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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03491215
Registration number
NCT03491215
Ethics application status
Date submitted
20/03/2018
Date registered
9/04/2018
Date last updated
22/06/2023
Titles & IDs
Public title
Study of Pharmacokinetics, Activity and Safety of Ruxolitinib in Pediatric Patients With Grade II-IV Acute Graft vs. Host Disease
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Scientific title
A Phase I/II Open-label, Single-arm, Multi-center Study of Ruxolitinib Added to Corticosteroids in Pediatric Patients With Grade II-IV Acute Graft vs. Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation
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Secondary ID [1]
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2018-000422-55
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Secondary ID [2]
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CINC424F12201
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Acute Graft Versus Host Disease
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Condition category
Condition code
Inflammatory and Immune System
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Other inflammatory or immune system disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Ruxolitinib
Experimental: Ruxolitinib - All patients received ruxolitinib in addition to corticosteroids +/-calcineurin inhibitor (CNI)
Treatment: Drugs: Ruxolitinib
Ruxolitinib taken orally (5mg tablets) or oral pediatric formulation and dosage based on age group
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Phase I: Measurement of pharmacokinetic (PK) parameter, AUC, in aGvHD and SR-aGvHD patients
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Assessment method [1]
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Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4
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Timepoint [1]
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28 days
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Primary outcome [2]
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Phase I: Measurement of PK parameter, Cmax, in aGvHD and SR-aGvHD patients
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Assessment method [2]
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Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
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Timepoint [2]
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28 days
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Primary outcome [3]
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Phase I: Measurement of PK parameter, T1/2, in aGvHD and SR-aGvHD patients
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Assessment method [3]
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Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
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Timepoint [3]
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28 days
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Primary outcome [4]
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Phase I: Measurement of PK parameter, Ctrough, in aGvHD and SR-aGvHD patients
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Assessment method [4]
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Phase I: Measurement will use be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
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Timepoint [4]
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28 days
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Primary outcome [5]
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Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2-4
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Assessment method [5]
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Phase I: Age-based determination of RP2D for was be based on observed PK parameters:
Group 2: age = 6 to < 12 years
Group 3: age = 2 to < 6 years
Group 4: age = 28 days to < 2 years
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Timepoint [5]
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28 days
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Primary outcome [6]
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Phase II: Overall response rate (ORR)
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Assessment method [6]
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Phase II: ORR is defined as the percentage of patients demonstrating a complete response (CR) or partial response (PR) without requirement for additional systemic therapies for an earlier progression, mixed response or non-response. Scoring of response will be relative to the organ stage at the start of the study treatment.
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Timepoint [6]
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28 days
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Secondary outcome [1]
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Percentage of all patients who achieved a complete response (CR) or partial response (PR)
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Assessment method [1]
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To assess the rate of durable ORR at Day 56
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Timepoint [1]
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56 Days
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Secondary outcome [2]
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Percentage of patients who achieved OR (CR+PR)
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Assessment method [2]
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14 days
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Timepoint [2]
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To estimate ORR at Day 14.
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Secondary outcome [3]
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PK parameter: Area under the curve (AUC) versus safety
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Assessment method [3]
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To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUC with safety)
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Timepoint [3]
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24 weeks
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Secondary outcome [4]
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Duration of response (DOR)
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Assessment method [4]
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DOR is assessed for responders only and is defined as the time from first response until aGvHD progression or the date of additional systemic therapies for aGvHD. Onset of chronic GvHD, or death without prior observation of aGvHD progression are considered as competing risks.
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Timepoint [4]
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48 weeks
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Secondary outcome [5]
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Weekly cumulative steroid dose for each patient
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Assessment method [5]
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To assess the cumulative steroid dose until Day 56
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Timepoint [5]
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up to 56 days
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Secondary outcome [6]
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Overall Survival (OS)
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Assessment method [6]
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OS is defined as the time from the start of treatment to the date of death due to any cause.
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Timepoint [6]
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2 years
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Secondary outcome [7]
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Event-Free Survival (EFS)
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Assessment method [7]
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EFS is defined as the time from start of treatment to the date of hematologic disease relapse/progression, graft failure, or death due to any cause.
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Timepoint [7]
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2 years
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Secondary outcome [8]
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Failure-Free Survival (FFS)
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Assessment method [8]
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FFS is defined as the time from the start of treatment to date of hematologic disease relapse/progression, non-relapse mortality, or addition of new systemic aGvHD treatment.
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Timepoint [8]
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2 years
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Secondary outcome [9]
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Non Relapse Mortality (NRM)
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Assessment method [9]
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NRM is defined as the time from start of treatment to date of death not preceded by hematologic disease relapse/progression.
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Timepoint [9]
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2 years
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Secondary outcome [10]
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Incidence of Malignancy Relapse/Progression (MR)
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Assessment method [10]
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MR is defined as the time from start of treatment to hematologic malignancy relapse/progression. Calculated for patients with underlying hematologic malignant disease.
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Timepoint [10]
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2 years
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Secondary outcome [11]
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Incidence of cGvHD
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Assessment method [11]
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cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe
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Timepoint [11]
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2 years
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Secondary outcome [12]
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Monitoring of donor cell chimerism
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Assessment method [12]
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Monitoring of donor cell chimerism to assess graft failure is defined as initial whole blood or marrow donor chimerism >5% declining to <5% on subsequent measurements compared to baseline.
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Timepoint [12]
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2 years
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Secondary outcome [13]
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Questionnaire on acceptability and palatability
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Assessment method [13]
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Responses from the acceptability and palatability questionnaire for ruxolitinib dose forms used after first dose, 1 month and 6 months.
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Timepoint [13]
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24 weeks
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Secondary outcome [14]
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PK parameter - maximum serum concentration (Cmax) versus efficacy
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Assessment method [14]
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To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with efficacy)
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Timepoint [14]
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24 weeks
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Secondary outcome [15]
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PK parameter: Minimum serum concentration (Ctrough) versus safety
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Assessment method [15]
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To assess pharmacokinetic/pharmacodynamic relationships (comparison of Ctrough with safety)
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Timepoint [15]
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24 weeks
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Secondary outcome [16]
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PK parameter: Cmax versus safety
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Assessment method [16]
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To assess pharmacokinetic/pharmacodynamics relationship (comparison of Cmax with safety)
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Timepoint [16]
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24 weeks
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Secondary outcome [17]
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PK parameter: Ctrough versus efficacy
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Assessment method [17]
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To assess pharmacokinetic/pharmacodynamics relationship (comparison of Ctrough with efficacy)
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Timepoint [17]
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24 weeks
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Secondary outcome [18]
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PK parameter: AUC versus efficacy
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Assessment method [18]
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To assess pharmacokinetic/pharmacodynamics relationship (comparison of AUC with efficacy)
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Timepoint [18]
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24 weeks
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Secondary outcome [19]
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PK parameter: AUC versus PD biomarkers
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Assessment method [19]
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To assess pharmacokinetics/pharmacodynamics relationship (Comparison of AUC with PD biomarkers)
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Timepoint [19]
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24 weeks
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Secondary outcome [20]
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PK parameter: Cmax versus PD biomarkers
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Assessment method [20]
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To assess pharmacokinetic/pharmocodynamic relationship (comparison of Cmax with PD biomarkers)
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Timepoint [20]
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24 weeks
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Secondary outcome [21]
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PK parameter: Ctrough versus PD biomarkers
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Assessment method [21]
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To assess pharmacokinetic/pharmacodynamics relationship (Ctrough with PD biomarkers)
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Timepoint [21]
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24 weeks
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Secondary outcome [22]
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Percentage of patients who achieved Overall Response (OR)
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Assessment method [22]
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Estimation of Best overall response (BOR) - is defined as percentage of patients OR (complete response (CR) + partial response (PR)) at any time and up to Day 28 and before the start of additional systemic aGvHD therapy
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Timepoint [22]
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Up to 28 days and before start of additional aGvHD therapy
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Eligibility
Key inclusion criteria
- Male or female patients age =28 days and <18 years at the time of informed consent.
- Patients who 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 myeloablative or reduced intensity conditioning are eligible.
- Patients with a clinically confirmed diagnosis of grades II-IV aGvHD within 48 hours
prior to study treatment start. Patients may have either: Treatment-naïve aGvHD
(criteria per Harris et al. 2016) OR Steroid refractory aGvHD as per institutional
criteria, or per physician decision in case institutional criteria are not available,
and the patient is currently receiving systemic corticosteroids.
- Evident myeloid engraftment with ANC > 1,000/µl and platelet count >20,000/µl. (Use of
growth factor supplementation and transfusion support is allowed.)
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Minimum age
28
Days
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Maximum age
17
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Has received the following systemic therapy for aGvHD: a) Treatment-naïve aGvHD
patients have received any prior systemic treatment of aGvHD except for a maximum 72h
of prior systemic corticosteroid therapy of methylprednisolone or equivalent after the
onset of acute GvHD. Patients are allowed to have received prior GvHD prophylaxis
which is not counted as systemic treatment (as long as the prophylaxis was started
prior to the diagnosis of aGvHD); OR b) SR-aGvHD patients have received two or more
prior systemic treatments for aGvHD in addition to corticosteroids
- 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).
- Failed prior alloSCT within the past 6 months.
- Presence of relapsed primary malignancy, or who have been treated for relapse after
the alloSCT was performed, or who may require rapid immune suppression withdrawal of
immune suppression as pre-emergent treatment of early malignancy relapse.
- Acute GvHD occurring after non-scheduled donor leukocyte infusion (DLI) administered
for pre-emptive treatment of malignancy recurrence. Note: Patients who have received a
scheduled DLI as part of their transplant procedure and not for management of
malignancy relapse are eligible.
- Any corticosteroid therapy for indications other than aGvHD at doses > 1 mg/kg/day
methylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days of
Screening. Routine corticosteroids administered during conditioning or cell infusion
is allowed.
- Patients who received JAK inhibitor therapy for any indication after initiation of
current alloSCT conditioning.
Other protocol-defined Inclusion/Exclusion may apply.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
21/02/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
2/02/2023
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Sample size
Target
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Accrual to date
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Final
45
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Recruitment in Australia
Recruitment state(s)
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Recruitment outside Australia
Country [1]
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Belgium
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State/province [1]
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Gent
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Country [2]
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Belgium
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State/province [2]
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Laeken
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Country [3]
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Canada
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State/province [3]
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Quebec
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Country [4]
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Denmark
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State/province [4]
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Copenhagen
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Country [5]
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France
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State/province [5]
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Lille
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Country [6]
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France
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State/province [6]
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Nantes Cedex 01
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Country [7]
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France
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State/province [7]
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Paris cedex 15
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Country [8]
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France
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State/province [8]
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Paris Cedex
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Country [9]
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France
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State/province [9]
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Rennes Cedex
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Country [10]
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France
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State/province [10]
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Vandoeuvre Les Nancy
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Country [11]
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Italy
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State/province [11]
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GE
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Country [12]
0
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Italy
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State/province [12]
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RM
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Country [13]
0
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Japan
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State/province [13]
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Aichi
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Country [14]
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Japan
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State/province [14]
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Saitama
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Country [15]
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Korea, Republic of
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State/province [15]
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Seoul
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Country [16]
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Spain
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State/province [16]
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Catalunya
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Country [17]
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Spain
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State/province [17]
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Barcelona
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Country [18]
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Spain
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State/province [18]
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Madrid
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
The study is an open-label, single-arm, Phase I/II multi-center study to investigate the PK,
activity and safety of ruxolitinib added to the patient's immunosuppressive regimen in
infants, children, and adolescents ages =28 days to <18 years old with either grade II-IV
aGvHD or grade II-IV SR-aGvHD. The trial design includes four age groups: Group 1 includes
patients =12y to <18y, Group 2 includes patients =6y to <12y, Group 3 includes patients =2y
to <6y, and Group 4 includes patients =28days to <2y.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03491215
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Trial related presentations / publications
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Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03491215
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