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Infliximab and Intravenous Immunoglobulin Therapy in Treating Patients With Steroid-Refractory Pneumonitis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04438382
Recruitment Status : Recruiting
First Posted : June 18, 2020
Last Update Posted : June 29, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group )

Tracking Information
First Submitted Date  ICMJE June 9, 2020
First Posted Date  ICMJE June 18, 2020
Last Update Posted Date June 29, 2020
Actual Study Start Date  ICMJE June 25, 2020
Estimated Primary Completion Date May 14, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 16, 2020)
Pneumonitis response rate [ Time Frame: At day 28 ]
Pneumonitis response will be defined as an improvement in partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) of >= 20% measured by PaO2 and recording of the FiO2 received by the patient at the time of the arterial blood gas assessment, on day 28 compared with day 1. Response rate will be reported with a proportion and its 90% confidence interval for each treatment arm. A comparison on the pneumonitis response rate between the two arms (infliximab vs. intravenous immunoglobulin [IVIG]) will be performed using Fisher's exact test.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2020)
  • Radiologic parameters of steroid-refractory pneumonitis [ Time Frame: At days 1, 14, and 28 ]
    Radiologic features of steroid-refractory pneumonitis will be assessed by percentage lung parenchyma involved, percentage of ground-glass opacity in lung parenchyma, and lung volume on computed tomography. The pneumonitis and lung volume will be graded "Definitely decreased", "Probably decreased", "No significant change", "Probably increased" and "Definitely increased". Response to study therapy will be defined by combining the categories "Definitely decreased" and "Probably decreased". The response rate will be compared between the arms using Fisher's exact test.
  • Functional parameters of steroid-refractory pneumonitis by spirometry [ Time Frame: At days 1, 14, and 28 ]
    Functional features of pneumonitis will be assessed by spirometry (forced vital capacity, forced expiratory volume in one second). These quantitative measures will be reported descriptively (by median, mean, and range) by timepoints and treatment arms. Pneumonitis improvement (from day 1 to day 14 and from day 1 to day 28) by each measure will be evaluated using the Wilcoxon signed-rank tests, by arm, without statistical adjustments.
  • Functional parameters of steroid-refractory pneumonitis by diffusion capacity [ Time Frame: At days 1, 14, and 28 ]
    Functional features of pneumonitis will be assessed by diffusion capacity of the lung. These quantitative measures will be reported descriptively (by median, mean, and range) by timepoints and treatment arms. Pneumonitis improvement (from day 1 to day 14 and from day 1 to day 28) by each measure will be evaluated using the Wilcoxon signed-rank tests, by arm, without statistical adjustments.
  • Functional parameters of steroid-refractory pneumonitis by oxygen saturation [ Time Frame: At days 1, 14, and 28 ]
    Functional features of pneumonitis will be assessed by oxygen saturation on room air at rest, collected as part of the vital signs. These quantitative measures will be reported descriptively (by median, mean, and range) by timepoints and treatment arms. Pneumonitis improvement (from day 1 to day 14 and from day 1 to day 28) by each measure will be evaluated using the Wilcoxon signed-rank tests, by arm, without statistical adjustments.
  • Number of reported deaths [ Time Frame: Up to 28 days ]
    Death reported in the 28-day period will be tabulated by treatment arm, and classified as pneumonitis-related, immunosuppression related, disease-related or other.
  • Incidence of adverse events [ Time Frame: Up to 28 days ]
    Will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The number and severity of treatment-related adverse events from infections in any organ system by the CTCAE reported in the 28-day period after additional immunosuppression.
  • Patient-reported outcomes of steroid-refractory pneumonitis [ Time Frame: At days 1, 14, and 28 ]
    Patient-reported outcomes of steroid-refractory pneumonitis will be measured by questionnaires (Functional Assessment of Cancer Therapy - Lung version 4) and the Borg scale). Functional Assessment of Cancer Therapy - Lung consists of 5 subscales and each subscale score will be computed separately. These quantitative measures will be reported descriptively (by median, mean, and range) by timepoints and treatment arms. Pneumonitis improvement (from day 1 to day 14 and from day 1 to day 28) by each measure will be evaluated using the Wilcoxon signed-rank tests, by arm, without statistical adjustments.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 16, 2020)
  • Assessment of features and phenotypic parameters [ Time Frame: At baseline ]
    Biospecimens from lung tissue and bronchoscopy will be collected to describe individual features and phenotypes from bronchoalveolar lavage (BAL) and lung tissue, respectively, using summary statistics (median/range or frequency/proportion where appropriate).
  • Biomarker analysis [ Time Frame: On days 1, 14, and 28 post-treatment ]
    Potential blood/serum biomarkers for pneumonitis will be assessed from serially collected blood/serum in accrued patients and controls, whose blood/serum will be obtained as part of a parallel tissue-collection protocol. Autoantibodies, T-cell expansions (negative/positive), and cytokine levels (e.g., IFN-gamma, IL-17, and VEG-F) will be summarized descriptively in patients with pneumonitis vs. controls, by time point and treatment arm (when appropriate). Fisher's exact test will be used to evaluate associations of pneumonitis (yes/no) with autoantibodies, T-cell expansions (negative/positive), and baseline cytokines (dichotomized by the median of each cytokine). The association of BAL phenotype with pneumonitis response (yes/no), functional and radiologic parameters of pneumonitis will be evaluated using Fisher's exact test or logistic regressions, where appropriate.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Infliximab and Intravenous Immunoglobulin Therapy in Treating Patients With Steroid-Refractory Pneumonitis
Official Title  ICMJE Optimizing Immunosuppression for Steroid-Refractory Anti-PD-1/PD-L1 Pneumonitis
Brief Summary This phase II trial studies how well infliximab and intravenous immunoglobulin therapy work in treating patients with pneumonitis that does not respond to steroid treatment. Immunotherapy with monoclonal antibodies such as, infliximab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Intravenous immunoglobulin therapy may improve pneumonitis. It is not yet known whether giving infliximab and intravenous immunoglobulin therapy will work better in treating patients with pneumonitis.
Detailed Description

