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

• ClinicalTrials.gov Identifier: NCT03491215
• Recruitment Status: Recruiting
• First Posted: April 9, 2018
• Last Update Posted: November 13, 2019
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

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. 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.

Condition or disease	Intervention/treatment	Phase
Acute Graft Versus Host Disease	Drug: Ruxolitinib	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 55 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: February 21, 2019
• Estimated Primary Completion Date: July 1, 2022
• Estimated Study Completion Date: June 2, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ruxolitinib; All patients will receive ruxolitinib in addition to corticosteroids +/-calcineurin inhibitor (CNI)	Drug: Ruxolitinib; Ruxolitinib taken orally (5mg tablets) or oral pediatric formulation and dosage based on age group; Other Name: INC424

Outcome Measures

Primary Outcome Measures :

1. 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
2. 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.
3. 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.
4. 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.
5. Age-based determination of RP2D for each of the groups 2-4 [ Time Frame: 28 days ]
   Phase I: Determination of RP2D for will be based on observed PK parameters.
6. Overall response rate (ORR) [ Time Frame: 28 days ]
   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.

Secondary Outcome Measures :

1. Percentage of all patients who achieve a CR or PR [ Time Frame: 56 Days ]
   To assess the rate of durable ORR at Day 56
2. Percentage of patients who achieved OR (CR+PR) [ Time Frame: To estimate ORR at Day 14. ]
   14 days
3. PK parameter: Area under the curve (AUC) versus safety [ Time Frame: 24 weeks ]
   To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUC with safety)
4. 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.
5. Weekly cumulative steroid dose for each patient [ Time Frame: up to 56 days ]
   To assess the cumulative steroid dose until Day 56
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. Incidence of cGvHD [ Time Frame: 2 years ]
    cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe
12. 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.
13. Questionnaire on acceptability and palatability [ Time Frame: 24 weeks ]
    To describe the acceptability and palatability assessments of the ruxolitinib formulation for dose forms used after first dose, 1 month and 6 months.
14. Percentage of all patients who achieve a complete response (CR) or partial response (PR) [ Time Frame: 56 days ]
    To assess the rate of durable ORR at Day 56
15. PK parameter - maximum serum concentration (Cmax) versus efficacy [ Time Frame: 24 weeks ]
    To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with efficacy)
16. PK parameter: Minimum serum concentration (Ctrough) versus safety [ Time Frame: 24 weeks ]
    To assess pharmacokinetic/pharmacodynamic relationships (comparison of Ctrough with safety)
17. PK parameter: Cmax versus safety [ Time Frame: 24 weeks ]
    To assess pharmacokinetic/pharmacodynamics relationship (comparison of Cmax with safety)
18. PK parameter: Ctrough versus efficacy [ Time Frame: 24 weeks ]
    To assess pharmacokinetic/pharmacodynamics relationship (comparison of Ctrough with efficacy)
19. PK parameter: AUC versus efficacy [ Time Frame: 24 weeks ]
    To assess pharmacokinetic/pharmacodynamics relationship (comparison of AUC with efficacy)
20. PK parameter: AUC versus PD biomarkers [ Time Frame: 24 weeks ]
    To assess pharmacokinetics/pharmacodynamics relationship (Comparison of AUC with PD biomarkers)
21. PK parameter: Cmax versus PD biomarkers [ Time Frame: 24 weeks ]
    To assess pharmacokinetic/pharmocodynamic relationship (comparison of Cmax with PD biomarkers)
22. PK parameter: Ctrough versus PD biomarkers [ Time Frame: 24 weeks ]
    To assess pharmacokinetic/pharmacodynamics relationship (Ctrough with PD biomarkers)
23. 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

Eligibility Criteria

• Ages Eligible for Study: up to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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, 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.

Contacts and Locations

Contacts

Contact: Novartis Pharmaceuticals; +41613241111; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +81337978748; novartis.email@novartis.com

Locations

Australia, Queensland

Novartis Investigative Site; Recruiting

Brisbane, Queensland, Australia, 4101

Australia, Victoria

Novartis Investigative Site; Recruiting

Parkville, Victoria, Australia, 3052

Belgium

Novartis Investigative Site; Recruiting

Bruxelles, Belgium, 1200

Novartis Investigative Site; Recruiting

Gent, Belgium, 9000

Novartis Investigative Site; Recruiting

Leuven, Belgium, 3000

Novartis Investigative Site; Recruiting

Liege, Belgium, 4000

Chile

Novartis Investigative Site; Recruiting

Santiago, Chile, 664 0166

France

Novartis Investigative Site; Recruiting

Lille, France, 59000

Novartis Investigative Site; Recruiting

Rennes Cedex, France, 35022

Germany

Novartis Investigative Site; Recruiting

Hamburg, Germany, 20246

Italy

Novartis Investigative Site; Recruiting

Genova, GE, Italy, 16147

Novartis Investigative Site; Recruiting

Roma, ITA, Italy, 00165

Japan

Novartis Investigative Site; Recruiting

Nagoya, Aichi, Japan, 466 8560

Novartis Investigative Site; Recruiting

Saitama, Japan, 330 8777

Slovenia

Novartis Investigative Site; Recruiting

Ljubljana, Slovenia, 1000

Spain

Novartis Investigative Site; Recruiting

Barcelona, Catalunya, Spain, 08035

Novartis Investigative Site; Recruiting

Barcelona, Cataluña, Spain, 08025

Novartis Investigative Site; Recruiting

Madrid, Spain, 28009

Novartis Investigative Site; Recruiting

Madrid, Spain, 28046

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03491215 History of Changes
• Other Study ID Numbers: CINC424F12201; 2018-000422-55 ( EudraCT Number )
• First Posted: April 9, 2018
• Last Update Posted: November 13, 2019
• Last Verified: November 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

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.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

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

Additional relevant MeSH terms:

Graft vs Host Disease; Immune System Diseases