Acute Graft-versus-host Disease
Conditions
Keywords
Acute graft-versus-host disease, GVHD, pediatric, JAK1 inhibitor, corticosteroids
Brief summary
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.
Interventions
DRUGItacitinib
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.
DRUGCorticosteroids
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.
Sponsors
Incyte Corporation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
28 Days to 18 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | up to 45 days | A TEAE was defined as an AE that began or worsened from Baseline after the first administration of study drug. |
| Phase 1: Cmax of Itacitinib When Administered With Corticosteroids | Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose | Cmax was defined as the maximum observed plasma concentration. |
| Phase 1: Cmin of Itacitinib When Administered With Corticosteroids | Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose | Cmin was defined as the minimum observed plasma concentration. |
| Phase 1: Tmax of Itacitinib When Administered With Corticosteroids | Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose | Tmax was defined as the time to the maximum concentration. |
| Phase 1: AUC of Itacitinib When Administered With Corticosteroids | Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose | AUC was defined as the area under the plasma concentration-time curve. |
| Phase 1: Cl/F of Itacitinib When Administered With Corticosteroids | Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose | Cl/F was defined as the apparent oral dose clearance. |
| Phase 2: Overall Response Rate up to Day 28 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Overall Response Rate | up to Day 28 | Overall response rate was defined as the number of participants demonstrating a CR, a VGPR, or a PR. |
| Phase 2: Non Relapse Mortality | up to 24 months | Non relapse mortality was defined as the number of participants who died due to causes other than underlying hematologic disorders relapse. |
| Phase 2: Duration of Response | up to approximately 12 months | Duration of response was defined as the time of the onset of response to the loss of response. |
| Phase 2: Time to Response | up to approximately 12 months | Time to response was defined as the interval from treatment initiation to the first response. |
| Phase 2: Relapse Rate of Malignant and Nonmalignant Disorders | up to approximately 12 months | Relapse rate was defined as the number of participants whose underlying disease relapsed. |
| Phase 2: Malignant and Nonmalignant Disorders Relapse-related Mortality Rate | up to approximately 12 months | Mortality rate was defined as the number of participants whose underlying hematologic disorder relapsed and had a fatal outcome. |
| Phase 2: Failure-free Survival | up to 6 months | 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. |
| Phase 2: Number of Participants With TEAEs | up to 12 months | A TEAE was defined as an AE that began or worsened from Baseline after the first administration of study drug. |
| Phase 2: Incidence Rate of Secondary Graft Failure | up to approximately 12 months | Analysis was to be conducted to assess the number of participants experiencing secondary graft failure. |
| Phase 2: Average Corticosteroid Use | up to 180 days | The average number of participants who discontinued corticosteroids was to be assessed. |
| Phase 2: Cumulative Corticosteroid Dose | up to 180 days | The number of participants with various cumulative corticosteroid doses was assessed. |
| Phase 2: Number of Participants Who Discontinued Corticosteroids | up to 100 days | The number of participants who discontinued corticosteroids was assessed. |
| Phase 2: Number of Participants Who Discontinued Immunosuppressive Medication | up to 100 days | The number of participants who discontinued immunosuppressive medication was assessed. |
| Phase 2: Number of Participants With aGVHD Flares | up to 100 Days | The number of participants who experienced aGVHD flares requiring treatment was assessed. |
| Phase 2: Number of Participants With Chronic Graft-versus-host Disease (cGVHD) | up to 365 days | The number of participants with a diagnosis of any cGVHD, including mild, moderate, severe, was assessed. |
| Phase 2: Overall Survival | up to approximately 12 months | Overall survival was defined as the interval from study enrollment to death due to any cause. |
| Phase 2: Cmax of Itacitinib When Administered With Corticosteroids | Day 7: predose; 1, 2, and 4 hours post-dose | Cmax was defined as the maximum observed plasma concentration. |
| Phase 2: Cmin of Itacitinib When Administered With Corticosteroids | Day 7: predose; 1, 2, and 4 hours post-dose | Cmin was defined as the minimum observed plasma concentration. |
| Phase 2: Tmax of Itacitinib When Administered With Corticosteroids | Day 7: predose; 1, 2, and 4 hours post-dose | Tmax was defined as the time to the maximum concentration. |
| Phase 2: AUC of Itacitinib When Administered With Corticosteroids | Day 7: predose; 1, 2, and 4 hours post-dose | AUC was defined as the area under the plasma concentration-time curve. |
| Phase 2: Cl/F of Itacitinib When Administered With Corticosteroids | Day 7: predose; 1, 2, and 4 hours post-dose | Cl/F was defined as the apparent oral dose clearance. |
| Phase 2: Overall Response Rate up to 100 Days | up to 100 days | Overall response rate was defined as the number of participants demonstrating a CR, a VGPR, or a PR. |
Countries
France, Germany, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
A study of itacitinib in combination with corticosteroids for the treatment of Grades II to IV acute graft-versus-host disease (aGVHD) in pediatric participants 28 days to \< 18 years old who were naïve to corticosteroids. The study was conducted from 31-Dec-2019 to 17-Feb-2020.
