Revised Ann Arbor Scoring Algorithm (April 2017) ......................................................... 8 
1.3 
Rationale for Inclusion of Ann Arbor 2 GVHD (July 2018) .............................................. 8 
1.4 
Study Agent(s) Background and Associated Known Toxicities ....................................... 9 
1.5 
Safety Data for Natalizumab Generated in this study (July 2018) ................................ 10 
1.6 
Other Agents .................................................................................................................. 11 
1.7 
Rationale ........................................................................................................................ 11 
1.8 
Correlative Studies ........................................................................................................ 11 
2.0 
STUDY OBJECTIVES.........................................................................................12 
2.1 
Primary Objectives ......................................................................................................... 12 
2.2 
Secondary Objectives .................................................................................................... 12 
2.3 
Endpoints ....................................................................................................................... 12 
3.0 
PATIENT ELIGIBILITY .......................................................................................13 
3.1 
Inclusion Criteria ............................................................................................................ 13 
3.2 
Exclusion Criteria ........................................................................................................... 14 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES ..............14 
5.0 
TREATMENT PLAN ............................................................................................17 
5.1 
Treatment Dosage and Administration .......................................................................... 17 
5.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 18 
5.3 
Concomitant Medications/Treatments ........................................................................... 19 
5.4 
Other Modalities or Procedures ..................................................................................... 19 
5.5 
Infection Prophylaxis (August 2017) .............................................................................. 19 


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Page iii of iv 
 
 
5.6 
Duration of Therapy ....................................................................................................... 19 
5.7 
Off Treatment Criteria .................................................................................................... 19 
5.8 
Duration of Follow-Up .................................................................................................... 20 
5.9 
Off Study Criteria ........................................................................................................... 20 
5.10 
Patient Replacement ..................................................................................................... 20 
6.0 
STUDY PROCEDURES ......................................................................................20 
6.1 
Screening/Baseline Procedures .................................................................................... 20 
6.2 
Procedures During Treatment ....................................................................................... 21 
6.3 
Follow-Up Procedures ................................................................................................... 21 
6.4 
Time and Events Table .................................................................................................. 22 
7.0 
GVHD CLINICAL STAGING ..............................................................................23 
7.1 
ENDPOINT AND RESPONSE CRITERIA..................................................................... 23 
7.2 
SAFETY/TOXICITY DEFINITIONS ............................................................................... 24 
7.3 
Safety/Tolerability .......................................................................................................... 25 
8.0 
ADVERSE EVENTS ............................................................................................26 
8.1 
NATALIZUMAB .............................................................................................................. 26 
8.2 
Adverse Event Reporting Requirements ....................................................................... 28 
8.3 
Definitions ...................................................................................................................... 28 
8.4 
Adverse Event Characteristics ...................................................................................... 30 
8.5 
Serious Adverse Event Reporting Guidelines ............................................................... 30 
8.6 
Routine Reporting .......................................................................................................... 31 
8.7 
Reporting of Unanticipated Problems ............................................................................ 32 
8.8 
Stopping Rules .............................................................................................................. 32 
9.0 
DRUG INFORMATION .......................................................................................33 
9.1 
NATALIZUMAB .............................................................................................................. 34 
9.2 
CORTICOSTEROIDS (Prednisone and Methylprednisolone) ...................................... 35 


________________________________________________________________________ 
 
Page iv of iv 
 
 
10.0 
CORRELATIVES/SPECIAL STUDIES .........................................................36 
10.1 
Sample Collection Guidelines ........................................................................................ 36 
10.2 
Assay Methodology ....................................................................................................... 36 
10.3 
Specimen Banking ......................................................................................................... 36 
11.0 
STATISTICAL CONSIDERATIONS .............................................................37 
11.1 
Study Design/Study Endpoints ...................................................................................... 37 
11.2 
Sample Size and Accrual .............................................................................................. 37 
11.3 
Data Analyses Plans...................................................................................................... 38 
12.0 
DATA AND SAFETY MONITORING ............................................................38 
12.1 
Multisite Clinical Monitoring Procedures........................................................................ 39 
13.0 
QUALITY ASSURANCE AND AUDITS .......................................................41 
14.0 
REFERENCES .................................................................................................42 
15.0 
APPENDICES ...................................................................................................44 


________________________________________________________________________ 
Page 1 of 44 
 
ABBREVIATIONS 
 
Examples Include [the list should be inclusive of the entire protocol]: 
6-MP 
6-mercaptopurine 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMT 
Bone Marrow Transplant 
BMT CTN 
Blood and Marrow Transplant Clinical Trials Network 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CD 
Crohn’s Disease 
CMP 
Comprehensive Metabolic Panel 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
Co-PI 
Co-Principal Investigator 
CR 
Complete Response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 
DSMR 
Data and Safety Monitoring Report 
EBV 
Epstein-Barr Virus 
ELISA 
Enzyme-Linked Immunosorbent Assay 
FDA 
Food and Drug Administration 
GI 
Gastrointestinal 
GVHD 
Graft-Versus-Host Disease 
HCT 
Hematopoietic Stem Cell Transplantation 
HHV6 
Human Herpes Virus 6 
HSV 
Herpes Simplex Virus 
IND 
Investigational New Drug 
IL2Rα 
Interleukin-2 receptor-alpha 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
JC 
John Cunningham (virus) 
MAGIC 
Mount Sinai Acute GVHD International Consortium  
MS 
Multiple Sclerosis 
NCI 
National Cancer Institute 
NOS 
Not Otherwise Specified 
NR 
No Response 


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Page 2 of 44 
 
NRM 
Non-Relapse Mortality 
OS 
Overall Survival 
PE 
Physical Exam 
PI 
Principal Investigator 
PJP 
Pneumocystis Jiroveci Pneumonia 
PML 
Progressive Multifocal Leukoencephalopathy 
PR 
Partial Response 
PTLD 
Post-Transplant Lymphoproliferative Disorder 
REG3α 
Regenerating islet-derived 3 alpha 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
ST2 
Suppressor of tumorigenicity-2 
TCI 
The Tisch Cancer Institute at the Mount Sinai Health System 
TNFR1 
Tumor necrosis factor receptor-1 
UGI 
Upper Gastrointestinal 
VZV 
Varicella-Zoster Virus 
 


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Page 3 of 44 
 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY SYNOPSIS 
Title 
PHASE II MULTICENTER STUDY OF NATALIZUMAB PLUS 
STANDARD STEROID TREATMENT FOR HIGH RISK ACUTE GRAFT-
VERSUS-HOST DISEASE 
Phase 
Phase II 
Methodology 
Open label single arm  
Study Duration 
3 years 
Study Center(s) 
Multicenter – Icahn School of Medicine at Mount Sinai, City of Hope, 
Columbia University, Emory University, University of Kansas, Mass 
General, Mayo Clinic, Memorial Sloan-Kettering, Northwestern 
University, Ohio State University, University of Pennsylvania, Vanderbilt 
University 
Objectives 
1. To improve day 28 GVHD complete response rate for high risk 
GVHD patients from the historical rate of 42.5% to 57.5% by 
treatment with natalizumab and high dose systemic corticosteroids 
(2 mg/kg). 
2. To decrease 6-month NRM from the historical rate of 32% to 22% in 
patients treated on this clinical trial. 
Number of Subjects 
84 subjects 
Pre- Screening Process 
New Onset 
Acute GVHD
Grade I- IV 
  
Collect 5ml 
Serum & Ship 
Overnight to 
Ferrara Lab 
 
Measure  
TNFR1, 
REG3α, ST2   
by ELISA  
(4- 6 H ours)  
  
Assign 
Ann Arbor 
Score 
Study 
Eligible 
Score 
2/3 
 
1  
Standard 
Therapy  
 
Up  To 48 Hours 


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Page 4 of 44 
 
Inclusion Criteria 
1. New onset high risk acute GVHD (Ann Arbor score 2 or 3 as defined 
in Appendix A) following allogeneic BMT. Any clinical severity 
(Glucksberg grade I-IV) is eligible.  Patients with prior or existing 
diagnosis of GVHD without any treatment are eligible.  Patients given 
only topical corticosteroids for skin GVHD are eligible.  
2. Any donor type (e.g., related, unrelated) or stem cell source (bone 
marrow, peripheral blood, cord blood). Recipients of non-
myeloablative and myeloablative transplants are eligible. 
3. No prior systemic treatment for acute GVHD except for a maximum of 
3 days of prednisone ≤2 mg/kg/day (or IV methylprednisolone). 
Topical skin steroid treatment, non-absorbable oral steroid treatment 
for GI GVHD, and resumption of GVHD prophylaxis agents (e.g., 
calcineurin inhibitors) are permissible. Patients enrolled in BMT CTN 
1501 who randomized to sirolimus are also eligible. Exceptions can 
be made on a case-by-case basis with Sponsor-Investigator approval. 
4. Age 18 years or older. 
5. Direct bilirubin must be <2 mg/dL unless the elevation is known to be 
due to Gilbert syndrome or aGVHD within 3 days of enrollment. 
6. ALT/SGPT and AST/SGOT must be <5 x the upper limit of the normal 
range within 3 days of enrollment, unless the elevation is due to liver 
GVHD.  
7. If the patient is a woman of child-bearing potential, the patient and 
their sexual partner must agree to practice effective contraception.   
8. Written informed consent from patient or legal representative. 
9. Biopsy of acute GVHD target organ is strongly recommended but not 
required. Enrollment should not be delayed for biopsy or pathology 
results. Patients who do not enroll within 3 days of initiation of 
systemic steroid treatment for acute GVHD are not permitted to 
participate. 
Exclusion Criteria 
1. Patients with malignancy that is suspected or proven to have 
progressed, relapsed, or be persistent since BMT 
2. Uncontrolled active infection 
3. Patients with chronic GVHD only. Patients with overlap syndrome 
are eligible. 
4. History of Progressive Multifocal Leukoencephalopathy (PML) 
5. Known hypersensitivity to natalizumab 
6. Pregnant or nursing (lactating) women 
7. Use of other drugs for the treatment of acute GVHD 
8. Steroid therapy for indications other than GVHD at doses >0.5 
mg/kg/d of methylprednisolone or equivalent within 7 days prior to 
initiation of GVHD treatment 
9. Patients on dialysis 
10. Patients requiring ventilator support 
11. Investigational agent within 30 days of enrollment without approval 
from the Sponsor-Investigator 
Study Product(s), Dose, 
Route, Regimen 
Natalizumab (Tysabri) 300 mg IV on days 0 and 14 
Prednisone (or IV methylprednisolone) 2 mg/kg/d on days 0 to 2 then 
tapered according to clinical criteria 


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Page 5 of 44 
 
Duration of 
Administration 
Natalizumab for 2 doses over 14 days, prednisone (or IV 
methylprednisolone) for 28 days 
Reference Therapy 
Prednisone (or IV methylprednisolone) 2 mg/kg/d orally  day 0 to 2, then 
tapered according to clinical criteria 
Statistical Methodology 
We will enroll 84 patients with Ann Arbor score 2 or 3 GVHD which 
provides 80% power to detect a 15% difference in day 28 CR rates (to 
57.5% compared to the historical rate of 42.5%), assuming a Type I error 
rate of 0.05.  
 
Secondary outcomes for efficacy, [e.g., overall response rate (CR+PR), 
the incidence of steroid refractory GVHD, the incidence of severe GI 
GVHD (stage 3 or 4), non-relapse mortality, relapse rates, overall survival], 
and for safety [e.g. serious infections and other adverse events] will be 
analyzed using descriptive statistics (cumulative incidence curves, 
Kaplan-Meier, etc.) and compared to historical controls. Outcomes will be 
analyzed for all patients and separately according to Ann Arbor GVHD 
score. 
 
Historical controls for this study consists of 256 patients who met the 
criteria for Ann Arbor score 2 or 3 GVHD (see background and rationale) 
and who were either (1) diagnosed at the University of Michigan or the 
University of Regensburg or (2) participated in the MAGIC consortium 
observational study between 2013-2017. Approximately 75% of these 
patients were diagnosed and treated since 2010, thus the historical control 
population is comprised primarily of fairly recently transplanted patients. 
 
 
 


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Page 6 of 44 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Acute GVHD 
 
Acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell 
transplantation (HCT) is the major cause of non-relapse mortality (NRM) and ~25% of 
patients with GVHD will die from this complication, yet it has been graded and treated in 
the same way for almost 40 years. The GVHD grading system [Przepiorka 1995] uses only 
clinical symptom severity which imposes major limitations. Maximal GVHD grade, which 
includes response to treatment, correlates with NRM; however the grade of acute GVHD 
at diagnosis does not correlate with outcome sufficiently to guide treatment. Thus, 
treatment is not intensified until primary therapy has failed. This is one reason why the 
treatment of acute GVHD has not advanced. 
 
Although acute GVHD can develop in the skin, liver or gastrointestinal (GI) tract, it is GI 
GVHD that is the primary driver of NRM. The vast majority of patients who develop GI 
GVHD that does not respond to high dose systemic steroids, the only effective treatment, 
will die [MacMillan 2012].  Unfortunately, the presence of GI GVHD symptoms at diagnosis 
does not predict well for NRM because the majority of these patients are steroid 
responsive. Patients with GI GVHD at diagnosis treated in the US and France (n=894, 
personal communication, Daniel Weisdorf) experienced NRM of 28%, which was not 
significantly different from patients with an isolated skin GVHD presentation (NRM=25%). 
 