PRIMARY OBJECTIVE:

I. To assess pneumonitis response to additional immunosuppression (infliximab or intravenous immunoglobulin therapy [IVIG]) in patients with steroid-refractory pneumonitis at 28-days.

SECONDARY OBJECTIVES:

I. To assess functional parameters of steroid-refractory pneumonitis at day 1, 14-days and 28-days after day 1 of receipt of additional immunosuppression (infliximab or IVIG).

II. To assess radiologic parameters of steroid-refractory pneumonitis at day 1, 14-days and 28-days after day 1 of receipt of additional immunosuppression (infliximab or IVIG).

III. To assess patient-reported outcomes of steroid-refractory pneumonitis at day 1, 14-days and 28-days after day 1 of receipt of additional immunosuppression (infliximab or IVIG).

IV. To assess death after additional immunosuppression. V. To assess the rate of infections in the 28-day period after additional immunosuppression.

EXPLORATORY OBJECTIVES:

I. To examine lung tissue, bronchoalveolar lavage (BAL) and serial blood samples in patients who develop steroid-refractory pneumonitis.

II. To examine associations between BAL phenotypes and pneumonitis response, functional and radiologic parameters of pneumonitis.

III. To evaluate associations between pneumonitis and autoantibodies, T-cell expansion, and baseline cytokines in the blood.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive infliximab intravenously (IV) on day 1 followed by prednisone taper IV or orally (PO) for 4-6 weeks in the absence of disease progression or unacceptable toxicity. Patients may receive an additional dose of infliximab IV on day 14 at the discretion of the treating physician.

ARM B: Patients receive intravenous immunoglobulin therapy IV over 2-5 days per institutional guidelines followed by prednisone taper IV or PO for 4-6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28, 42 and 56 days.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hematopoietic and Lymphoid Cell Neoplasm
  • Malignant Solid Neoplasm
  • Steroid-Refractory Pneumonitis
Intervention  ICMJE
  • Biological: Infliximab
    Given IV
    Other Names:
    • Avakine
    • cA2
    • Remicade
    • Remsima
  • Biological: Intravenous Immunoglobulin Therapy
    Given IV
    Other Names:
    • Gamma Globulin
    • Gamma Globulin Therapy
    • Immune Globulin
    • Immune Globulin Therapy
    • Intravenous Immunoglobulin
    • IVIG
    • IVIG Therapy
  • Drug: Prednisone
    Given IV or PO
    Other Names:
    • .delta.1-Cortisone
    • 1, 2-Dehydrocortisone
    • Adasone
    • Cortancyl
    • Dacortin
    • DeCortin
    • Decortisyl
    • Decorton
    • Delta 1-Cortisone
    • Delta-Dome
    • Deltacortene
    • Deltacortisone
    • Deltadehydrocortisone
    • Deltasone
    • Deltison
    • Deltra
    • Econosone
    • Lisacort
    • Meprosona-F
    • Metacortandracin
    • Meticorten
    • Ofisolona
    • Orasone
    • Panafcort
    • Panasol-S
    • Paracort
    • Perrigo Prednisone
    • PRED
    • Predicor
    • Predicorten
    • Prednicen-M
    • Prednicort
    • Prednidib
    • Prednilonga
    • Predniment
    • Prednisone Intensol
    • Prednisonum
    • Prednitone
    • Promifen
    • Rayos
    • Servisone
    • SK-Prednisone
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies
Study Arms  ICMJE
  • Experimental: Arm A (infliximab)
    Patients receive infliximab IV on day 1 followed by prednisone taper IV or PO for 4-6 weeks in the absence of disease progression or unacceptable toxicity. Patients may receive an additional dose of infliximab IV on day 14 at the discretion of the treating physician.
    Interventions:
    • Biological: Infliximab
    • Drug: Prednisone
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
  • Experimental: Arm B (intravenous immunoglobulin therapy)
    Patients receive intravenous immunoglobulin therapy IV over 2-5 days per institutional guidelines followed by prednisone taper IV or PO for 4-6 weeks in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Biological: Intravenous Immunoglobulin Therapy
    • Drug: Prednisone
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 16, 2020)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 14, 2024
Estimated Primary Completion Date May 14, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must be English-speaking and be able to provide informed consent
  • Patient must be willing and able to undergo arterial blood gas assessment as per the treating investigator. Patient must not have contraindication for arterial blood gas assessment
  • Women must not be pregnant or breast-feeding due to the potential risk to the fetus of infliximab or IVIG. All females of childbearing potential must have a blood test or urine test within 14 days prior to randomization to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  • Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method(s) of contraception or to abstain from sexual intercourse for a minimum of 56 days (the duration of their participation in the study)
  • Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3
  • Patient may have received any number of lines of prior systemic therapy
  • Patient may have any solid tumor or hematologic malignancy is eligible
  • Patient must have received treatment with an anti-PD-1/PD-L1 agent either alone or in combination with another anti-cancer agent, as their most recent therapy prior to development of pneumonitis
  • Patient must have steroid-refractory pneumonitis defined as:

