Safety and Efficacy of Ruxolitinib Versus Best Available Therapy in Patients With Corticosteroid-refractory Acute Graft vs. Host Disease After Allogeneic Stem Cell Transplantation

Study Overview
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Brief Summary
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Assess the efficacy and safety of ruxolitinib compared to Best Available Therapy (BAT) in patients with corticosteroid-refractory acute graft vs. host disease (aGvHD) after allogeneic stem cell transplantation.

Detailed Description
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This randomized, phase III, open-label study investigated the efficacy and safety of ruxolitinib vs. BAT added to the patient's immunosuppressive regimen in adults and adolescents (≥ 12 years old) with grade II-IV Steroid-refractory Acute Graft vs. Host Disease (SR-aGvHD). During the screening period, patients were monitored for a diagnosis of SR-aGvHD, which was defined as patients who had high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or combined with CNI, who either: Progressed based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR Failed to achieve at a minimum a partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR Failed corticosteroid taper defined as fulfilling either one of the following criteria: Requirement for an increase in the corticosteroid dose to methylprednisolone ≥ 2 mg/kg/day (or equivalent prednisone dose ≥ 2.5 mg/kg/day) OR Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent prednisone dose <0.6 mg/kg/day) for a minimum 7 days. Patients meeting eligibility criteria were randomized 1:1 to receive either ruxolitinib or BAT stratifying on aGvHD grade at the time of randomization (Grade II vs III vs IV). Study treatment began on Day 1 (no later than 72 hours after randomization) followed by regular visits for assessments of efficacy and safety. Study treatment was administered until the patient met any of the criteria for discontinuation of study treatment or, in responders (i.e. patients achieving PR or CR) until the dosing schedule for ruxolitinib or BAT was completed. All responders were to be tapered off during the treatment period by, first tapering from corticosteroids, followed by CNI and ruxolitinib. A slow tapering extending beyond 24 weeks was permitted for ruxolitinib at Investigator's discretion rather than an abrupt cessation, as the latter could result in an aGvHD flare. During the Treatment Period, patients randomized to BAT could have crossed over to ruxolitinib between Day 28 and Week 24 if they: Failed to meet the primary endpoint response definition (CR or PR) at Day 28 OR Lost the response thereafter and met criteria for progression, mixed response, or no response, necessitating new additional systemic immunosuppressive treatment for aGvHD. AND - Did not have signs/symptoms of chronic Graft vs. Host Disease (cGvHD) (overlap syndrome, progressive, or de novo cGvHD) Patients who crossed over to ruxolitinib were followed until completion of treatment with ruxolitinib and received the same treatment and tapering schedule as patients randomized to ruxolitinib treatment. The End of Treatment (EOT) visit occurred when the patient completed the study treatment period or earlier if the patient met any of the criteria for discontinuation of study treatment. Patient's treatment period was up to 6 months (Week 24). However, ruxolitinib taper could be delayed up to 2 years from randomization due to an aGvHD flare or other safety concerns.

