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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02133924
Recruitment Status : Recruiting
First Posted : May 8, 2014
Last Update Posted : November 12, 2020
Information provided by (Responsible Party):
John Levine, Icahn School of Medicine at Mount Sinai

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.

Condition or disease Intervention/treatment Phase
Acute Graft Versus Host Disease Drug: natalizumab Drug: steroids Phase 2

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 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (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
Actual Study Start Date : August 2016
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : April 2022

Arm Intervention/treatment
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.

Drug: natalizumab
Natalizumab 300mg on days 0 and 14.
Other Name: Tysabri

Drug: steroids
Prednisone 2mg/kg/d (or methyl-prednisolone IV equivalent)
Other Names:
  • Prednisone
  • methylprednisolone equivalent IV

Primary Outcome Measures :
  1. Complete Response (CR) [ Time Frame: Day 28 ]
    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.

Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: 1 year ]
  2. Non-Relapse Mortality (NRM) [ Time Frame: 1 year ]
    Cumulative incidence of Non-Relapse Mortality (NRM)at 6 months and 1 year

  3. Incidence of treatment-refractory GVHD [ Time Frame: Day 28 ]
    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)

  4. Time to discontinuation of steroid therapy [ Time Frame: Day 28 ]
  5. Number of additional GVHD therapies [ Time Frame: 1 year ]
    Number of additional GVHD therapies (defined as the initiation of a new acute GVHD therapy, regardless of duration)

  6. Number of serious infections [ Time Frame: 6 months ]
    Number of serious infections (defined as score 3 by the Blood and Marrow Transplant Clinical Trials Network)

  7. Overall response rate (CR + PR) [ Time Frame: Day 28 ]
    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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02133924

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Contact: John E Levine, MD 212-241-1469
Contact: James Ferrara, MD 212-824-9365

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United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Monzr Al Malki, MD    626-256-4673   
Principal Investigator: Monzr Al Malki, MD         
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30008
Contact: Zaid Al-Kadhimi, MD   
Principal Investigator: Zaid Al-Kadhimi, MD         
United States, Illinois
Northwestern Recruiting
Chicago, Illinois, United States, 60611
Contact: Clinical Research Office    312-695-1300   
Principal Investigator: Kehinde Adekola, MD         
United States, Kansas
The University of Kansas Cancer Center Recruiting
Westwood, Kansas, United States, 66205
Contact: Kelly Daniels    913-945-6591   
Principal Investigator: Sunil Abhyankar, MD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Yi-Bin Chen, MD    617-724-1124   
Principal Investigator: Yi-Bin Chen, MD         
United States, Michigan
University of Michigan Withdrawn
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
Mayo Clinical Recruiting
Rochester, Minnesota, United States, 55905
Contact: Anton Mett, MD    507-538-9812   
Principal Investigator: William Hogan, MB, B Ch         
United States, New York
Mount Sinai Health System Recruiting
New York, New York, United States, 10029
Contact: Anne Renteria, MD    212-241-6021   
Principal Investigator: John Levine, MD         
Columbia University Recruiting
New York, New York, United States, 10032
Contact    212-305-5098   
Principal Investigator: Ran Reshef, MD         
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Doris Ponce, MD    212-639-4838   
Principal Investigator: Doris Ponce, MD         
United States, Ohio
Ohio State University Recruiting
Columbus, Ohio, United States, 43210
Contact: Yvonne Efebera, MD    614-293-5066   
Principal Investigator: Yvonne Efebera, MD         
United States, Pennsylvania
University of Pennsylvania, Abramson Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: David Porter, MD    215-662-2862   
Principal Investigator: David Porter, MD         
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37232
Contact: VICC Clinical Trials Information Office, MD    800-811-8480      
Principal Investigator: Carrie Kitko, MD         
Sponsors and Collaborators
John Levine
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Study Chair: John E Levine, MD Icahn School of Medicine at Mount Sinai
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Responsible Party: John Levine, Professor of Internal Medicine and Pediatrics, Director of BMT Clinical Research, Icahn School of Medicine at Mount Sinai Identifier: NCT02133924    
Other Study ID Numbers: GCO 15-1624
First Posted: May 8, 2014    Key Record Dates
Last Update Posted: November 12, 2020
Last Verified: November 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by John Levine, Icahn School of Medicine at Mount Sinai:
Graft vs Host Disease
Graft vs Host Reaction
allogeneic bone marrow transplantation
allogeneic hematopoietic stem cell transplantation
adverse effects
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Anti-Inflammatory Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Neuroprotective Agents
Protective Agents
Immunologic Factors