Graft-versus-host Disease (GVHD)
Conditions
Keywords
Graft-versus-host disease (GVHD), acute GVHD, steroid-refractory, ruxolitinib, Janus kinase inhibitor
Brief summary
The purpose of this study was to assess the efficacy of ruxolitinib in combination with corticosteroids in subjects with Grades II to IV steroid-refractory acute graft-versus-host disease (GVHD).
Interventions
DRUGRuxolitinib
DRUGPrednisone or methylprednisolone
Either oral prednisone or IV methylprednisolone may be used to begin corticosteroid treatment at the investigator's discretion.
Sponsors
Incyte Corporation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have undergone first allogeneic hematopoietic stem cell transplantation (allo-HSCT) from any donor source using bone marrow, peripheral blood stem cells, or cord blood for hematologic malignancies. Recipients of nonmyeloablative and myeloablative conditioning regimens are eligible. * Clinically suspected Grades II to IV acute GVHD as per MAGIC guidelines, occurring after allo-HSCT with any conditioning regimen and any anti-GVHD prophylactic program. * Subjects with steroid-refractory acute GVHD, defined as any of the following: * Subjects with progressive GVHD (ie, increase in stage in any organ system or any new organ involvement) after 3 days of primary treatment with methylprednisolone ≥ 2 mg/kg per day (or equivalent). * Subjects with GVHD that has not improved (ie, decrease in stage in at least 1 involved organ system) after 7 days of primary treatment with methylprednisolone ≥ 2 mg/kg per day (or equivalent). * Subjects who previously began corticosteroid therapy at a lower dose (at least 1 mg/kg per day methylprednisolone) but develop new GVHD in another organ system. * Subjects who cannot tolerate a corticosteroid taper, that is, begin corticosteroids at 2.0 mg/kg per day, demonstrate response, but progress before a 50% decrease from the initial starting dose of corticosteroids is achieved. * Evidence of myeloid engraftment (eg, absolute neutrophil count ≥ 0.5 × 10\^9/L for 3 consecutive days if ablative therapy was previously used). Use of growth factor supplementation is allowed. * Be willing to avoid pregnancy or fathering children
Exclusion criteria
* Has received more than 1 allo-HSCT. * Has received more than 1 systemic treatment in addition to corticosteroids for acute GVHD. * Presence of GVHD overlap syndrome as per NIH guidelines. * Subjects who have had a splenectomy. * Presence of an active uncontrolled infection. An active uncontrolled infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs, or radiographic findings attributable to infection. Persisting fever without signs or symptoms will not be interpreted as 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. Subjects whose immune status is unknown or uncertain must have results confirming immune status before enrollment. * Serum creatinine \> 2.0 mg/dL or creatinine clearance \< 40 mL/min measured or calculated by Cockcroft-Gault equation. * Subjects with evidence of relapsed primary disease, or subjects who have been treated for relapse after the allo-HSCT was performed. * Unresolved toxicity or complications (other than acute GVHD) due to previous allo-HSCT. * Any corticosteroid therapy for indications other than GVHD at doses of methylprednisolone or equivalent \> 1 mg/kg per day within 7 days of enrollment. * Severe organ dysfunction unrelated to underlying GVHD, including: * Cholestatic disorders or unresolved veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to GVHD and ongoing organ dysfunction). * Clinically significant or uncontrolled cardiac disease including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, circulatory collapse requiring vasopressor or inotropic support, or arrhythmia that requires therapy. * Clinically significant respiratory disease that requires mechanical ventilation support or 50% oxygen. * Currently breast feeding. * Received Janus kinase inhibitor (JAK) 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. Subjects participating in a GVHD prophylaxis study or conditioning regimen should be discussed with the sponsor's medical monitor before enrollment. * Any condition 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 subject; 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 (ORR) at Day 28 | From baseline to 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 |
|---|---|---|
| Nonrelapse Mortality (NRM) | From baseline to Months 6, 9, 12, and 24 | Defined as the proportion of subjects who died due to causes other than malignancy relapse. |
| Percentage of Participants With Six-month Duration of Response (DOR) | From Baseline up to 6 months | Defined as the time from first response until graft-versus-host disease (GVHD) progression or death. DOR was assessed when all participants who were on the study completed the Day 180 visit. |
| Percentage of Participants With Three-month DOR | From Baseline up to 3 months | Defined as the time from first response until GVHD progression or death. DOR was assessed when all participants who were on the study completed the Day 84 visit. |
| Relapse Rate | From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months) | Defined as the percentage of participants whose underlying malignancy relapsed. |
| Overall Response Rate (ORR) | From baseline to days 14, 56, and 100 | Defined as the percentage of participants demonstrating a CR, VGPR, or PR. |
| Failure-free Survival (FFS) | From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months) | Defined as the time from first dose of ruxolitinib to the earliest date that a participant died, had a relapse/progression of the underlying malignancy, required additional therapy for aGVHD, or demonstrated signs or symptoms of chronic graft-versus-host disease (cGVHD). |
| Overall Survival (OS) | From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months) | Defined as the time from study enrollment (first day of ruxolitinib treatment) to death due to any cause. |
| Number of Participants With Treatment-emergent Adverse Events (TEAES), Serious TEAEs, And Grade 3 or Higher TEAEs | From signing the informed consent form up to 30-35 days after the last dose of study treatment (up to 24 months) | AE was any unfavorable and unintended sign, symptom, or disease temporally associated with use of medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. Serious AE was any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization. TEAE was an AE that was reported for the first time, or worsening of a pre-existing event after the first dose of study drug (until 30 days after the last dose of study drug). Severity of AEs was described and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03). Grade 3 and above would constitute a severe, life-threatening, or death event. |
| Relapse-related Mortality Rate | From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months) | Defined as the percentage of participants whose malignancy relapsed and had a fatal outcome. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 26 study centers in the United States.
