Study of Enbrel (Etanercept) for the Treatment Sub-Acute Pulmonary Dysfunction After Allogeneic Stem Cell Transplant

• Sponsor: University of Michigan Rogel Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00141726
• Collaborator: (none)
• Enrollment: 34
• Location: 1
• Arm: 1
• Duration (Months): 64.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the effectiveness of etanercept in the treatment of patients with sub-acute lung injury following a bone marrow transplant. This study will also examine the toxicity of treatment with etanercept as well as whether there is an improved quality of life in these patients.

Condition or Disease	Intervention/Treatment	Phase
Lung Injury, Acute; Respiratory Distress Syndrome, Adult; Bronchiolitis Obliterans	Drug: Etanercept	Phase 2

Detailed Description

Lung or breathing problems can develop several months to years following a bone marrow transplant. In some cases, these breathing problems develop without any signs of germs or infection in the lungs. The name for this type of breathing problem is called "Sub-Acute Lung Injury". Sub-acute lung injury often develops many months, even years following a bone marrow transplant. It is often characterized by shortness of breath, cough, wheezing and fatigue.

Sub-acute lung injury can either lead to the formation of scar tissue in the lungs (making it difficult to take deep breaths), or it can cause the lungs to get weak (making people feel out of breath easily). Approximately 25 - 50% of patients with sub-acute lung injury may eventually die from the damage in their lungs. Typically, such patients die from infections that develop inside the damaged lungs.

In this study, treatment with an experimental drug called Etanercept will be used. (Enbrel). The physicians feel there is the possibility that Etanercept may help improve breathing. Breathing ability will be assessed prior to treatment as well as during and after treatment so that comparisons can be made.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Soluble Tumor Necrosis Factor Receptor: Enbrel (Etanercept) for the Treatment of Sub-Acute Pulmonary Dysfunction Following Allogeneic Stem Cell Transplantation. A Phase II Study
• Study Start Date: Oct 1, 2003
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Feb 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: etanercept treatment Etanercept for lung injury	Drug: Etanercept; Etanercept will be given on an open label, single arm basis to patients with non-infectious, sub-acute lung injury. 0.4 mg/kg/dose to a maximum of 25 mg, subcutaneously, twice weekly, for a total of 24 dosages.; Other Names: Enbrel

Outcome Measures

Primary Outcome Measures

1. Percent of Patients With a Greater Than or Equal to 10% Improvement in FEV1, or FVC, and DLCO [week 12 post therapy]

   Response was defined as a greater than or equal to 10% improvement in the absolute value for FEV1 (for obstructive defects) or FVC (for restrictive defects), and DLCO (Diffusing Capacity of the Lungs for Carbon Monoxide) .

Secondary Outcome Measures

1. Percentage of Participants That Experience Grade 3 to 4 Adverse Events [continuously (and week 4, week 8 and week 12, week 20)]

   To evaluate the toxicity of etanercept therapy in patients with sub-acute lung injury > 100 days post transplant, the percent incidence of grade 3 to 4 adverse events among evaluable patients was calculated.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Recipients of allogeneic bone marrow, cord blood, or peripheral blood stem cell transplants are eligible

• Age >6 years and able to complete pulmonary function testing

• Patients with evidence of sub-acute, non-infectious pulmonary dysfunction (OLD or RLD)

• Recipients of sub-ablative transplant regimens are eligible

• Recipients of donor leukocyte infusions (DLI) post-transplant are eligible

• Patients must be > 100 days post transplant

Exclusion Criteria:

• Patients with hypotension requiring inotropic agents other than dopamine < 5mcg/ kg/ minute for blood pressure support.

• Patients with a positive quantitative bacterial culture from the BAL fluid (≥ 104 CFU/ ml is considered positive)

• Patients whose BAL fluid is positive for significant bacterial pathogens or pathogenic nonbacterial microorganisms (as defined by protocol) by special stain, culture or PCR analysis

• Patients who are enrolled on a phase I or phase II trial for the prophylaxis or treatment of GVHD (acute or chronic) within 7 days of study entry.

• Patients with known hypersensitivity to etanercept.

• Patients who are pregnant.

• Patients with CMV seropositivity at the time of study entry. Testing may include wither CMV PCR analysis or CMV pp65 testing.

• Evidence for multi-system organ failure.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Michigan Cancer Center	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• University of Michigan Rogel Cancer Center

Investigators

• Principal Investigator: Gregory A Yanik, MD, The University of Michigan Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT00141726
• Other Study ID Numbers: UMCC 3-31; IRBMED 2003-0590 and HUM 46747
• First Posted: Sep 1, 2005
• Last Update Posted: Dec 3, 2015
• Last Verified: Nov 1, 2015

• Keywords provided by University of Michigan Rogel Cancer Center: Enbrel; Stem Cell Transplantation; Lung Injury
• Additional relevant MeSH terms: Bronchiolitis; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Lung Injury; Bronchiolitis Obliterans; Acute Lung Injury; Etanercept

Study Results

Participant Flow

Recruitment Details	Study subjects were recruited from the Blood and Marrow Stem Cell Program at the University of Michigan Medical Center between 2001 and 2008, all subjects having received an allogeneic Stem Cell Transplant (SCT) at least 100 days before study entry.

Arm/Group Title	Etanercept Treatment
Arm/Group Description	Etanercept for lung injury Etanercept: Etanercept will be given on an open label, single arm basis to patients with non-infectious, sub-acute lung injury. 0.4 mg/kg/dose to a maximum of 25 mg, subcutaneously, twice weekly, for a total of 24 dosages.
Period Title: Overall Study
STARTED	34
COMPLETED	31
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Etanercept Treatment
Arm/Group Description	Etanercept for lung injury Etanercept: Etanercept will be given on an open label, single arm basis to patients with non-infectious, sub-acute lung injury. 0.4 mg/kg/dose to a maximum of 25 mg, subcutaneously, twice weekly, for a total of 24 dosages.
Overall Participants	34
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	39
Sex: Female, Male (Count of Participants)
Female	14 41.2%
Male	20 58.8%
Diagnosis (participants) [Number]
AML/MDS/MF	16 47.1%
Acute Lymphoblastic Leukemia (ALL)	3 8.8%
Chronic Mylogenous Leukemia (CML)	5 14.7%
NHL/CLL	6 17.6%
Myeloma	2 5.9%
Nonmalignant	2 5.9%
Human Leukocyte Antigen (HLA) Match (participants) [Number]
HLA Matched	31 91.2%
Mismatch	3 8.8%
Cell Source (participants) [Number]
Pluripotent Stem Cell (PSC)	25 73.5%
Marrow	9 26.5%
Donor Type (participants) [Number]
Matched Related Donor (MRD)	22 64.7%
Unrelated Donor (URD)	12 35.3%
Chronic Graft Versus Host Disease (GVHD) Present (participants) [Number]
Yes	34 100%
No	0 0%
Lung Injury Pattern (participants) [Number]
Restrictive	9 26.5%
Obstructive	25 73.5%

Outcome Measures

1. Primary Outcome

Title	Percent of Patients With a Greater Than or Equal to 10% Improvement in FEV1, or FVC, and DLCO
Description	Response was defined as a greater than or equal to 10% improvement in the absolute value for FEV1 (for obstructive defects) or FVC (for restrictive defects), and DLCO (Diffusing Capacity of the Lungs for Carbon Monoxide) .
Time Frame	week 12 post therapy

Outcome Measure Data

Analysis Population Description

34 subjects were enrolled. Thirty-one of 34 subjects were evaluable for response, with three subjects completing <50% of scheduled dosing.

Arm/Group Title	Etanercept Treatment
Arm/Group Description	Etanercept for lung injury Etanercept: Etanercept will be given on an open label, single arm basis to patients with non-infectious, sub-acute lung injury. 0.4 mg/kg/dose to a maximum of 25 mg, subcutaneously, twice weekly, for a total of 24 dosages.
Measure Participants	31
≥10% Improvement in FEV1 / FVC	32 94.1%
≥10% Improvement in DLCO	16 47.1%

2. Secondary Outcome

Title	Percentage of Participants That Experience Grade 3 to 4 Adverse Events
Description	To evaluate the toxicity of etanercept therapy in patients with sub-acute lung injury > 100 days post transplant, the percent incidence of grade 3 to 4 adverse events among evaluable patients was calculated.
Time Frame	continuously (and week 4, week 8 and week 12, week 20)

Outcome Measure Data

Analysis Population Description

34 subjects were enrolled and evaluated for adverse events.

Arm/Group Title	Etanercept Treatment
Arm/Group Description	Etanercept for lung injury Etanercept: Etanercept will be given on an open label, single arm basis to patients with non-infectious, sub-acute lung injury. 0.4 mg/kg/dose to a maximum of 25 mg, subcutaneously, twice weekly, for a total of 24 dosages.
Measure Participants	34
Incidence of Grad 3 to 4 Infection	14 41.2%
Incidence of Grade 3 to 4 Electrolyte Toxicities	11 32.4%
Incidence of Grade 3 to 4 Hyperglycemia	8 23.5%
Incidence of Grade 3 to 4 Renal/GU Toxicities	6 17.6%
Incidence of Grade 3 to 4 Hepatic Toxicities	6 17.6%
Incidence of Grade 3 to 4 Pain	6 17.6%
Incidence of Grade 3 to 4 Hypertension	3 8.8%
Incidence of Grade 3 to 4 GI Toxicities	3 8.8%
Incidence of Grade 3 to 4 CNS Toxicities	3 8.8%
Incidence of Grade 3 to 4 Thrombocytopenia	3 8.8%

Adverse Events

Time Frame	Adverse Events (AEs) were collected for each patient from time of administration of the first dose of drug up to 28 days after the final dose of study drug.
Adverse Event Reporting Description	Serious Adverse Events (SAEs) are defined as Grade 4 or 5 (Adverse events will use the descriptions and grading scales found in the revised National Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 2.0.) non-pulmonary toxicities.
Arm/Group Title	Etanercept Treatment
Arm/Group Description	Etanercept for lung injury Etanercept: Etanercept will be given on an open label, single arm basis to patients with non-infectious, sub-acute lung injury. 0.4 mg/kg/dose to a maximum of 25 mg, subcutaneously, twice weekly, for a total of 24 dosages.
All Cause Mortality
	Etanercept Treatment
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Etanercept Treatment
	Affected / at Risk (%)	# Events
Total	5/34 (14.7%)
Infections and infestations
Bacteremia/Infection	1/34 (2.9%)	1
Metabolism and nutrition disorders
Hyperglycemia	1/34 (2.9%)	1
Hypophosphatemia	1/34 (2.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
AML Relapse	1/34 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/34 (2.9%)	1
Other (Not Including Serious) Adverse Events
	Etanercept Treatment
	Affected / at Risk (%)	# Events
Total	21/34 (61.8%)
Blood and lymphatic system disorders
Anemia	7/34 (20.6%)	7
leukopenia	3/34 (8.8%)	3
lymphopenia	3/34 (8.8%)	3
thrombocytopenia	3/34 (8.8%)	3
Cardiac disorders
irregular heart beat	2/34 (5.9%)	2
Endocrine disorders
cushingoid appearance	3/34 (8.8%)	3
Gastrointestinal disorders
constipation	2/34 (5.9%)	2
diarrhea	3/34 (8.8%)	3
dysphagia	2/34 (5.9%)	2
gastroenteritis	2/34 (5.9%)	2
nausea	4/34 (11.8%)	4
vomiting	3/34 (8.8%)	3
General disorders
chills	2/34 (5.9%)	2
fatigue	4/34 (11.8%)	4
fever	2/34 (5.9%)	2
leg edema	4/34 (11.8%)	4
lower extremity soreness	2/34 (5.9%)	2
tremors	2/34 (5.9%)	2
weakness	3/34 (8.8%)	3
Infections and infestations
infection	3/34 (8.8%)	3
UTI	3/34 (8.8%)	4
Investigations
elevated Alkaline Phoshpatase	8/34 (23.5%)	8
elevated ALT	12/34 (35.3%)	12
elevated AST	12/34 (35.3%)	12
elevated Creatinine	8/34 (23.5%)	8
elevated T-bili	3/34 (8.8%)	3
weight gain	3/34 (8.8%)	3
weight loss	2/34 (5.9%)	2
Metabolism and nutrition disorders
anorexia	2/34 (5.9%)	2
hypercalcemia	3/34 (8.8%)	3
hyperglycemia	16/34 (47.1%)	16
hyperkalemia	5/34 (14.7%)	5
hyperphosphatemia	4/34 (11.8%)	4
hypertriglyceridemia	2/34 (5.9%)	2
hypoalbuminemia	8/34 (23.5%)	8
hypocalcemia	5/34 (14.7%)	5
hypoglycemia	3/34 (8.8%)	3
hypokalemia	4/34 (11.8%)	4
hypomagnesemia	5/34 (14.7%)	5
hyponatremia	4/34 (11.8%)	4
hypophosphatemia	6/34 (17.6%)	6
Musculoskeletal and connective tissue disorders
muscle cramps	8/34 (23.5%)	8
musculoskeletal range of motion	3/34 (8.8%)	3
Nervous system disorders
dizzyness	2/34 (5.9%)	2
headache	2/34 (5.9%)	2
Psychiatric disorders
insomnia	3/34 (8.8%)	3
Renal and urinary disorders
dysuria	2/34 (5.9%)	2
hematuria	3/34 (8.8%)	4
nocturia	2/34 (5.9%)	2
Respiratory, thoracic and mediastinal disorders
bronchoalveolar lavage - positive for bacteria	4/34 (11.8%)	6
dyspnea	12/34 (35.3%)	12
epistaxis	2/34 (5.9%)	2
hypoxia	2/34 (5.9%)	2
nasal congestion	3/34 (8.8%)	3
pleural effusion	2/34 (5.9%)	2
rhinorrhea	4/34 (11.8%)	5
upper respiratory infection	2/34 (5.9%)	2
Skin and subcutaneous tissue disorders
blisters	2/34 (5.9%)	2
dry skin	2/34 (5.9%)	2
pruitis	4/34 (11.8%)	4
rash	5/34 (14.7%)	5
Vascular disorders
DVT	2/34 (5.9%)	2
Ecchymosis	2/34 (5.9%)	2
hypertension	4/34 (11.8%)	5
hypotension	2/34 (5.9%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.