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

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.

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