Study of Pharmacokinetics, Activity and Safety of Ruxolitinib in Pediatric Patients With Grade II-IV Acute Graft vs. Host Disease
Primary Purpose
Acute Graft Versus Host Disease
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Ruxolitinib
Sponsored by
About this trial
This is an interventional treatment trial for Acute Graft Versus Host Disease focused on measuring Graft versus host disease, GvHD, acute graft versus host disease, aGvHD, Steroid refractory acute graft versus host disease, SR-aGvHD, Ruxolitinib, INC424, allogeneic stem cell transplantation, treatment naive
Eligibility Criteria
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.)
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.
Sites / Locations
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Ruxolitinib
Arm Description
All patients received ruxolitinib in addition to corticosteroids +/-calcineurin inhibitor (CNI)
Outcomes
Primary Outcome Measures
Phase I: Measurement of pharmacokinetic (PK) parameter, AUC, in aGvHD and SR-aGvHD patients
Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4
Phase I: Measurement of PK parameter, Cmax, in aGvHD and SR-aGvHD patients
Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
Phase I: Measurement of PK parameter, T1/2, in aGvHD and SR-aGvHD patients
Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
Phase I: Measurement of PK parameter, Ctrough, in aGvHD and SR-aGvHD patients
Phase I: Measurement will use be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2-4
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
Phase II: Overall response rate (ORR)
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.
Secondary Outcome Measures
Percentage of all patients who achieved a complete response (CR) or partial response (PR)
To assess the rate of durable ORR at Day 56
Percentage of patients who achieved OR (CR+PR)
14 days
PK parameter: Area under the curve (AUC) versus safety
To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUC with safety)
Duration of response (DOR)
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.
Weekly cumulative steroid dose for each patient
To assess the cumulative steroid dose until Day 56
Overall Survival (OS)
OS is defined as the time from the start of treatment to the date of death due to any cause.
Event-Free Survival (EFS)
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.
Failure-Free Survival (FFS)
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.
Non Relapse Mortality (NRM)
NRM is defined as the time from start of treatment to date of death not preceded by hematologic disease relapse/progression.
Incidence of Malignancy Relapse/Progression (MR)
MR is defined as the time from start of treatment to hematologic malignancy relapse/progression. Calculated for patients with underlying hematologic malignant disease.
Incidence of cGvHD
cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe
Monitoring of donor cell chimerism
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.
Questionnaire on acceptability and palatability
Responses from the acceptability and palatability questionnaire for ruxolitinib dose forms used after first dose, 1 month and 6 months.
PK parameter - maximum serum concentration (Cmax) versus efficacy
To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with efficacy)
PK parameter: Minimum serum concentration (Ctrough) versus safety
To assess pharmacokinetic/pharmacodynamic relationships (comparison of Ctrough with safety)
PK parameter: Cmax versus safety
To assess pharmacokinetic/pharmacodynamics relationship (comparison of Cmax with safety)
PK parameter: Ctrough versus efficacy
To assess pharmacokinetic/pharmacodynamics relationship (comparison of Ctrough with efficacy)
PK parameter: AUC versus efficacy
To assess pharmacokinetic/pharmacodynamics relationship (comparison of AUC with efficacy)
PK parameter: AUC versus PD biomarkers
To assess pharmacokinetics/pharmacodynamics relationship (Comparison of AUC with PD biomarkers)
PK parameter: Cmax versus PD biomarkers
To assess pharmacokinetic/pharmocodynamic relationship (comparison of Cmax with PD biomarkers)
PK parameter: Ctrough versus PD biomarkers
To assess pharmacokinetic/pharmacodynamics relationship (Ctrough with PD biomarkers)
Percentage of patients who achieved Overall Response (OR)
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
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03491215
Brief Title
Study of Pharmacokinetics, Activity and Safety of Ruxolitinib in Pediatric Patients With Grade II-IV Acute Graft vs. Host Disease
Official 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
Study Type
Interventional
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Completed
Study Start Date
February 21, 2019 (Actual)
Primary Completion Date
March 11, 2021 (Actual)
Study Completion Date
February 2, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
Detailed Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Graft Versus Host Disease
Keywords
Graft versus host disease, GvHD, acute graft versus host disease, aGvHD, Steroid refractory acute graft versus host disease, SR-aGvHD, Ruxolitinib, INC424, allogeneic stem cell transplantation, treatment naive
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
45 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Ruxolitinib
Arm Type
Experimental
Arm Description
All patients received ruxolitinib in addition to corticosteroids +/-calcineurin inhibitor (CNI)
Intervention Type
Drug
Intervention Name(s)
Ruxolitinib
Other Intervention Name(s)
INC424
Intervention Description
Ruxolitinib taken orally (5mg tablets) or oral pediatric formulation and dosage based on age group
Primary Outcome Measure Information:
Title
Phase I: Measurement of pharmacokinetic (PK) parameter, AUC, in aGvHD and SR-aGvHD patients
Description
Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4
Time Frame
28 days
Title
Phase I: Measurement of PK parameter, Cmax, in aGvHD and SR-aGvHD patients
Description
Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
Time Frame
28 days
Title
Phase I: Measurement of PK parameter, T1/2, in aGvHD and SR-aGvHD patients
Description
Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
Time Frame
28 days
Title
Phase I: Measurement of PK parameter, Ctrough, in aGvHD and SR-aGvHD patients
Description
Phase I: Measurement will use be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
Time Frame
28 days
Title
Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2-4
Description
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
Time Frame
28 days
Title
Phase II: Overall response rate (ORR)
Description
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.
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Percentage of all patients who achieved a complete response (CR) or partial response (PR)
Description
To assess the rate of durable ORR at Day 56
Time Frame
56 Days
Title
Percentage of patients who achieved OR (CR+PR)
Description
14 days
Time Frame
To estimate ORR at Day 14.
Title
PK parameter: Area under the curve (AUC) versus safety
Description
To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUC with safety)
Time Frame
24 weeks
Title
Duration of response (DOR)
Description
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.
Time Frame
48 weeks
Title
Weekly cumulative steroid dose for each patient
Description
To assess the cumulative steroid dose until Day 56
Time Frame
up to 56 days
Title
Overall Survival (OS)
Description
OS is defined as the time from the start of treatment to the date of death due to any cause.
Time Frame
2 years
Title
Event-Free Survival (EFS)
Description
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.
Time Frame
2 years
Title
Failure-Free Survival (FFS)
Description
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.
Time Frame
2 years
Title
Non Relapse Mortality (NRM)
Description
NRM is defined as the time from start of treatment to date of death not preceded by hematologic disease relapse/progression.
Time Frame
2 years
Title
Incidence of Malignancy Relapse/Progression (MR)
Description
MR is defined as the time from start of treatment to hematologic malignancy relapse/progression. Calculated for patients with underlying hematologic malignant disease.
Time Frame
2 years
Title
Incidence of cGvHD
Description
cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe
Time Frame
2 years
Title
Monitoring of donor cell chimerism
Description
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.
Time Frame
2 years
Title
Questionnaire on acceptability and palatability
Description
Responses from the acceptability and palatability questionnaire for ruxolitinib dose forms used after first dose, 1 month and 6 months.
Time Frame
24 weeks
Title
PK parameter - maximum serum concentration (Cmax) versus efficacy
Description
To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with efficacy)
Time Frame
24 weeks
Title
PK parameter: Minimum serum concentration (Ctrough) versus safety
Description
To assess pharmacokinetic/pharmacodynamic relationships (comparison of Ctrough with safety)
Time Frame
24 weeks
Title
PK parameter: Cmax versus safety
Description
To assess pharmacokinetic/pharmacodynamics relationship (comparison of Cmax with safety)
Time Frame
24 weeks
Title
PK parameter: Ctrough versus efficacy
Description
To assess pharmacokinetic/pharmacodynamics relationship (comparison of Ctrough with efficacy)
Time Frame
24 weeks
Title
PK parameter: AUC versus efficacy
Description
To assess pharmacokinetic/pharmacodynamics relationship (comparison of AUC with efficacy)
Time Frame
24 weeks
Title
PK parameter: AUC versus PD biomarkers
Description
To assess pharmacokinetics/pharmacodynamics relationship (Comparison of AUC with PD biomarkers)
Time Frame
24 weeks
Title
PK parameter: Cmax versus PD biomarkers
Description
To assess pharmacokinetic/pharmocodynamic relationship (comparison of Cmax with PD biomarkers)
Time Frame
24 weeks
Title
PK parameter: Ctrough versus PD biomarkers
Description
To assess pharmacokinetic/pharmacodynamics relationship (Ctrough with PD biomarkers)
Time Frame
24 weeks
Title
Percentage of patients who achieved Overall Response (OR)
Description
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
Time Frame
Up to 28 days and before start of additional aGvHD therapy
10. Eligibility
Sex
All
Minimum Age & Unit of Time
28 Days
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.)
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Gent
ZIP/Postal Code
9000
Country
Belgium
Facility Name
Novartis Investigative Site
City
Laeken
ZIP/Postal Code
1020
Country
Belgium
Facility Name
Novartis Investigative Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada
Facility Name
Novartis Investigative Site
City
Copenhagen
ZIP/Postal Code
DK-2100
Country
Denmark
Facility Name
Novartis Investigative Site
City
Lille
ZIP/Postal Code
59000
Country
France
Facility Name
Novartis Investigative Site
City
Nantes Cedex 01
ZIP/Postal Code
44093
Country
France
Facility Name
Novartis Investigative Site
City
Paris cedex 15
ZIP/Postal Code
75015
Country
France
Facility Name
Novartis Investigative Site
City
Paris Cedex
ZIP/Postal Code
75019
Country
France
Facility Name
Novartis Investigative Site
City
Rennes Cedex
ZIP/Postal Code
35022
Country
France
Facility Name
Novartis Investigative Site
City
Vandoeuvre Les Nancy
ZIP/Postal Code
54511
Country
France
Facility Name
Novartis Investigative Site
City
Genova
State/Province
GE
ZIP/Postal Code
16147
Country
Italy
Facility Name
Novartis Investigative Site
City
Roma
State/Province
RM
ZIP/Postal Code
00165
Country
Italy
Facility Name
Novartis Investigative Site
City
Nagoya
State/Province
Aichi
ZIP/Postal Code
466 8560
Country
Japan
Facility Name
Novartis Investigative Site
City
Saitama
ZIP/Postal Code
330 8777
Country
Japan
Facility Name
Novartis Investigative Site
City
Seoul
ZIP/Postal Code
03080
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08035
Country
Spain
Facility Name
Novartis Investigative Site
City
Barcelona
ZIP/Postal Code
08041
Country
Spain
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28009
Country
Spain
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28046
Country
Spain
12. IPD Sharing Statement
Plan to Share IPD
Undecided
IPD Sharing Plan Description
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.
Learn more about this trial
Study of Pharmacokinetics, Activity and Safety of Ruxolitinib in Pediatric Patients With Grade II-IV Acute Graft vs. Host Disease
We'll reach out to this number within 24 hrs