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.
The study is designed as a Phase III, multi-center randomized, double-blind, placebo-controlled trial investigating the use of etanercept for the treatment of acute, non-infectious pulmonary dysfunction (IPS) occurring after allogeneic hematopoietic cell transplantation (HCT).