Activity, Safety and Pharmacokinetics in Pediatric Subjects With Moderate and Severe Chronic Graft vs. Host Disease After Allogeneic Stem Cell Transplant

A Phase II Open-label, Single-arm, Multi-center Study of Ruxolitinib Added to Corticosteroids in Pediatric Subjects With Moderate and Severe Chronic Graft vs. Host Disease After Allogeneic Stem Cell Transplantation

This open-label, single-arm, Phase II multi-center study will enroll approximately 42 subjects and investigate the activity, pharmacokinetics and safety of ruxolitinib added to the subject's immunosuppressive regimen among infants, children, and adolescents aged ≥28 days to <18 years old with either moderate to severe treatment-naive cGvHD or SR-cGvHD. Subjects will be grouped according to their age as follows: Group 1 includes subjects ≥12y to <18y, Group 2 includes subjects ≥6y to <12y, Group 3 includes subjects ≥2y to <6y, and Group 4 includes subjects ≥28days to <2y.

Study Overview

• Status: Active, not recruiting
• Conditions: Graft vs Host Disease
• Intervention / Treatment: Drug: INC424

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Sao Paulo, Brazil, 04039 001
    • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Novartis Investigative Site
• Czechia
  • Praha 5, Czechia, 150 06
    • Novartis Investigative Site
• India
  • Delhi, India, 110 085
    • Novartis Investigative Site
  • Chennai
    • Tamil Nadu, Chennai, India, 600035
      • Novartis Investigative Site
  • Karnataka
    • Bangalore, Karnataka, India, 560099
      • Novartis Investigative Site
  • Maharashtra
    • Pune, Maharashtra, India, 411004
      • Novartis Investigative Site
• Italy
  • RM
    • Roma, RM, Italy, 00165
      • Novartis Investigative Site
• Japan
  • Saitama, Japan, 330 8777
    • Novartis Investigative Site
  • Aichi
    • Nagoya, Aichi, Japan, 466 8560
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 05505
    • Novartis Investigative Site
• Russian Federation
  • Saint Petersburg, Russian Federation, 197022
    • Novartis Investigative Site
• Slovakia
  • Bratislava, Slovakia, 833 40
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Switzerland
  • Zuerich, Switzerland, 8032
    • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
• Turkey
  • Adana, Turkey, 1330
    • Novartis Investigative Site
  • Antalya, Turkey, 07070
    • Novartis Investigative Site
  • Antalya, Turkey, 07000
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female subjects age ≥28 days and <18 years at the time of informed consent.
• Subjects 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.

• Subjects with diagnosed moderate to severe cGvHD according to NIH 2014 Consensus Criteria (Section 16.2) prior to Cycle 1 Day 1. Other possible diagnoses for clinical symptoms supporting cGvHD diagnoses must be excluded (e.g., infection, drug side effects, malignancy). Subjects must be either:

  • Treatment-naive cGvHD subjects that have not received any prior systemic treatment for cGvHD except for a maximum 72h of prior systemic corticosteroid therapy of methylprednisolone or equivalent after the onset of chronic GvHD. Subjects are allowed to have received prior systemic treatment for cGvHD prophylaxis (as long as the prophylaxis was started prior to the diagnosis of cGvHD).

OR o Steroid-refractory moderate to severe cGvHD as per institutional criteria, or per physician decision in case institutional criteria are not available, and still receiving systemic corticosteroids for the treatment of cGvHD for a duration of <18 months prior to Cycle 1 Day 1. In case the corticosteroids were previously interrupted due to response, the duration of < 18 months applies to the last period of corticosteroid use.

Exclusion Criteria:

• SR-cGvHD subjects with a prior cGvHD treatment with a JAK1- or a JAK2- or a JAK1/2-inhibitor, except when the subject achieved complete or partial response and has been off JAK inhibitor treatment for at least 4 weeks prior to Cycle Day 1 or up to 5 times the half-life of the prior JAK inhibitor, whichever is longer.

  * Subjects who initiated systemic calcineurin inhibitors (CNI; cyclosporine or tacrolimus) within 3 weeks prior to start of ruxolitinib on Cycle 1 Day 1. Note: systemic CNI are allowed when initiated > 3 weeks from start of ruxolitinib.

• Failed prior alloSCT within the past 6 months
• Significant respiratory disease including subjects who are on mechanical ventilation or who have a resting oxygen saturation < 90% by pulse-oximetry on room-air.
• Impairment of gastrointestinal (GI) function (unrelated to GvHD) or GI disease (unrelated to GvHD) that may significantly alter the absorption of oral ruxolitinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection),
• Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to cGvHD and ongoing organ dysfunction)
• Presence of clinically active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment.
• Known human immunodeficiency virus (HIV) infection.
• Evidence of uncontrolled hepatitis B virus (HBV) or hepatitis C virus (HCV) based on assessment done by Investigator or delegate.
• Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds.
• History of bone disorders such as osteogenesis imperfecta, rickets, renal osteodystrophy, osteomyelitis, osteopenia, fibrous dysplasia, osteomalacia etc. prior to the underlying diagnosis which resulted in the alloSCT.
• History of endocrine or kidney related growth retardation prior to the underlying diagnosis which resulted in the alloSCT.
• Evidence of clinically active tuberculosis (clinical diagnosis per local practice)
• Any corticosteroid therapy for indications other than cGvHD at doses > 1 mg/kg/daymethylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days of the screening visit.
• History of progressive multifocal leuko-encephalopathy (PML).
• Presence of severely impaired renal function

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: INC424 (ruxolitinib); Subjects who will be administered 5mg ruxolitinib tablet or ruxolitinib oral pediatric formulation twice a day.	Drug: INC424; Ruxolitinib is taken orally either as 5mg tablets or as pediatric formulation (dosage based on age group); Other Names: Ruxolitinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	ORR is defined as the proportion of subjects demonstrating a complete response (CR) or partial response (PR) without the requirement of additional systemic therapies for an earlier progression, mixed response or non-response. The response is assessed per NIH consensus criteria (Lee et al 2015) and scoring of response will be relative to the organ stage at the start of study treatment.	Cycle 7 Day 1 (Day 168)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ruxolitinib concentrations by timepoint	PK of ruxolitinib in treatment-naïve cGvHD and SR-cGvHD pediatric subjects	Cycle 7 Day 1 (from baseline to Day 168)
Duration of response (DOR)	Time from first response until cGvHD progression, death, or the date of addition of systemic therapies for cGvHD	From baseline up to end of study treatment, up to 36 months
Overall Response Rate (ORR)	Proportion of subjects who achieve OR (CR+PR)	Cycle 4 Day 1 (Day 84)
Best overall response (BOR)	Proportion of subjects who achieved OR (CR+PR) at any time point	Until Cycle 7 Day 1 (Day 168) or the start of additional systemic therapy for cGvHD
Failure free survival (FFS)	Composite time to event endpoint incorporating the following FFS events: i) relapse or recurrence of underlying disease or death due to underlying disease, ii) non-relapse mortality, or iii) addition or initiation of another systemic therapy for cGvHD	From baseline up to 35 days after end of study treatment, up to 37 months
Cumulative incidence of malignancy relapse/recurrence (MR)	Defined as the time from date of treatment assignment to hematologic malignancy relapse/recurrence. Calculated for subjects with underlying hematologic malignant disease	From baseline up to 35 days after end of study treatment, up to 37 months
Non-relapse mortality (NRM)	Defined as the time from date of treatment assignment to date of death not preceded by underlying disease relapse/recurrence	From baseline up to 35 days after end of study treatment, up to 37 months
Overall survival (OS)	Defined as the time from the date of treatment assignment to the date of death due to any cause	From baseline up to 35 days after end of study treatment, up to 37 months
Percentage of participants with ≥50% reduction from baseline in daily corticosteroid dose	Reduction of at least ≥50% in daily corticosteroid use	Cycle 7 Day 1 (Day 168)
Percentage of participants with a reduction to a low dose corticosteriod	Reduction in daily corticosteroid dose to ≤0.2mg/kg/day methylprednisolone(or equivalent dose of ≤0.25mg/kg/day prednisone or prednisolone)	Cycle 7 Day 1 (Day 168)
Graft failure	Assess using donor cell chimerism, defined as initial whole blood or marrow donor chimerism for those who had ≥ 5% donor cell chimerism at baseline. If donor cell chimerism declines to <5% on subsequent measurements, the graft failure is declared	From baseline up to 35 days after end of study treatment, up to 37 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2020
• Primary Completion (Actual): February 25, 2022
• Study Completion (Estimated): October 5, 2024

Study Registration Dates

• First Submitted: December 11, 2018
• First Submitted That Met QC Criteria: December 11, 2018
• First Posted (Actual): December 12, 2018

Study Record Updates

• Last Update Posted (Estimated): February 22, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: pediatric; INC424; corticosteroids; ruxolitinib; allogeneic stem cell transplant; Chronic Graft versus Host Disease; moderate and severe chronic graft vs. host disease
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: CINC424G12201; 2018-003296-35 (EudraCT Number)

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