Study of Pharmacokinetics, Activity and Safety of Ruxolitinib in Pediatric Patients With Grade II-IV Acute Graft vs. Host Disease

June 16, 2023 updated by: Novartis Pharmaceuticals

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

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.

Study Overview

Status

Completed

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

45

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Gent, Belgium, 9000
        • Novartis Investigative Site
      • Laeken, Belgium, 1020
        • Novartis Investigative Site
    • Quebec
      • Montreal, Quebec, Canada, H3T 1C5
        • Novartis Investigative Site
      • Copenhagen, Denmark, DK-2100
        • Novartis Investigative Site
      • Lille, France, 59000
        • Novartis Investigative Site
      • Nantes Cedex 01, France, 44093
        • Novartis Investigative Site
      • Paris Cedex, France, 75019
        • Novartis Investigative Site
      • Paris cedex 15, France, 75015
        • Novartis Investigative Site
      • Rennes Cedex, France, 35022
        • Novartis Investigative Site
      • Vandoeuvre Les Nancy, France, 54511
        • Novartis Investigative Site
    • GE
      • Genova, GE, Italy, 16147
        • Novartis Investigative Site
    • RM
      • Roma, RM, Italy, 00165
        • Novartis Investigative Site
      • Saitama, Japan, 330 8777
        • Novartis Investigative Site
    • Aichi
      • Nagoya, Aichi, Japan, 466 8560
        • Novartis Investigative Site
      • Seoul, Korea, Republic of, 03080
        • Novartis Investigative Site
      • Barcelona, Spain, 08041
        • Novartis Investigative Site
      • Madrid, Spain, 28046
        • Novartis Investigative Site
      • Madrid, Spain, 28009
        • Novartis Investigative Site
    • Catalunya
      • Barcelona, Catalunya, Spain, 08035
        • Novartis Investigative Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

4 weeks to 17 years (Child)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ruxolitinib
All patients received ruxolitinib in addition to corticosteroids +/-calcineurin inhibitor (CNI)
Ruxolitinib taken orally (5mg tablets) or oral pediatric formulation and dosage based on age group
Other Names:
  • INC424

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Phase I: Measurement of pharmacokinetic (PK) parameter, AUC, in aGvHD and SR-aGvHD patients
Time Frame: 28 days
Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4
28 days
Phase I: Measurement of PK parameter, Cmax, in aGvHD and SR-aGvHD patients
Time Frame: 28 days
Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
28 days
Phase I: Measurement of PK parameter, T1/2, in aGvHD and SR-aGvHD patients
Time Frame: 28 days
Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
28 days
Phase I: Measurement of PK parameter, Ctrough, in aGvHD and SR-aGvHD patients
Time Frame: 28 days
Phase I: Measurement will use be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
28 days
Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2-4
Time Frame: 28 days

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
28 days
Phase II: Overall response rate (ORR)
Time Frame: 28 days
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.
28 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of patients who achieved OR (CR+PR)
Time Frame: To estimate ORR at Day 14.
14 days
To estimate ORR at Day 14.
PK parameter: Area under the curve (AUC) versus safety
Time Frame: 24 weeks
To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUC with safety)
24 weeks
Duration of response (DOR)
Time Frame: 48 weeks
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.
48 weeks
Weekly cumulative steroid dose for each patient
Time Frame: up to 56 days
To assess the cumulative steroid dose until Day 56
up to 56 days
Overall Survival (OS)
Time Frame: 2 years
OS is defined as the time from the start of treatment to the date of death due to any cause.
2 years
Event-Free Survival (EFS)
Time Frame: 2 years
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.
2 years
Failure-Free Survival (FFS)
Time Frame: 2 years
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.
2 years
Non Relapse Mortality (NRM)
Time Frame: 2 years
NRM is defined as the time from start of treatment to date of death not preceded by hematologic disease relapse/progression.
2 years
Incidence of Malignancy Relapse/Progression (MR)
Time Frame: 2 years
MR is defined as the time from start of treatment to hematologic malignancy relapse/progression. Calculated for patients with underlying hematologic malignant disease.
2 years
Incidence of cGvHD
Time Frame: 2 years
cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe
2 years
Monitoring of donor cell chimerism
Time Frame: 2 years
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.
2 years
Questionnaire on acceptability and palatability
Time Frame: 24 weeks
Responses from the acceptability and palatability questionnaire for ruxolitinib dose forms used after first dose, 1 month and 6 months.
24 weeks
PK parameter - maximum serum concentration (Cmax) versus efficacy
Time Frame: 24 weeks
To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with efficacy)
24 weeks
PK parameter: Minimum serum concentration (Ctrough) versus safety
Time Frame: 24 weeks
To assess pharmacokinetic/pharmacodynamic relationships (comparison of Ctrough with safety)
24 weeks
PK parameter: Cmax versus safety
Time Frame: 24 weeks
To assess pharmacokinetic/pharmacodynamics relationship (comparison of Cmax with safety)
24 weeks
PK parameter: Ctrough versus efficacy
Time Frame: 24 weeks
To assess pharmacokinetic/pharmacodynamics relationship (comparison of Ctrough with efficacy)
24 weeks
PK parameter: AUC versus efficacy
Time Frame: 24 weeks
To assess pharmacokinetic/pharmacodynamics relationship (comparison of AUC with efficacy)
24 weeks
PK parameter: AUC versus PD biomarkers
Time Frame: 24 weeks
To assess pharmacokinetics/pharmacodynamics relationship (Comparison of AUC with PD biomarkers)
24 weeks
PK parameter: Cmax versus PD biomarkers
Time Frame: 24 weeks
To assess pharmacokinetic/pharmocodynamic relationship (comparison of Cmax with PD biomarkers)
24 weeks
PK parameter: Ctrough versus PD biomarkers
Time Frame: 24 weeks
To assess pharmacokinetic/pharmacodynamics relationship (Ctrough with PD biomarkers)
24 weeks
Percentage of patients who achieved Overall Response (OR)
Time Frame: Up to 28 days and before start of additional aGvHD therapy
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
Up to 28 days and before start of additional aGvHD therapy
Percentage of all patients who achieved a complete response (CR) or partial response (PR)
Time Frame: 56 Days
To assess the rate of durable ORR at Day 56
56 Days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 21, 2019

Primary Completion (Actual)

March 11, 2021

Study Completion (Actual)

February 2, 2023

Study Registration Dates

First Submitted

March 20, 2018

First Submitted That Met QC Criteria

April 5, 2018

First Posted (Actual)

April 9, 2018

Study Record Updates

Last Update Posted (Actual)

June 22, 2023

Last Update Submitted That Met QC Criteria

June 16, 2023

Last Verified

June 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD 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.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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