Etanercept in Treating Young Patients With Idiopathic Pneumonia Syndrome After Undergoing a Donor Stem Cell Transplant

Study Overview
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Brief Summary
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This phase II trial is studying how well etanercept works in treating young patients with idiopathic pneumonia syndrome after undergoing a donor stem cell transplant. Etanercept may be effective in treating patients with idiopathic pneumonia syndrome after undergoing a donor stem cell transplant.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the response rate, defined as survival and complete discontinuation of supplemental oxygen at day 28, in pediatric patients with acute noninfectious pulmonary dysfunction (idiopathic pneumonia syndrome [IPS]) after undergoing allogeneic stem cell transplantation treated with etanercept. SECONDARY OBJECTIVES: I. Estimate the day 56 survival rate in patients treated with this drug. II. Determine the overall survival distribution in patients treated with this drug. III. Determine the pulmonary response, as defined as the time to discontinuation of supplemental oxygen, in patients treated with this drug. IV. Evaluate the toxicity of etanercept therapy in patients with IPS. V. Evaluate levels of pro-inflammatory cytokines, in both bronchoalveolar lavage (BAL) fluid and serum, in patients with IPS. VI. Describe C-reactive protein (CRP) levels at baseline, day 7, 14, 21, and 28 and their association with response in patients with IPS. OUTLINE: This is an open-label, nonrandomized, multicenter study. Patients receive etanercept IV over 30 minutes on day 0 and subcutaneously on days 3, 7, 10, 14, 17, 21, and 24. Treatment continues in the absence of an infectious pathogen, disease progression, or unacceptable toxicity. Patients also receive methylprednisolone (or corticosteroid equivalent) IV on days 0-2 and then orally with a taper until day 56. After completion of study treatment, patients are followed periodically for 5 years.

Official Title
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Soluble Tumor Necrosis Factor Receptor: Enbrel® (Etanercept) for the Treatment of Acute Non-Infectious Pulmonary Dysfunction (Idiopathic Pneumonia Syndrome) Following Allogeneic Stem Cell Transplantation

Conditions
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Accelerated Phase Chronic Myelogenous Leukemia, Blastic Phase Chronic Myelogenous Leukemia, Childhood Acute Lymphoblastic Leukemia in Remission, Childhood Acute Myeloid Leukemia in Remission, Childhood Chronic Myelogenous Leukemia, Childhood Myelodysplastic Syndromes, Chronic Phase Chronic Myelogenous Leukemia, de Novo Myelodysplastic Syndromes, Disseminated Neuroblastoma, Juvenile Myelomonocytic Leukemia, Previously Treated Childhood Rhabdomyosarcoma, Previously Treated Myelodysplastic Syndromes, Pulmonary Complications, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Recurrent Childhood Large Cell Lymphoma, Recurrent Childhood Lymphoblastic Lymphoma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Childhood Small Noncleaved Cell Lymphoma, Recurrent Neuroblastoma, Recurrent Wilms Tumor and Other Childhood Kidney Tumors, Recurrent/Refractory Childhood Hodgkin Lymphoma, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes

Intervention / Treatment
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* Biological: etanercept
* Drug: methylprednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of acute, noninfectious idiopathic pulmonary dysfunction (IPS) as defined by the following: Evidence of diffuse lung injury occurring within the first several months after hematopoietic stem cell transplantation for which an infectious etiology is not identified. To meet the criteria for IPS there must be: Evidence of widespread alveolar injury Diffuse multi-lobar infiltrates on chest x-ray or CT scan Evidence for abnormal respiratory physiology based upon 1 of the following: Room air oxygen saturation < 93% Supplemental oxygen required to maintain an oxygen saturation ≥ 93% Absence of active lower respiratory tract infection, defined as Bronchoalveolar lavage (BAL)-negative for infection based on one of the following: Gram stain, fungal stain, acid-fast bacilli stain Bacterial culture (a quantitative culture ≥ 10^4 colony-forming units/mL is considered positive) Fungal culture Mycobacterial culture Viral culture (respiratory syncytial virus [RSV], parainfluenza, adenovirus, influenza A and B, and cytomegalovirus [CMV]) If direct fluorescent antibody (DFA) screening is performed on BAL, it must be negative for all viruses listed above Pneumocystis carinii pneumonia by polymerase chain reaction (PCR), DFA stain, or cytology Evidence of bilateral pulmonary infiltrates (on chest radiograph) Patients may have diffuse alveolar hemorrhage (DAH) or peri-engraftment respiratory distress syndrome (PERDS) Presence of mixed oral flora, rare Candida species, or the presence of a Penicillium species reported on BAL fluid analysis allowed A radiographic finding of pulmonary edema does not exclude the diagnosis of IPS, provided the other criteria have been met and provided the treating physician concludes by clinical (or echocardiographic) criteria that the pulmonary edema is not secondary to cardiac dysfunction or iatrogenic fluid overload Patients must require supplemental oxygen Must have undergone an allogeneic bone marrow, cord blood, or peripheral blood stem cell transplantation within the past 120 days There are no restrictions based upon underlying disease, donor source, the degree of HLA match, the intensity of the pre-transplant conditioning regimen, or the use of a prior donor leukocyte infusion Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No documented invasive fungal or systemic viral infection within the past 14 days Patients with asymptomatic viruria allowed No signs of CMV reactivation (by CMV, PCR, antigenemia, or shell vial culture) within the past 14 days No sepsis syndrome or hypotension that requires inotropic support (except dopamine < 5mcg/kg/minute) No documented bacteremia within the past 48 hours Persistent fever allowed No evidence of cardiac failure by clinical or echocardiographic findings No known hypersensitivity to etanercept No known history of tuberculosis (Tb) or prior Tb exposure No prior chronic hepatitis B or hepatitis C infection Concurrent treatment for acute or chronic GVHD allowed More than 14 days since prior etanercept More than 7 days since prior investigational drug trials (phase I, II, or III) for the treatment of acute graft-versus-host disease (GVHD) Not on mechanical ventilation for > 48 continuous hours prior to study entry Must not be receiving > 2 mg/kg/day of methylprednisolone or corticosteroid equivalent within 24 hours of study entry Concurrent continuous veno-venous hemofiltration or hemodialysis allowed

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 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: Etanercept and corticosteroid therapy<br>Patients receive etanercept IV (dose 0.4 mg/kg- max 25 mg) over 30 minutes on day 0 and subcutaneously (dose 0.4 mg/kg- max 25 mg) on days 3, 7, 10, 14, 17, 21, and 24. Treatment continues in the absence of an infectious pathogen, disease progression, or unacceptable toxicity. Patients also receive methylprednisolone (or corticosteroid equivalent) IV (dose 2.0 mg/kg/day) on days 0-2 and then orally with a taper beginning day 7. Dose on days 7-20 (1.0 mg/kg/day), days 21-34 (0.5 mg/kg/day), days 35-48 (0.25 mg/kg/day) and days 49-56 (0.25 mg/kg/every other day) discontinuing on day 56. | Biological: etanercept<br>* Given IV and subcutaneously<br>* Other names: Tumor Necrosis Factor Receptor IgG Chimera;Drug: methylprednisolone<br>* Given IV and orally<br>* Other names: Wyacort;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response of IPS (Idiopathic Pneumonia Syndrome) to Etanercept Plus Corticosteroid Therapy by Day 28. | Response to therapy is defined as survival to Day 28 of study, PLUS complete discontinuation all supplemental oxygen support by Day 28 of study. Subjects must be able to remain off all supplemental oxygen support for > 72 consecutive hours. Subjects who discontinue supplemental oxygen within the last 72 hours of the observation period will be followed until they have completed 72 consecutive hours off oxygen or failed prior to assessing response. | At day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival Rate | Estimated Day 56 survival rate following initiation of etanercept + corticosteroid therapy for patients with IPS. | Up to day 56 | 
| Estimate Percentage Pulmonary Response in Patients With IPS Treated With Etanercept + Corticosteroid Therapy | Pulmonary response is defined as alive & come off of oxygen . | up to day 56 | 
| Toxicity of Etanercept Plus Corticosteroid Therapy Using the Common Terminology Criteria Version 4.0 | Grade 3-5 organ toxicities attributable to etanercept. | Up to 56 days | 
| Plasma Cytokine IL6 Level | Estimated mean and standard error of IL6 level | From baseline to days 7 and 28 | 
| C-reactive Protein Levels | Estimated mean and standard deviation | From baseline to days 7, 14, 21, and 28 |