Graft-versus-host Disease (GVHD)
Conditions
Keywords
Acute graft-versus-host disease, Janus kinase (JAK) inhibitor, itacitinib, corticosteroids, allogeneic hematopoietic stem cell transplant (allo-HSCT)
Brief summary
The purpose of this study is to evaluate itacitinib or placebo in combination with corticosteroids as first-line treatment of participants with Grade II to IV acute graft-versus-host disease (aGVHD).
Interventions
DRUGItacitinib
Itacitinib at the protocol-defined dose administered orally once daily (QD) plus corticosteroids.
DRUGPlacebo
Matching placebo tablets administered orally once daily (QD) plus corticosteroids.
DRUGPrednisone
Oral prednisone may be used to begin standard corticosteroid background treatment at the investigator's discretion, at a dose equivalent to methylprednisolone 2 mg/kg per day.
DRUGMethylprednisolone
Methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at a dose appropriate for the severity of disease as background treatment.
Sponsors
Incyte Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Double Blind
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has undergone 1 allo-HSCT from any donor (related or unrelated with any degree of HLA matching) and any donor source (bone marrow, peripheral blood stem cells, or cord blood) for a hematologic malignancy or disorder. Recipients of myeloablative and reduced-intensity conditioning regimens are eligible. * Clinically suspected Grade II to IV aGVHD as per MAGIC criteria, occurring after allo-HSCT and any GVHD prophylaxis regimen. * Evidence of myeloid engraftment. Use of growth factor supplementation is allowed. * Serum creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 40 mL/min measured or calculated by Cockroft Gault equation. * Willing to avoid pregnancy or fathering children. * Able to give written informed consent and comply with all study visits and procedures. * Able to swallow and retain oral medication.
Exclusion criteria
* Has received more than 1 allo-HSCT. * Has received more than 2 days of systemic corticosteroids for aGVHD. * Presence of GVHD overlap syndrome. * Presence of an active uncontrolled infection. * Known human immunodeficiency virus infection. * Active hepatitis B virus (HBV) or hepatitis C virus infection that requires treatment or at risk for HBV reactivation. * Participants with evidence of relapsed primary disease, or participants who have been treated for relapse after the allo-HSCT was performed. * Any corticosteroid therapy for indications other than GVHD at doses \> 1 mg/kg per day methylprednisolone (or prednisone equivalent) within 7 days of randomization. * Severe organ dysfunction unrelated to underlying GVHD, including: * Cholestatic disorders or unresolved veno-occlusive disease of the liver. * Clinically significant or uncontrolled cardiac disease. * Clinically significant respiratory disease that requires mechanical ventilation support or 50% oxygen. * Currently breast feeding. * Received JAK inhibitor therapy after allo-HSCT for any indication. Treatment with a JAK inhibitor before allo-HSCT is permitted. * Treatment with any other investigational agent, device, or procedure within 21 days (or 5 half-lives, whichever is greater) of enrollment. * Any medical complications or conditions that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data. * Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate Based on Center for International Blood and Marrow Transplant Research (CIBMTR) Response Index | Day 28 | Defined as the percentage of participants demonstrating a complete response (CR), very good partial response (VGPR), or partial response (PR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | Baseline through 30-35 days after end of treatment, total particpation expected to average 24 months | Defined as the interval from first response until GVHD progression or death. |
| Cmax of Itacitinib When Administered in Combination With Corticosteroids | Protocol-defined timepoints up to Day 28 | Defined as maximum observed plasma concentration. |
| Cmin of Itacitinib When Administered in Combination With Corticosteroids | Protocol-defined timepoints up to Day 28 | Defined as minimum observed plasma concentration. |
| Tmax of Itacitinib When Administered in Combination With Corticosteroids | Protocol-defined timepoints up to Day 28 | Defined as time to maximum plasma concentration. |
| AUC of Itacitinib When Administered in Combination With Corticosteroids | Protocol-defined timepoints up to Day 28 | Defined as area under the concentration-time curve. |
| CL/F of Itacitinib When Administered in Combination With Corticosteroids | Protocol-defined timepoints up to Day 28 | Defined as oral dose clearance. |
| Time to Response | End of Study, total particpation expected to average 24 months | Defined as the interval from treatment initiation to first response |
| Relapse Rate of Malignant and Nonmalignant Hematologic Disease | Randomization through end of Study, study duration expected to average 24 months | Defined as the proportion of subjects whose underlying hematologic disease relapses |
