Effectiveness of Etanercept for Idiopathic Pneumonia Syndrome Following Stem Cell Transplantation

Condition(s) targeted: Pneumonia; Idiopathic Pneumonia Syndrome

Intervention: Etanercept (Drug); Placebo + corticosteroid (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: National Heart, Lung, and Blood Institute (NHLBI)

Official(s) and/or principal investigator(s):
John Wingard, MD, Principal Investigator, Affiliation: University of Florida College of Medicine (Shands)
Jennifer Schwartz, MD, Principal Investigator, Affiliation: Indiana University School of Medicine
Javier Bolanos-Meade, MD, Principal Investigator, Affiliation: Johns Hopkins University
Vincent Ho, MD, Principal Investigator, Affiliation: DFCI/Partners Cancer Center
Gregory Yanik, MD, Study Chair, Affiliation: University of Michigan
Brian McClune, DO, Principal Investigator, Affiliation: University of Minnesota - Clinical and Translational Science Institute
Bekele Afessa, MD, Principal Investigator, Affiliation: Mayo Clinic
Gwynn Long, MD, Principal Investigator, Affiliation: Duke University
Hillard Lazarus, MD, Principal Investigator, Affiliation: University Hospitals of Cleveland/Case Western
Edward Stadtmann, MD, Principal Investigator, Affiliation: University of Pennsylvania
Sergio Giralt, MD, Principal Investigator, Affiliation: M.D. Anderson Cancer Center
David Madtes, MD, Principal Investigator, Affiliation: Fred Hutchinson Cancer Research Center
Jan Jansen, MD, PhD, Principal Investigator, Affiliation: Indiana BMT at Beech Grove
Hugo Castro-Malaspina, MD, Principal Investigator, Affiliation: Memorial Sloan-Kettering Cancer Center
Brandon Hayes-Lattin, MD, Principal Investigator, Affiliation: Oregon Health and Science University

Overall contact:
Mary Horowitz, MD, MS, Email: marymh@mcw.edu

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).

Official title: A Randomized Double-Blind, Placebo-Controlled Trial of Soluble Tumor Necrosis Factor Receptor: Enbrel (Etanercept) for the Treatment of Acute Non-Infectious Pulmonary Dysfunction (Idiopathic Pneumonia Syndrome) Following Allogeneic Cell Transplantation (BMT CTN #0403)

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome: Day 28 response rate (response will be defined as (a) survival to Day 28 of study, plus (b) discontinuation of all supplemental oxygen support for more than 72 consecutive hours by Day 28)

Secondary outcome:

Response to therapy at Day 56

Overall mortality

Discontinuation of supplemental oxygen

Pro-inflammatory markers of pulmonary disease, in both BAL fluid and plasma

Serious infection

Dermatologic reaction

Detailed description: 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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 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 RSV, adenovirus, parainfluenza, influenza A and B, and CMV

4. Fungal and mycobacterial cultures

5. Pneumocystis carinii pneumonia (PCP) assay, by 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/U01 HL069294-05 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

Mary Horowitz, MD, MS, Email: marymh@mcw.edu

University of Florida College of Medicine (Shands), Gainesville, Florida 32610, United States; Recruiting
John Wingard, MD, Phone: 352-273-8021, Email: wingajr@medicine.ufl.edu
John Wingard, MD, Principal Investigator

Indiana BMT at Beech Grove, Beech Grove, Indiana 46107, United States; Recruiting
Jan Jansen, MD, PhD, Phone: 317-865-5500, Email: jjansen@ibmtindy.com
Jan Jansen, MD, PhD, Principal Investigator

Indiana University Medical Center, Indianapolis, Indiana 46202, United States; Recruiting
Jennifer Schwartz, MD, Phone: 317-278-7576, Email: jeschwar@iupui.edu
Jennifer Schwartz, MD, Principal Investigator

Johns Hopkins University, Baltimore, Maryland 21218, United States; Recruiting
Javier Bolanos-Meade, MD, Phone: 410-614-0738, Email: Fbolano2@jhmi.edu
Javier Bolanos-Meade, MD, Principal Investigator

DFCI/Partners Cancer Center, Boston, Massachusetts 02118, United States; Recruiting
Vincent Ho, MD, Phone: 617-632-5938, Email: vtho@partners.org
Vincent Ho, MD, Principal Investigator

University of Michigan Medical Center, Ann Arbor, Michigan 48105, United States; Recruiting
Gregory Yanik, MD, Phone: 734-936-8785, Email: gyanik@umich.edu
Gregory Yanki, MD, Principal Investigator
Kenneth Cooke, MD, Sub-Investigator

University of Minnesota, Minneapolis, Minnesota 55455, United States; Recruiting
Brian McClune, DO, Email: bmcclune@umn.edu
Brian McClune, DO, Principal Investigator

Mayo Clinic, Rochester, Minnesota 55905, United States; Recruiting
Bekele Afessa, MD, Email: afessa.bekele@mayo.edu
Bekele Afessa, MD, Principal Investigator

University of Nebraska Medical Center, Omaha, Nebraska 68198-7680, United States; Active, not recruiting

Memorial Sloan Kettering Cancer Center, New York, New York 10174, United States; Recruiting
Hugo Castro-Malaspina, MD, Email: castro-h@mskcc.org
Hugo Castro-Malaspina, MD, Principal Investigator

Duke University Medical Center, Durham, North Carolina 27710, United States; Recruiting
Gwynn Long, MD, Email: long0045@mc.duke.edu
Gwynn Long, MD, Principal Investigator

University Hospitals of Cleveland/Case Western, Cleveland, Ohio 44106, United States; Not yet recruiting
Hillard Lazarus, MD, Phone: 216-844-3629, Email: hillard.lazarus@case.edu
Hillard Lazarus, MD, Principal Investigator

Oregon Health & Science University, Portland, Oregon 97239, United States; Recruiting
Brandon Hayes-Lattin, MD, Email: hayeslat@ohsu.edu
Richard Maziarz, MD, Phone: 503-494-1551, Email: maziarzr@ohsu.edu
Richard Maziarz, MD, Principal Investigator

University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104, United States; Recruiting
Edward Stadtmauer, MD, Phone: 215-662-7910, Email: edward.stadtmauer@uphs.upenn.edu
Edward Stadtmauer, MD, Principal Investigator

University of Texas/MD Anderson Cancer Center, Houston, Texas 77030, United States; Recruiting
Sergio Giralt, MD, Phone: 713-794-5745, Email: sgiralt@mail.mdanderson.org
Sergio Giralt, MD, Principal Investigator

Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States; Recruiting
David Madtes, MD, Phone: 206-667-4589, Email: dmadtes@fhcrc.org
David Madtes, MD, Principal Investigator

Starting date: August 2007
Last updated: November 20, 2009