Multicenter Study Of Natalizumab Plus Standard Steroid Treatment For High Risk Acute Graft-Versus-Host Disease

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 most patients with Ann Arbor score 3 GVHD, will not respond well to
steroid treatment. The investigators research shows that almost half of the patients with Ann
Arbor grade 3 GVHD, will 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 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 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.

Inclusion Criteria:

- New onset high risk acute GVHD (Ann Arbor score 3 as defined in Appendix C of the
protocol) following allogeneic bone marrow transplantation. 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.

- 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.

- 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.

- Age 18 years or older.

- 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.

- 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.

- If the patient is a woman of child-bearing potential, the patient and their sexual
partner must agree to practice effective contraception.

- Written informed consent from patient.

- 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 systemic steroid treatment for acute GVHD are not permitted to
participate.

Exclusion Criteria:

- Progressive or relapsed malignancy since BMT

- Uncontrolled active infection

- Patients with chronic GVHD only. Patient with overlap syndrome are eligible.

- History of Progressive Multifocal Leukoencephalopathy (PML)

- Known hypersensitivity to natalizumab

- Pregnant or nursing (lactating) women

- Use of other drugs for the treatment of acute GVHD

- 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

- Patients on dialysis

- Patients requiring ventilator support

- Investigational agent within 30 days of enrollment without approval from the
Sponsor-Investigator