Ann Arbor GVHD Scoring 
 
Given the limitations of the current GVHD clinical staging system, we strategized to develop 
a GVHD grading system at onset that possessed the following four key attributes: (1) 
reproducible across different BMT centers and practices, (2) objective, that is, uses 
biomarkers only, (3) simple, and (4) each score should crisply define a risk group (low, 
medium, high). GVHD response to steroids strongly correlates to NRM. Most clinical trials, 
including this one, use day 28 response rates for the primary endpoint as it is a surrogate 
for GVHD survival [Levine 2010, MacMillan 2010, Saliba 2012]. Use of the standard day 
28 response endpoint will facilitate comparisons with other trials of GVHD treatment 
reported in the literature. However, analysis of multi-center data has shown that grading of 
clinical GVHD is often inaccurate without the adjudication of expert panels [Weisdorf 2003], 
which is impractical during the conduct of a clinical trial. The vast majority (>90%, primarily 
due to steroid refractory GI GVHD) of 6 month NRM is due to GVHD that fails to respond 
to steroids. We therefore chose to define risk for Ann Arbor scoring according to 6 month 
NRM instead of GVHD treatment response because they are closely correlated and 
because NRM is more objective. Furthermore, steroid refractory GI GVHD alone accounts 
for >80% of 6 month NRM. 
 
Next, we determined that score 1 GVHD should have a 6 month NRM <10%, similar to the 
6% NRM seen in patients transplanted at the University of Michigan who do not develop 
acute GVHD. We then conferred with national GVHD experts to recommend the NRM risk 
that would be sufficiently high to warrant experimental treatments as primary GVHD 
therapy. The consensus opinion was that score 3 GVHD should be defined as a 6 month 
NRM ≥40%. We therefore allowed score 2 GVHD to somewhere in-between score 1 and 
3. 
 
Having set the desired attributes of a new GVHD scoring system, which we have named 
Ann Arbor GVHD Scoring, we measured the concentrations of five validated biomarkers 
[Paczesny 2009, Paczesny 2010, Ferrara 2011, Vander Lugt 2013] with the strongest 
individual correlations with NRM (TNFR1, IL2Rα, elafin, REG3α, and ST2) in samples 
obtained at diagnosis of new onset acute GVHD grades I-IV  in 492 patients from either 
the University of Michigan or the University of Regensburg, Germany. We randomly divided 


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Page 7 of 44 
 
the samples into a training set (328 patients) and an independent validation set (164 
patients). We then used competing risks regression, with relapse after GVHD onset as the 
competing risk, to model 6 month NRM using combinations of the log-transformed absolute 
values of the five biomarkers. A model using three biomarkers (TNFR1, REG3α, and ST2) 
fit the training data well, and the fit was not significantly improved by including either of the 
other biomarkers (elafin and IL2Rα). Thus, we selected the simplest, three biomarker 
model, for further development. We then ordered the 328 training patients from lowest to 
highest according to their predicted probability (p̂ ), of NRM within 6 months of GVHD onset, 
and selected thresholds that stratified patients into NRM risk groups as defined above (Fig 
1). Notably, there was more than one threshold that met our defined criteria; therefore we 
selected thresholds within the middle of the acceptable range. The 6 month NRM rates 
(score 1, 9%; score 2, 28%; score 3, 47%) were highly statistically different from each other 
(Panel A). When we applied the Ann Arbor scoring system to the independent validation 
set the results were remarkably similar (score 1, 9%; score 2, 27%; score 3, 45%) (Panel 
B). 
 
 
 
The gold standard for reproducibility of a grading system is its performance in the multi-
center setting. Therefore, we analyzed samples from 300 patients enrolled in two 
multicenter trials of primary treatment for acute GVHD conducted by the BMT CTN (0302 
and 0802) [Alousi 2009, Bolanos-Meade 2014]. The eligibility criteria for these studies were 
new onset acute GVHD grades I-IV. Patients were randomized to prednisone 2 mg/kg/d 
(or methylprednisolone IV equivalent) and either etanercept, denileukin diftitox, 
pentostatin, mycophenolate or placebo. There were no significant differences in complete 
response rates or survival with any of the treatment arms. Panel C shows that in this 
second independent validation cohort the Ann Arbor scoring system provides reproducible 
6 month NRM rates (score 1, 5%; score 2, 19%; score 3, 43%). Importantly, the post-GVHD 
relapse rate of ~14% was evenly distributed across all 3 Ann Arbor GVHD scores in all 
cohorts, so the overall survival curves closely mirror the NRM curves. Finally, we confirmed 
score 
scores 
scores 


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Page 8 of 44 
 
that Ann Arbor GVHD scores correspond to early treatment response rates, which is 
important for clinical trial design (Fig 2).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ann Arbor score 3 identifies steroid refractory GI GVHD. 
A major innovation of Ann Arbor scoring is that the risk scores do not depend on GI tract 
involvement when GVHD is first diagnosed. For example, the NRM of Ann Arbor high risk 
GVHD is 45%. The vast majority of these deaths (85%) are from steroid resistant GI 
GVHD, even though 50% of high risk patients do not have clinical GI symptoms at 
diagnosis. This clinical trial will use the day 28 CR rate as the primary endpoint. The trial 
is powered to detect an increase from the 30% CR rate (in red, Fig 2) to 45% [Levine 2015]. 
 
1.2 
Revised Ann Arbor Scoring Algorithm (April 2017) 
 
A biomarker algorithm that uses only two biomarkers (ST2 and REG3α) to predict lethal 
GVHD on day 7 after BMT was developed and validated in a large multicenter study 
population of 1287 patients [Hartwell 2017]. The two biomarker algorithm was then shown 
to accurately predict outcomes at diagnosis of acute GVHD as well as at other time points 
post-BMT (such as one week after the initiation of steroid treatment for GVHD) [Major-
Monfried 2016]. The two biomarker algorithm has been adapted to produce identical scores 
to the original Ann Arbor scoring algorithm and replaces the three biomarker algorithm 
previously used for eligibility for this trial 
 
1.3 
Rationale for Inclusion of Ann Arbor 2 GVHD (August 2018) 
Outcomes for patients with Ann Arbor 3 GVHD are dismal, with a 45% non-relapse 
mortality rate within 6 months of diagnosis. Outcomes for patients with Ann Arbor 2 GVHD 
are also poor with unacceptably high rates of treatment failure (49%) and NRM (27%) as 
shown in Figures 1 and 2 above. We confirmed that these outcomes have not improved 
recently by analyzing outcomes of 120 MAGIC patients with Ann Arbor 2 GVHD since 
2015. The six month NRM rate in these patients remains stubbornly high at 24%. Patients 
with Ann Arbor 2 GVHD are therefore in need of better treatments than the current standard 
of care. 
 
Since this study opened we have screened 229 patients with newly diagnosed GVHD. The 
proportion of patients with Ann Arbor 3 GVHD is somewhat lower than expected (13% 
Score  
score 
score 
Score 


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Page 9 of 44 
 
compared to an expected 20%). Ann Arbor 2 GVHD comprises 21% of all patients 
screened. While an intervention that improves outcomes for Ann Arbor 3 GVHD would 
represent a significant advance in the field, an effective intervention for all patients with 
high risk GVHD (Ann Arbor 2 and 3) is highly desirable. We have therefore redesigned the 
statistical plan (section 11) such that we can retain the knowledge gained from the patients 
with Ann Arbor 3 GVHD already enrolled on this trial and expand the eligibility to patients 
with Ann Arbor 2 GVHD. The expanded eligibility will shorten the time to complete 
enrollment by 50%. 
1.4 
Study Agent(s) Background and Associated Known Toxicities 
GI GVHD requires T cells to home to the intestinal mucosa [Snider and Liang 2001]. Thus 
it is unsurprising that blocking T cell trafficking to the intestine abrogates GVHD mortality 
in animal models. This can be accomplished by interfering with chemokine receptors [Choi 
2007] or the integrin-ligand interactions [Murai 2003, Waldman 2006, Ueha 2007] that are 
necessary for T cells to migrate into the intestinal mucosa. The α4β7-MAdCAM-1 (mucosal 
vascular addressin) interaction is key in this regard. 
 
The mechanism of action of the monoclonal antibody natalizumab makes it an attractive 
agent to study for patients at high risk for steroid refractory GI GVHD. Natalizumab binds 
to the α4 component of the α4β7 integrin and thus inhibits T-cell mediated damage to the 
GI tract [Yu 2013]. Multiple studies have shown natalizumab to be an effective treatment 
for active, treatment resistant, Crohn’s disease, in which the intestinal tissues are injured, 
similar to GVHD for >10 years [Gordon 2001, Ghosh 2003, Sandborn 2005, Targan 2007, 
Kane 2012, Juillerat 2013, Sakuraba 2013]. The most important of these studies was the 
ENCORE trial which randomized 509 patients with moderately to severely active Crohn’s 
disease to receive natalizumab 300 mg or placebo intravenously at weeks 0, 4, and 8. The 
primary endpoint was induction of response. Additional efficacy endpoints included the 
proportion of patients with sustained remission and response or remission over time. 
Response at Week 8 sustained through Week 12 occurred in 48% of natalizumab-treated 
patients and 32% of patients receiving placebo (P < .001). Sustained remission occurred 
in 26% of natalizumab-treated patients and 16% of patients receiving placebo (P = .002). 
Week 4 response rates were 51% for natalizumab and 37% for placebo (P = .001). 
Responses remained significantly higher at subsequent assessments (P < .001) in 
natalizumab-treated patients. Natalizumab-treated patients also had significantly higher 
remission rates at Weeks 4, 8, and 12 (P < or = .009). The frequency and types of adverse 
events were similar between treatment groups [Targan 2007]. Natalizumab was FDA-
approved in 2008 for use in for the treatment of moderate-to-severe Crohn's disease in 
patients with evidence of inflammation who have had an inadequate response to, or are 
unable to tolerate, conventional Crohn's disease therapies. 
 
A recent meta-analysis included 5 randomized clinical trials of 1,771 patients who received 
natalizumab or placebo in order to induce remission in active Crohn’s disease. Failure to 
achieve remission occurred in 810 (65.4%) of 1,238 patients receiving natalizumab at 2 to 
12 weeks, compared with 412 (77.3%) of 533 randomized to placebo. The RR of not 
achieving remission was reduced with natalizumab (0.88; 95% CI 0.83–0.94, I2=0%, 
P=0.72), with no statistically significant funnel plot asymmetry (Egger test, P=0.29) [Ford 
2011].  
 
The safety profile of natalizumab has been extensively evaluated with ~100,000 patients 
treated since FDA approval in 2004 for multiple sclerosis and in 2008 for Crohn’s disease. 
Progressive multifocal encephalopathy (PML) is a serious but rare complication that has 
been reported in patients treated with natalizumab for either condition.  Risk factors include 
concomitant immunosuppression and seropositivity for JC virus but long duration of 
treatment (>2 years) is the primary risk factor. It is reassuring that the incidence of PML in 
patients treated with natalizumab for fewer than 12 months was 4/100,000 [Bloomgren 
2012].  The risk of PML in patients treated with immunosuppression is 2/1000 [Biogen 


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2015]. While unanticipated complications could occur, large clinical trials that included 
>1400 patients, have shown no other increased risks for natalizumab. However, because 
natalizumab has not been used to treat GVHD before, this study will be conducted under 
an IND from the FDA which requires robust safety measures and strict adverse event 
reporting. 
 
1.5 
Safety Data for Natalizumab Generated in this Study (August 2018) 
To date, no toxicities observed on this study have been attributed as probably or definitely 
related to natalizumab. There have been no serious cardiac, pulmonary or liver toxicities. 
One patient developed renal failure seven months after completion of study treatment in 
the context of severe chronic GVHD and failure to thrive. This complication was considered 
unrelated to natalizumab. 
 
Infections have been carefully monitored on this study. Enrollment to this trial was paused 
once a predetermined threshold of serious infections was observed in order to allow for 
analysis and safety assessment. The analysis concluded that natalizumab was not 
contributing to the incidence of serious infections.  
 
Fifteen serious infections were observed in 12 patients (out of 32 study subjects) which 
include bacterial (n=9), fungal (n=3) and viral (n=3). The most common infection was 
bacterial sepsis with an enteric organism (Klebsiella, n=5, E coli, n=2; E. faecium, n=1). In 
7/8 cases, the bacterial sepsis developed in the context of steroid-refractory stage 4 GI 
GVHD, a setting in which the intestinal architecture is extensively damaged and bacterial 
translocation is a well-known complication. One case of Klebsiella sepsis that developed 
on study day 8 in a patient responding to the combination of high dose steroids and 
natalizumab and was considered possibly related to natalizumab. The median time to 
develop a serious bacterial infection was study day 25 (range 2-85 days). The majority of 
these infections developed after additional immunosuppression had been given for lack of 
response to GVHD treatment. One presumed aspiration pneumonia that developed 14 
days after the last dose of natalizumab was considered unlikely to be related to 
natalizumab. 
 
The three fungal infections were cases of candida sepsis that developed on study day 14, 
37, and 71 in the context of steroid refractory GI GVHD after additional immunosuppression 
had been initiated for lack of GVHD treatment response.  
 
In two of three viral infections, symptoms were present before the first dose of natalizumab 
(one case each of EBV PTLD and HHV6 encephalitis). Both of these cases were 
considered unrelated to natalizumab. One case of CMV colitis that developed on study day 
20 in a patient with steroid refractory GI GVHD was considered possibly related to 
natalizumab.  
 
In summary, the vast majority of serious infections observed on this study have occurred 
in patients with steroid refractory GVHD who are known to be at very high risk for infections. 
The types of organisms, the GVHD severity and involvement of the GI tract, the timing 
relative to natalizumab infusions and the occurrence often after initiation of additional 
immunosuppression led investigators to attribute these 13/15 infections to causes other 
than natalizumab. This assessment is consistent with a recent report that GI GVHD treated 
with steroids is the major risk factor for bacterial and fungal sepsis after allogeneic BMT 
[Mori 2018]. The two infections that were considered possibly related to do not significantly 
alter the risk-benefit ratio for this study. 
 


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1.6 
Other Agents 
Prednisone (or methylprednisolone) will be co-administered with natalizumab. Systemic 
corticosteroid therapy has been the standard treatment for acute GVHD for 40 years and 
its efficacy and risks are well understood [Martin 2012]. Detailed information on adverse 
events and potential risks are detailed in section 9.0. 
1.7 
Rationale 
The newly developed Ann Arbor GVHD scoring system risk-stratifies patients at diagnosis. 
Patients with Ann Arbor score 3 GVHD represent a high risk strata enriched for the 
development of steroid refractory GI GVHD and early death. The six month NRM for 
patients with Ann Arbor score 3 GVHD is 1.6 times that of those with GI GVHD at diagnosis 
(45% vs. 28%). Early identification of patients at high risk for steroid refractory GI GVHD is 
important as early treatment is more likely to be effective. Furthermore, the low complete 
response rates (30%) and high NRM rates in patients with Ann Arbor score 3 GVHD 
warrants experimental treatment. Natalizumab effectively inhibits T-cell trafficking to the GI 
tract and has shown exceptional efficacy in Crohn’s disease with response rates 16% 
higher than placebo after a single dose. The administration of an agent that inhibits T-cell 
trafficking to the GI tract to patients with Ann Arbor score 3 GVHD, which includes patients 
who are at high risk of developing GI GVHD but have not yet done so, is an attractive 
approach to a highly lethal disease.  
 
The clinical response on day 28 of treatment correlates with long term survival in patients 
with GVHD [Levine 2010, MacMillan 2010]. Therefore, we chose the day 28 CR rate as the 
trial’s primary endpoint. Because we expect improvements in day 28 CR to translate into 
better long-term outcomes, 1 year NRM and 1 year survival will be secondary endpoints. 
Additional secondary endpoints related to efficacy will include the day 28 overall response 
rate (CR + PR), the proportion of patients who develop treatment-refractory GVHD (defined 
as those who do not achieve CR or PR by day 28 or who receive additional 
immunosuppression prior to day 28), time to discontinuation of steroid therapy, number of 
lines of GVHD therapy, and cumulative incidence of chronic GVHD. Secondary endpoints 
related to safety include 6 month and 1 year relapse rates and incidence of serious 
infections by 6 months. All patients who receive at least one dose of natalizumab will be 
considered evaluable for both safety and efficacy. 
1.8 
Correlative Studies 
 
GI biopsies. We have previously shown that GI pathologic grade [Ferrara 2011] and more 
recently, that Paneth cell numbers from GI biopsies correlate with GI GVHD outcomes 
[Levine 2013].  However, major gaps exist in our understanding of how pathologic changes 
correlate with clinical outcomes such as treatment response and NRM. While not mandated 
as part of study participation, endoscopic evaluations with biopsies are routinely performed 
in patients with suspected GVHD and GI symptoms (nausea, vomiting, diarrhea, etc.). 
When consent is provided, we will analyze small and large bowel biopsy samples obtained 
from these patients using immunohistochemical staining for cells and proteins with known 
associations with GI GVHD including Paneth cells, intestinal stem cells, RORγt+ NKp46+ 
cells producing IL-22, regulatory T cells, α4β7T-cells, and cellular expression of toll-like 
receptors, NOD-like receptors, α-defensins, and Reg3α.  
 
Furthermore, a recent publication showed that repeating endoscopic evaluations in 
patients with persistent GI symptoms is helpful [Martinez 2012]. In that retrospective study, 
histological findings of repeat endoscopic biopsies led to a change in clinical management 
in 77% of the cases, such as altering the intensity of immunosuppression and/or adding 
specific treatment for a coexisting infectious disease. From the 84 study patients with Ann 
Arbor score 2 or 3 GVHD, we estimate that onset biopsies will be available for 90% of the 
42 patients with GI symptoms at onset, or 38 patients. We further estimate that 


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Page 12 of 44 
 
approximately 40% of these patients, or 15, will undergo repeat endoscopic evaluation at 
day 28 for persistent GI symptoms.  
 
Serial serum biomarkers. GVHD biomarkers measured during treatment correlate with 
clinical outcomes such as treatment response and survival [Levine 2008, Levine 2012].  
For example, a biomarker panel on day 14 of treatment identified patients in CR who were 
most likely to experience a GVHD flare [Levine 2012]. Therefore, we expect that GVHD 
biomarker concentrations during treatment measure GVHD alloreactivity independently of 
clinical symptoms. We will collect and store serum samples during treatment for these 
future analyses from consenting patients. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
2.1.1 
To improve day 28 GVHD complete response rate for Ann Arbor score 2 and 3 
GVHD patients from the historical rate of 42.5% to 57.5% by treatment with 
natalizumab and high dose prednisone (or methylprednisolone) (2 mg/kg). 
2.2 
Secondary Objectives  
 
2.2.1 
To decrease 6-month NRM from the historical rate of 32% to 22% in patients 
treated on this clinical trial. 
 
2.2.2 
To determine the overall survival and NRM rates at 1 year and the cumulative 
incidence of treatment-refractory GVHD (defined as no improvement or worsening 
in any target organ by day 28 of treatment or who receive additional 
immunosuppression prior to day 28), the day 28 overall response rate (CR + PR), 
time to discontinuation of steroid therapy, number of lines of GVHD therapy, and 
cumulative incidence of chronic GVHD in patients treated on this clinical trial. 
Outcomes will be analyzed for all patients and separately for Ann Arbor 2 and 3 
GVHD patients. 
 
2.2.3 
To determine the cumulative incidence of 6 month and 1 year relapse and the 
incidence of serious infections by 6 months in patients treated on this clinical trial. 
 
2.2.4 
To assess the safety of natalizumab for the treatment of high risk GVHD. 
 
2.2.5 
To assess the improvement in day 28 GVHD complete response rate for Ann Arbor 
score 2 and 3 patients separately in order to evaluate any differences in response 
to the treatment between two groups. 
 
 
2.3 
Endpoints 
The primary endpoint for this clinical study is the proportion of complete response (that is, 
the percent of patients with skin, liver, and GI GVHD all stage 0) at day 28 of study 
treatment. 
 
The secondary endpoints are: 
1. Overall survival at 1 year 
2. Cumulative incidence of NRM at 6 months and 1 year  
3. Overall response rate (CR + PR) at day 28. PR is defined as improvement in one 
or more organs involved with GVHD symptoms without progression in others. For 


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a response to be scored as PR on day 28, the patient must be in PR on day 28 
and have had no intervening non-study therapy for acute GVHD. 
4. Cumulative incidence of treatment-refractory GVHD (defined as absence of CR or 
PR on day 28 of treatment or who receive additional immunosuppression prior to 
day 28) 
5. Cumulative incidence of severe GI GVHD stage 3 or 4 
6. Time to discontinuation of steroid therapy 
7. Number of lines of GVHD therapy (defined as the initiation of a new acute GVHD 
therapy, regardless of duration) 
8. Cumulative incidence of chronic GVHD 
9. Number of serious infections (defined as grade 3 by the Blood and Marrow 
Transplant Clinical Trials Network) 
 
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled to the study. Study 
treatment may not begin until a subject is enrolled. 
3.1 
Inclusion Criteria 
 
3.1.1 
New onset acute GVHD Ann Arbor score 2 or 3 following allogeneic BMT. Any 
clinical severity (Glucksberg grade I-IV) is eligible. Patients with prior or existing 
diagnosis of GVHD without any treatment are eligible.  Patients given only topical 
corticosteroids for skin GVHD are eligible. 
 
3.1.2 
Any donor type (e.g., related, unrelated) or stem cell source (bone marrow, 
peripheral blood, cord blood). Recipients of non-myeloablative and myeloablative 
transplants are eligible. 
 
3.1.3 
No prior systemic treatment for acute GVHD except for a maximum of 3 days of 
prednisone (or IV methylprednisolone) ≤2 mg/kg/day. Topical skin steroid 
treatment, non-absorbable oral steroid treatment for GI GVHD, and resumption of 
GVHD prophylaxis agents (e.g., calcineurin inhibitors) are permissible. Patients 
enrolled in BMT CTN 1501 who randomized to sirolimus are also eligible. 
Exceptions can be made on a case-by-case basis with Sponsor-Investigator 
approval. 
 
3.1.4 
Age 18 years or older. 
 
3.1.5 
Direct bilirubin must be <2 mg/dL unless the elevation is known to be due to Gilbert 
syndrome or aGVHD within 3 days of enrollment. 
 
3.1.6 
ALT/SGPT and AST/SGOT must be <5 x the upper limit of the normal range within 
3 days of enrollment unless the elevation is due to liver GVHD.  
  
3.1.7 
If the patient is a woman of child-bearing potential, the patient and their sexual 
partner must agree to practice effective contraception.   
 
3.1.8 
Written informed consent from patient or legal representative. 
 
3.1.9 
Biopsy of acute GVHD target organ is strongly recommended but not required. 
Enrollment should not be delayed for biopsy or pathology results. Patients who do 


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not enroll within 3 days of initiation of systemic steroid treatment for acute GVHD 
are not permitted to participate. 
3.2 
Exclusion Criteria 
 
3.2.1 
Patients with malignancy that is suspected or proven to have progressed, 
relapsed, or be persistent since BMT 
 
3.2.2 
Uncontrolled active infection 
 
3.2.3 
Patients with chronic GVHD only. Patients diagnosed with overlap syndrome are 
still eligible.  
 
3.2.4 
History of or current diagnosis of progressive multifocal leukoencephalopathy 
(PML) 
 
3.2.5 
Known hypersensitivity to natalizumab 
 
3.2.6 
Pregnant or nursing (lactating) women 
 
3.2.7 
Use of other drugs for the treatment of acute GVHD 
 
3.2.8 
Steroid therapy for indications other than GVHD at doses >0.5 mg/kg/d of 
methylprednisolone or equivalent within 7 days prior to initiation of GVHD 
treatment 
 
3.2.9 
Patients on dialysis 
 
3.2.10 Patients requiring ventilator support 
 
3.2.11 Investigational agent within 30 days of enrollment without approval from the 
Sponsor-Investigator (PI)  
 
3.2.12 History of allergic reaction to natalizumab 
 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
 
PRESCREENING PROCESS 
To be eligible for this study, patients must be diagnosed with Ann Arbor score 2 or 3 GVHD. Most 
patients will be recruited from centers participating in the Mount Sinai Acute GVHD International 
Consortium (MAGIC) and will already have consented prior to transplant for clinical data and 
research blood sample submission to the Ferrara Lab at pre-specified time points post-BMT as well 
as at the onset of acute GVHD. Thus, written informed consent for the pre-screening process to 
determine eligibility will already have been obtained at each center on a separate, IRB-approved 
protocol. Patients who initially were not offered or declined to participate in the MAGIC study who 
consent at the time of onset of acute GVHD can provide the pre-screening research sample needed 
for Ann Arbor scoring. Because the vast majority of patients consent at time of transplant to the 
sample collection protocols, this latter option will be infrequently utilized. 
 
The pre-screening process is outlined in the figure below. Pre-screening takes place entirely under 
the previously provided informed consent detailed above. The process is explained here for 
completeness. Five mL of serum will be collected from patients with new onset acute GVHD on the 
day of diagnosis of GVHD (preferable) or up to 48 hours after initiation of steroid treatment for 


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Page 15 of 44 
 
GVHD. However, first dose of Natalizumab must be initiated within 3 days after the start of steroid 
treatment for GVHD.  Exceptions to this timeline can be made on a case-by-case basis with 
Sponsor-Investigator approval. Once a sample has been collected, it will be (1) registered in the 
remote data entry system using the unique natalizumab identification number assigned to the 
patient at time of registration in the database and (2) shipped priority overnight to the laboratory of 
Dr. James Ferrara for early AM arrival (see MAGIC Sample Collection and Storage manual for 
shipping procedures). Samples can be received Tuesday through Saturday. Once received in 
the laboratory, the GVHD biomarkers used to assign the Ann Arbor GVHD score will be measured 
by ELISA using standard technical procedures (see Appendix A for details). Processing, 
measuring, and confirming the ELISA assay results take 4.5 hours (range 4-6 hours). Once the 
Ann Arbor score is confirmed by Dr. Ferrara (or Dr. Levine in Dr. Ferrara’s absence), the 
investigator at the participating center will be notified of the Ann Arbor score by telephone with 
email written confirmation. Only patients with confirmed Ann Arbor score 2 or 3 GVHD will be 
eligible to enroll onto the clinical trial. 
 
 
 
SCREENING AND REGISTRATION PROCESS 
Patients must provide informed consent for this clinical trial prior to release of the Ann Arbor Score. 
It is preferred to obtain informed consent prior to shipping the sample. Enrollment must be complete 
by the end of the 3 day window; therefore investigators are encouraged to begin the informed 
consent process at the same time as the pre-screening research serum sample is obtained. 
Patients who sign informed consent but are not eligible to participate because they do not have 
Ann Arbor score 2 or 3 GVHD will be considered screen failures as well as any patient who does 
not meet all the inclusion and exclusion criteria.  
 
Patient registration for this trial will be centrally managed by the MAGIC Data Coordinating Center 
of the Icahn School of Medicine at Mount Sinai as described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on the Screening and 
Enrollment Log provided by the MAGIC Data Coordinating Center (DCC).  
 
It is the responsibility of the local site investigator to confirm patient eligibility for the clinical trial. 
Confirmation of Ann Arbor score 2 or 3 GVHD will be provided directly to the identified Primary Site 
contact from the participating site by Dr. Ferrara, Dr. Levine or designee. All other eligibility criteria 
will be provided by the participating site. After patient eligibility has been determined, a copy of the 
completed Eligibility form will be submitted by the requesting site to the MAGIC Data Coordinating 
Center by email to magic@mssm.edu with local site investigator signature and supporting source 
documentation.  
 
The MAGIC Coordinator, who acts as the registrar, will review the submitted documents and 
process the registration. Sites should inform the MAGIC Coordinator of a potential registration once 
a research sample has been submitted for Ann Arbor score assignment given the time sensitivities 
in this study.   
 
An email will be sent by the registrar to the requesting site registrar to confirm patient registration. 


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Page 16 of 44 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These patients will not 
receive study treatment. 
 
 
 


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Page 17 of 44 
 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
 
Protocol treatment must start within 3 days of initiation of systemic steroid treatment 
for acute GVHD. For example, a patient diagnosed with acute GVHD who starts systemic 
steroid treatment on Monday (day 0), who has a research sample shipped to the Ferrara 
Lab on Tuesday (day 1), will have their Ann Arbor score assigned on Wednesday (day 2). 
Such a patient should begin study treatment no later than Thursday (day 3).  Exceptions 
to this time line can be made on a case-by-case basis with Sponsor-Investigator approval. 
5.1.1 
Study treatment will consist of two drugs: Prednisone (or methylprednisolone) 
which is standard treatment for acute GVHD and natalizumab, the drug under 
study. 
5.1.2 
Corticosteroid dosing and taper 
All patients enrolled on this trial will receive steroids at a dose of prednisone 2 
mg/kg/day orally (or IV methylprednisolone). Centers may use a starting dose of 2 
mg/kg of methylprednisolone if that is their institutional practice.  The dose of 
steroids cannot be tapered before study day 2 (day 0 is defined as the day of the 
first dose of natalizumab), but afterwards local institutional tapering practices can 
be followed. Steroid therapy can also be given up to 3 days prior to the first dose 
of natalizumab (day -3 to -1), i.e., during the period from the initiation of systemic 
steroid treatment for acute GVHD until study therapy begins. 
 
The following is a suggested steroid taper (identical to that used in Blood and 
Marrow Transplant Clinical Trials Network primary GVHD therapy studies): 
 
2 mg/kg/day of steroid divided once or twice/day days 1-6 
1.5 mg/kg/day once daily days 7-13 
1 mg/kg/day once daily days 14-21 
0.5 mg/kg/day once daily days 22-28 
Patients should be tapered as tolerated to no less than 0.5 mg/kg/day. 
Then taper according to institutional guidelines with a goal to reach ≤0.2 
mg/per/kg per day of prednisone or ≤0.16 mg/per/kg per day of 
methylprednisolone by day 56. 
 
Study Schema 
Day 28 
Response 
Assessment 
Begin within 3 days of systemic steroid treatment for 
acute GVHD 
Ann Arbor  
Score 2/3  
Natalizumab 
300mg  
on days 0 and 14 
CR = Success  
Not CR = Failure 
Prednisone 2mg/kg/d 
(or methylprednisolone 
 IV) 


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Page 18 of 44 
 
5.1.3 
Natalizumab dosing and schedule 
Natalizumab will be obtained from Biogen. Each participating site will have a 
sufficient supply of natalizumab on hand to begin treatment, additional doses will 
be shipped to the participating site to complete treatment.  See section 9.1 for 
preparation, dispensing, and administration information. 
 
The first dose of natalizumab must be administered within 3 days of start of 
systemic steroid treatment for acute GVHD. The first day of natalizumab will be 
day 0 of the study. Exceptions to this time line can be made on a case-by-case 
basis with Sponsor-Investigator approval. 
 
Natalizumab will be administered at a dose of 300 mg intravenously on days 0 and 
14. If, for reasons other than toxicity, the second dose cannot be administered on 
day 14, the acceptable window for administration is day 12-16. 
5.1.4 
GVHD Prophylaxis Medications 
Medications such as cyclosporine, tacrolimus, sirolimus (if used as GVHD 
prophylaxis when acute GVHD developed) should be continued at therapeutic 
doses (according to institutional standards) adjusted as necessary for renal, 
central nervous system (CNS) or other toxicity using conventional management 
guidelines.   
 
5.1.5 
Topical and Ancillary GVHD therapies  
Topical therapy for acute GVHD of the skin and non-absorbable steroids for GI 
GVHD are allowed.  
Ancillary/supportive care measures for acute GVHD such as the use of anti-motility 
agents for diarrhea, including octreotide, is allowed at the discretion of the treating 
physician.  Use of ursodiol to prevent/reduce gall bladder sludging, or prevent 
hepatic transplant complications is also allowed according to institutional 
guidelines 
5.1.6 
Supportive Care Guidelines 
In addition to prescribed study drug plus corticosteroids, all patients should receive 
the following: 
 
• 
Transfusion support per institutional practice 
• 
Anti-infective prophylaxis against herpes virus is required but otherwise 
institutional practice can be followed. 
• 
Anti-infective prophylaxis against Pneumocystis jiroveci, bacterial and 
fungal infections according to standard institutional guidelines. 
• 
Pre-emptive monitoring and treatment for CMV and EBV infections are 
required but otherwise institutional practice can be followed. 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section 6.4). Toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity.  
 
The dose of natalizumab will not be modified on this study for toxicities or co-morbidities 
that develop between the first and second dose. In the event that a toxicity develops that 


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the treating physician deems poses an unacceptable risk to administering natalizumab, the 
dose should not be given and the patient will be removed from study therapy. 
 
The second dose of natalizumab should be administered on day 14 of the study. However, 
if for reasons other than toxicity the second dose cannot be administered on day 14, the 
acceptable window is day 12-16. 
5.3 
Concomitant Medications/Treatments 
Concomitant use of other investigational agents is not permitted during the treatment phase 
of the study.   
5.4 
Other Modalities or Procedures 
Patients who have undergone allogeneic hematopoietic cell transplantation and developed 
acute GVHD typically are simultaneously being treated for other conditions and transplant-
related complications. Such treatments, including the use of steroid therapy as GVHD 
treatment are considered standard of care and will be considered distinct from the study 
drug treatment, natalizumab. 
5.5 
Infection Prophylaxis (August 2017) 
This trial originally expected a 24% incidence of severe infections (BMT CTN grade 3) 
based on an expected distribution of enrollment of 25% grade 1 (mild skin) GVHD, 50% 
grade II (moderate skin and or mild GI) and 25% grade III/IV (primarily severe GI) GVHD. 
However, this trial has disproportionately enrolled patients with severe GVHD grade III/IV 
(12/20, 60%). Patients with severe GI GVHD have considerable damage to the GI mucosa 
and are at increased risk of translocation of enteric bacteria from the GI lumen into the 
bloodstream and sepsis. As a result, the incidence of BMT CTN grade 3 infections in the 
first 20 patients enrolled on this trial (45%) significantly exceeded the expected 24% rate, 
because more patients at high risk for this complication enrolled than expected. To reduce 
the risk of this complication, the study DSMC required the protocol include mandatory gram 
negative antibiotic coverage (fluoroquinolone or institutional preference) from study day 0 
to study day 42, which encompasses this high risk period. Antibiotic prophylaxis can be 
continued beyond day 42 per institutional preference. 
5.6 
Duration of Therapy 
The duration of protocol therapy on this study is 14 days (two doses of natalizumab 
administered on day 0 and 14). Protocol therapy will end after the second dose of 
natalizumab has been administered or if any of the following criteria apply: 
 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient voluntarily withdraws from treatment OR 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
5.7 
Off Treatment Criteria  
Patients will be removed from protocol therapy when any of the criteria listed in Section 5.6 
apply. The reason for ending protocol therapy and the date the patient was removed from 
treatment will be documented in the study record. All patients who discontinue treatment 
should comply with protocol specific follow-up procedures as outlined in Section 5.8. The 
only exception to this requirement is when a subject withdraws consent for all study 
procedures. 


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Page 20 of 44 
 
5.8 
Duration of Follow-Up 
Patients will be followed for 1 year after removal from treatment or until death, whichever 
occurs first. Patients with acute GVHD are followed closely and frequent clinical 
evaluations are the norm. The following outlines the minimum frequency of follow-up 
evaluations, it is anticipated that the majority of patients will be evaluated more frequently.  
 
During the first 6 weeks of participation (i.e., through 4 weeks after the last dose of 
natalizumab), patients will be evaluated at least weekly for acute toxicity assessment, 
GVHD staging and management. For the next 6 weeks, patients will be evaluated at least 
every other week for GVHD staging and management. Thereafter, patients will be 
evaluated every 3 months (±2 weeks) until 1 year from start of study treatment. 
5.9 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be withdrawn 
at the discretion of the investigator for safety, behavioral or administrative reasons. The 
reason(s) for discontinuation from study will be documented and may include: 
5.9.1 
Patient withdraws consent (termination of treatment and follow-up); 
5.9.2 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment;  
5.9.3 
Patient is unable to comply with protocol requirements; 
5.9.4 
Treating physician judges continuation on the study would not be in the patients 
best interest; 
5.9.5 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.9.6 
Termination of the study; 
5.9.7 
Patient completes protocol treatment and follow-up criteria. 
5.10 
Patient Replacement 
Patients who enroll in the study but do not receive any study treatment will be replaced. 
The number of patients and reason(s) for replacement will be recorded and will be used to 
assess the feasibility of the study design. 
 
6.0 
STUDY PROCEDURES 
6.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 3 days prior to registration unless 
otherwise stated. The screening procedures include: 


________________________________________________________________________ 
Page 21 of 44 
 
6.1.1 Informed Consent 
6.1.2 Demographics 
Age, gender, race, ethnicity 
6.1.3 Review subject eligibility criteria 
6.1.4 Review concomitant medications 
6.1.5 GVHD staging 
6.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
6.1.7 Adverse event assessment 
Baseline adverse events will be assessed and preexisting conditions will be 
recorded. See Section 8.0 for Adverse Event monitoring and reporting. 
6.1.8 Hematology 
Complete blood count and differential 
6.1.9 Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, 
ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, 
chloride, bicarbonate), glucose, and total bilirubin. 
6.1.10 Pregnancy test (only for females of child bearing potential) 
6.2 
Procedures During Treatment 
6.2.1 
Prior to Each Natalizumab Dose 
• Physical exam, vital signs 
• Biomarker serum sample 
• Hematology 
• Serum chemistries 
6.2.2 
GVHD staging, concomitant medication review, toxicity evaluations and 
adverse event reporting as per time and events table below 
6.2.3 
30 days after treatment termination 
• Toxicity assessment 
• Physical exam, vital signs 
• Hematology 
• Serum chemistries 
6.3 
Follow-Up Procedures 
The minimum frequency of follow-up evaluations is as follows:   
 
During the first 6 weeks of participation (i.e., through 4 weeks after the last dose of 
natalizumab), patients will be evaluated at least weekly for acute toxicity assessment, 
GVHD staging and management. For the next 6 weeks, patients will be evaluated at least 
every other week for GVHD staging and management. Thereafter, patients will be 


________________________________________________________________________ 
Page 22 of 44 
 
evaluated every 3 months (±2 weeks) until 1 year from start of study treatment. Follow-up 
studies are detailed in the Time and Events Table is section 6.4. 
 
6.4 
Time and Events Table 
 
Pre-
study 
Day 0 
Day 7 
(±2 
days) 
Day 14 
(±2 
days) 
Day 21 
(±2 
days) 
Day 281 
(±1 day) 
Day 35, 
42 
(±3 days) 
Week 8, 
10, 12 
(±6 
days) 
Month 3, 
6, 9, 12 
(±2 
weeks) 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
History and PE 
X 
X 
 
X 
 
 
 
 
 
Pregnancy Test2 
X 
 
 
 
 
 
 
 
 
Contraceptive 
Counseling2 
X 
 
 
 
 
 
 
 
 
Toxicity 
Evaluations3 
 
X 
X 
X 
X 
X 
X 
 
X4 
Progressive 
Multifocal Leuko-
encephalopathy 
(PML)5 
Assess for PML at least every 2 weeks from baseline visit to 6 months (assessment can be 
performed at scheduled visits or by phone) 
Adverse Event 
Evaluations 
 
Report adverse events from the time of the initial study treatment (Day 0) through 
30 days after the last dose of natalizumab. Report serious adverse events as they 
occur. 
GVHD staging6 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
Medication 
Review7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Natalizumab 
Administration 
 
X 
 
X 
 
 
 
 
 
LABORATORY STUDIES 
Serum Chemistry 
X 
X 
X 
X 
X 
X 
X 
 
 
CBC 
X 
X 
X 
X 
X 
X 
X 
 
 
CORRELATIVE STUDIES 
Serum Sample  
(5 ml) 
 
X 
X 
X 
X 
X 
 
 
 
GI biopsies  
(if clinically 
indicated)8 
Optional: Submit formalin fixed paraffin embedded GI biopsies obtained for standard of care 
purposes, provided that the tissue is no longer needed for further clinical use. 
1 Day 28 is the primary response endpoint. GVHD staging should be performed this day, or if 
needed, within a 1 day window. 
2 Pregnancy test is required only for women of childbearing potential defined as Tanner stage I, 
post-menopausal for at least 24 consecutive months or post-hysterectomy, salpingotomy, and/or 
bilateral oophorectomy. Women who are not of reproductive potential are not required to undergo 
contraceptive counseling. Acceptable documentation includes written or oral documentation by 
the clinician of one of the following: physical examination indicates Tanner stage I, physician 
report/letter, operative report or other source documentation in the patient record, discharge 
summary, or follicle stimulating hormone measurement elevated into the menopausal range. 
3 Toxicity assessment does not replace adverse event reporting, but rather collects the occurrence 
of any events known to be associated with natalizumab. A baseline toxicity assessment is 
performed on day 0 prior to the first dose of natalizumab. Known or suspected toxicities include 
hepatoxicity (elevated hepatic enzymes and/or total bilirubin), hematologic abnormalities 
(increased circulating lymphocytes, monocytes, eosinophils, basophils, nucleated red blood 
cells), allergic reactions, depression, headache, fatigue, rash, nausea, vomiting, and/or diarrhea. 


________________________________________________________________________ 
Page 23 of 44 
 
Patients will be evaluated for these toxicities at each assessment time point up to day 42, 
including pre-treatment baseline and their presence will be recorded. 
4 At months 3, 6, 9, and 12 report only PML, BMT CTN Grade 3 infections, viral reactivations, and 
any other toxicity if deemed related to natalizumab by the local investigator. (appendix B for BMT 
CTN Grade 3 Infection criteria) 
5 Ask patients about difficulty with vision, speech, arm/leg weakness, clumsiness, personality 
changes, or confusion. 
6 GVHD staging will follow the detailed guidelines provided in the MAGIC Acute GVHD Staging       
Guidance. Weekly GVHD data will be required for patients co-enrolled on the MAGIC 
Observational study when patient is still within 3 months of HCT.  This data can also be provided 
for patients not co-enrolled on MAGIC if the patient is seen.   
7 Concomitant medication review will record all other immunosuppressants administered during the 
reporting period. 
8 Biopsies will be requested and batch shipped after the tissue is no longer needed for further 
clinical use (minimum six months from biopsy acquisition). See Section 10.3. 
 
7.0 
GVHD CLINICAL STAGING 
GVHD clinical staging will be according to the established criteria used for Blood and Marrow 
Transplant Clinical Trials Network GVHD staging (modified Glucksberg criteria). Clinical stage will 
be used to evaluate patients for the primary endpoint, day 28 CR. 
 
 
Stage 0 
Stage 1 
Stage 2 
Stage 3 
Stage 4 
Skin 
No rash 
Rash < 25% BSA 
25-50% 
> 50% Generalized 
erythroderma 
Plus bullae and 
desquamation 
>5% BSA 
Liver 
Bilirubin ≤  2 mg/dl 
2.1-3 mg/dl 
3.1-6mg/dl 
6.1-15mg/dl 
>15mg/dl 
GI tract 
Adult: < 500 
ml/day 
 
Adult: 500–1000 
ml/day  
 
Adult: 1001-1500 
ml/day  
 
Adult: >1500 
ml/day  
 
Severe abdominal 
pain +/- ileus, flank 
blood or melena 
(regardless of stool 
volume) 
UGI 
 
Severe 
nausea/vomiting 
 
 
 
• 
For stage 4 GI GVHD, severe abdominal pain is defined as (1) pain that requires opioid use and (2) pain that 
significantly impacts on performance status as determined by the treating physician 
• 
Comprehensive GVHD staging guidance is provided in the MAGIC GVHD Staging Guidance. 
Overall Clinical Grade: 
Grade 0 
No stage 1-4 of any organ 
Grade I  
Stage 1-2 skin and no liver or GI involvement 
Grade II 
Stage 3 skin and/or Stage 1 liver and/or Stage 1 GI 
Grade III 
Stage 0-3 skin with Stage 2-3 liver and/or Stage 2-3 GI 
Grade IV 
Stage 4 in any target organ (skin, liver, GI) 
7.1 
ENDPOINT AND RESPONSE CRITERIA 
7.1.1 
Definitions 
Evaluable for response: All patients will be evaluable for toxicity and response from 
the time of their first treatment with natalizumab. 
 


________________________________________________________________________ 
Page 24 of 44 
 
Complete Response (CR): All evaluable organs (skin, liver, GI tract) stage 0. For 
a response to be scored as CR on day 28, the patient must be in CR on that day 
and have had no intervening additional GVHD therapy. 
 
Partial Response (PR): An improvement in one or more organ involved with GVHD 
symptoms without worsening in others. For a response to be scored as PR on day 
28, the patient must be in PR on that day and have had no intervening additional 
GVHD therapy. 
 
No response (NR): All responses that are not CR or PR. Patients who receive any 
GVHD therapy other than steroid therapy, natalizumab, non-absorbable oral 
steroid therapy, and topical steroids will be scored as NR on day 28 regardless of 
organ staging.  
7.1.2 
Proportion of CR and CR+PR 
Scoring of CR and PR on day 28 are in comparison to the patient’s acute GVHD 
staging on day 0 of the study. 
7.1.3 
Treatment refractory GVHD 
Patients who are scored as no response on day 28 or who receive additional 
immunosuppression prior to day 28 (i.e., no response) will be considered treatment 
refractory. 
7.1.4 
Steroid discontinuation 
The date of discontinuation of steroid therapy will be recorded. 
7.1.5 
Lines of GVHD therapy 
Any new acute GVHD therapy will be considered a line of therapy. Resumption or 
changes in GVHD prophylaxis are not considered new lines of therapy. 
7.1.6 
Non-Relapse Mortality (NRM) 
Any death that occurs after onset of GVHD not attributable to relapse of the 
underlying disease will be considered a non-relapse death. 
7.1.7 
Chronic GVHD 
The occurrence of chronic GVHD, including date of diagnosis, will be recorded.  
7.1.8 
Relapse 
Relapse, including date of relapse, of the underlying malignancy will be recorded. 
7.2 
SAFETY/TOXICITY DEFINITIONS 
7.2.1 
Known or plausible toxicities that may be related to natalizumab will reported. 
Guidance of determining whether a toxicity is an adverse event attributable to 
natalizumab is provided in section 8. 
7.2.2 
Hepatotoxicity 
Elevated hepatic enzymes (ALT, AST) and/or total bilirubin > 1.5 times the baseline 
values on day 0 or higher than the upper limit of normal, whichever is higher, will 
be considered evidence of hepatoxicity.  


________________________________________________________________________ 
Page 25 of 44 
 
7.2.3 
Hematologic abnormalities 
The absolute value of lymphocytes, monocytes, eosinophils, basophils, or 
nucleated red blood cells will be recorded as a hematologic abnormality if the value 
is >1.5 times the upper limit of normal. 
7.2.4 
Systemic Infections 
Infections are common in patients with acute GVHD. Any grade 3 infection as 
defined by the Blood and Marrow Transplant Clinical Trials Network will be 
reported.  
 
Grade 3 Bacterial Infections: 
a. 
Bacteremia with deep organ involvement 
b. 
Severe sepsis with bacteremia 
c. 
Fasciitis requiring debridement 
d. 
Pneumonia requiring intubation 
e. 
Brain abscess or meningitis without bacteremia 
f. 
Clostridium difficile toxin positive stool with toxic dilatation or renal 
insufficiency with/without diarrhea. 
 
Grade 3 Fungal Infections: 
a. 
Fungemia, including candidemia 
b. 
Proven or probable invasive fungal infections (e.g. Aspergillus, Mucor, 
Fusarium, Scedosporium) 
c. 
Disseminated fungal infections 
d. 
Pneumocystis jiroveci pneumonia 
 
Grade 3 Viral Infections: 
a. 
Severe VZV infection with either associated coagulopathy or organ 
involvement 
b. 
CMV end organ involvement 
c. 
EBV Post-transplant lymphoproliferative disorder (PTLD) 
d. 
Adenovirus with end organ involvement (except adenoviral conjunctivitis 
or upper respiratory tract disease) 
e. 
All lower respiratory tract viruses 
f.  
Viral encephalitis or meningitis 
7.2.5 
Viral Reactivations 
Because viral reactivations often require treatment in the BMT population, even in 
the absence of end organ disease, the following viral infections/reactivations will 
be reported: 
 
The date, anatomical site or body fluid (e.g., blood, nasopharyngeal swab, stool, 
etc.), and method of detection for CMV, EBV, HHV6, VZV, HSV and adenovirus 
will be reported. 
7.2.6 
Progressive multifocal leukoencephalopathy (PML) 
The occurrence of PML will be reported. 
7.3 
Safety/Tolerability 
 
 Analyses will be performed for all patients having received at least one dose of study drug. 
The study will use the CTCAE version 4.0 for reporting of adverse events 
(http://ctep.cancer.gov/reporting/ctc.html). 
 


________________________________________________________________________ 
Page 26 of 44 
 
8.0 
ADVERSE EVENTS 
8.1 
NATALIZUMAB 
For the most recent safety update, please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information. 
8.1.1 
Contraindications 
 
 
Patients who have or have had PML 
 
 
Patients who have had a hypersensitivity reaction to natalizumab 
8.1.2 
Special Warnings and Precautions for Use 
• 
Herpes encephalitis and meningitis: Life-threatening and fatal cases have 
occurred.  
• 
Hepatotoxicity: Significant liver injury, including liver failure requiring transplant, 
has occurred. 
• 
Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) 
have occurred.  
• 
Immunosuppression/Infections: Natalizumab may increase the risk for certain 
infections.  
8.1.3 
Interaction with other medications 
The use of concomitant immunosuppressants or inhibitors of TNFα increase the 
risk of PML and other infections. 
8.1.4 
Adverse Reactions 
The most serious adverse reactions with natalizumab are: 
• Progressive Multifocal Leukoencephalopathy (PML) 
• Hypersensitivity 
• Immunosuppression/Infections 
 
The most common adverse reactions (incidence ≥ 10%) were headache and 
fatigue in both multiple sclerosis (MS) and Crohn’s disease (CD) studies. Other 
common adverse reactions (incidence ≥ 10%) in the MS population were 
arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, 
vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and 
rash. Other common adverse reactions (incidence ≥ 10%) in the CD population 
were upper respiratory tract infections and nausea. 
 
The most frequently reported adverse reactions resulting in clinical intervention 
(i.e., discontinuation of natalizumab), in the MS studies were urticaria (1%) and 
other hypersensitivity reactions (1%), and in the CD studies were the exacerbation 
of Crohn’s disease (4.2%) and acute hypersensitivity reactions (1.5%).  
 
Infections 
Progressive Multifocal Leukoencephalopathy (PML) occurred in three patients who 
received natalizumab in clinical trials. Two cases of PML were observed in the 
1869 patients with multiple sclerosis who were treated for a median of 120 weeks. 
These two patients had received natalizumab in addition to interferon beta-1a. The 
third case occurred after eight doses in one of the 1043 patients with Crohn’s 
disease who were evaluated for PML. In the post marketing setting, additional 
cases of PML have been reported in natalizumab-treated multiple sclerosis and 
Crohn’s disease patients who were not receiving concomitant immunomodulatory 
therapy. 
 


________________________________________________________________________ 
Page 27 of 44 
 
In multiple sclerosis studies, the rate of any type of infection was approximately 
1.5 per patient-year in both natalizumab-treated patients and placebo-treated 
patients. The infections were predominately upper respiratory tract infections, 
influenza, and urinary tract infections. In one multiple sclerosis study, the incidence 
of serious infection was approximately 3% in both natalizumab-treated patients 
and placebo-treated patients. Most patients did not interrupt treatment with 
natalizumab during infections. The only opportunistic infection in the multiple 
sclerosis clinical trials was a case of cryptosporidial gastroenteritis with a 
prolonged course. 
 
In Crohn’s disease studies, the rate of any type of infection was 1.7 per patient-
year in natalizumab-treated patients and 1.4 per patient-year in placebo-treated 
patients. The most common infections were nasopharyngitis, upper respiratory 
tract infection, and influenza. The majority of patients did not interrupt natalizumab 
therapy during infections and recovery occurred with appropriate treatment. 
Concurrent use of natalizumab in CD clinical trials with chronic steroids and/or 
methotrexate, 6-MP, and azathioprine did not result in an increase in overall 
infections compared to natalizumab alone; however, the concomitant use of such 
agents could lead to an increased risk of serious infections.  
 
In two CD studies, the incidence of serious infection was approximately 2.1% in 
both natalizumab-treated patients and placebo-treated patients. In a third CD 
study, the incidence of serious infection was approximately 3.3% in natalizumab-
treated patients and approximately 2.8% in placebo-treated patients. In clinical 
studies for CD, opportunistic infections (Pneumocystis carinii pneumonia, 
pulmonary Mycobacterium avium intracellulare, bronchopulmonary aspergillosis, 
and Burkholderia cepacia) have been observed in <1% of natalizumab-treated 
patients; some of these patients were receiving concurrent immunosuppressants.  
Two serious nonbacterial meningitides occurred in natalizumab-treated patients 
compared to none in placebo treated patients. 
 
Infusion-related Reactions 
An infusion-related reaction was defined in clinical trials as any adverse event 
occurring within two hours of the start of an infusion. Observe subjects for one hour 
after end of infusion. In MS clinical trials, approximately 24% of natalizumab-
treated multiple sclerosis patients experienced an infusion-related reaction, 
compared to 18% of placebo-treated patients. In the controlled CD clinical trials, 
infusion-related reactions occurred in approximately 11% of patients treated with 
natalizumab compared to 7% of placebo-treated patients. Reactions more 
common in the natalizumab-treated MS patients compared to the placebo-treated 
MS patients included headache, dizziness, fatigue, urticaria, pruritus, and rigors. 
 
Acute urticaria was observed in approximately 2% of patients. Other 
hypersensitivity reactions were observed in 1% of patients receiving natalizumab. 
Serious systemic hypersensitivity infusion reactions occurred in <1% of patients. 
All patients recovered with treatment and/or discontinuation of the infusion. 
 
Infusion-related reactions more common in CD patients receiving natalizumab 
than those receiving placebo included headache, nausea, urticaria, pruritus, and 
flushing. Serious infusion reactions occurred in CD studies at an incidence of <1% 
in natalizumab-treated patients. 
 
MS and CD patients who became persistently positive for antibodies to 
natalizumab were more likely to have an infusion-related reaction than those who 
were antibody-negative. 


________________________________________________________________________ 
Page 28 of 44 
 
8.2 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll 
in future studies using similar agents. Data on adverse events will be collected from the 
time of the initial study treatment (day 0) through 30 days after the last dose of natalizumab. 
Any serious adverse event that occurs more than 30 days after the last natalizumab dose 
and is considered related to the study treatment must also be reported. Serious Adverse 
Events (SAEs) will continue to be followed until: 
• 
Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
• 
There is satisfactory explanation other than the study treatment for the changes 
observed; or  
• 
Death. 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration is considered to be pre-existing in nature. Any known pre-existing 
conditions that are ongoing at time of study entry should be considered medical history. 
All events meeting the criteria and definition of an AE (CTCAE grade 3 or higher) or SAE, 
as defined in Section 8.3, occurring from the initial study treatment administration through 
30 days following the last dose of the study treatment or study intervention must be 
recorded as an adverse event in the patient’s source documents and on the CRF 
regardless of frequency, or assessed relationship to the study treatment.  
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of 
a pre-existing condition that occurs after the patient begins study treatment is also 
considered an adverse event and must be reported if the severity is CTCAE grade 3 or 
higher. 
8.3 
Definitions 
8.3.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention.  
 
• 
Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) 
procedures will not be reported as adverse events. However, the medical 
condition for which the procedure was performed must be reported if it meets 
the definition of an adverse event unless it is a pre-existing (prior to protocol 
treatment) condition. 
 
• 
Event reporting for GVHD treatment protocols can be complicated and 
confusing for investigators, data managers, and regulatory oversight bodies 
because patients typically develop numerous complications as part of the 
typical treatment course not related to study therapy. Furthermore, transplant-
related complications often occur both simultaneously and in series, as one 


________________________________________________________________________ 
Page 29 of 44 
 
complication leads to a series of downstream events. Therefore, a well-
conceived event reporting plan separates background transplant and GVHD 
noise as might be seen with any transplant where GVHD develops from study 
related events that are relevant to patient safety. On this study, we will not 
report CTCAE grade 1 and 2 adverse events (which make up the majority of 
events) unless the investigator determines the event should be reported to 
protect subject safety. 
 
• 
Symptoms of the original or targeted disease are not to be considered adverse 
events for this study. The following symptoms are indicative of the underlying 
disease, GVHD, and will not be reported as adverse events (unless the event 
is considered serious or deemed by the investigator to be a natalizumab 
infusion reaction): 
 
• 
Nausea, vomiting, diarrhea, anorexia 
• 
Skin rash 
• 
Fever 
 
• 
Abnormal laboratory values or test results constitute adverse events if they 
induce clinical signs or symptoms or require therapy. They are to be captured 
under the signs, symptoms or diagnoses associated with them. 
8.3.2 Serious Adverse Event 
An adverse event is considered “serious” if, in the view of the investigator, it results 
in any of the following outcomes: 
  
o 
Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
o 
A life-threatening adverse event 
An adverse event is considered ‘life-threatening’ if, in the view of either the 
investigator, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event that, had it occurred in a more 
severe form, might have caused death.  
 
o 
Inpatient hospitalization or prolongation of existing hospitalization for > 24 
hours. 
 
o 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
o 
A congenital anomaly/birth defect 
 
o 
Important medical event 
Any event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition 
of “Serious Adverse Event”. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home; convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse. 
 


________________________________________________________________________ 
Page 30 of 44 
 
Previously planned (prior to signing the informed consent form) surgeries should 
not be reported as SAEs unless the underlying medical condition has worsened 
during the course of the study. Preplanned hospitalizations or procedures for 
preexisting conditions that are already recorded in the patient’s medical history at 
the time of study enrollment should not be considered SAEs. Hospitalization or 
prolongation of hospitalization without a precipitating clinical AE (for example, for 
the administration of study therapy or other protocol-required procedure) should 
not be considered SAEs. However, if the preexisting condition worsened during 
the course of the study, it should be reported as an SAE. 
 
8.3.3 Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
• 
For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label).  
• 
For investigational new drugs or devices, those adverse events are 
described in the FDA Investigator’s Brochure.  
• 
In clinical research studies, information on expected adverse events is 
also summarized in the protocol and in the consent document.  See 
section 9.1 for the list of expected adverse events related to the drug under 
study. 
8.3.4 Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the 
Package Insert, Investigator’s Brochure, in published medical literature, in the 
protocol, or in the informed consent document.  
8.4 
Adverse Event Characteristics 
8.4.1 CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be down 
loaded from the CTEP web site. (http://ctep.cancer.gov) 
8.4.2 Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.5 
Serious Adverse Event Reporting Guidelines 
 
The Sponsor Investigator will report SAEs to regulatory bodies and to the participating 
sites in the following manner: 
 
Sponsor SAE Reporting  


________________________________________________________________________ 
Page 31 of 44 
 
Event occurring 
within 30 Days 
post last 
Natalizumab 
infusion 
Report to: 
Event occurring 
after 30 Days 
post last 
Natalizumab 
infusion 
Report to: 
FDA / IRB 
Consortium 
FDA / IRB 
Consortium 
All SAEs;  
 Expected or 
Unexpected 
 Unrelated, 
Unlikely, 
Possible, 
Probable, or 
Definite  
5 Days 
from 
knowledge 
Monthly 
SAEs –  
 Expected or 
Unexpected 
 Possible, 
Probable, or 
Definite 
5 Days 
from 
knowledge 
Monthly 
SAEs –  
 Expected 
 Unrelated, 
Unlikely, 
Possible, 
Probable, or 
Definite 
Annually 
Monthly 
8.5.2 
The Sponsor Investigator must be notified within 5 business day of study team’s 
knowledge of any event meeting the criteria and definition of a serious adverse 
event, regardless of attribution, occurring during the study or within 30 days of the 
last administration of the natalizumab.  PML must be reported within 24 hours to 
the sponsor investigator. 
8.5.3 
The investigator must report all events meeting the criteria and definition of a 
serious adverse event that are unexpected and possibly related (definite, probable 
or possible to study treatment administration) to the local IRB as per local IRB 
policy.  
8.5.4 
All Serious Adverse Events whether expected or unexpected and possibly related 
(definite, probable or possible) to study treatment administration will be reported 
using the Serious Adverse Event form within 5 days of first awareness of the event 
to the MAGIC Data Coordinating Center. A copy of the form should be sent to the 
MAGIC Coordinator via email to magic@mssm.edu. 
 
The MAGIC Data Coordinating Center will disseminate information regarding 
serious adverse events to the participating sites within 5 days of review of the 
information by Drs. Ferrara or Levine only in the case that the event(s) is believed 
to be related (i.e. probably, or definitely) to the study medication. All other Serious 
Adverse Events will be discussed on monthly webinars held with all participating 
centers (see section 12). 
 
The Sponsor Investigator will be responsible for reporting of events to the FDA and 
supporters, as appropriate and defined in the regulations under 21 CFR 312.32.  
8.6 
Routine Reporting 
All other adverse events that are not SAEs as defined in section 8.3—such as those that 
are expected, or are unlikely or definitely not related to the study participation—are to be 
reported annually as part of regular data submission and as per the local IRB policies. 


________________________________________________________________________ 
Page 32 of 44 
 
8.7 
Reporting of Unanticipated Problems 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem involving risks to subjects or others, 
the investigator should assess whether the incident, experience, or outcome represents an 
unanticipated problem. The incident, experience or outcomes are considered unanticipated 
if it meets all of the following criteria: 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of harm than 
was previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the MAGIC Data Coordinating 
Center within 5 days of first awareness of the events, and to the local IRB as per local IRB 
policy. 
8.8 
Stopping Rules  
Natalizumab has not previously been studied as a treatment of acute GVHD, therefore this 
study will use strict stopping rules to mitigate risks to study subjects. These stopping rules 
were designed keeping in mind the high rates of treatment failure with standard treatment 
and 6 month non-relapse mortality (32% in AA2 and AA3 patients combined) experienced 
by the high risk GVHD population under study. 
 
The following risks were considered in the development of the stopping rules. Progressive 
multifocal leukoencephalopathy is a serious, potentially lethal complication and is listed as 
a black box warning on the prescribing information brochure for natalizumab. Other serious 
infections, including herpes encephalitis and meningitis, have been reported with 
natalizumab. Patients with GVHD and on immunosuppression are already at increased risk 
for development of serious infections. The degree to which natalizumab may further 
increase that risk is unknown. Therefore we will follow the below stopping rules designed 
to minimize any increased risk by adding natalizumab to GVHD standard therapy. 
 
STOPPING RULE #1: PML 
The clinical study will be stopped if one case of PML develops. Notification from the site to 
the Sponsor Investigator must occur within 24 hours of event.  A webinar will be scheduled 
within 3 days of Sponsor knowledge for the participating sites to discuss the case.  In the 
event of one case, the informed consent will be revised to inform potential subjects that a 
case of PML was observed on this clinical trial. The trial will only be re-opened to accrual 
with approval by the Tisch Cancer Institute (TCI) DSMC, the external advisory board, and 
the FDA after review of all safety data available and after any additional safety measures 
are implemented. If a second case of PML develops, the study will be closed to accrual 
and no further doses of natalizumab will be administered to any patient currently 
undergoing treatment. 
 
STOPPING RULE #2: EXCESS NON-RELAPSE MORTALITY 
Although we do not expect natalizumab to increase the incidence of fatal infections or 
contribute to increased mortality, for safety reasons we will continuously monitor the 
incidence of non-relapse mortality throughout the study. If natalizumab adversely affects 
the risk of non-relapse mortality we expect that effect to manifest itself during the early 
follow-up period after administration of the drug.  
 
We will continuously monitor non-relapse mortality occurring within 100 days of study 
administration. If the incidence of NRM occurring within 100 days of study administration 
is greater than the associated boundary value bk listed in the table below, among the k 
patients enrolled in the trial, then accrual will be halted for safety considerations. We 


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estimated the stopping boundaries based on the crude non-relapse mortality rates of the 
updated historical controls (13% for AA2 and 41% for AA3). 
 
Maximum # of AA2 
Patients, k 
1-15 
16-30 
31-42 
Boundary, bk 
2 
3 
4 
 
Maximum # of AA3 
Patients, k 
20 
21- 25 
26-30 
31- 35 
36-40 
41- 42 
Boundary, bk 
9 
10 
12 
14 
15 
16 
 
 
Specifically, given different risks for NRM by Ann Arbor score, we will monitor NRM for 
patients with Ann Arbor 2 and Ann Arbor 3 GVHD separately. For patients with Ann Arbor 
2 GVHD, if more than 2 out of the first 15 patients, 3 out of the first 30, or 4 out of the first 
42 patients, experience NRM within 100 days of study drug administration, the trial will be 
halted for safety reasons. We have already enrolled 32 patients with Ann Arbor 3 GVHD 
out of a planned 42 patients and more than 10 patients completed their follow-up for NRM. 
For patients with Ann Arbor 3 GVHD, if more than 9 of the first 20 patients, 10 out of the 
first 25 patients, 12 out of the first 30 patients,14 of the first 35 patients, 15 out of the first 
40 patients or 16 of the first 42 patients experience NRM within 100 days of study drug 
administration, the trial will be halted for safety considerations 
 
The operating characteristics of this stopping rule are as follows: 
  
  AA2 patients 
True Toxicity Rate 
5% 
10% 
13% 
15% 
Probability of Early Stopping 
0.09 
0.44 
0.68 
0.78 
  
  AA3 patients 
True Toxicity Rate 
27% 
30% 
41% 
45% 
Probability of Early Stopping 
0.08 
0.16 
0.68 
0.82 
 
 
Using these boundaries, for the patients with Ann Arbor 2 GVHD, if the true toxicity rate is 
5%, 10%, 13% or 15%, the probability of stopping the trial early is 0.09, 0.44, 0.68, and 
0.78 respectively. For the patients with Ann Arbor 3 GVHD, if the true toxicity rate is 27%, 
30%, 41% or 45%, the probability of stopping the trial early is 0.08, 0.16, 0.68, and 0.82 
respectively. This stopping rule was computed using the toxbdry function in R and 
calculations of this function as published [Jennison and Turnbull 2000, Ivanova 2005]. 
  
An enrollment rule to prevent an excessive number of toxicities as described in Song and 
Ivanova will be used to inform us of the number of additional patients we can recruit when 
the current patient has not yet completed follow-up[Song and Ivanova 2015]. Formally, the 
trial can enroll m new patients such that r + x + m ≤bn+m + M, r + x + m– 1 < bn+m−1 + M, 
and n + m ≤ K where r is defined as the number of patients that have not completed follow-
up and are still being followed for toxicity; x is the number of patients that have experienced 
toxicity n is the total number of patients enrolled to date and M is the fixed design 
parameter. To be able to complete the study in a timely manner, we allow M to be 26. 
 
   
9.0 
 
DRUG INFORMATION 


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Page 34 of 44 
 
9.1 
NATALIZUMAB 
• 
Other names for the drug: TYSABRI  
 
• 
Description: Natalizumab is supplied as 300 mg natalizumab in 15 mL (20 mg/mL) in 
a sterile, single-use vial free of preservatives.   
 
• 
Classification - type of agent: Immunomodulator 
 
• 
Mode of action: Natalizumab binds to the α4-subunit of α4β1 and α4β7 integrins 
expressed on the surface of all leukocytes except neutrophils, and inhibits the α4-
mediated adhesion of leukocytes to their counter-receptor(s). 
 
• 
Pharmacokinetics: In patients with CD, following the repeat intravenous administration 
of a 300 mg dose of natalizumab, the mean ± SD maximum observed serum 
concentration was 101 ± 34 mcg/mL. The mean ± SD average steady-state trough 
concentration was 10 ± 9 mcg/mL. The estimated time to steady-state was 
approximately 16 to 24 weeks after every four weeks of dosing. The mean ± SD half-
life, volume of distribution, and clearance of natalizumab were 10 ± 7 days, 5.2 ± 2.8 
L, and 22 ± 22 mL/hour, respectively. The effects of total body weight, age, gender, 
race, selected hematology and serum chemistry measures, co-administered 
medications (infliximab, immunosuppressants, or steroids), and the presence of anti-
natalizumab antibodies were investigated in a population pharmacokinetic analysis 
(n=1156). The presence of anti-natalizumab antibodies was observed to increase 
natalizumab clearance. Pharmacokinetics of natalizumab in patients with renal or 
hepatic insufficiency have not been studied. 
 
• 
Side effects: See section 8.1 of this document for complete listing of adverse effects.  
 
• 
Drug Interactions: Natalizumab interacts with immunosuppressant agents and 
increases the risk of infection. 
 
• 
Storage and stability: TYSABRI single-use vials must be refrigerated between 2 to 8°C 
(36° to 46°F). Do not use beyond the expiration date stamped on the carton and vial 
label. DO NOT SHAKE OR FREEZE. Protect from light. Natalizumab must be stored 
in a secure, limited access area.   
 
• 
Preparation and Dispensing:  
 
1. Use aseptic technique when preparing natalizumab solution for intravenous 
infusion. Each vial is intended for single use only.  
2. Natalizumab is a colorless, clear to slightly opalescent concentrate. Inspect the 
natalizumab vial for particulate material and discoloration prior to dilution and 
administration. If visible particulates are observed and/or the liquid in the vial is 
discolored, the vial must not be used. 
3. To prepare the solution, withdraw 15 mL of natalizumab concentrate from the vial 
using a sterile needle and syringe. Inject the concentrate into 100 mL 0.9% Sodium 
Chloride Injection, USP. No other IV diluents may be used to prepare the 
natalizumab solution.  
4. Gently invert the natalizumab solution to mix completely. Do not shake. Inspect the 
solution visually for particulate material prior to administration.  
5. The final dosage solution has a concentration of 2.6 mg/mL.  
6. Following dilution, infuse natalizumab solution immediately, or refrigerate solution 
at 2 to 8°C, and use within 8 hours. If stored at 2 to 8°C, allow the solution to warm 
to room temperature prior to infusion. DO NOT FREEZE. 


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Page 35 of 44 
 
 
• 
Administration:  
1. Infuse natalizumab 300 mg in 100 mL 0.9% Sodium Chloride Injection, USP, over 
approximately one hour (infusion rate approximately 5 mg per minute). Do not 
administer natalizumab as an intravenous push or bolus injection. After the infusion 
is complete, flush with 0.9% Sodium Chloride Injection, USP. 
2. Observe patients during the infusion and for one hour after the infusion is 
complete. Promptly discontinue the infusion upon the first observation of any signs 
or symptoms consistent with a hypersensitivity-type reaction 
3. Use of filtration devices during administration has not been evaluated. Other 
medications should not be injected into infusion set side ports or mixed with 
natalizumab. 
 
• 
Availability: Provided by Biogen Idec, Inc. 
• 
Return and Retention of Study Drug: 
Any remaining/expired/used is to be destroyed on site according to the institution 
standard operating procedure for drug destruction and documented on the drug 
accountability logs. 
 
• 
Drug Accountability: 
The principal investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of the investigational drug, 
natalizumab. The drug accountability records will capture drug receipt, drug 
dispensing, drug return and final disposition.   
9.2 
CORTICOSTEROIDS (Prednisone and Methylprednisolone)  
Glucocorticoids produce widespread and diverse physiologic effects on carbohydrate, 
protein, and lipid metabolism, electrolyte and water balance, functions of the cardiovascular 
system, kidney, skeletal muscle, and the nervous systems. Glucocorticoids reduce the 
concentration of thymus- dependent lymphocytes (T-lymphocytes), monocytes, and 
eosinophils. Glucocorticoids selectively bind to the cortisol receptors on human lymphoid 
cells. They also decrease binding of immunoglobulin to cell surface receptors and inhibit 
the synthesis and/or release of interleukins, thereby decreasing T-lymphocyte 
blastogenesis and reducing expansion of the primary immune response. The specific 
cellular mechanisms that act to halt DNA synthesis are thought to be related to inhibition 
of glucose transport or phosphorylation, retardation of mitosis, and inhibition of protein 
synthesis. 
 
Toxicities/Side Effects of Corticosteroids  
 
Common  
(>20%) 
Occasional 
5-20% 
Rare 
<5% 
Immediate: 
Within 1-2 days of 
receiving drug 
Insomnia, Hyperphagia 
Gastritis 
Hyperuricemia 
Prompt: 
Within 2-3 weeks, 
Immunosuppression, 
personality changes (mood 
swings, euphoria, anxiety, 
depression), pituitary-adrenal 
axis suppression, acne  
Hyperglycemia, facial 
erythema, poor 
wound healing, 
infections 
(bacterial, fungal, 
parasitic, viral), 
edema 
Pancreatitis (L), increased intraocular 
pressure (L), hypertension, 
psychosis, vertigo; headache 


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Page 36 of 44 
 
Delayed: 
Any time later during 
therapy 
Cushing’s syndrome (moon 
facies, truncal obesity) 
Striae and thinning of 
the skin, easy 
bruising, muscle 
weakness, osteopenia 
Spontaneous fractures (L), growth 
suppression, Peptic ulcer and GI 
bleeding, pseudotumor cerebri 
(increased intracranial pressure with 
papilledema, headache), aseptic 
necrosis of the femoral and humeral 
heads (L) 
Late: 
Any time after 
completion of 
treatment 
 
Cataracts 
 
 
(L) Toxicity may also occur later. 
 
Formulation, Stability, Guidelines for administration:  Numerous preparations of commercially 
available corticosteroids are available. This study permits any commercially available form of 
prednisone or methylprednisolone to be used. The package insert should be referenced for further 
information. 
 
10.0 
CORRELATIVES/SPECIAL STUDIES 
The goal of the planned laboratory correlative studies is to improve our understanding of the 
biological processes that drive GVHD and its clinical outcomes. 
 
10.1 
Sample Collection Guidelines 
The correlative sample collection schedule is detailed in section 6.4 above. Serum will be 
collected in no additive, silicone coated glass or plastic tubes containing no anticoagulant 
(red or gold top tube). Samples will be processed at the participating center and batch 
shipped to Ferrara Laboratory quarterly for storage. Sample processing details are found 
in Appendix A. Instructions for quarterly batch shipping are found in the MAGIC Sample 
Collection and Storage Manual. 
10.2 
Assay Methodology 
See Appendix A. 
10.3 
Specimen Banking 
 Patient samples collected for this study will be retained at the Icahn School of Medicine at 
Mount Sinai.  Specimens will be stored indefinitely or until they are used up. If future use 
is denied or withdrawn by the patient, best efforts will be made to stop any additional 
studies and to destroy the specimens. 
 
When consent is provided, we will analyze small and large bowel biopsy samples obtained 
from these patients using immunohistochemical staining for cells and proteins with known 
associations with GI GVHD. Sites will be asked to submit formalin fixed paraffin embedded 
GI biopsies that were obtained for standard of care purposes, provided that this tissue is 
no longer needed for further clinical use. These biopsies will be requested and batch 
shipped after the tissue is no longer needed for further clinical use (minimum six months 
from biopsy acquisition). 
 
Drs. Ferrara and Levine will be responsible for reviewing and approving requests for clinical 
specimen from potential research collaborators from within the MAGIC consortium.  
 
The specimens, DNA, and their derivatives may have significant therapeutic or commercial 
value. The Informed Consent form contains this information and informs the subject that 


________________________________________________________________________ 
Page 37 of 44 
 
there is the potential for financial gain by the Icahn School of Medicine at Mount Sinai, the 
investigator or a collaborating researcher or entity.  
 
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available:  
• 
Diagnosis  
• 
Collection time in relation to study treatment 
• 
Clinical outcome – if available 
• 
Demographic data 
11.0 
STATISTICAL CONSIDERATIONS 
11.1 
Study Design/Study Endpoints 
This is a phase II open label multicenter clinical trial. The primary study endpoint is day 28 
CR rate was chosen due to its correlation with long term survival in patients with GVHD.  
 
Because we expect improvements in day 28 CR to translate into better long-term 
outcomes, secondary endpoints include 1 year NRM and 1 year survival.  Additional 
secondary endpoints related to efficacy will include the day 28 overall response rate (CR 
+ PR), the proportion of patients who develop treatment-refractory GVHD (defined as not 
CR/PR by day 28 of treatment or who receive additional immunosuppression prior to day 
28), time to discontinuation of steroid therapy, number of lines of GVHD therapy, and 
cumulative incidence of chronic GVHD. Secondary endpoints related to safety include 6 
month and 1 year relapse rates and incidence of serious infections by 6 months.  
 
Because natalizumab has not been studied as a treatment for acute GVHD, we have 
developed stopping rules to maximize patient safety protection. A single case of PML will 
cause suspension of study enrollment until (1) a safety review has been conducted and (2) 
the informed consent is modified to include that a case of PML developed on this study. A 
second case of PML will cause the study to terminate. 
 
. 
 
Because we are changing the design of the study and enrolling another cohort in addition 
to the patients currently enrolled, the planned interim analysis will not be applicable. We 
therefore calculated the conditional power, i.e., the probability that the study results will 
be statistically significant given the data observed thus far. We have so far enrolled 32 
patients with Ann Arbor 3 GVHD and 28 have sufficient follow-up for the primary endpoint 
assessment (28 day response). We observed 12 CRs, 6 PRs and 10 NRs. Given these 
data, the conditional power of the study based on the previous design (90 patients with 
Ann Arbor 3 GVHD to be enrolled and 37 CRs to be observed in order to reject the null 
hypothesis) is 0.81 using an exact binomial test. Therefore, our conditional power 
analysis indicates that the new study design is sufficiently powered. 
 
 
The historical controls for this study consists of 256 patients who met the criteria for Ann 
Arbor score 2 (n=142) or 3 (n=114) GVHD and who were either (1) diagnosed at the 
University of Michigan or the University of Regensburg or (2) participated in the MAGIC 
consortium observational study between 2013-2017. Approximately 75% of these patients 
were diagnosed and treated since 2010, thus the historical control population is comprised 
primarily of fairly recently transplanted patients. 
11.2 
Sample Size and Accrual 
We revised the study design to allow us to include patients with Ann Arbor 2 GVHD without 
losing the data already generated for patients with Ann Arbor 3 GVHD. We have fixed the 


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Page 38 of 44 
 
numbers of patients with Ann Arbor 2 and Ann Arbor 3 GVHD to provide a final study ratio 
of 1:1. This allows us to weight the two GVHD scores equally for the calculation of the 
predicted magnitude of improvement and the accompanying power and sample size. eWe 
maintained a conservative estimate of 15% for the magnitude of improvement in weighted 
day 28 CR (from 42.5% to 57.5%), similar to the 14% effect size seen within 4 weeks (i.e. 
after one dose of natalizumab) in active Crohn’s disease. We chose our sample size based 
on both feasibility and power requirements.  A sample size of 84 (42 AA2 and 42 AA3 
patients) will provide 80% power to detect a 15% difference in CR rates, with a Type I error 
rate of 0.05. Finally, we have re-estimated the historical day 28 CR rate using the most up-
to-date data available (256 patients transplanted up until 7/2017). 
 
11.3 
Data Analyses Plans 
The primary endpoint is day 28 CR rate. Death, lack of CR at day 28, or initiation of 
additional immunosuppressive therapy will be considered failures for this endpoint. The 
day 28 CR rate in the study patients will be compared to the historical control rate of 42.5%. 
 
Secondary outcomes such as the overall response rate (CR+PR), the incidence of steroid 
refractory GVHD, the incidence of severe GI GVHD (stage 3 or 4), non-relapse mortality, 
relapse rates, overall survival, will be analyzed using descriptive statistics (cumulative 
incidence curves, Kaplan-Meier, etc.) and compared to historical controls. Outcomes will 
be analyzed for all patients and separately according to Ann Arbor GVHD score. 
 
 
12.0 
DATA AND SAFETY MONITORING 
The safety of subjects is paramount and supersedes all other concerns. This study will employ 
several layers of oversight to ensure that patient safety is protected. These layers (described in 
more detail further below) are: 
 
1. The local Data and Safety Monitoring Committee (DSMC) at each site which will be responsible 
for monthly reviews of patient data at each site 
2. The Protocol Data and Safety Monitoring Committee (DSMC), composed of the individual site 
PI’s which will review all facets of study conduct at all sites on monthly webinars 
3. The External Advisory Board (see below for membership), which is composed of national 
experts in BMT and GVHD who will be responsible to (1) review and advise on the interim 
analysis when performed and (2) recommend whether the study can reopen whenever a 
stopping rule is triggered (see section 8.8). A meeting of the EAB will be scheduled in a timely 
fashion as needed in order to accomplish these review functions and subsequently these 
recommendations will be provided to the TCI DSMC and to each IRB. 
4. The Tisch Cancer Institute Data and Safety Monitoring Committee (TCI DSMC) of the Mount 
Sinai Health System is the DSMB of record for this study. The DSMB will be compliant with the 
NIH approved DSMP Charter. This committee will be responsible for monitoring the safety and 
data integrity of the trial. It is a DSMB entirely composed of members with no connection to this 
clinical trial. The DSMB will have final authority on interpreting the interim analysis and whether 
the study can reopen whenever a stopping is triggered. 
5. The IRBs at each participating site and the Mount Sinai Health System. 
6. The FDA which will receive safety reporting as required by IND regulations (21 CFR 312.3). 
 
Thus, the investigators conducting the trial will review the trial conduct at their own site as well as 
each other’s sites on a monthly basis, thereby providing a high level of attention to any safety 
concerns that may develop. Additionally, authority is vested in three independent bodies (the 
External Advisory Board, the TCI DSMC, and the IRBs) to monitor, and if safety concerns warrant, 
close the clinical trial. Lastly, this trial will be conducted in a manner compliant with the Federal 
regulations pertaining to clinical trials conducted under an IND. 


________________________________________________________________________ 
Page 39 of 44 
 
 
Local DSMC: Each participating site is required to have its own Data and Safety Monitoring 
Committee (DSMC) for the study.  This committee will be composed of the local site principal 
investigator, site co-investigator(s), site data manager or study coordinator and other members of 
the study staff involved in the conduct of the trial.   
 
During the committee’s monthly meeting, the principal investigator will discuss matters related to: 
 
 Enrollment rate relative to expectations, characteristics of participants 
 Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 Retention of study participants 
 
These meetings are to be documented by the site data manager or study coordinator using the 
Protocol Specific Data and Safety Monitoring Report (DSMR), signed by the site principal 
investigator.  Each site is required to submit the completed DSMR to the MAGIC Coordinator at the 
Icahn School of Medicine at Mount Sinai on a monthly basis together with other pertinent 
documents. 
 
Similarly, protocol deviations are to be documented using the Notice of Protocol Deviation Form 
and requires the signatures of both the site’s data manager or study coordinator and the site 
principal investigator. These reports are to be sent to the MAGIC Coordinator at the Icahn School 
of Medicine at Mount Sinai within 7 calendar days of awareness of the event and on a monthly 
basis with the Protocol Specific Data and Safety Monitoring Report. 
 
Protocol DSMB: The centers participating in this study are collaborating centers in MAGIC (Mount 
Sinai Acute GVHD International Consortium) which has been holding monthly webinars to review 
GVHD clinical data from each of these sites since January 2013. The local site principal 
investigator, data manager, and study coordinator participates in these monthly webinars. While 
this study is open, in addition to the local DSMC meetings, the monthly MAGIC webinars will provide 
an additional forum for discussion of the above matters, which will keep all participating centers 
current on all data and safety issues that arise, thereby providing an additional layer of safety 
oversight. 
 
The MAGIC Data Coordinating Center is responsible for collating all the Data and Safety Monitoring 
Reports from all the participating sites, and providing the information to the TCI Data Safety 
Monitoring Committee. 
 
External Advisory Board: The scientific advisory board is composed of national experts in BMT 
and GVHD. The members are Chair -; Joseph Antin, MD, Chief, Adult Oncology Hematopoietic 
Stem Cell Transplantation Program, Dana-Farber Cancer Institute, Nelson Chao, MD, Chief, 
Division of Hematologic Malignancies and Cellular Therapy/BMT, Duke Cancer Institute and 
Steven Burakoff, MD, Dean for Cancer Innovation at the Icahn School of Medicine at Mount Sinai. 
 
TCI DSMC: The TCI DSMC serves as the data and safety monitoring board (DSMB) for investigator 
initiated studies conducted under the auspices of the Tisch Cancer Institute (TCI) at the Mount 
Sinai Health System. It is compliant with the National Institutes of Health and National Cancer 
Institute charter for DSMBs. This board will be responsible for monitoring the safety and data 
integrity of the trial. It is a DSMB entirely composed of members with no connection to this clinical 
trial. 
 
12.1 
Multisite Clinical Monitoring Procedures 
This clinical study will be coordinated by the MAGIC Data Coordinating Center (DCC) of 
the Icahn School of Medicine at Mount Sinai. As such it will be conducted in accordance 


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Page 40 of 44 
 
with the ethical principles that are consistent with Good Clinical Practices (GCP) and in 
compliance with other applicable regulatory requirements. 
 
This study will be monitored by a representative of the MAGIC Data Coordinating Center. 
Monitoring visits will be made during the conduct of the study and at study close-out. 
 
Prior to subject recruitment, a participating site will undergo site initiation meeting to be 
conducted by the DCC. This will be done as an actual site visit, teleconference, 
videoconference, or web-based meeting after the site has been given access to the study 
database and assembled a study reference binder.  The site’s principal investigator and 
his study staff should make every effort in attending the site initiation meeting. Study-
related questions or issues identified during the site initiation meeting will be followed-up 
by the appropriate DCC personnel until they have been answered and resolved. 
 
Monitoring of this study will include both ‘Centralized Monitoring’, the review of source 
documents at the DCC and ‘On-site Monitoring’, an actual site visit.  The first ‘Centralized’ 
visit will occur after the first subject enrolled completes treatment (i.e., two doses of 
natalizumab).  The study site will send the de-identified source documents to the DCC for 
monitoring.  ‘Centralized’ monitoring may be requested by the DCC if an amendment 
requires changes to the protocol procedures. The site will send in pertinent de-identified 
source documents, as defined by the DCC for monitoring.  
 
The first annual ‘On-site’ monitoring visit should occur after the first five study participants 
are enrolled or twelve months after a study opens, whichever occurs first.  The annual visit 
may be conducted as a ‘Centralized’ visit if less than three subjects have enrolled at the 
study site.  The type of visit is at the discretion of the DCC.  At a minimum, a routine 
monitoring visit will be done at least once a year, or once during the course of the study if 
the study duration is less than 12 months. The purpose of these visits is to verify: 
 
 
Adherence to the protocol 
 
Completeness and accuracy of study data and samples collected 
 
Proper storage, dispensing and inventory of study medication 
 
Compliance with regulations 
 
During a monitoring visit to a site, access to relevant hospital and clinical records must be 
given by the site investigator to the DCC representative conducting the monitoring visit to 
verify consistency of data collected on the CRFs with the original source data.  While most 
patient cases will be selected from patients accrued since the previous monitoring visit, 
any patient case has the potential for review.  At least one or more unannounced cases 
will be reviewed, if the total accruals warrant selection of unannounced cases.  
 
The MAGIC Data Coordinating Center (DCC) expects the relevant investigational staff to 
be available to facilitate the conduct of the visit, that source documents are available at the 
time of the visit, and that a suitable environment will be provided for review of study-related 
documents. Any issues identified during these visits will be communicated to the site and 
are expected to be resolved by the site in a timely manner.  For review of study-related 
documents at the DCC, the site will be required to ship or fax documents to be reviewed.   
 
Participating site will also undergo a site close-out upon completion, termination or 
cancellation of a study to ensure fulfillment of study obligations during the conduct of the 
study, and that the site Investigator is aware of his/her ongoing responsibilities. In general, 
a site close-out is conducted during a site visit; however, site close-out can occur without 
a site visit if all of the following apply: 
 
 
No patient has signed the Informed Consent Form and has enrolled into the study 
 
Investigational agent has not been dispensed 


________________________________________________________________________ 
Page 41 of 44 
 
 
All investigational agent and materials have been returned as defined for the study 
or destroyed and accounted for properly. 
 
13.0 
QUALITY ASSURANCE AND AUDITS 
The Data Safety Monitoring Board can request a ‘for cause’ audit of the trial if the board identifies 
a need for a more rigorous evaluation of study-related issues. A “for cause” audit would be 
conducted by the Project Manager of the MAGIC Data Coordinating Center. 
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the MAGIC Data Coordinating Center that 
such a request has been made. 
 


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Page 42 of 44 
 
14.0 
REFERENCES 
 
 
Alousi AM, Weisdorf DJ, Logan BR, et al. Etanercept, mycophenolate, denileukin, or pentostatin plus 
corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow 
Transplant Clinical Trials Network. Blood 114(3): 511-517, 2009. 
 
Biogen. Physician Information and Management Guidelines for Multiple Sclerosis Patients on TYSABRI 
Therapy. Version 14. Maidenhead; Biogen, 2015. 
 
Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal 
leukoencephalopathy. N Engl J Med 366(20): 1870-1880, 2012. 
 
Bolanos-Meade J, Logan BR, Alousi AM, et al. Phase 3 clinical trial of steroids/mycophenolate mofetil vs 
steroids/placebo as therapy for acute GVHD: BMT CTN 0802. Blood 124(22): 3221-3227, 2014. 
 
Choi SW, Hildebrandt GC, Olkiewicz KM, et al. CCR1/CCL5 (RANTES) receptor-ligand interactions 
modulate allogeneic T-cell responses and graft-versus-host disease following stem-cell transplantation. 
Blood 110(9): 3447-3455, 2007. 
 
Ferrara JL, Harris AC, Greenson JK, et al. Regenerating islet-derived 3-alpha is a biomarker of 
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15.0 
APPENDICES 
Appendix A: Ann Arbor Scoring Manual 
Appendix B: BMT CTN Infection Severity Grading guide