corticosteroid-refractory acute graft vs. host disease after allogeneic stem cell transplantation MedDRA version: 20.1 Level: PT Classification code 10066260 Term: Acute graft versus host disease System Organ Class: 10021428 - Immune system disorders MedDRA version: 20.1 Level: PT Classification code 10066262 Term: Acute graft versus host disease in skin System Organ Class: 10021428 - Immune system disorders MedDRA version: 20.1 Level: PT Classification code 10066264 Term: Acute graft versus
Conditions
Sponsors
Novartis Pharma Services AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Have undergone 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 corticosteroid refractory aGvHD (confirmed within 48h prior to study treatment start) 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 =65 years) yes F.1.3.1 Number of subjects for this age range 12
Exclusion criteria
Exclusion criteria: - Has received more than one systemic treatment for steriod refractory aGvHD, - Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features (as defined by Jagasia, et al. 2015) - 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 CMV, EBV, HHV-6, HBV, or HCV based on assessment by the treating physicial. - 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. Other protocol-defined inclusion/exclusion criteria may apply.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The main objective of the trial is to compare the efficacy of ruxolitinib with best available therapy in patients with corticosteroid refractory acute Graft vs. Host Disease by assessing the overall response rate (either complete or partial response without requiring additional systemic therapies) based on organ stage scoring. ;Secondary Objective: The key secondary objectif of the trial is to measure the durable response rate of patients who are corticosteroid refractory acute graft vs. host disease and to compare those patients treated with ruxolitinib vs. best available therapy. The other secondary objectives relate to further measurements comparing patients treated with ruxolitinib vs. best available therapy: Their survival over a 2 year time period. Whether steroids are successfully tapered to lower doses. Whether they develop chronic graft vs. host disease, and other standard transplant outcomes including control of their underlying hematologic disease for which the transplant was performed. The safety of ruxolitinib and best available therapy. Measurements of each patient’s reported quality of life will be compared in patients treated with ruxolitinib vs. best available therapy for their corticosteroid refractory acute graft vs. host disease. To estimate the rate of Best Overall Response (BOR);Primary end point(s): Overall Response Rate (ORR) • ORR is defined as the proportion of patients with a best overall response defined as complete response or partial response without requirement for additional systemic therapy for an early progression, mixed response, or non response.;Timepoint(s) of evaluation of this end point: 28 Days | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Durable Overall Response Rate o Proportion of all patients in each arm who achieve a complete response (CR) or partial response (PR) at Day 28 and maintain a CR or PR at Day 56. 2.Proportion of patients who achieved OR (CR+PR) at Day 14. 3. Duration of response o DOR is the time from first response until aGvHD progression or the date of additional systemic therapies for aGvHD. 4. Cumulative steroid dose o Weekly cumulative steroid dose for each subject up to Day 56 or end of treatment 5. Overall Survival (OS) o OS is defined as the time from the date of randomization to the date of death due to any cause. 6. Event-free survival o Event-free survival, 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. 7. Failure-Free survival (FFS) o FFS is 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. 8. Non Relapse Mortality (NRM) o NRM is defined as the time from date of randomization to date of death not preceded by hematologic disease relapse/progression 9. Malignancy Relapse/Progression (MR) o MR is defined as the time from date of randomization to hematologic malignancy relapse/progression. Calculated for patients with underlying hematologic malignant disease. 10. Incidence of cGvHD o cGvHD, defined as the diagnosis of any cGvHD including mild, moderate, severe 11.Best Overall Response (BOR), defined as proportion of patients who achieved RO(CR+PR) at any time pointup to and including D28 and before the start of additional systemic therapy for aGvHD 12. Pharmacokinetics (PK) of ruxolitinib in Steroid Refractory -acute GvHD patients o Ruxolitinib plasma concentrations after a single dose and at steady state. 13. Exposure-response relationship of ruxolitinib in SR-aGvHD o Pharmacokinetics (exposure) and eff | — |
Countries
Argentina, Australia, Austria, Bulgaria, Canada, Czechia, Czech Republic, Denmark, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Korea, Republic of, Netherlands, Norway, Poland, Portugal, Russian Federation, Saudi Arabia, Spain, Sweden, Taiwan, Turkey, United Kingdom
Contacts
Public ContactMedizinischer Infoservice (MCC)
Novartis Pharma GmbH
Outcome results
None listed