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

Phase 2

Completed

Conditions: Graft vs Host Disease

Interventions: Drug: INC424

Registration Number: NCT03774082

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This open-label, single-arm, Phase II multi-center study enrolled 46 participants and investigated 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.

Although 46 participants were enrolled,1 participant (enrolled in the ≥6y to \<12y age group) received study treatment beyond protocol requirements and was excluded from analyses.

Detailed Description: Subjects were grouped according to their age as follows:

* Group 1 included subjects ≥12y to \<18y

* Group 2 included subjects ≥6y to \<12y

* Group 3 included subjects ≥2y to \<6y and

* Group 4 included subjects ≥28days to \<2y. Enrollment initiation into the youngest age group, Group 4, was subject to the availability of data in this age group from another study, as well as a review of available PK, safety, and activity data generated from Groups 1 to 3 in the current study. At least 5 evaluable participants per group were needed for the primary analysis in Groups 1, 2 and 3. No minimum number of evaluable participants were needed in Group 4. Enrollment was completed prior to the availability of the data and so no subjects were enrolled in Group 4.

After a screening period of Day -28 to Day -1: eligible subjects started study treatment on Cycle

1 Day 1 and were treated for up to a maximum of 3 years (39 cycles/156 weeks) or until early discontinuation. Subjects who discontinued study treatment for any reason earlier than 39 cycles were followed every 6 months until 3 years from their first dose of study treatment was reached.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 46

Inclusion Criteria

Male or female subjects age ≥28 days and <18 years at the time of informed consent.
Subjects who have undergone a successful 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 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
INC424 (ruxolitinib)	INC424	All pediatric participants received ruxolitinib twice a day (BID) in either tablet or oral solution (liquid), depending on the group they were in.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR) at Cycle 7 Day 1	At Cycle 7 Day 1 (Day 168); Cycle = 28 Days	ORR is defined as the percentage of participants 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 National Institute of Health (NIH) consensus criteria and scoring of response was relative to the organ stage at the start of study treatment.

Secondary Outcome Measures

Name	Time	Method
Ruxolitinib Concentrations by Timepoint	Cycle 1 Day 1: 0.5, 2 and 6 hours post-dose; Pre-dose on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 3 Day 1, Cycle 5 Day 1 and Cycle 7 Day 1; Cycle = 28 Days	Pharmacokinetics (PK) of ruxolitinib by age groups (and formulation tablet vs liquid).
Duration of Response (DOR)	From baseline up to 39 cycles; Cycle = 28 Days	Time from first response until chronic Graft vs. host disease (cGvHD) progression, death, or the date of addition of systemic therapies for cGvHD assessed for responders only based on BOR up to Cycle 7 Day 1. Presented as percentage of participants to still be in response at different time points in months (per Kaplan-Meier estimates). Participants without event will be censored at the date of their last response assessment prior to or at the analysis cut-off date if no events occurred on or before 12 weeks (84 days) after the last GvHD assessment. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups.
Overall Response Rate (ORR) at Cycle 4 Day 1	At Cycle 4 Day 1 (Day 84); Cycle = 28 Days	ORR is defined as the percentage of participants 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 National Institute of Health (NIH) consensus criteria and scoring of response will be relative to the organ stage at the start of study treatment at Cycle 4 Day 1.
Best Overall Response (BOR)	Until Cycle 7 Day 1 (Day 168) or the start of additional systemic therapy for cGvHD; Cycle = 28 Days	Percentage of participants who achieved overall response (complete response (CR) or partial response (PR)) at any time point until Cycle 7 Day 1 or the start of additional systemic therapy for chronic GvHD.
Failure Free Survival (FFS)	From baseline up to 39 cycles; Cycle = 28 Days	Failure-free survival was defined as the time from date of treatment to any of the following 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 per Kaplan-Meier estimates. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups.
Cumulative Incidence of Malignancy Relapse/Recurrence (MR)	From baseline up to 39 cycles; Cycle = 28 Days	MR was defined as the time from date of treatment assignment to the date of hematologic malignancy relapse/recurrence. Calculated for subjects with underlying hematologic malignant disease. The cumulative incidence (CI) of malignancy relapse/recurrence at 1, 2, 6, 12, 18, 24, 30 and 36 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups.
Non-relapse Mortality (NRM)	From baseline up to 39 cycles; Cycle = 28 Days	NRM is defined as the time from date of treatment assignment to date of death not preceded by underlying disease relapse/recurrence calculated for all participants. The cumulative incidence (CI) of non-relapse mortality at 1, 2, 6, 12, 18, 24, 30 and 36 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups.
Overall Survival (OS)	From baseline up to 39 cycles; Cycle = 28 Days	OS is defined as the time from the date of treatment assignment to the date of death due to any cause. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups.
Percentage of Participants With ≥50% Reduction From Baseline in Daily Corticosteroid Dose	Baseline to Cycle 7 Day 1 (Day 168); Cycle = 28 Days	Reduction of at least ≥50% from baseline in daily corticosteroid use by Cycle 7 Day 1 (regardless of reason). As planned in the SAP, this outcome measure is provided for all participants instead of per age groups, for those who received corticosteroids at baseline.
Percentage of Participants With a Reduction to a Low Dose Corticosteriod	Baseline to Cycle 7 Day 1 (Day 168); Cycle = 28 Days	Reduction to low dose corticosteroids, is defined as the percentage of participants with reduction from baseline in daily corticosteroid dose to methylprednisolone-equivalent steroid dose of ≤ 0.2 mg/kg/day (or equivalent dose of ≤ 0.25 mg/kg/day prednisone or prednisolone). As planned in the SAP, this outcome measure is provided for all participants instead of per age groups, for those who received corticosteroids at baseline.
Graft Failure	From baseline up to 39 cycles; Cycle = 28 Days	Reported are the number of participants with graft failure from all age groups together. Graft failure was assessed by 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 declined to \< 5% on subsequent measurements, graft failure was declared. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups.