Etanercept in Treating Young Patients With Idiopathic Pneumonia Syndrome After Undergoing a Donor Stem Cell Transplant

Soluble Tumor Necrosis Factor Receptor: Enbrel® (Etanercept) for the Treatment of Acute Non-Infectious Pulmonary Dysfunction (Idiopathic Pneumonia Syndrome) Following Allogeneic Stem Cell Transplantation

This phase II trial is studying how well etanercept works in treating young patients with idiopathic pneumonia syndrome after undergoing a donor stem cell transplant. Etanercept may be effective in treating patients with idiopathic pneumonia syndrome after undergoing a donor stem cell transplant.

Study Overview

• Status: Completed
• Conditions: Juvenile Myelomonocytic Leukemia; Secondary Acute Myeloid Leukemia; Childhood Acute Myeloid Leukemia in Remission; Accelerated Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Recurrent Neuroblastoma; Recurrent Childhood Rhabdomyosarcoma; Pulmonary Complications; Disseminated Neuroblastoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Blastic Phase Chronic Myelogenous Leukemia
• Intervention / Treatment: Biological: etanercept; Drug: methylprednisolone

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the response rate, defined as survival and complete discontinuation of supplemental oxygen at day 28, in pediatric patients with acute noninfectious pulmonary dysfunction (idiopathic pneumonia syndrome [IPS]) after undergoing allogeneic stem cell transplantation treated with etanercept.

SECONDARY OBJECTIVES:

I. Estimate the day 56 survival rate in patients treated with this drug. II. Determine the overall survival distribution in patients treated with this drug.

III. Determine the pulmonary response, as defined as the time to discontinuation of supplemental oxygen, in patients treated with this drug.

IV. Evaluate the toxicity of etanercept therapy in patients with IPS. V. Evaluate levels of pro-inflammatory cytokines, in both bronchoalveolar lavage (BAL) fluid and serum, in patients with IPS.

VI. Describe C-reactive protein (CRP) levels at baseline, day 7, 14, 21, and 28 and their association with response in patients with IPS.

OUTLINE: This is an open-label, nonrandomized, multicenter study.

Patients receive etanercept IV over 30 minutes on day 0 and subcutaneously on days 3, 7, 10, 14, 17, 21, and 24. Treatment continues in the absence of an infectious pathogen, disease progression, or unacceptable toxicity. Patients also receive methylprednisolone (or corticosteroid equivalent) IV on days 0-2 and then orally with a taper until day 56.

After completion of study treatment, patients are followed periodically for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Arcadia, California, United States, 91006-3776
      • Children's Oncology Group
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • District of Columbia
    • Washington, D.C., District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta - Egleston
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Childrens Memorial Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Medical Center
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Cancer Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70118
      • Children's Hospital-Main Campus
  • Maryland
    • Baltimore, Maryland, United States, 21287-8936
      • Johns Hopkins University
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • San Antonio, Texas, United States, 78229
      • Methodist Children's Hospital of South Texas
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 17 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of acute, noninfectious idiopathic pulmonary dysfunction (IPS) as defined by the following:

  • Evidence of diffuse lung injury occurring within the first several months after hematopoietic stem cell transplantation for which an infectious etiology is not identified. To meet the criteria for IPS there must be:

    • Evidence of widespread alveolar injury

      • Diffuse multi-lobar infiltrates on chest x-ray or CT scan

      • Evidence for abnormal respiratory physiology based upon 1 of the following:

        • Room air oxygen saturation < 93%
        • Supplemental oxygen required to maintain an oxygen saturation ≥ 93%

    • Absence of active lower respiratory tract infection, defined as Bronchoalveolar lavage (BAL)-negative for infection based on one of the following:

      • Gram stain, fungal stain, acid-fast bacilli stain
      • Bacterial culture (a quantitative culture ≥ 10^4 colony-forming units/mL is considered positive)
      • Fungal culture
      • Mycobacterial culture

      • Viral culture (respiratory syncytial virus [RSV], parainfluenza, adenovirus, influenza A and B, and cytomegalovirus [CMV])

        • If direct fluorescent antibody (DFA) screening is performed on BAL, it must be negative for all viruses listed above
      • Pneumocystis carinii pneumonia by polymerase chain reaction (PCR), DFA stain, or cytology
  • Evidence of bilateral pulmonary infiltrates (on chest radiograph)
  • Patients may have diffuse alveolar hemorrhage (DAH) or peri-engraftment respiratory distress syndrome (PERDS)
  • Presence of "mixed oral flora," "rare Candida species," or the presence of a Penicillium species reported on BAL fluid analysis allowed
  • A radiographic finding of pulmonary edema does not exclude the diagnosis of IPS, provided the other criteria have been met and provided the treating physician concludes by clinical (or echocardiographic) criteria that the pulmonary edema is not secondary to cardiac dysfunction or iatrogenic fluid overload
• Patients must require supplemental oxygen

• Must have undergone an allogeneic bone marrow, cord blood, or peripheral blood stem cell transplantation within the past 120 days

  • There are no restrictions based upon underlying disease, donor source, the degree of HLA match, the intensity of the pre-transplant conditioning regimen, or the use of a prior donor leukocyte infusion
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