Official Title
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A Phase III Randomized Open-label Multi-center Study of Ruxolitinib Versus Best Available Therapy in Patients With Corticosteroid-refractory Acute Graft vs. Host Disease After Allogeneic Stem Cell Transplantation

Conditions
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Corticosteroid Refractory Acute Graft vs Host Disease

Intervention / Treatment
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* Drug: Ruxolitinib (RUX)
* Drug: Best Available Therapy (BAT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have undergone Allogeneic Stem Cell Transplanttaion (alloSCT) from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of non- myeloablative, myeloablative, and reduced intensity conditioning are eligible Clinically diagnosed Grades II to IV acute GvHD as per standard criteria occurring after alloSCT requiring systemic immune suppressive therapy. Biopsy of involved organs with aGvHD is encouraged but not required for study screening. Confirmed diagnosis of steroid refractory aGvHD defined as patients administered high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or combined with calcineurin inhibitors (CNI) and either: Progressing based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR Failure to achieve at a minimum partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,OR Patients who fail corticosteroid taper defined as fulfilling either one of the following criteria: Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 mg/kg/day (or equivalent prednisone dose ≥2.5 mg/kg/day) , OR Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent prednisone dose <0.6 mg/kg/day) for a minimum 7 days. Exclusion Criteria: Has received more than one systemic treatment for steroid refractory aGvHD. Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection. Evidence of uncontrolled viral infection including Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Human Herpes Virus-6 (HHV-6), Hepatitis Virus (HBV), or Hepatitis C Virus (HCV) based on assessment by the treating physician. Presence of relapsed primary malignancy, or who have been treated for relapse after the alloHSCT was performed, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib<br>These patients were administered Ruxolitinib orally twice per day (b.i.d) at a dose of 10 mg bid, as two 5-mg tablets. Ruxolitinib was taken without regards to food. | Drug: Ruxolitinib (RUX)<br>* Ruxolitinib was provided as 5 mg tablets for oral use.<br>* Other names: INC424;|
| Active Comparator: Best Available Therapy (BAT)<br>These patients were administered BAT per the Investigator's best judgement based on a specific list of BAT. | Drug: Best Available Therapy (BAT)<br>* BAT was based on the investigator's best judgment, taking into account the manufacturer's instructions, labeling, patient's medical condition, and institutional guidelines for any dose adjustment. The BAT in this study was identified by the investigator prior to patient randomization among the following treatments currently used in this setting: anti-thymocyte globulin (ATG), extracorporeal photopheresis (ECP), mesenchymal stromal cells (MSC), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), etanercept, or infliximab. No other types or combinations of BAT were permitted.<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 | Overall response rate at Day 28 after randomization was defined as the percentage participants in each arm demonstrating a complete response (CR) or partial response (PR), based on investigator assessment & according to standard criteria, without requirement for additional systemic therapies for an earlier progression, mixed response or non-response. Scoring of response was relative to the organ stage at the time of randomization. CR was defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs & symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Durable Overall Response Rate (DORR) (Key Secondary Endpoint) at Day 56 | Percentage of all participants in each arm who achieved a complete response (CR) or partial response (PR) at Day 28 (primary endpoint) AND maintained a CR or PR at Day 56 based on investigator assessment and according to standard criteria. CR was defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD. | Day 56 | 
| Overall Response Rate (ORR) at Day 14 | ORR at Da4 14 is the percentage of participants who achieved overall response (CR+PR) at Day 14 based on investigator assessment and according to standard criteria. CR was defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD. | Day 14 | 
| Duration of Response (DOR) | Duration of response was defined for patients who had a CR or PR at Day 28. This was the interval between the date of first documented response of CR or PR (i.e., the start date of response), till the date of progression or addition of systemic therapies for aGvHD on or after Day 28. Death without prior observation of aGvHD progression and onset of chronic GvHD were considered. Duration of response was censored at the last response assessment prior to or at the analysis cut-off date, if no events/competing risk occurred before or at the cut-off date. | Up to 24 months | 
| Cumulative Steroid Dosing Until Day 56 | Weekly cumulative steroid dose for each participant up to Day 56 or discontinuation of randomized treatment. Participants should have undergone tapering of steroids if it had been required. Tapering the immunosuppression therapy was performed in 2 steps: Taper of corticosteroids: initiated not earlier than Day 7, and performed as per institutional guidelines. Only patients with assessments done at each time point are reported. This is the reason that the overall number per treatment is higher and the number of participants with responses vary over time. | up to Day 56 | 
| Kaplan Meier Estimates of Probability of Overall Survival (OS) by Time Interval | OS was defined as the time from the date of randomization to date of death due to any cause. If a patient was not known to have died, then OS was censored at the latest date the patient was known to be alive (on or before the cut-off date). Results are based on Kaplan Meier (KM) estimates. | 1, 2, 6, 12, 18 & 24 months | 
| Kaplan Meier Estimates of Probability of Event-free Survival (EFS) by Time Interval | Event-free survival was defined as the time from the date of randomization to the date of hematologic disease relapse/progression, graft failure, or death due to any cause. If a patient was not known to have any event, then EFS was censored at the latest date the patient was known to be alive (on or before the cut-off date). Results are based on Kaplan Meier (KM) estimates. | 1, 2, 6, 12, 18 & 24 months | 
| Cumulative Incidence Rate of Failure-Free Survival (FFS) | FFS was defined as the time from the date of randomization to date of hematologic disease relapse/progression, non-relapse mortality, or addition of new systemic aGvHD treatment. Probability of FFS with 95% CIs are presented for each treatment group, accounting for onset of chronic GvHD as the competing risk. | 1, 2, 6, 12, 18, & 24 Months | 
| Cumulative Probability of Non Relapse Mortality (NRM) | NRM was defined as the time from date of randomization to date of death not preceded by hematologic disease relapse/progression. Hematologic disease relapse/progression was considered a competing risk for NRM with the date of hematologic disease relapse/progression being the earlier of documented hematologic disease relapse/progression or institution of therapy to treat potential hematologic disease relapse/progression. If a patient was not known to have died or to have relapsed/progressed, then NRM was censored at the latest date the patient was known to be alive (on or before the cut-off date). Data is provided based on cumulative probability of hematologic disease relapse/progression. | 1, 2, 6, 12, 18 & 24 months | 
| Cumulative Probability of Malignancy Relapse/Progression (MR) | MR was defined as the time from date of randomization to hematologic malignancy relapse/progression. Deaths not preceded by hematologic malignancy relapse/progression were considered competing risks. If a patient was not known to have event or competing risks, then MR was censored at the latest date the patient was known to be alive (on or before the cut-off date). Calculated for patients with underlying hematologic malignant disease. | 1, 2, 6, 12 , 18 & 24 months | 
| Cumulative Probability of Chronic Graft Versus Host Disease (cGvHD) | Incidence of cGvHD was the time from date of randomization to onset of cGvHD is the diagnosis of any cGvHD including mild, moderate, severe. Deaths without prior onset of cGvHD and hematologic disease relapse/progression were competing risks. If a patient was not known to have event or competing risks, then the incidence of cGvHD was censored at the latest date the patient was known to be alive (on or before the cut-off date). | 1, 2, 6, 12, 18 & 24 months | 
| Exposure-efficacy Relationship of Ruxolitinib in Corticosteroid Refractory aGvHD: PK-Overall Response Rate | Exposure-efficacy relationship of ruxolitinib in terms of concentration-effect and dose-effect. ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR) as assessed by local investigators. CR was defined as a score of 0 for the Acute Graft vs. Host Disease (aGvHD) grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD. | Day 28 | 
| Exposure-efficacy Relationship of Ruxolitinib in Corticosteroid Refractory aGvHD: PK- Durable Overall Response Rate (DORR) | Exposure-efficacy relationship of ruxolitinib in terms of concentration-effect and dose-effect. DORR is the percentage of all participants in each arm who achieved a complete response (CR) or partial response (PR) at Day 28 (primary endpoint) AND maintained a CR or PR at Day 56. CR was defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD. | Day 56 | 
| Exposure-efficacy Relationship of Ruxolitinib in Corticosteroid Refractory aGvHD: PK-Overall Survival | Exposure-efficacy relationship of ruxolitinib in terms of concentration-effect and dose-effect. This represents the percentage of Ruxolitinib-exposed participants dead at 24 months. Overall survival (OS) was defined as the time from the date of randomization to date of death due to any cause. If a patient was not known to have died, then OS was censored at the latest date the patient was known to be alive (on or before the cut-off date).the date of death due to any cause. | up to 24 months | 
| Best Overall Response Rate (BOR) | Percentage of participants who achieved overall response (OR) (CR+PR) at any time point up to and including Day 28 and before the start of additional systemic therapy for aGvHD. CR was defined as a score of 0 for the Acute Graft vs. Host Disease (aGvHD) grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD. | up to Day 28 | 
| Patient Reported Outcomes (PROs): Change From Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) Total Score | The Functional assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT) is a 50-item self-report questionnaire that measures the effect of a therapy on domains including physical, functional, social/family and emotional well-being, together with additional concerns relevant for bone marrow transplantation patients. Patients indicated their response on a scale of 0 to 4 on each statement, with 0 indicating worst score and 4 the best score. All individual scores were combined to calculate the total score. Total score was reported with score range: 0-148 which was calculated as the sum of all unweighted subscale scores. The higher the total score the better the result. Descriptive statistics and change from baseline were calculated in total score at each scheduled assessment time point. | Baseline, Week 24 | 
| Patient Reported Outcomes (PROs): Change From Baseline in EuroQol-5D-5L UK Score | The EQ-5D descriptive classification consists of five dimensions of health: mobility, self-care, usual activities, anxiety/depression and pain/discomfort. Patients are requested to select the statement which best describes their condition on that day for each dimension. For overall health that day, the EuroQoL-5D-5L scale is numbered from 0 to 100, with 100 being the best health you can imagine and 0 being the worst health you can imagine. Descriptive statistics (mean, standard deviation, median, Q1, Q3, minimum, and maximum) were calculated based on the scored scales at each scheduled assessment time point. In order to measure Quality-of-Life (QoL) among aGvHD patients, and potential changes over time, change from baseline in EuroQol-5D-5L scores at the time of each assessment were also calculated. Missing items data in a scale will be handled based on each instrument manual. No imputation will be applied if the total or subscale scores are missing at a visit. | Baseline, Week 24 | 
| Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC) (AUCinf, AUClast, AUCtau) of Ruxolitinib | AUClast: The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) AUCinf: The AUC from time zero to infinity (mass x time x volume-1) AUCtau: The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1). Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients was assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose | 
| Pharmacokinetic (PK) Parameter: Plasma Concentration at Peak (Cmax) of Ruxolitinib | Cmax is the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (mass X volume-1). Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients was assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose | 
| Pharmacokinetic (PK) Parameter: CL/F of Ruxolitinib | CL/F is the total body clearance of ruxolitinib from the plasma after a single dose and at steady state. Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients was assayed for Ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose | 
| Pharmacokinetic (PK) Parameter: VzF of Ruxolitinib | VzF is the apparent volume of distribution during terminal phase after a single dose and at steady state. Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients will be assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose | 
| Pharmacokinetic (PK) Parameter: Lambda_z of Ruxolitinib | Lambda_z is the smallest (slowest) disposition (hybrid) rate constant (hr-1) may also be used for terminal elimination rate constant (hr-1). Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients will be assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose | 
| Pharmacokinetic (PK) Parameter: T1/2 of Ruxolitinib | T1/2 is the elimination half-life associated with the terminal slope of a semi logarithmic concentration-time curve (hr). Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients will be assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose | 
| Pharmacokinetic (PK) Parameter: Tmax of Ruxolitinib | Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose and repeated dose administration (hr). Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients will be assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose | 
| Pharmacokinetic (PK) Parameter: Racc of Ruxolitinib | Racc is the accumulation ratio (AUC at steady state/AUC Day 1). Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients was be assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose | 
| Pharmacokinetic (PK) Parameter: Ctrough of Ruxolitinib | Minimum concentration (Ctrough) of ruxolitinib and at steady state in corticosteroid refractory acute GVHD patients. Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients will be assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) | pre-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GvHD (Graft versus Host Disease), INC424, ruxolitinib, best available therapy (BAT), corticosteroid-refractory acute graft vs. host disease, allogeneic stem cell transplantation, steroid refractory acute graft vs. host disease, Janus Kinase (JAK) inhibitor