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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03491215




Registration number
NCT03491215
Ethics application status
Date submitted
20/03/2018
Date registered
9/04/2018
Date last updated
21/09/2020

Titles & IDs
Public title
Study of Pharmacokinetics, Activity and Safety of Ruxolitinib in Pediatric Patients With Grade II-IV Acute Graft vs. Host Disease
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
Secondary ID [1] 0 0
2018-000422-55
Secondary ID [2] 0 0
CINC424F12201
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Graft Versus Host Disease 0 0
Condition category
Condition code
Inflammatory and Immune System 0 0 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Ruxolitinib

Experimental: Ruxolitinib - All patients will receive 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

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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
Timepoint [1] 0 0
28 days
Primary outcome [2] 0 0
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.
Timepoint [2] 0 0
28 days
Primary outcome [3] 0 0
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.
Timepoint [3] 0 0
28 days
Primary outcome [4] 0 0
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.
Timepoint [4] 0 0
28 days
Primary outcome [5] 0 0
Age-based determination of RP2D for each of the groups 2-4 - Phase I: Determination of RP2D for will be based on observed PK parameters.
Timepoint [5] 0 0
28 days
Primary outcome [6] 0 0
Overall response rate (ORR) - Phase II: ORR is defined as the proportion 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.
Timepoint [6] 0 0
28 days
Secondary outcome [1] 0 0
Percentage of all patients who achieve a CR or PR - To assess the rate of durable ORR at Day 56
Timepoint [1] 0 0
56 Days
Secondary outcome [2] 0 0
Percentage of patients who achieved OR (CR+PR) - 14 days
Timepoint [2] 0 0
To estimate ORR at Day 14.
Secondary outcome [3] 0 0
PK parameter: Area under the curve (AUC) versus safety - To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUC with safety)
Timepoint [3] 0 0
24 weeks
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
48 weeks
Secondary outcome [5] 0 0
Weekly cumulative steroid dose for each patient - To assess the cumulative steroid dose until Day 56
Timepoint [5] 0 0
up to 56 days
Secondary outcome [6] 0 0
Overall Survival (OS) - OS is defined as the time from the start of treatment to the date of death due to any cause.
Timepoint [6] 0 0
2 years
Secondary outcome [7] 0 0
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.
Timepoint [7] 0 0
2 years
Secondary outcome [8] 0 0
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.
Timepoint [8] 0 0
2 years
Secondary outcome [9] 0 0
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.
Timepoint [9] 0 0
2 years
Secondary outcome [10] 0 0
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.
Timepoint [10] 0 0
2 years
Secondary outcome [11] 0 0
Incidence of cGvHD - cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe
Timepoint [11] 0 0
2 years
Secondary outcome [12] 0 0
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.
Timepoint [12] 0 0
2 years
Secondary outcome [13] 0 0
Questionnaire on acceptability and palatability - To describe the acceptability and palatability assessments of the ruxolitinib formulation for dose forms used after first dose, 1 month and 6 months.
Timepoint [13] 0 0
24 weeks
Secondary outcome [14] 0 0
Percentage of all patients who achieve a complete response (CR) or partial response (PR) - To assess the rate of durable ORR at Day 56
Timepoint [14] 0 0
56 days
Secondary outcome [15] 0 0
PK parameter - maximum serum concentration (Cmax) versus efficacy - To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with efficacy)
Timepoint [15] 0 0
24 weeks
Secondary outcome [16] 0 0
PK parameter: Minimum serum concentration (Ctrough) versus safety - To assess pharmacokinetic/pharmacodynamic relationships (comparison of Ctrough with safety)
Timepoint [16] 0 0
24 weeks
Secondary outcome [17] 0 0
PK parameter: Cmax versus safety - To assess pharmacokinetic/pharmacodynamics relationship (comparison of Cmax with safety)
Timepoint [17] 0 0
24 weeks
Secondary outcome [18] 0 0
PK parameter: Ctrough versus efficacy - To assess pharmacokinetic/pharmacodynamics relationship (comparison of Ctrough with efficacy)
Timepoint [18] 0 0
24 weeks
Secondary outcome [19] 0 0
PK parameter: AUC versus efficacy - To assess pharmacokinetic/pharmacodynamics relationship (comparison of AUC with efficacy)
Timepoint [19] 0 0
24 weeks
Secondary outcome [20] 0 0
PK parameter: AUC versus PD biomarkers - To assess pharmacokinetics/pharmacodynamics relationship (Comparison of AUC with PD biomarkers)
Timepoint [20] 0 0
24 weeks
Secondary outcome [21] 0 0
PK parameter: Cmax versus PD biomarkers - To assess pharmacokinetic/pharmocodynamic relationship (comparison of Cmax with PD biomarkers)
Timepoint [21] 0 0
24 weeks
Secondary outcome [22] 0 0
PK parameter: Ctrough versus PD biomarkers - To assess pharmacokinetic/pharmacodynamics relationship (Ctrough with PD biomarkers)
Timepoint [22] 0 0
24 weeks
Secondary outcome [23] 0 0
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
Timepoint [23] 0 0
Up to 28 days and before start of additional aGvHD therapy

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, 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.)
Minimum age
No limit
Maximum age
17 Years
Gender
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Brisbane
Recruitment hospital [2] 0 0
Novartis Investigative Site - Parkville
Recruitment postcode(s) [1] 0 0
4101 - Brisbane
Recruitment postcode(s) [2] 0 0
3052 - Parkville
Recruitment outside Australia
Country [1] 0 0
Belgium
State/province [1] 0 0
Bruxelles
Country [2] 0 0
Belgium
State/province [2] 0 0
Gent
Country [3] 0 0
Belgium
State/province [3] 0 0
Laeken
Country [4] 0 0
Belgium
State/province [4] 0 0
Leuven
Country [5] 0 0
Belgium
State/province [5] 0 0
Liege
Country [6] 0 0
Canada
State/province [6] 0 0
Quebec
Country [7] 0 0
Chile
State/province [7] 0 0
Santiago
Country [8] 0 0
Denmark
State/province [8] 0 0
Copenhagen
Country [9] 0 0
France
State/province [9] 0 0
Lille
Country [10] 0 0
France
State/province [10] 0 0
Nantes Cedex 01
Country [11] 0 0
France
State/province [11] 0 0
Paris cedex 15
Country [12] 0 0
France
State/province [12] 0 0
Paris Cedex
Country [13] 0 0
France
State/province [13] 0 0
Rennes Cedex
Country [14] 0 0
France
State/province [14] 0 0
Vandoeuvre Les Nancy
Country [15] 0 0
Germany
State/province [15] 0 0
Berlin
Country [16] 0 0
Germany
State/province [16] 0 0
Duesseldorf
Country [17] 0 0
Germany
State/province [17] 0 0
Hamburg
Country [18] 0 0
Germany
State/province [18] 0 0
Ulm
Country [19] 0 0
Germany
State/province [19] 0 0
Wuerzburg
Country [20] 0 0
Italy
State/province [20] 0 0
GE
Country [21] 0 0
Italy
State/province [21] 0 0
ITA
Country [22] 0 0
Japan
State/province [22] 0 0
Aichi
Country [23] 0 0
Japan
State/province [23] 0 0
Saitama
Country [24] 0 0
Korea, Republic of
State/province [24] 0 0
Seoul
Country [25] 0 0
Slovenia
State/province [25] 0 0
Ljubljana
Country [26] 0 0
Spain
State/province [26] 0 0
Catalunya
Country [27] 0 0
Spain
State/province [27] 0 0
Cataluña
Country [28] 0 0
Spain
State/province [28] 0 0
Madrid
Country [29] 0 0
Spain
State/province [29] 0 0
Valencia

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

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. This trial will utilize 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.
Trial website
https://clinicaltrials.gov/show/NCT03491215
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Country 0 0
Phone 0 0
+41613241111
Fax 0 0
Email 0 0
novartis.email@novartis.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03491215