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

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

A Randomized Double-Blind, Placebo-Controlled Trial of Soluble Tumor Necrosis Factor Receptor: Enbrel (Etanercept) for the Treatment of Acute Idiopathic Pneumonia Syndrome Following Allogeneic Cell Transplantation (BMTCTN0403)

Blood and Marrow Transplant Clinical Trials Network, National Cancer Institute (NCI), National Marrow Donor Program

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).

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.

Etanercept will be given eight doses of study drug over a 4-week period. The initial dose of etanercept will be administered intravenously on Day 0, with subsequent doses administered subcutaneously (SQ). Dosing will be administered twice weekly over 4 consecutive weeks. Additionally, patients in both arms will receive corticosteroids (2 mg/kg/day) Day 0 through Day 7, with subsequent taper as clinically indicated.

Patients will receive a total of eight doses of placebo over a 4-week period. The initial dose of 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.

Response will be defined as survival to Day 28 of study, plus discontinuation of all supplemental oxygen support for more than 72 consecutive hours by Day 28.

Response will be defined as the ability to survive to Day 56 of study, plus the ability to completely discontinue all supplemental oxygen support for > 72 consecutive hours during this time period.

The "time required to discontinue supplemental oxygen" will be measured in the number of days from study entry.

Patients were treated with systemic corticosteroids with methylprednisolone at 2 mg/kg/day on day 0, with taper allowed after day 7.

Percentage of patients who experience relapse. Deaths without relapse are considered as a competing risk.

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: Acid fast bacilli stain (AFB) Bacterial culture (a quantitative culture of at least 10(4) CFU/mL is considered positive) Viral cultures for respiratory pathogens, including Respiratory syncytial virus (RSV), adenovirus, parainfluenza, influenza A and B, and Cytomegalovirus (CMV) Fungal and mycobacterial cultures 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

Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).

Yanik GA, Horowitz MM, Weisdorf DJ, Logan BR, Ho VT, Soiffer RJ, Carter SL, Wu J, Wingard JR, Difronzo NL, Ferrara JL, Giralt S, Madtes DK, Drexler R, White ES, Cooke KR. Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow transplant clinical trials network protocol. Biol Blood Marrow Transplant. 2014 Jun;20(6):858-64. doi: 10.1016/j.bbmt.2014.02.026. Epub 2014 Mar 7.