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

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.

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