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

Phase 2

Completed

Conditions: 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

Interventions: Biological: etanercept
Drug: methylprednisolone

Registration Number: NCT00309907

Lead Sponsor: Children's Oncology Group

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 39

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Etanercept and corticosteroid therapy	etanercept	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.
Etanercept and corticosteroid therapy	methylprednisolone	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.

Primary Outcome Measures

Name	Time	Method
Response of IPS (Idiopathic Pneumonia Syndrome) to Etanercept Plus Corticosteroid Therapy by Day 28.	At 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.

Secondary Outcome Measures

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

Trial Locations

Locations (26): Children's Healthcare of Atlanta - Egleston
🇺🇸
Atlanta, Georgia, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
University of Texas Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Children's Oncology Group
🇺🇸
Arcadia, California, United States
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
All Children's Hospital
🇺🇸
Saint Petersburg, Florida, United States
Children's National Medical Center
🇺🇸
Washington, D.C., District of Columbia, United States
Indiana University Cancer Center
🇺🇸
Indianapolis, Indiana, United States
Childrens Memorial Hospital
🇺🇸
Chicago, Illinois, United States
Indiana University Medical Center
🇺🇸
Indianapolis, Indiana, United States
Johns Hopkins University
🇺🇸
Baltimore, Maryland, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
New York Medical College
🇺🇸
Valhalla, New York, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Methodist Children's Hospital of South Texas
🇺🇸
San Antonio, Texas, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Midwest Children's Cancer Center
🇺🇸
Milwaukee, Wisconsin, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Children's Hospital-Main Campus
🇺🇸
New Orleans, Louisiana, United States