• No documented invasive fungal or systemic viral infection within the past 14 days

  • Patients with asymptomatic viruria allowed
• No signs of CMV reactivation (by CMV, PCR, antigenemia, or shell vial culture) within the past 14 days
• No sepsis syndrome or hypotension that requires inotropic support (except dopamine < 5mcg/kg/minute)

• No documented bacteremia within the past 48 hours

  • Persistent fever allowed
• No evidence of cardiac failure by clinical or echocardiographic findings
• No known hypersensitivity to etanercept
• No known history of tuberculosis (Tb) or prior Tb exposure
• No prior chronic hepatitis B or hepatitis C infection
• Concurrent treatment for acute or chronic GVHD allowed
• More than 14 days since prior etanercept
• More than 7 days since prior investigational drug trials (phase I, II, or III) for the treatment of acute graft-versus-host disease (GVHD)
• Not on mechanical ventilation for > 48 continuous hours prior to study entry
• Must not be receiving > 2 mg/kg/day of methylprednisolone or corticosteroid equivalent within 24 hours of study entry
• Concurrent continuous veno-venous hemofiltration or hemodialysis allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Etanercept and corticosteroid therapy; Patients receive etanercept IV (dose 0.4 mg/kg- max 25 mg) over 30 minutes on day 0 and subcutaneously (dose 0.4 mg/kg- max 25 mg) on days 3, 7, 10, 14, 17, 21, and 24. Treatment continues in the absence of an infectious pathogen, disease progression, or unacceptable toxicity. Patients also receive methylprednisolone (or corticosteroid equivalent) IV (dose 2.0 mg/kg/day) on days 0-2 and then orally with a taper beginning day 7. Dose on days 7-20 (1.0 mg/kg/day), days 21-34 (0.5 mg/kg/day), days 35-48 (0.25 mg/kg/day) and days 49-56 (0.25 mg/kg/every other day) discontinuing on day 56.

Biological: etanercept; Given IV and subcutaneously; Other Names: ETN; Enbrel; TNFR:Fc; Tumor Necrosis Factor Receptor IgG Chimera; Drug: methylprednisolone; Given IV and orally; Other Names: Depo-Medrol; Medrol; MePRDL; Solu-Medrol; Wyacort

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response of IPS (Idiopathic Pneumonia Syndrome) to Etanercept Plus Corticosteroid Therapy by Day 28.	Response to therapy is defined as survival to Day 28 of study, PLUS complete discontinuation all supplemental oxygen support by Day 28 of study. Subjects must be able to remain off all supplemental oxygen support for > 72 consecutive hours. Subjects who discontinue supplemental oxygen within the last 72 hours of the observation period will be followed until they have completed 72 consecutive hours off oxygen or failed prior to assessing response.	At day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival Rate	Estimated Day 56 survival rate following initiation of etanercept + corticosteroid therapy for patients with IPS.	Up to day 56
Estimate Percentage Pulmonary Response in Patients With IPS Treated With Etanercept + Corticosteroid Therapy	Pulmonary response is defined as alive & come off of oxygen .	up to day 56
Toxicity of Etanercept Plus Corticosteroid Therapy Using the Common Terminology Criteria Version 4.0	Grade 3-5 organ toxicities attributable to etanercept.	Up to 56 days
Plasma Cytokine IL6 Level	Estimated mean and standard error of IL6 level	From baseline to days 7 and 28
C-reactive Protein Levels	Estimated mean and standard deviation	From baseline to days 7, 14, 21, and 28

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Gregory Yanik, MD, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (ACTUAL): September 1, 2011
• Study Completion (ACTUAL): September 1, 2011

Study Registration Dates

• First Submitted: March 29, 2006
• First Submitted That Met QC Criteria: March 29, 2006
• First Posted (ESTIMATE): April 3, 2006

Study Record Updates

• Last Update Posted (ACTUAL): September 29, 2017
• Last Update Submitted That Met QC Criteria: September 1, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lung Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Neoplasms, Glandular and Epithelial; Disease Attributes; Disease; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Myeloproliferative Disorders; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Kidney Neoplasms; Neoplastic Processes; Neoplastic Syndromes, Hereditary; Neoplasms, Complex and Mixed; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Sarcoma; Neuroectodermal Tumors, Primitive; Cell Transformation, Neoplastic; Carcinogenesis; Neoplasms, Muscle Tissue; Neuroectodermal Tumors, Primitive, Peripheral; Myosarcoma; Lymphoma; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasm Metastasis; Pneumonia; Recurrence; Lymphoma, Non-Hodgkin; Preleukemia; Leukemia, Myelomonocytic, Juvenile; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Blast Crisis; Neuroblastoma; Leukemia, Myeloid, Accelerated Phase; Rhabdomyosarcoma; Wilms Tumor; Rhabdomyosarcoma, Embryonal; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Etanercept
• Other Study ID Numbers: ASCT0521; U10CA098543 (U.S. NIH Grant/Contract); NCI-2009-00429 (REGISTRY: CTRP (Clinical Trial Reporting Program)); COG-PBMTC-SUP051 (OTHER: Children's Oncology Group); COG-ASCT0521 (OTHER: Children's Oncology Group); CDR0000456407 (OTHER: Clinical Trials.gov)