Effectiveness of Etanercept for Idiopathic Pneumonia Syndrome Following Stem Cell Transplantation (BMT CTN 0403)

BACKGROUND:

Over the last two decades, allogeneic hematopoietic cell transplantation (HCT) has emerged as
an important treatment for a number of malignant and non-malignant disorders. Unfortunately,
several complications, including graft-versus-host disease (GVHD) and pulmonary dysfunction,
limit the utility of this aggressive form of therapy. Infectious and non-infectious lung
complications occur in 25% to 55% of HCT recipients and account for up to 50% of
transplant-related mortality. In about half of affected patients, no infectious organisms are
identified in the lungs. Two major types of non-infectious pulmonary injury are recognized:
acute idiopathic pneumonia syndrome (IPS) and sub-acute lung injury (obstructive airway
disease or bronchiolitis obliterans [BrOb] and restrictive lung disease). The current study
will examine the use of etanercept in patients with IPS.

DESIGN NARRATIVE:

Eligible patients will be randomized to receive one of two arms of therapy: (A) etanercept
plus corticosteroids, or (B) placebo plus corticosteroids. Patients will receive a total of
eight doses of etanercept (or placebo) over a 4-week period. The initial dose of etanercept
(or placebo) will be administered intravenously on Day 0, with subsequent doses administered
subcutaneously (SQ). Dosing will be administered twice weekly over 4 consecutive weeks. The
placebo will be the inert diluent used for the etanercept formulation.

Additionally, patients in both arms will receive corticosteroids (2 mg/kg/day) Day 0 through
Day 7, with subsequent taper as clinically indicated. Chest radiographs shall be obtained
weekly through Day 28. Plasma cytokine profiles will be obtained on Days 0, 7, and 28.

For patients < 30 days post-transplant: If the patient's clinical condition is such that a
broncho-alveolar lavage (BAL) is deemed "not possible to be performed" by the treating
physician (or pulmonologist), then the "on study" BAL may be waived. In such circumstances,
the patient may register and be randomized to study therapy without the BAL being undertaken.

For patients not on mechanical ventilation: If a BAL is not done, appropriate virology
studies on a nasal swab (or nasal washing) are required as a minimum procedure to study
entry.

For patients on mechanical ventilation: Microbiologic studies of a deep endotracheal aspirate
are allowed in lieu of a formal bronchoscopy procedure. However, no protocol-specified
biologic studies (see Section 4.4) will be done on these specimens.

For patients 31-180 days post-transplant: An "on study" bronchoscopy is required in all
cases.

If, at any point following initiation of study drug therapy, previously obtained BAL fluid
cultures or other BAL fluid analysis become positive for an infectious pathogen, study drug
therapy shall be discontinued at that point, and not re-instituted. The patient will
discontinue study drug therapy, but will still be followed for outcome.

The primary study endpoint is response at Day 28. Patients who discontinue study drug therapy
for any reason will still be followed for primary and secondary study endpoints.

Inclusion Criteria:

Patients fulfilling the following criteria will be eligible for registration in this study:

- Recipient of an allogeneic bone marrow, cord blood, or peripheral blood stem cell
transplant. There are no restrictions based upon underlying disease, donor source,
degree of human leukocyte antigen (HLA) match, intensity of the pre-transplant
conditioning regimen, or the use of a prior donor leukocyte infusion

- Evidence of acute lung injury, based upon the presence of bilateral pulmonary
infiltrates (on chest radiograph) and a supplemental oxygen requirement

- No more than 180 days post transplant

Patients fulfilling the following criteria will be eligible for random assignment in this
study:

- BAL fluid negative for pathogenic microorganisms as assessed by gram stain and fungal
stain

- BAL fluid negative for pathogenic microorganisms, or test result pending, as assessed
by the following tests:

1. Acid fast bacilli stain (AFB)

2. Bacterial culture (a quantitative culture of at least 10(4) CFU/mL is considered
positive)

3. Viral cultures for respiratory pathogens, including Respiratory syncytial virus
(RSV), adenovirus, parainfluenza, influenza A and B, and Cytomegalovirus (CMV)

4. Fungal and mycobacterial cultures

5. Pneumocystis carinii pneumonia (PCP) assay, by polymerase chain reaction (PCR),
direct fluorescent antibody (DFA) stain, or cytology (per institutional
guidelines)

Exclusion Criteria:

- Sepsis syndrome or hypotension in which inotropic support (excluding dopamine of no
more than 5 mcg/kg/minute) is required

- Bacteremia within 48 hours prior to study registration

- Documented invasive fungal or systemic viral infection (excluding asymptomatic
viruria) within 14 days prior to study registration

- Evidence of CMV infection, based upon an abnormal PCR assay, antigenemia assay, or
shell vial culture within 14 days of study registration

- On mechanical ventilation for more than 48 hours at study registration

- Evidence of congestive heart failure by clinical assessment

- Participating in other investigational studies (Phase I, II, or III) for the treatment
of acute GVHD within 7 days of study registration (patients enrolled in BMT CTN 0302
are ineligible for study entry)

- Received etanercept within 14 days prior to study registration

- Pregnant or breastfeeding

- On more than 2 mg/kg/day of methylprednisolone equivalent for more than 48 hours,
within 7 days prior to study registration

- Known hypersensitivity to etanercept

- History of active tuberculosis (TB) infection

- History of chronic active hepatitis B or hepatitis C infection

- Patients who have undergone a BAL within 72 hours of study registration are ineligible
if the BAL fluid is known to be positive for pathogenic microorganisms

- Patients who have relapsed or have developed progressive disease post-transplant