| Malignancy Relapse-related Mortality Rate | Randomization through end of Study, study duration expected to average 24 months | Defined as the proportion of subjects whose malignancy relapses and has a fatal outcome. |
| Nonrelapse Mortality | Month 6,9,12 and 24 | Defined as the percentage of participants who died due to causes other than malignancy relapse. |
| Overall Survival (OS) | End of Study up to approximately 24 months | Defined as the interval from study enrollment to death due to any cause. |
| Number of Treatment-emergent Adverse Events With INCB39110 | 30-35 days after end of treatment, approximately 24 months | Adverse events reported for the first time or worsening of a pre-existing event after the first dose of study treatment |
| Incidence Rate of Secondary Graft Failure | Randomization through end of Study, study duration expected to average 24 months | Defined as \> 95% recipient cells any time after engraftment with no signs of relapse, OR retransplantation because of secondary neutropenia (\< 0.5 × 109/L) and/or thrombocytopenia (\< 20 × 109/L) within 2 months of transplantion |
| Proportion of Subjects Who Discontinue Corticosteroids | Days 28, 56, 100, and 180 | Average and cumulative corticosteroid dose usage will be calculated and proportion of subjects discontinuing corticosteroids will be tabulated |
| Proportion of Subjects Who Discontinue Immunosuppressive Medications | Days 56 and 100 | Summary statistics of subjects discontinuing immunosuppressive medications will be calculated |
| Incidence Rate of aGVHD Flares | up to day 100 | — |
| Incidence Rate of cGVHD | Days 180 and 365 | — |
| Objective Response Rate | Days 14, 56 and 100 | — |
| Failure-free Survival | 6 months from randomization | Defined as the proportion of subjects who are still alive, have not relapsed, have not required additional therapy for aGVHD, and have not demonstrated signs or symptoms of chronic graft-versus-host disease (cGVHD) |
Countries
Australia, Austria, Belgium, Czechia, Finland, France, Germany, Greece, Israel, Italy, New Zealand, Poland, Portugal, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 128 investigative sites in 19 different countries.
Pre-assignment details
A total of 498 participants were screened for this study, of which 59 participants were screen failures and 439 participants were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Itacitinib Plus Corticosteroids Itacitinib was administered at a starting dose of 200 mg orally once daily QD (2 × 100 mg tablets) in combination with steroids i.e. methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at a dose that is appropriate for the severity of the disease. | 219 |
| Placebo Plus Corticosteroids Matching placebo was administered orally once daily QD in combination with steroids i.e. methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at a dose that is appropriate for the severity of the disease. | 220 |
| Total | 439 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 65 | 67 |
| Overall Study | Final EOS data missing due to COVID-19 restrictions that affected on-site monitoring | 5 | 3 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Other | 7 | 3 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Study Terminated by Sponsor | 122 | 127 |
| Overall Study | Withdrawal by Subject | 16 | 17 |
Baseline characteristics
| Characteristic | Placebo Plus Corticosteroids | Total | Itacitinib Plus Corticosteroids |
|---|---|---|---|
| Age, Continuous | 54.0 years STANDARD_DEVIATION 12.96 | 53.8 years STANDARD_DEVIATION 13.23 | 53.6 years STANDARD_DEVIATION 13.53 |
| Race/Ethnicity, Customized American-Indian/Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 8 Participants | 4 Participants |
| Race/Ethnicity, Customized Black/African-American | 5 Participants | 13 Participants | 8 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 22 Participants | 39 Participants | 17 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 5 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 169 Participants | 336 Participants | 167 Participants |
| Race/Ethnicity, Customized Not Reported | 14 Participants | 31 Participants | 17 Participants |
| Race/Ethnicity, Customized Other | 11 Participants | 21 Participants | 10 Participants |
| Race/Ethnicity, Customized Unknown | 9 Participants | 21 Participants | 12 Participants |
| Race/Ethnicity, Customized White/Caucasian | 194 Participants | 390 Participants | 196 Participants |
| Sex: Female, Male Female | 91 Participants | 173 Participants | 82 Participants |
| Sex: Female, Male Male | 129 Participants | 266 Participants | 137 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 69 / 215 | 69 / 216 | 138 / 431 |
| other Total, other adverse events | 207 / 215 | 206 / 216 | 413 / 431 |
| serious Total, serious adverse events | 133 / 215 | 131 / 216 | 264 / 431 |
Outcome results
Primary
Overall Response Rate Based on Center for International Blood and Marrow Transplant Research (CIBMTR) Response Index
Defined as the percentage of participants demonstrating a complete response (CR), very good partial response (VGPR), or partial response (PR).
