A Study of Ruxolitinib in Combination With Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease (REACH-1)

Study Overview
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Brief Summary
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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).

Official Title
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A Single-Cohort, Phase 2 Study of Ruxolitinib in Combination With Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease (REACH-1)

Conditions
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Graft-versus-host Disease (GVHD)

Intervention / Treatment
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* Drug: Ruxolitinib
* Drug: Prednisone or methylprednisolone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 12 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: Ruxolitinib in combination with corticosteroids<br>Participants began oral administration of ruxolitinib at 5 mg twice daily (BID); if stable after the first 3 days of treatment, the dose could be increased to 10 mg BID. | Drug: Ruxolitinib<br> <br> * Other names: INCB018424;Drug: Prednisone or methylprednisolone<br>* Either oral prednisone or IV methylprednisolone may be used to begin corticosteroid treatment at the investigator's discretion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | From baseline to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Defined as the percentage of participants demonstrating a CR, VGPR, or PR. | From baseline to days 14, 56, and 100 | 
| Nonrelapse Mortality (NRM) | Defined as the proportion of subjects who died due to causes other than malignancy relapse. | From baseline to Months 6, 9, 12, and 24 | 
| 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. | From Baseline up to 6 months | 
| 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. | From Baseline up to 3 months | 
| Relapse Rate | Defined as the percentage of participants whose underlying malignancy relapsed. | From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months) | 
| Relapse-related Mortality Rate | Defined as the percentage of participants whose malignancy relapsed and had a fatal outcome. | From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months) | 
| 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). | From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months) | 
| Overall Survival (OS) | Defined as the time from study enrollment (first day of ruxolitinib treatment) to death due to any cause. | From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months) | 
| 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. | From signing the informed consent form up to 30-35 days after the last dose of study treatment (up to 24 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Graft-versus-host disease (GVHD), acute GVHD, steroid-refractory, ruxolitinib, Janus kinase inhibitor