Participants by arm
| Arm | Count |
|---|---|
| Ruxolitinib in Combination With Corticosteroids Participants began oral administration of ruxolitinib at 5 mg BID; if stable after the first 3 days of treatment, the dose may be increased to 10 mg BID. Participants did receive prednisone 2.5 mg/kg per day orally (PO) or methylprednisolone 2.0 mg/kg per day IV. | 71 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 20 |
| Overall Study | Death | 7 |
| Overall Study | Includes 2 participants who discontinued ruxolitinib treatment because of clinical improvement | 5 |
| Overall Study | Participants were transferred to commercial product. | 3 |
| Overall Study | Physician Decision | 23 |
| Overall Study | Progressive Disease of GVHD | 7 |
| Overall Study | Relapse of Underlying Malignancy | 3 |
| Overall Study | Withdrawal by participant | 3 |
Baseline characteristics
| Characteristic | Ruxolitinib in Combination With Corticosteroids |
|---|---|
| Age, Continuous | 52.9 years STANDARD_DEVIATION 14.18 |
| Age, Customized < 65 years | 58 Participants |
| Age, Customized ≥ 65 years | 13 Participants |
| Body Mass Index (BMI) | 26.83 kg/m^2 STANDARD_DEVIATION 6.193 |
| Body Surface Area (BSA) | 1.91 m^2 STANDARD_DEVIATION 0.301 |
| Eastern Cooperative Oncology Group (ECOG) grade at baseline ECOG - 0 | 3 Participants |
| Eastern Cooperative Oncology Group (ECOG) grade at baseline ECOG - 1 | 24 Participants |
| Eastern Cooperative Oncology Group (ECOG) grade at baseline ECOG - 2 | 25 Participants |
| Eastern Cooperative Oncology Group (ECOG) grade at baseline ECOG - 3 | 17 Participants |
| Eastern Cooperative Oncology Group (ECOG) grade at baseline ECOG - 4 | 1 Participants |
| Eastern Cooperative Oncology Group (ECOG) grade at baseline ECOG - 5 | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) grade at baseline Missing | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Height | 170.2 cm STANDARD_DEVIATION 10.64 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 66 Participants |
| Sex: Female, Male Female | 36 Participants |
| Sex: Female, Male Male | 35 Participants |
| Weight | 78.64 kg STANDARD_DEVIATION 21.651 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 46 / 71 |
| other Total, other adverse events | 69 / 71 |
| serious Total, serious adverse events | 59 / 71 |
Outcome results
Primary
Overall Response Rate (ORR) at Day 28
Defined as the percentage of participants demonstrating a complete response (CR), very good partial response (VGPR), or partial response (PR).
Time frame: From baseline to Day 28
Population: Efficacy Evaluable Participants who had a CR, VGPR, or PR at Day 28 response assessment or other response assessments within ± 2 days of Day 28, on or before the start of new anti-GVHD therapy
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ruxolitinib in Combination With Corticosteroids | Overall Response Rate (ORR) at Day 28 | Responders - CR | 19 Participants |
| Ruxolitinib in Combination With Corticosteroids | Overall Response Rate (ORR) at Day 28 | Responders - VGPR | 7 Participants |
| Ruxolitinib in Combination With Corticosteroids | Overall Response Rate (ORR) at Day 28 | Responders - PR | 13 Participants |
95% CI: [42.7, 66.8]
Secondary
Failure-free Survival (FFS)
Defined as the time from first dose of ruxolitinib to the earliest date that a participant died, had a relapse/progression of the underlying malignancy, required additional therapy for aGVHD, or demonstrated signs or symptoms of chronic graft-versus-host disease (cGVHD).
Time frame: From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months)
Population: Efficacy Evaluable Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ruxolitinib in Combination With Corticosteroids | Failure-free Survival (FFS) | 85.0 days |
Secondary
Nonrelapse Mortality (NRM)
Defined as the proportion of subjects who died due to causes other than malignancy relapse.
Time frame: From baseline to Months 6, 9, 12, and 24
Population: Efficacy Evaluable Participants including all responders as of the data cutoff (02 JUL 2018).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ruxolitinib in Combination With Corticosteroids | Nonrelapse Mortality (NRM) | 6 months | 44.4 percentage of participants |
| Ruxolitinib in Combination With Corticosteroids | Nonrelapse Mortality (NRM) | 9 months | 48.2 percentage of participants |
| Ruxolitinib in Combination With Corticosteroids | Nonrelapse Mortality (NRM) | 12 months | 52.9 percentage of participants |
| Ruxolitinib in Combination With Corticosteroids | Nonrelapse Mortality (NRM) | 24 months | 64.8 percentage of participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAES), Serious TEAEs, And Grade 3 or Higher TEAEs
AE was any unfavorable and unintended sign, symptom, or disease temporally associated with use of medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. Serious AE was any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization. TEAE was an AE that was reported for the first time, or worsening of a pre-existing event after the first dose of study drug (until 30 days after the last dose of study drug). Severity of AEs was described and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03). Grade 3 and above would constitute a severe, life-threatening, or death event.
Time frame: From signing the informed consent form up to 30-35 days after the last dose of study treatment (up to 24 months)
Population: Safety Evaluable Population included all participants enrolled in the study who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ruxolitinib in Combination With Corticosteroids | Number of Participants With Treatment-emergent Adverse Events (TEAES), Serious TEAEs, And Grade 3 or Higher TEAEs | TEAEs | 71 Participants |
| Ruxolitinib in Combination With Corticosteroids | Number of Participants With Treatment-emergent Adverse Events (TEAES), Serious TEAEs, And Grade 3 or Higher TEAEs | Serious TEAEs | 59 Participants |
| Ruxolitinib in Combination With Corticosteroids | Number of Participants With Treatment-emergent Adverse Events (TEAES), Serious TEAEs, And Grade 3 or Higher TEAEs | Grade 3 or Higher TEAEs | 69 Participants |
Secondary
Overall Response Rate (ORR)
Defined as the percentage of participants demonstrating a CR, VGPR, or PR.
Time frame: From baseline to days 14, 56, and 100
Population: Efficacy Evaluable Population included all participants enrolled in this study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ruxolitinib in Combination With Corticosteroids | Overall Response Rate (ORR) | Day 100 | 32.4 percentage of participants |
| Ruxolitinib in Combination With Corticosteroids | Overall Response Rate (ORR) | Day 14 | 62.0 percentage of participants |
| Ruxolitinib in Combination With Corticosteroids | Overall Response Rate (ORR) | Day 56 | 36.6 percentage of participants |
Secondary
Overall Survival (OS)
Defined as the time from study enrollment (first day of ruxolitinib treatment) to death due to any cause.
Time frame: From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months)
Population: Efficacy Evaluable Participants: Participants who had CR, VGPR, or PR on or before the start of new anti-GVHD therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ruxolitinib in Combination With Corticosteroids | Overall Survival (OS) | 232.0 days |
Secondary
Percentage of Participants With Six-month Duration of Response (DOR)
Defined as the time from first response until graft-versus-host disease (GVHD) progression or death. DOR was assessed when all participants who were on the study completed the Day 180 visit.
Time frame: From Baseline up to 6 months
Population: Efficacy Evaluable Population included all participants enrolled in this study. Participants who achieved ORR were analyzed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ruxolitinib in Combination With Corticosteroids | Percentage of Participants With Six-month Duration of Response (DOR) | 68.2 percentage of participants |
Secondary
Percentage of Participants With Three-month DOR
Defined as the time from first response until GVHD progression or death. DOR was assessed when all participants who were on the study completed the Day 84 visit.
Time frame: From Baseline up to 3 months
Population: Efficacy Evaluable Population included all participants enrolled in this study. Participants who achieved ORR were analyzed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ruxolitinib in Combination With Corticosteroids | Percentage of Participants With Three-month DOR | 84.5 percentage of participants |
Secondary
Relapse Rate
Defined as the percentage of participants whose underlying malignancy relapsed.
Time frame: From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months)
Population: Efficacy Evaluable Population included all participants enrolled in this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ruxolitinib in Combination With Corticosteroids | Relapse Rate | 7.0 percentage of participants |
Secondary
Relapse-related Mortality Rate
Defined as the percentage of participants whose malignancy relapsed and had a fatal outcome.
Time frame: From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months)
Population: Efficacy Evaluable Population included all participants enrolled in this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ruxolitinib in Combination With Corticosteroids | Relapse-related Mortality Rate | 5.6 percentage of participants |