Pre-assignment details
A total of 2 participants were screened and included in the study.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 : Itacitinib + Corticosteroids Itacitinib was administered once a day orally in combination with corticosteroids as per local treatment guidelines. | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Study Terminated by Sponsor | 1 |
Baseline characteristics
| Characteristic | Cohort 1 : Itacitinib + Corticosteroids |
|---|---|
| Age, Categorical <=18 years | 2 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 13.5 years STANDARD_DEVIATION 2.12 |
| Race/Ethnicity, Customized Not Hispanic or Latino | 2 Participants |
| Race/Ethnicity, Customized White | 2 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 2 |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 2 / 2 |
Outcome results
Primary
Phase 1: AUC of Itacitinib When Administered With Corticosteroids
AUC was defined as the area under the plasma concentration-time curve.
Time frame: Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose
Population: Due to the small sample size (n=2), data cannot be reported without risking participant re-identification. Data are not being reported in order to protect participants' privacy.
Primary
Phase 1: Cl/F of Itacitinib When Administered With Corticosteroids
Cl/F was defined as the apparent oral dose clearance.
Time frame: Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose
Population: Due to the small sample size (n=2), data cannot be reported without risking participant re-identification. Data are not being reported in order to protect participants' privacy.
Primary
Phase 1: Cmax of Itacitinib When Administered With Corticosteroids
Cmax was defined as the maximum observed plasma concentration.
Time frame: Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose
Population: Due to the small sample size (n=2), data cannot be reported without risking participant re-identification. Data are not being reported in order to protect participants' privacy.
Primary
Phase 1: Cmin of Itacitinib When Administered With Corticosteroids
Cmin was defined as the minimum observed plasma concentration.
Time frame: Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose
Population: Due to the small sample size (n=2), data cannot be reported without risking participant re-identification. Data are not being reported in order to protect participants' privacy.
Primary
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.
Time frame: up to 45 days
Population: All enrolled participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 : Itacitinib + Corticosteroids | Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 2 Participants |
Primary
Phase 1: Tmax of Itacitinib When Administered With Corticosteroids
Tmax was defined as the time to the maximum concentration.
Time frame: Day 1: 1, 2, 4, and 6 hours post-dose. Day 7: predose; 1, 2, 4, and 6 hours post-dose
Population: Due to the small sample size (n=2), data cannot be reported without risking participant re-identification. Data are not being reported in order to protect participants' privacy.
Primary
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).
Time frame: up to Day 28
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 1: Overall Response Rate
Overall response rate was defined as the number of participants demonstrating a CR, a VGPR, or a PR.
Time frame: up to Day 28
Population: The study was terminated before participants reached Day 28, the time point for analysis.
Secondary
Phase 2: AUC of Itacitinib When Administered With Corticosteroids
AUC was defined as the area under the plasma concentration-time curve.
Time frame: Day 7: predose; 1, 2, and 4 hours post-dose
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Average Corticosteroid Use
The average number of participants who discontinued corticosteroids was to be assessed.
Time frame: up to 180 days
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Cl/F of Itacitinib When Administered With Corticosteroids
Cl/F was defined as the apparent oral dose clearance.
Time frame: Day 7: predose; 1, 2, and 4 hours post-dose
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Cmax of Itacitinib When Administered With Corticosteroids
Cmax was defined as the maximum observed plasma concentration.
Time frame: Day 7: predose; 1, 2, and 4 hours post-dose
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Cmin of Itacitinib When Administered With Corticosteroids
Cmin was defined as the minimum observed plasma concentration.
Time frame: Day 7: predose; 1, 2, and 4 hours post-dose
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Cumulative Corticosteroid Dose
The number of participants with various cumulative corticosteroid doses was assessed.
Time frame: up to 180 days
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Duration of Response
Duration of response was defined as the time of the onset of response to the loss of response.
Time frame: up to approximately 12 months
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
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.
Time frame: up to 6 months
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Incidence Rate of Secondary Graft Failure
Analysis was to be conducted to assess the number of participants experiencing secondary graft failure.
Time frame: up to approximately 12 months
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
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.
Time frame: up to approximately 12 months
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
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.
Time frame: up to 24 months
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Number of Participants Who Discontinued Corticosteroids
The number of participants who discontinued corticosteroids was assessed.
Time frame: up to 100 days
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Number of Participants Who Discontinued Immunosuppressive Medication
The number of participants who discontinued immunosuppressive medication was assessed.
Time frame: up to 100 days
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Number of Participants With aGVHD Flares
The number of participants who experienced aGVHD flares requiring treatment was assessed.
Time frame: up to 100 Days
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
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.
Time frame: up to 365 days
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
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.
Time frame: up to 12 months
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
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.
Time frame: up to 100 days
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Overall Survival
Overall survival was defined as the interval from study enrollment to death due to any cause.
Time frame: up to approximately 12 months
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Relapse Rate of Malignant and Nonmalignant Disorders
Relapse rate was defined as the number of participants whose underlying disease relapsed.
Time frame: up to approximately 12 months
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Time to Response
Time to response was defined as the interval from treatment initiation to the first response.
Time frame: up to approximately 12 months
Population: No participants enrolled in Phase 2 due to early termination of the study.
Secondary
Phase 2: Tmax of Itacitinib When Administered With Corticosteroids
Tmax was defined as the time to the maximum concentration.
Time frame: Day 7: predose; 1, 2, and 4 hours post-dose
Population: No participants enrolled in Phase 2 due to early termination of the study.