Clinical trial NCT02133924: Multicenter Study Of Natalizumab Plus Standard Steroid Treatment For High Risk Acute Graft-Versus-Host Disease
Official title: Phase II Multicenter Study Of Natalizumab Plus Standard Steroid Treatment For High Risk Acute Graft-Versus-Host Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Graft Versus Host Disease
Keywords: Graft vs Host Disease
Graft vs Host Reaction
allogeneic bone marrow transplantation
allogeneic hematopoietic stem cell transplantation
adverse effects
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: Biogen
First posted: 2014-05-08
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 many patients with Ann Arbor score 2 or 3 GVHD, will not respond well to steroid treatment and 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 2 or 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 2 or 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.

Eligibility criteria: Inclusion Criteria:

* New onset high risk acute GVHD (Ann Arbor score 2 or3 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

Primary outcomes:
measure: Number of Participants With Complete Response (CR)
timeFrame: Day 28
Secondary outcomes:
measure: Number of Participants With Overall Survival (OS)
timeFrame: 1 year
measure: Number of Participants With Non-Relapse Mortality (NRM)
timeFrame: 6 months and 1 year
measure: Number of Participants With SR GVHD
timeFrame: 1 year
measure: Time to Discontinuation of Steroid Therapy
timeFrame: up to 365 days
measure: Number of Participants Who Received Additional GVHD Therapies
timeFrame: 1 year
measure: Number of Serious Infections
timeFrame: 6 months
measure: Number of Participants With Overall Response Rate (CR + PR)
timeFrame: Day 28
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern
state: Illinois
city: Westwood
country: United States
facility: The University of Kansas Cancer Center
state: Kansas
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinical
state: Minnesota
city: New York
country: United States
facility: Mount Sinai Health System
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania, Abramson Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: John E Levine, MD
role: STUDY_CHAIR
References: