Study of Etanercept for the Prevention of Complications Resulting From Hematopoietic Stem Cell Transplantation (HSCT)

Study Overview
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Brief Summary
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This is a clinical trial to see if the addition of etanercept to standard preventative medicines helps in preventing two major complications of hematopoietic stem cell transplantation (HSCT): decrease the rate of acute graft-vs-host disease (GVHD) and the risk of death.

Detailed Description
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This is a clinical trial to see if the addition of etanercept helps in preventing two major complications of hematopoietic stem cell transplantation (HSCT). The main objective will be to see whether the addition of etanercept to standard preventative medicines will decrease the rate of acute graft-vs-host disease (GVHD) and the risk of death by 100 days following allogeneic HSCT from volunteer donors. GVHD is a common complication following a bone marrow transplant from another donor. GVHD occurs after transplant when the donor's blood cells recognize parts of the body as foreign. During this process, chemicals called cytokines are released that may damage certain body tissues, including the gut, liver and skin. Some of the main effects can include red skin rash, diarrhea, sometimes with blood, and yellow jaundice. It can range from mild to life threatening and often requires admission to the hospital for treatment. The standard treatment for acute GVHD is a combination of steroids and another drug that suppress the immune system, such as tacrolimus or cyclosporine. Etanercept is a drug that blocks a chemical called Tumor Necrosis Factor (TNF) from causing damage to your tissue. The purpose of etanercept is to help improve the response to standard treatment for GVHD. Previous studies have shown that less than 50% of patients respond fully to GVHD treatment. Without a good response, patients often have a prolonged treatment for this disease, often involving hospitalization and sometimes even death. Etanercept (Enbrel) will be added to the standard treatment to see if we can lower the rate of GVHD and the risk of death from GVHD by blocking TNF.

Official Title
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The Addition of Etanercept to Standard GVHD Prophylaxis in Patients Undergoing a Full Intensity Allogeneic Hematopoietic Stem Cell Transplant for the Prevention of Transplant Related Complications

Conditions
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Graft-Versus-Host Disease

Intervention / Treatment
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* Drug: Etanercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be between 1 and 60 years of age and be a candidate for myeloablative donor stem cell transplantation Patients must receive myeloablative regimen using fludarabine and busulfan For related donors: The donor and recipient must have a 5/6 match at the HLA A, B, and DRB1 loci. [Patients with a 6/6 related donor are NOT eligible.] For unrelated donors: The donor and recipient must have a 5/6 or 6/6 match at the HLA A, B, and DRB1 loci. The typing level to define a match at the A and B locus must be at the level of mid-resolution DNA typing. The acceptable level to define a match at DRB1 will be by allelic typing by high resolution DNA sequencing. Any disease for which myeloablative transplantation is appropriate is eligible except: Progressive or poorly controlled malignancies for which the likelihood of durable disease control [i.e., patients expected to have at least 6 months PFS from date of transplant] is <25%. Exclusion Criteria: Not a candidate for myeloablative conditioning regimen using the current BMT program clinical guidelines. Patient has a 6/6 HLA-matched related donor Karnofsky or Lansky performance status of < 60% at the time of admission for HSCT Patients with evidence of HIV infection or other opportunistic infection including but not limited to tuberculosis and histoplasmosis. Any conditions, in the opinion of the transplant team such as substance abuse, or severe personality disorder that would keep the patients from complying with the needs of the protocol and would markedly increase the morbidity and mortality from the procedure. Pregnancy. T-cell depleted allograft Patients with documented infections, not responding well to antibiotic therapy. Patients with bacteremia.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GVHD prophylaxis<br>GVHD prophylaxis with etanercept | Drug: Etanercept<br>* Etanercept 0.4 mg/kg per dose [maximum dose 25 mg] SC for prophylaxis. To start in the 24 hour time period along with the initiation of the preparative regimen for the stem cell transplant. Etanercept will be administered twice weekly until day +56 (8 weeks) post transplant.<br>* Other names: Enbrel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants Experiencing Acute GVHD After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) | In order to determine whether etanercept, given prophylactically along with a standard Graft Versus Host Disease (GVHD) prevention regimen, will decrease the 100-day mortality and the rate of acute GVHD after allogeneic hematopoietic stem cell transplantation(HSCT), the incidence of grades 2-4 and grades 3-4 GVHD were calculated. GVHD can be clinically graded as 0, I, II, III, or IV. Definition of grades are: Grade 0 - No stage 1-4 of any organ Grade I - Stage 1-2 rash and no liver or gut involvement Grade II - Stage 3 rash, or Stage 1 liver involvement, or Stage 1 gastrointestinal involvement Grade III - Stage 0-3 skin, with STage 2-3 liver, or Stage 2-3 gastrointestinal involvement Grade IV - Stage 4 skin, liver, or gastrointestinal involvement | 100 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Experiencing Etanercept Toxicity | Toxicity of etanercept was evaluated by the following: the number of patients experiencing allergic reactions, the number of patients that discontinued etanercept early, the number of patients experiencing bacteremia, and the number of patients experiencing viral reactivations. | 100 days | 
| The Number of Patients That Experience Idiopathic Pulmonary Syndrome (IPS) | The Effect of etanercept on the incidence of idiopathic pulmonary syndrome (IPS). Patients who received Total Body Irradiation (TBI) transplant conditioning were compared to those who received another form of transplant conditioning. | 100 days | 
| Day +7 TNFR1 Ratio in TBI-Treated Patients vs. Non-TBI-Treated Patients | The effect of etanercept on plasma cytokine levels after Hematopoietic Stem Cell Transplantation (HSCT) was analyzed. Tumor Necrosis Factor Receptor 1 (TNFR1) ratios (TNFR1 posttransplantation day+7 / TNFR1pretransplantation baseline were calculated. Patients who received Total Body Irradiation (TBI) transplant conditioning were compared to those who received another form of transplant conditioning. | Day+7, post transplant | 
| The Impact of Tumor Necrosis Factor (TNF) Polymorphisms on Response to Therapy. |  | 100 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stem Cell Transplantation, Graft-Versus-Host Disease, prophylaxis