Time frame: Day 28
Population: Full Analysis Set (FAS) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itacitinib Plus Corticosteroids | Overall Response Rate Based on Center for International Blood and Marrow Transplant Research (CIBMTR) Response Index | 74.0 Percentage of Participants |
| Placebo Plus Corticosteroids | Overall Response Rate Based on Center for International Blood and Marrow Transplant Research (CIBMTR) Response Index | 66.4 Percentage of Participants |
Comparison: binomial distributionp-value: 0.078295% CI: [0.959, 2.204]Cochran-Mantel-Haenszel
Secondary
AUC of Itacitinib When Administered in Combination With Corticosteroids
Defined as area under the concentration-time curve.
Time frame: Protocol-defined timepoints up to Day 28
Population: All subjects who receive at least 1 dose of study drug and provide at least 1 plasma sample after study drug administration will be considered as potential PK evaluable subjects. The data presented is from Day 7.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itacitinib Plus Corticosteroids | AUC of Itacitinib When Administered in Combination With Corticosteroids | 6720 nM*h | Standard Deviation 6210 |
Secondary
CL/F of Itacitinib When Administered in Combination With Corticosteroids
Defined as oral dose clearance.
Time frame: Protocol-defined timepoints up to Day 28
Population: All subjects who receive at least 1 dose of study drug and provide at least 1 plasma sample after study drug administration will be considered as potential PK evaluable subjects. The data presented is from Day 7.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itacitinib Plus Corticosteroids | CL/F of Itacitinib When Administered in Combination With Corticosteroids | 104 L/h | Standard Deviation 76.7 |
Secondary
Cmax of Itacitinib When Administered in Combination With Corticosteroids
Defined as maximum observed plasma concentration.
Time frame: Protocol-defined timepoints up to Day 28
Population: All subjects who receive at least 1 dose of study drug and provide at least 1 plasma sample after study drug administration will be considered as potential PK evaluable subjects. The data presented is from Day 7.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itacitinib Plus Corticosteroids | Cmax of Itacitinib When Administered in Combination With Corticosteroids | 796 nM | Standard Deviation 642 |
Secondary
Cmin of Itacitinib When Administered in Combination With Corticosteroids
Defined as minimum observed plasma concentration.
Time frame: Protocol-defined timepoints up to Day 28
Population: All subjects who receive at least 1 dose of study drug and provide at least 1 plasma sample after study drug administration will be considered as potential PK evaluable subjects. The data presented is from Day 7 as this is more representative of true steady state. Day 28 is positively biased as non responders are withdrawn from study by D28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itacitinib Plus Corticosteroids | Cmin of Itacitinib When Administered in Combination With Corticosteroids | 72.5 nM | Standard Deviation 121 |
Secondary
Duration of Response
Defined as the interval from first response until GVHD progression or death.
Time frame: Baseline through 30-35 days after end of treatment, total particpation expected to average 24 months
Population: Full Analysis Set (FAS) Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Itacitinib Plus Corticosteroids | Duration of Response | 587 days |
| Placebo Plus Corticosteroids | Duration of Response | NA days |
Secondary
Failure-free Survival
Defined as the proportion of subjects who are still alive, have not relapsed, have not required additional therapy for aGVHD, and have not demonstrated signs or symptoms of chronic graft-versus-host disease (cGVHD)
Time frame: 6 months from randomization
Population: Full Analysis Set (FAS) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itacitinib Plus Corticosteroids | Failure-free Survival | 44.29 proportion of participants |
| Placebo Plus Corticosteroids | Failure-free Survival | 40.00 proportion of participants |
Secondary
Incidence Rate of aGVHD Flares
Time frame: up to day 100
Population: Full Analysis Set (FAS) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itacitinib Plus Corticosteroids | Incidence Rate of aGVHD Flares | 42 participants |
| Placebo Plus Corticosteroids | Incidence Rate of aGVHD Flares | 48 participants |
Secondary
Incidence Rate of cGVHD
Time frame: Days 180 and 365
Population: Full Analysis Set (FAS) Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Itacitinib Plus Corticosteroids | Incidence Rate of cGVHD | Day 180 | 25 participants |
| Itacitinib Plus Corticosteroids | Incidence Rate of cGVHD | Day 365 | 43 participants |
| Placebo Plus Corticosteroids | Incidence Rate of cGVHD | Day 180 | 36 participants |
| Placebo Plus Corticosteroids | Incidence Rate of cGVHD | Day 365 | 58 participants |
Secondary
Incidence Rate of Secondary Graft Failure
Defined as \> 95% recipient cells any time after engraftment with no signs of relapse, OR retransplantation because of secondary neutropenia (\< 0.5 × 109/L) and/or thrombocytopenia (\< 20 × 109/L) within 2 months of transplantion
Time frame: Randomization through end of Study, study duration expected to average 24 months
Population: Full Analysis Set (FAS) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itacitinib Plus Corticosteroids | Incidence Rate of Secondary Graft Failure | 2 participants |
| Placebo Plus Corticosteroids | Incidence Rate of Secondary Graft Failure | 0 participants |
Secondary
Malignancy Relapse-related Mortality Rate
Defined as the proportion of subjects whose malignancy relapses and has a fatal outcome.
Time frame: Randomization through end of Study, study duration expected to average 24 months
Population: Full Analysis Set (FAS) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itacitinib Plus Corticosteroids | Malignancy Relapse-related Mortality Rate | 6.4 percentage |
| Placebo Plus Corticosteroids | Malignancy Relapse-related Mortality Rate | 7.7 percentage |
Secondary
Nonrelapse Mortality
Defined as the percentage of participants who died due to causes other than malignancy relapse.
Time frame: Month 6,9,12 and 24
Population: Full Analysis Set (FAS) Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Itacitinib Plus Corticosteroids | Nonrelapse Mortality | 6 Months | 36 participants |
| Itacitinib Plus Corticosteroids | Nonrelapse Mortality | 9 Months | 46 participants |
| Itacitinib Plus Corticosteroids | Nonrelapse Mortality | 12 Months | 51 participants |
| Itacitinib Plus Corticosteroids | Nonrelapse Mortality | 24 Months | 56 participants |
| Placebo Plus Corticosteroids | Nonrelapse Mortality | 24 Months | 52 participants |
| Placebo Plus Corticosteroids | Nonrelapse Mortality | 6 Months | 37 participants |
| Placebo Plus Corticosteroids | Nonrelapse Mortality | 12 Months | 52 participants |
| Placebo Plus Corticosteroids | Nonrelapse Mortality | 9 Months | 45 participants |
Secondary
Number of Treatment-emergent Adverse Events With INCB39110
Adverse events reported for the first time or worsening of a pre-existing event after the first dose of study treatment
Time frame: 30-35 days after end of treatment, approximately 24 months
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itacitinib Plus Corticosteroids | Number of Treatment-emergent Adverse Events With INCB39110 | 208 participants |
| Placebo Plus Corticosteroids | Number of Treatment-emergent Adverse Events With INCB39110 | 214 participants |
Secondary
Objective Response Rate
Time frame: Days 14, 56 and 100
Population: Full Analysis Set (FAS) Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Itacitinib Plus Corticosteroids | Objective Response Rate | Day 14 | 170 participants |
| Itacitinib Plus Corticosteroids | Objective Response Rate | Day 56 | 138 participants |
| Itacitinib Plus Corticosteroids | Objective Response Rate | Day 100 | 92 participants |
| Placebo Plus Corticosteroids | Objective Response Rate | Day 14 | 160 participants |
| Placebo Plus Corticosteroids | Objective Response Rate | Day 56 | 124 participants |
| Placebo Plus Corticosteroids | Objective Response Rate | Day 100 | 96 participants |
Secondary
Overall Survival (OS)
Defined as the interval from study enrollment to death due to any cause.
Time frame: End of Study up to approximately 24 months
Population: Full Analysis Set (FAS) Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Itacitinib Plus Corticosteroids | Overall Survival (OS) | 365 days |
| Placebo Plus Corticosteroids | Overall Survival (OS) | 348.5 days |
Secondary
Proportion of Subjects Who Discontinue Corticosteroids
Average and cumulative corticosteroid dose usage will be calculated and proportion of subjects discontinuing corticosteroids will be tabulated
Time frame: Days 28, 56, 100, and 180
Population: Safety Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Itacitinib Plus Corticosteroids | Proportion of Subjects Who Discontinue Corticosteroids | Day 100 | 39 participants |
| Itacitinib Plus Corticosteroids | Proportion of Subjects Who Discontinue Corticosteroids | Day 28 | 3 participants |
| Itacitinib Plus Corticosteroids | Proportion of Subjects Who Discontinue Corticosteroids | Day 180 | 39 participants |
| Itacitinib Plus Corticosteroids | Proportion of Subjects Who Discontinue Corticosteroids | Day 56 | 16 participants |
| Placebo Plus Corticosteroids | Proportion of Subjects Who Discontinue Corticosteroids | Day 180 | 45 participants |
| Placebo Plus Corticosteroids | Proportion of Subjects Who Discontinue Corticosteroids | Day 28 | 3 participants |
| Placebo Plus Corticosteroids | Proportion of Subjects Who Discontinue Corticosteroids | Day 100 | 45 participants |
| Placebo Plus Corticosteroids | Proportion of Subjects Who Discontinue Corticosteroids | Day 56 | 11 participants |
Secondary
Proportion of Subjects Who Discontinue Immunosuppressive Medications
Summary statistics of subjects discontinuing immunosuppressive medications will be calculated
Time frame: Days 56 and 100
Population: Full Analysis Set (FAS) Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Itacitinib Plus Corticosteroids | Proportion of Subjects Who Discontinue Immunosuppressive Medications | Day 56 | 12 participants |
| Itacitinib Plus Corticosteroids | Proportion of Subjects Who Discontinue Immunosuppressive Medications | Day 100 | 11 participants |
| Placebo Plus Corticosteroids | Proportion of Subjects Who Discontinue Immunosuppressive Medications | Day 56 | 10 participants |
| Placebo Plus Corticosteroids | Proportion of Subjects Who Discontinue Immunosuppressive Medications | Day 100 | 8 participants |
Secondary
Relapse Rate of Malignant and Nonmalignant Hematologic Disease
Defined as the proportion of subjects whose underlying hematologic disease relapses
Time frame: Randomization through end of Study, study duration expected to average 24 months
Population: Full Analysis Set (FAS) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itacitinib Plus Corticosteroids | Relapse Rate of Malignant and Nonmalignant Hematologic Disease | 12.4 percentage |
| Placebo Plus Corticosteroids | Relapse Rate of Malignant and Nonmalignant Hematologic Disease | 11.4 percentage |
Secondary
Time to Response
Defined as the interval from treatment initiation to first response
Time frame: End of Study, total particpation expected to average 24 months
Population: Full Analysis Set (FAS) Population who were responders
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itacitinib Plus Corticosteroids | Time to Response | 9.9 days | Standard Deviation 6.25 |
| Placebo Plus Corticosteroids | Time to Response | 10.1 days | Standard Deviation 5.37 |
Secondary
Tmax of Itacitinib When Administered in Combination With Corticosteroids
Defined as time to maximum plasma concentration.
Time frame: Protocol-defined timepoints up to Day 28
Population: All subjects who receive at least 1 dose of study drug and provide at least 1 plasma sample after study drug administration will be considered as potential PK evaluable subjects. The data presented is from Day 7.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Itacitinib Plus Corticosteroids | Tmax of Itacitinib When Administered in Combination With Corticosteroids | 2.1 hrs |