Multicenter Study Of Natalizumab Plus Standard Steroid Treatment For High Risk Acute Graft-Versus-Host Disease
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.
Acute Graft Versus Host Disease
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||PHASE II Multicenter Study Of Natalizumab Plus Standard Steroid Treatment For High Risk Acute Graft-Versus-Host Disease|
- Complete Response (CR) [ Time Frame: Day 28 ] [ Designated as safety issue: No ]The primary endpoint for this clinical study is the proportion of complete response, CR (that is, the percent of patients with skin, liver, and GI GVHD - all stage 0) at day 28 of study treatment.
- Overall survival (OS) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
- Non-Relapse Mortality (NRM) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]Cumulative incidence of Non-Relapse Mortality (NRM)at 6 months and 1 year
- incidence of treatment-refractory GVHD [ Time Frame: Day 28 ] [ Designated as safety issue: No ]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)
- Time to discontinuation of steroid therapy [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
- Number of additional GVHD therapies [ Time Frame: 1 year ] [ Designated as safety issue: No ]Number of additional GVHD therapies (defined as the initiation of a new acute GVHD therapy, regardless of duration)
- Number of serious infections [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]Number of serious infections (defined as score 3 by the Blood and Marrow Transplant Clinical Trials Network)
- Overall response rate (CR + PR) [ Time Frame: Day 28 ] [ Designated as safety issue: No ]Overall response rate (CR + PR) at day 28. Partial Response (PR) is defined as improvement in one or more organs involved with GVHD symptoms without progression in others. For 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.
|Study Start Date:||November 2015|
|Estimated Study Completion Date:||August 2019|
|Estimated Primary Completion Date:||August 2018 (Final data collection date for primary outcome measure)|
Experimental: Natalizumab with steroids
For subjects whose GVHD assay is Ann Arbor score 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.
Natalizumab 300mg (or 4.3 mg/kg for subjects <18y or <50kg) on days 0 and 14.
Other Name: TysabriDrug: steroids
Prednisone 2mg/kg/d (or methyl-prednisolone IV equivalent)
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 their clinical diagnosis of 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, and also because it has not been studied in pediatric patients (patients under the age of 18), even for its approved uses.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02133924
|Contact: John E Levine, MDemail@example.com|
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|United States, Massachusetts|
|Massachusetts General Hospital||Not yet recruiting|
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|Contact: Yi-Bin Chen, MD 617-724-1124 email@example.com|
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|United States, Michigan|
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|Ann Arbor, Michigan, United States, 48109|
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|United States, Ohio|
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|Study Chair:||John E Levine, MD||Ichan School of Medicine at Mount Sinai|