    • Grade 2 pneumonitis that has not clinically improved by a Common Terminology Criteria for Adverse Events (CTCAE) grade in greater than 72 hours or maximum of 14 days or
    • Grade 3 or higher pneumonitis that has not clinically improved by a CTCAE grade in greater than 48 hours or maximum of 14 days with high dose corticosteroids (methylprednisolone or prednisone 1-4 mg/kg/equivalent) as their most recent treatment for pneumonitis, as determined by the treating investigator
  • Patient may have received anti-PD-1/PD-L1 therapy as standard-of-care or part of a clinical trial
  • Patient must have had pathogen-negative infectious diagnostic evaluation within 14 days prior to randomization, and at a minimum these should include: blood culture, urine culture, sputum culture, and viral panel: rapid flu, respiratory syncytial virus (RSV), herpes simplex virus (HSV). Empiric antibiotics for culture negative infections are not an exclusion for study entry
  • Patient must have had a pathogen-negative bronchoscopic assessment of BAL fluid within 14 days prior to randomization. A minimum assessment for pathogens on BAL must include: gram stain, fungal panel, viral panel
  • Patient must have a negative tuberculosis assessment (TB spot test, quantiferon gold or tuberculin skin test) within 14 days prior to randomization
  • Patient must have chest computed tomography (CT) scan without contrast performed =< 14 days before randomization. Patient must not have a contraindication for CT

Exclusion Criteria:

  • Patient must not have clinical evidence of cardiac dysfunction (as determined by the treating investigator) as an alternative diagnosis to steroid-refractory pneumonitis
  • Patient must not be receiving anti-PD-1/-PD-L1 agent in combination with any of the following anti-cancer agents: docetaxel, cyclophosphamide, gefitinib, erlotinib, osimertinib, crizotinib, bleomycin, afatinib
  • Patient must not be receiving concurrent radiation therapy to the chest
  • Patient must not be deemed to have radiation pneumonitis. Patients with a history of stable radiation pneumonitis not requiring corticosteroid therapy within the last 3 months prior to randomization will be allowed on study
  • Patient must not have pre-existing interstitial lung disease or pneumonitis requiring corticosteroid therapy from any other cause, as determined by the treating investigator
  • Patient must not have an absolute contraindication to IVIG or infliximab, including: clinical history of severe hypersensitivity reaction, selective IgA deficiency, active hepatitis B, active tuberculosis, active human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) where a study subject has a CD4 count of =< 200 at screening, or drug interaction
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04438382
Other Study ID Numbers  ICMJE EAQ172
NCI-2018-02825 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EAQ172 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
ECOG-ACRIN-EAQ172 ( Other Identifier: DCP )
ECOG-ACRIN-EAQ172 ( Other Identifier: CTEP )
UG1CA189828 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group )
Study Sponsor  ICMJE ECOG-ACRIN Cancer Research Group
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Jarushka Naidoo ECOG-ACRIN Cancer Research Group
PRS Account Eastern Cooperative Oncology Group
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP