Study of Pharmacokinetics, Activity and Safety of Ruxolitinib in Pediatric Patients With Grade II-IV Acute Graft vs. Host Disease

The study was an open-label, single-arm, Phase I/II multi-center study to investigate the PK, activity and safety of ruxolitinib added to the patient's immunosuppressive regimen in infants, children, and adolescents ages ≥28 days to \<18 years old with either grade II-IV aGvHD or grade II-IV SR-aGvHD. The trial design included four age groups: Group 1 included patients ≥12y to \<18y, Group 2 included patients ≥6y to \<12y, Group 3 included patients ≥2y to \<6y, and Group 4 included patients ≥28days to \<2y.

This Phase I/II, open-label, uncontrolled, single-arm, multi-center study investigated PK, activity and safety of ruxolitinib when added to the subject's immunosuppressive regimen in infants, children, and adolescents aged ≥ 28 days to \< 18 years with either grade II-IV treatment naive acute GvHD or grade II-IV SR-acute GvHD following allogeneic HSCT.

The trial subjects were grouped by age as follows:

* Group 1: subjects ≥ 12y to \< 18y,
* Group 2: subjects ≥ 6y to \< 12y
* Group 3: subjects ≥ 2y to \< 6y
* Group 4 was to include subjects ≥ 28 days to \< 2y

Subjects remained in the designated age group throughout the duration of the study, based on their age at the start of treatment. All subjects in this study were enrolled and treated for 24 weeks (approximately 6 months) or until early discontinuation.

All subjects were followed for an additional 18 months (total duration = 2 years from enrolment). Where the occurrence of acute GvHD flare require re-initiation of treatment or when extended tapering resulted in ruxolitinib not having been discontinued by the end of 24 weeks, subjects could continue to taper ruxolitinib beyond 24 weeks up to a maximum of 48 weeks.

Subjects ≥ 12 y to \< 18 y (Group 1) were treated with 10 mg BID, this dose was the RP2D, and was used to treat all subjects in this age group in Phase II of Study CINC424F12201. All other age groups were treated with the RP2D determined during Phase I of study CINC424F12201.

Therefore, all ≥12 to \<18 year old subjects were automatically enrolled in Phase II. The first 5 subjects treated in Group 1 underwent extensive PK sampling to inform the RP2D determination of the younger age groups in Phase I.

Eligibility Criteria:
Inclusion Criteria:

* Male or female patients age ≥28 days and \<18 years at the time of informed consent.
* Patients 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.
* Patients with a clinically confirmed diagnosis of grades II-IV aGvHD within 48 hours prior to study treatment start. Patients may have either: Treatment-naïve aGvHD (criteria per Harris et al. 2016) OR Steroid refractory aGvHD as per institutional criteria, or per physician decision in case institutional criteria are not available, and the patient is currently receiving systemic corticosteroids.
* Evident myeloid engraftment with ANC \> 1,000/µl and platelet count \>20,000/µl. (Use of growth factor supplementation and transfusion support is allowed.)

Exclusion Criteria:

* Has received the following systemic therapy for aGvHD: a) Treatment-naïve aGvHD patients have received any prior systemic treatment of aGvHD except for a maximum 72h of prior systemic corticosteroid therapy of methylprednisolone or equivalent after the onset of acute GvHD. Patients are allowed to have received prior GvHD prophylaxis which is not counted as systemic treatment (as long as the prophylaxis was started prior to the diagnosis of aGvHD); OR b) SR-aGvHD patients have received two or more prior systemic treatments for aGvHD in addition to corticosteroids
* Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features (as defined by Jagasia et al 2015).
* Failed prior alloSCT within the past 6 months.
* Presence of relapsed primary malignancy, or who have been treated for relapse after the alloSCT was performed, or who may require rapid immune suppression withdrawal of immune suppression as pre-emergent treatment of early malignancy relapse.
* Acute GvHD occurring after non-scheduled donor leukocyte infusion (DLI) administered for pre-emptive treatment of malignancy recurrence. Note: Patients who have received a scheduled DLI as part of their transplant procedure and not for management of malignancy relapse are eligible.
* Any corticosteroid therapy for indications other than aGvHD at doses \> 1 mg/kg/day methylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days of Screening. Routine corticosteroids administered during conditioning or cell infusion is allowed.
* Patients who received JAK inhibitor therapy for any indication after initiation of current alloSCT conditioning.

Other protocol-defined Inclusion/Exclusion may apply.