Safety and Efficacy of Itacitinib in Participants With Bronchiolitis Obliterans Syndrome Following Lung Transplantation

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of itacitinib in participants with post-lung transplant bronchiolitis obliterans syndrome (BOS).

Official Title
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An Open-Label, Single-Arm, Phase 1/2 Study Evaluating the Safety and Efficacy of Itacitinib in Participants With Bronchiolitis Obliterans Syndrome Following Lung Transplantation

Conditions
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Bronchiolitis Obliterans Syndrome

Intervention / Treatment
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* Drug: Itacitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Double lung transplantation ≥ 1 year before informed consent. Confirmed BOS progression to Grade 1, 2, or 3 diagnosed within 1 year of screening *Confirmed BOS progression to Grade 1, 2, or 3 diagnosed within 2 years of screening AND: A ≥ 200 mL decrease in FEV1 in the previous 12 months OR *A ≥ 50 mL decrease in FEV1 in the last 2 measurements. • Willingness to avoid pregnancy or fathering children. Exclusion Criteria: History of a single lung transplant FEV1 decline attributable to cause(s) other than BOS. Participants who have had any significant change (eg, addition of new agents) in an immunosuppressive regimen in the 4 weeks before screening. Untreated and/or symptomatic gastroesophageal reflux disease. Significant infectious comorbidities including invasive fungal disease, B. Cepacia, non TB mycobacteria, or TB. Receipt of JAK inhibitor therapy after lung transplant for any indication. Treatment with a JAK inhibitor before lung transplant is permitted. Laboratory values at screening outside the protocol-defined ranges. Active HBV or HCV infection that requires treatment, or at risk for HBV reactivation (ie, positive HBsAg). Known HIV infection. History of active malignancy within 3 years of screening. Women who are pregnant or breastfeeding. Treatment with an investigational agent, procedure, or device within 30 days of enrollment, or within 5 half-lives of the investigational product, whichever is longer.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1 Itacitinib administered orally followed by phase 2; Itacitinib administered orally at the recommended dose from Phase 1.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Itacitinib 300 mg<br>Phase 1: Itacitinib 300 mg twice daily. There can be required dose adjustments in the protocol for concurrent CYP3A administration. | Drug: Itacitinib<br>* Itacitinib administered orally at the specified dose.<br>* Other names: INCB039110;|
| Experimental: Itacitinib 400 mg<br>Phase 1: Itacitinib 400 mg once daily. There can be required dose adjustments in the protocol for concurrent CYP3A administration. | Drug: Itacitinib<br>* Itacitinib administered orally at the specified dose.<br>* Other names: INCB039110;|
| Experimental: Itacitinib 600 mg<br>Phase 1: Itacitinib 600 mg once daily. There can be required dose adjustments in the protocol for concurrent CYP3A administration | Drug: Itacitinib<br>* Itacitinib administered orally at the specified dose.<br>* Other names: INCB039110;|
| Experimental: Itacitinib<br>Phase 2: Itacitinib administered orally at the recommended dose from Phase 1. | Drug: Itacitinib<br>* Itacitinib administered orally at the specified dose.<br>* Other names: INCB039110;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of treatment-emergent adverse events | Defined as any adverse event either reported for the first time or worsening of a pre-existing event after first dose of study drug until 30 days after the last dose of study drug. | Up to approximately 24 months | 
| Phase 1: Change from baseline in forced expiratory volume in 1 second (FEV1) |  | Week 12 | 
| Phase 2: Change from baseline in FEV1 response rate | Defined as the proportion of participants demonstrating a ≥ 10% absolute increase in FEV1 compared to baseline. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 and 2: Duration of FEV1 response | Defined as the time of the onset of response (≥ 10% absolute increase in FEV1 compared to baseline) to BOS progression or loss of clinical benefit as determined by the investigator. | Up to approximately 24 months | 
| Phase 1 and 2: Time to progression | Defined as the interval between the start of treatment and BOS progression (≥ 10% absolute decrease in FEV1 compared to baseline), or death. | Up to approximately 24 months | 
| Phase 1 and 2: Change from baseline in SGRQ total score | St. Georges Respiratory Questionnaire, a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airway disease. | Up to approximately 24 months | 
| Phase 1 and 2: Change from baseline in QOL-SF-12 questionnaire | A 12-item subset of the SF-36 v2 scale that will capture changes in health status during the course of treatment. | Up to approximately 24 months | 
| Phase 1 and 2: Categorical summary or change from baseline in EQ-5D-3L questionnaire | A descriptive classification consisting of 5 dimensions of health: mobility, self-care, usual activities, anxiety/depression, and pain/discomfort. | Up to approximately 24 months | 
| Phase 2: Overall Survival | Defined as the interval between the start of treatment and the date of re-transplantation or death due to any cause. | Up to approximately 24 months | 
| Phase 1 and 2: Cmax of itacitinib | Maximum observed concentration. | Up to Week 4 | 
| Phase 1 and 2: Cmin of itacitinib | Minimum observed plasma or serum concentration over the dose interval. | Up to Week 4 | 
| Phase 1 and 2: Tmax of itacitinib | Time to maximum concentration. | Up to Week 4 | 
| Phase 1 and 2: AUC0-t of itacitinib | Area under the plasma or serum concentration-time curve from time = 0 to the last measurable concentration at time = t. | Up to Week 4 | 
| Phase 1 and 2: Cl/F of itacitinib | Apparent oral dose clearance. | Up to Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bronchiolitis obliterans syndrome, lung transplant, JAK1 inhibitor