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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03774082

Collaborator

(none)

Enrollment

Locations

Arm

52.9

Anticipated Duration (Months)

2.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Graft vs Host Disease	Drug: INC424	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

46 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 20, 2020

Actual Primary Completion Date :

Feb 25, 2022

Anticipated Study Completion Date :

Oct 17, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Overall response rate (ORR) [Cycle 7 Day 1 (Day 168)]
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.

Secondary Outcome Measures

Ruxolitinib concentrations by timepoint [Cycle 7 Day 1 (from baseline to Day 168)]
PK of ruxolitinib in treatment-naïve cGvHD and SR-cGvHD pediatric subjects
Duration of response (DOR) [From baseline up to end of study treatment, up to 36 months]
Time from first response until cGvHD progression, death, or the date of addition of systemic therapies for cGvHD
Overall Response Rate (ORR) [Cycle 4 Day 1 (Day 84)]
Proportion of subjects who achieve OR (CR+PR)
Best overall response (BOR) [Until Cycle 7 Day 1 (Day 168) or the start of additional systemic therapy for cGvHD]
Proportion of subjects who achieved OR (CR+PR) at any time point
Failure free survival (FFS) [From baseline up to 35 days after end of study treatment, up to 37 months]
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
Cumulative incidence of malignancy relapse/recurrence (MR) [From baseline up to 35 days after end of study treatment, up to 37 months]
Defined as the time from date of treatment assignment to hematologic malignancy relapse/recurrence. Calculated for subjects with underlying hematologic malignant disease
Non-relapse mortality (NRM) [From baseline up to 35 days after end of study treatment, up to 37 months]
Defined as the time from date of treatment assignment to date of death not preceded by underlying disease relapse/recurrence
Overall survival (OS) [From baseline up to 35 days after end of study treatment, up to 37 months]
Defined as the time from the date of treatment assignment to the date of death due to any cause
Percentage of participants with ≥50% reduction from baseline in daily corticosteroid dose [Cycle 7 Day 1 (Day 168)]
Reduction of at least ≥50% in daily corticosteroid use
Percentage of participants with a reduction to a low dose corticosteriod [Cycle 7 Day 1 (Day 168)]
Reduction in daily corticosteroid dose to ≤0.2mg/kg/day methylprednisolone(or equivalent dose of ≤0.25mg/kg/day prednisone or prednisolone)
Graft failure [From baseline up to 35 days after end of study treatment, up to 37 months]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

28 Days to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Sao Paulo		Brazil	04039 001
2	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 1X8
3	Novartis Investigative Site	Praha 5		Czechia	150 06
4	Novartis Investigative Site	Tamil Nadu	Chennai	India	600035
5	Novartis Investigative Site	Bangalore	Karnataka	India	560099
6	Novartis Investigative Site	Pune	Maharashtra	India	411004
7	Novartis Investigative Site	Delhi		India	110 085
8	Novartis Investigative Site	Roma	RM	Italy	00165
9	Novartis Investigative Site	Nagoya	Aichi	Japan	466 8560
10	Novartis Investigative Site	Saitama		Japan	330 8777
11	Novartis Investigative Site	Seoul		Korea, Republic of	03080
12	Novartis Investigative Site	Seoul		Korea, Republic of	05505
13	Novartis Investigative Site	Sain Petersburg		Russian Federation	197022
14	Novartis Investigative Site	Bratislava		Slovakia	833 40
15	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
16	Novartis Investigative Site	Zuerich		Switzerland	8032
17	Novartis Investigative Site	Taipei		Taiwan	10002
18	Novartis Investigative Site	Bangkok		Thailand	10400
19	Novartis Investigative Site	Adana		Turkey	1330
20	Novartis Investigative Site	Antalya		Turkey	07000
21	Novartis Investigative Site	Antalya		Turkey	07070