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

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.

• Infliximab (Biological), also known as Remicade: Given IV
• Intravenous Immunoglobulin Therapy (Biological), also known as Gamma Globulin, Gamma Globulin Therapy, Immune Globulin, Immune Globulin Therapy, Intravenous Immunoglobulin, IVIG: Given IV
• Prednisone (Drug), also known as Deltasone, Orasone, Meticorten, Panasol-S, Liquid-Pred: Given IV or PO
• Methylprednisolone (Drug), also known as Methylprednisolone sodium succinate (Solu-Medrol), methylprednisolone acetate (Depo-Medrol), Methylprednisolone (Medrol): Given IV or PO

Primary outcomes

• Pneumonitis Response Rate [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.

Secondary outcomes

• Proportion of Patients With Radiologic Response for Steroid-refractory Pneumonitis [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".
• Functional Parameters of Steroid-refractory Pneumonitis by Spirometry [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.
• Functional Parameters of Steroid-refractory Pneumonitis by Diffusion Capacity [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.
• Functional Parameters of Steroid-refractory Pneumonitis by Oxygen Saturation [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.
• Number of Deaths Within 28 Days [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 [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.
• Total Score of Functional Assessment of Cancer Therapy - Lung Version 4 [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 \[FACT-L\]). FACT-L consists of 5 subscales and the total score is calculated by summing the scores of the 36 items. The score ranges between 0 and 136. The higher the score, the better the quality of life.

Other outcomes

• Distribution of Biomarkers in Patients Who Develop Steroid-refractory Pneumonitis [Days 1, 14 and 28 after study treatment]: Potential blood/serum biomarkers for pneumonitis will be assessed from serially collected blood/serum in accrued patients (on Days 1, 14 and 28 after study treatment) and controls, whose blood/serum will be obtained as part of a parallel tissue-collection protocol.
• To Evaluate Associations Between Pneumonitis and Autoantibodies, T Cell Expansion, and Baseline Cytokines in the Blood [On days 1, 14, and 28 post-treatment]: To evaluate associations between pneumonitis and autoantibodies, T cell expansion, and baseline cytokines in the blood.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Pneumonitis Response Rate (Primary)
• Proportion of Patients With Radiologic Response for Steroid-refractory Pneumonitis (Secondary)
• Functional Parameters of Steroid-refractory Pneumonitis by Spirometry (Secondary)
• Functional Parameters of Steroid-refractory Pneumonitis by Diffusion Capacity (Secondary)
• Functional Parameters of Steroid-refractory Pneumonitis by Oxygen Saturation (Secondary)
• Number of Deaths Within 28 Days (Secondary)
• Incidence of Adverse Events (Secondary)
• Total Score of Functional Assessment of Cancer Therapy - Lung Version 4 (Secondary)
• Distribution of Biomarkers in Patients Who Develop Steroid-refractory Pneumonitis (Other pre specified)
• To Evaluate Associations Between Pneumonitis and Autoantibodies, T Cell Expansion, and Baseline Cytokines in the Blood (Other pre specified)

Adverse events

Time frame: Assessed every 4 weeks until 30 days after treatment completion, up to 3 years

Limitations and caveats: Only one patient was enrolled on this study. Due to the concern on confidentiality, individual data was not reported.

• Results publication: Beattie J, Rizvi H, Fuentes P, Luo J, Schoenfeld A, Lin IH, Postow M, Callahan M, Voss MH, Shah NJ, Betof Warner A, Chawla M, Hellmann MD. Success and failure of additional immune modulators in steroid-refractory/resistant pneumonitis related to immune checkpoint blockade. J Immunother Cancer. 2021 Feb;9(2):e001884. doi: 10.1136/jitc-2020-001884. PMID 33568350

• Study Protocol and Statistical Analysis Plan (PDF, 2022-10-19)

• Jarushka Naidoo, Principal investigator, ECOG-ACRIN Cancer Research Group

NIH grants: UG1CA189828