Phase II Trial of Natalizumab + Prednisone for Initial Therapy of Acute GI GVHD

Study Overview
=================
Brief Summary
-----------------
This research study is a Phase II clinical trial, which tests the safety and effectiveness of an investigational drug Natalizumab in treating Acute Graft-Versus-Host Disease (GVHD) in the Gastrointestinal (GI) Tract.

Detailed Description
-----------------
Natalizumab is a drug that was initially discovered as a treatment for autoimmune conditions. Natalizumab has been approved for use in patients with Multiple Sclerosis and Crohn's disease. In these diseases, the drug works to inhibit dysfunctional immune cells that are responsible for the symptoms seen in these diseases. Acute graft versus host disease is caused by a similar dysfunction of immune cells; Natalizumab is thought to inhibit these immune cells, similarly to how it does in Multiple Sclerosis and Crohn's disease. In this research study,the investigators are looking to see whether Natalizumab provides additional benefit to patients receiving standard treatment for acute graft versus host disease of the gastrointestinal tract. Participants who fulfill eligibility criteria will be entered into the trial to receive Natalizumab. Participant will receive a dose of the natalizumab through intravenous infusion. Participants may receive a second dose at Day 28 if they experience a partial response or very good partial response. Scheduled Physical Examination at screening, during the week of first dose and at 28 days, 56 days, 100 days, 180 days and one year.

Official Title
-----------------
Phase II Trial of Natalizumab (Tysabri®) Plus Prednisone for Initial Therapy of Acute Graft Versus Host Disease (aGVHD) of the Gastrointestinal Tract

Conditions
-----------------
Graft Versus Host Disease

Intervention / Treatment
-----------------
* Drug: Natalizumab
* Drug: Methylprednisolone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants must meet the following criteria on screening examination to be eligible to participate in the study: Participants must have acute Graft-Versus-Host Disease (GVHD) of the lower gastrointestinal tract as defined by the clinical impression of the treating physician, requiring systemic treatment. Minimum criteria for GI GVHD includes diarrhea of greater than 500 mL/day. Biopsy of the GI tract is required for study entry and must confirm the diagnosis of acute GVHD. Stool samples to rule out infectious causes of diarrhea, including norovirus, Clostridium difficile and other clinically indicated infections must also be negative. Eligibility includes: Acute GVHD developing after allogeneic hematopoietic stem cell transplantation (HSCT) using bone marrow, peripheral blood stem cells, or umbilical cord blood. Recipients of non-myeloablative, reduced intensity and myeloablative transplants are eligible. Patients who develop acute GVHD after donor lymphocyte infusion (DLI) are eligible. There is no specified time window after day 0 of transplant as acute GVHD is only defined by clinical manifestations. Patients must have experienced neutrophil engraftment after HSCT as defined by absolute neutrophil counts ≥ 500 / µL × 3 consecutive measurements. Absolute neutrophil count (ANC) should be calculated using the standard formula (Neut + Bands)(WBC × 101). The presence of hepatic, upper GI and/or cutaneous acute GVHD is permitted. Steroids can be started up to 7 days prior to the administration of natalizumab. Age ≥ 18 Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study: Patients with the entity of Acute/Chronic GVHD overlap syndromes. Requiring mechanical ventilation Vasopressor requirement Concurrent hepatic veno-occlusive disease (VOD) based on clinical examination Karnofsky performance status < 30 Participants may not be receiving any other study agents for at least 7 days prior to enrollment Prior use of natalizumab for any reason is not allowed Pregnant women are excluded from this study because of the potential teratogenic effects of natalizumab. Because natalizumab enters breast milk, and the effect is unknown in infants, breastfeeding should be discontinued if the mother is treated with natalizumab.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Natalizumab<br>Natalizumab- (Day 0 and 28) Fixed dose Intravenous infusion over one hour. 2 hours observation completion of the infusion At 4 weeks, if there has been less than a complete response participants can be treated with a second dose of natalizumab. If participants have no response after one dose, they will be not be given a second dose. Participants who receive a second dose of natalizumab will be evaluated for response at day 56 after first treatment dose administered. Participants will be assessed for response to therapy with natalizumab at day +28, day +56, day +100, day + 180, and day +365. Commercial supplies of Methylprednisolone (or equivalent steroid) will be utilized. The formulation, preparation and route of administration will be as per package insert | Drug: Natalizumab<br> <br> * Other names: Tysabri®;Drug: Methylprednisolone<br> <br> * Other names: Steroid;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GVHD-free Survival Rate | Graft-versus-host disease (GVHD) free survival is defined as achieving complete response without death or relapse or requiring secondary immunosuppressive therapy . Proportions are reported descriptively. GVHD-free survival was assessed using the Kaplan-Meier method. | Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Graft-verus-host Disease (GVHD) Response Rate | Complete Response (CR) is defined as resolution of all signs and symptoms of acute GVHD. Very Good Partial Response (VGPR) is defined by no rash or residual erythematous rash involving less than 25% of the body surface, and total serum bilirubin concentration less than 2 mg/dL or less than 25% of baseline at enrollment and tolerating food or enteral feeding, predominantly formed stools, no overt gastrointestinal bleeding or abdominal cramping, and no more than occasional nausea and vomiting. Partial Response (PR) is defined as an improvement of one stage in one or more organs without progression in any other organ. Non-response (NR) is defined as no reduction in any GVHD organ staging. Progression is defined as either new organ involvement on day +8 or thereafter, or increased organ specific symptoms sufficient to increase the organ stage by one or more or the initiation of an additional GVHD agent. Overall Response Rate (ORR) is the sum of CR, VGPR, and PR. | 28 Days, 56 Days | 
| GI aGVHD Response Rate | Gastrointestinal (GI) acute graft-versus-host disease (GVHD) Response is defined by complete response, very good partial response, or partial response in signs and symptoms of GI aGVHD. | Day 28, Day 56 | 
| Overall Survival (OS) Rate | Overall survival (OS) is defined from the date of natalizumab infusion to death or censored at last clinical evaluation. OS was estimated using the Kaplan-Meier method. | 2 years | 
| Rate of GVHD Flares | Number of subjects who experienced graft-versus-host disease (GVHD) flares requiring therapy after initial complete response (CR) or partial response (PR) by day 28 after the first dose of Natalizumab. | by Day 28 | 
| Percentage Steroid Dose Was Reduced at Day 28, 56, and 100 in Comparison to Steroid Dose at First Administration of Natalizumab. | Median percentage steroid dose was reduced at Day 28, Day 56, and Day 100 in comparison to steroid dose at first administration of Natalizumab. | Day 28, 56, and 100 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Graft Versus Host Disease