Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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.
 
ClinicalTrials.gov Identifier: NCT02133924
Recruitment Status : Recruiting
First Posted : May 8, 2014
Last Update Posted : January 13, 2020
Sponsor:
Collaborator:
Biogen
Information provided by (Responsible Party):
John Levine, Icahn School of Medicine at Mount Sinai

Tracking Information
First Submitted Date  ICMJE May 6, 2014
First Posted Date  ICMJE May 8, 2014
Last Update Posted Date January 13, 2020
Actual Study Start Date  ICMJE August 2016
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 7, 2014)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 15, 2015)
  • Overall survival (OS) [ Time Frame: 1 year ]
  • Non-Relapse Mortality (NRM) [ Time Frame: 1 year ]
    Cumulative incidence of Non-Relapse Mortality (NRM)at 6 months and 1 year
  • 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)
  • Time to discontinuation of steroid therapy [ Time Frame: Day 28 ]
  • 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)
  • 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)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 7, 2014)
  • Overall survival (OS) [ Time Frame: 1 year ]
  • Non-Relapse Mortality (NRM) [ Time Frame: 1 year ]
    Cumulative incidence of Non-Relapse Mortality (NRM)at 6 months and 1 year
  • 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)
  • Time to discontinuation of steroid therapy [ Time Frame: Day 28 ]
  • 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)
  • Number of serious infections [ Time Frame: 6 months ]
    Number of serious infections (defined as grade 3 by the Blood and Marrow Transplant Clinical Trials Network)
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Multicenter Study Of Natalizumab Plus Standard Steroid Treatment For High Risk Acute Graft-Versus-Host Disease
Official Title  ICMJE Phase II Multicenter Study Of Natalizumab Plus Standard Steroid Treatment For High Risk Acute Graft-Versus-Host Disease
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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Graft Versus Host Disease
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.

Interventions:
  • Drug: natalizumab
  • Drug: steroids
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 7, 2014)
90
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: John E Levine, MD 212-241-1469 john.levine@mssm.edu
Contact: James Ferrara, MD 212-824-9365 james.ferrara@mssm.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02133924
Other Study ID Numbers  ICMJE GCO 15-1624
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party John Levine, Icahn School of Medicine at Mount Sinai
Study Sponsor  ICMJE John Levine
Collaborators  ICMJE Biogen
Investigators  ICMJE
Study Chair: John E Levine, MD Icahn School of Medicine at Mount Sinai
PRS Account Icahn School of Medicine at Mount Sinai
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP