Safety and Efficacy of Itacitinib in Combination With Corticosteroids for Treatment of Graft-Versus-Host Disease in Pediatric Subjects

Study Overview
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Brief Summary
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The purpose of this study is to evaluate itacitinib in combination with corticosteroids for the treatment of Grades II to IV acute graft-versus-host disease (aGVHD) in steroid-naive pediatric participants.

Official Title
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An Open-Label, Single-Arm, Phase 1/2 Study Evaluating the Safety and Efficacy of Itacitinib in Combination With Corticosteroids for the Treatment of Steroid-Naive Acute Graft-Versus-Host Disease in Pediatric Subjects

Conditions
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Acute Graft-versus-host Disease

Intervention / Treatment
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* Drug: Itacitinib
* Drug: Corticosteroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants: 12 to < 18 years old (Cohort 1), 6 to < 12 years old (Cohort 2), 2 to < 6 years old (Cohort 3), Weighing > 8 kg to < 2 years old (Cohort 4), and 28 days old to weighing ≤ 8 kg (Cohort 5). Undergone 1 allogeneic hematopoietic stem cell transplantation (allo-HSCT) from any donor and source for hematological malignancies or disorders. Recipients of myeloablative and reduced-intensity conditioning regimens are eligible. Clinically suspected Grade II to IV aGVHD as per Mount Sinai Acute GVHD International Consortium (MAGIC) criteria, occurring after allo-HSCT and any GVHD prophylactic medication. Evidence of myeloid engraftment. Exclusion Criteria: More than 1 allo-HSCT. Received more than 2 days of systemic corticosteroids for aGVHD before the first study drug administration. Presence of GVHD overlap syndrome. Presence of an active uncontrolled infection. Known HIV infection. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection that requires treatment or at risk for HBV reactivation. Evidence of relapsed primary disease or have been treated for relapse after the allo-HSCT was performed. Any corticosteroid therapy for indications other than GVHD at doses > 1 mg/kg once daily of methylprednisolone (or equivalent) within 7 days of the first study drug administration. Receipt of live (including attenuated) vaccines or anticipation of need for such vaccines during the study. Receipt of JAK inhibitor therapy after allo-HSCT for any indication. Treatment with any other investigational agent, device, or procedure within 21 days (or 5 half-lives, whichever is greater) of enrollment.

Ages Eligible for Study
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Minimum Age: 28 Days
Maximum 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Itacitinib + Corticosteroids<br> | Drug: Itacitinib<br>* Phase 1: Itacitinib administered orally once daily at the protocol-defined dose according to age cohort, with dose reductions or modifications based on safety assessments. Phase 2: Itacitinib administered orally once daily at the recommended dose from Phase 1.<br>* Other names: INCB039110;Drug: Corticosteroids<br>* Phase 1 and 2: Methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at a dose that is appropriate for the severity of disease as outlined per local treatment guidelines as background treatment.<br>* Other names: prednisone, methylprednisolone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | A TEAE was defined as an AE that began or worsened from Baseline after the first administration of study drug. | up to 45 days | 
| Phase 1: Cmax of Itacitinib When Administered With Corticosteroids | Cmax was defined as the maximum observed plasma concentration. | Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose | 
| Phase 1: Cmin of Itacitinib When Administered With Corticosteroids | Cmin was defined as the minimum observed plasma concentration. | Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose | 
| Phase 1: Tmax of Itacitinib When Administered With Corticosteroids | Tmax was defined as the time to the maximum concentration. | Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose | 
| Phase 1: AUC of Itacitinib When Administered With Corticosteroids | AUC was defined as the area under the plasma concentration-time curve. | Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose | 
| Phase 1: Cl/F of Itacitinib When Administered With Corticosteroids | Cl/F was defined as the apparent oral dose clearance. | Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose | 
| Phase 2: Overall Response Rate up to Day 28 | Overall response rate was defined as the number of participants demonstrating a complete response (CR), a very good partial response (VGPR), or a partial response (PR). | up to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Number of Participants With TEAEs | A TEAE was defined as an AE that began or worsened from Baseline after the first administration of study drug. | up to 12 months | 
| Phase 2: Cmax of Itacitinib When Administered With Corticosteroids | Cmax was defined as the maximum observed plasma concentration. | Day 7: predose; 1, 2, and 4 hours post-dose | 
| Phase 2: Cmin of Itacitinib When Administered With Corticosteroids | Cmin was defined as the minimum observed plasma concentration. | Day 7: predose; 1, 2, and 4 hours post-dose | 
| Phase 2: Tmax of Itacitinib When Administered With Corticosteroids | Tmax was defined as the time to the maximum concentration. | Day 7: predose; 1, 2, and 4 hours post-dose | 
| Phase 2: AUC of Itacitinib When Administered With Corticosteroids | AUC was defined as the area under the plasma concentration-time curve. | Day 7: predose; 1, 2, and 4 hours post-dose | 
| Phase 2: Cl/F of Itacitinib When Administered With Corticosteroids | Cl/F was defined as the apparent oral dose clearance. | Day 7: predose; 1, 2, and 4 hours post-dose | 
| Phase 2: Overall Response Rate up to 100 Days | Overall response rate was defined as the number of participants demonstrating a CR, a VGPR, or a PR. | up to 100 days | 
| Phase 1: Overall Response Rate | Overall response rate was defined as the number of participants demonstrating a CR, a VGPR, or a PR. | up to Day 28 | 
| Phase 2: Non Relapse Mortality | Non relapse mortality was defined as the number of participants who died due to causes other than underlying hematologic disorders relapse. | up to 24 months | 
| Phase 2: Duration of Response | Duration of response was defined as the time of the onset of response to the loss of response. | up to approximately 12 months | 
| Phase 2: Time to Response | Time to response was defined as the interval from treatment initiation to the first response. | up to approximately 12 months | 
| Phase 2: Relapse Rate of Malignant and Nonmalignant Disorders | Relapse rate was defined as the number of participants whose underlying disease relapsed. | up to approximately 12 months | 
| Phase 2: Malignant and Nonmalignant Disorders Relapse-related Mortality Rate | Mortality rate was defined as the number of participants whose underlying hematologic disorder relapsed and had a fatal outcome. | up to approximately 12 months | 
| Phase 2: Failure-free Survival | Failure-free survival was defined as the number of participants who were still alive, had not relapsed, had not required additional therapy for acute graft-versus-host disease (aGVHD), and had not demonstrated signs or symptoms of chronic GVHD. | up to 6 months | 
| Phase 2: Overall Survival | Overall survival was defined as the interval from study enrollment to death due to any cause. | up to approximately 12 months | 
| Phase 2: Incidence Rate of Secondary Graft Failure | Analysis was to be conducted to assess the number of participants experiencing secondary graft failure. | up to approximately 12 months | 
| Phase 2: Average Corticosteroid Use | The average number of participants who discontinued corticosteroids was to be assessed. | up to 180 days | 
| Phase 2: Cumulative Corticosteroid Dose | The number of participants with various cumulative corticosteroid doses was assessed. | up to 180 days | 
| Phase 2: Number of Participants Who Discontinued Corticosteroids | The number of participants who discontinued corticosteroids was assessed. | up to 100 days | 
| Phase 2: Number of Participants Who Discontinued Immunosuppressive Medication | The number of participants who discontinued immunosuppressive medication was assessed. | up to 100 days | 
| Phase 2: Number of Participants With aGVHD Flares | The number of participants who experienced aGVHD flares requiring treatment was assessed. | up to 100 Days | 
| Phase 2: Number of Participants With Chronic Graft-versus-host Disease (cGVHD) | The number of participants with a diagnosis of any cGVHD, including mild, moderate, severe, was assessed. | up to 365 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GVHD, Acute graft-versus-host disease, pediatric, JAK1 inhibitor, corticosteroids