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

Study Overview
=================
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.

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

Conditions
-----------------
Graft vs Host Disease

Intervention / Treatment
-----------------
* Drug: INC424


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 28 Days
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
INC424, pediatric, Chronic Graft versus Host Disease, moderate and severe chronic graft vs. host disease, allogeneic stem cell transplant, ruxolitinib, corticosteroids