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

Phase 1

Completed

Conditions: Acute Graft Versus Host Disease

Interventions: Drug: Ruxolitinib

Registration Number: NCT03491215

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 45

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Ruxolitinib	Ruxolitinib	All pediatric participants received ruxolitinib twice a day (BID) for a planned duration of 24 weeks in either tablet, capsule or oral solution (liquid), depending on the group they were in.

Primary Outcome Measures

Name	Time	Method
Phase I: Measurement of Pharmacokinetic (PK) Parameter, AUClast, in aGvHD and SR-aGvHD Patients	Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose	Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 sparse sampling in Group 4. AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).
Phase I: Measurement of PK Parameter, Cmax, in aGvHD and SR-aGvHD Patients	Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose	Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. Cmax: The maximum (peak) observed plasma drug concentration
Phase I: Measurement of PK Parameter, T1/2, in aGvHD and SR-aGvHD Patients	Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose	Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. T1/2: The elimination half-life associated with the terminal slope (Lambda_z ) of a semi logarithmic concentration-time curve
Phase I: Measurement of PK Parameter, Ctrough, in aGvHD and SR-aGvHD Patients	Day 7 at pre-dose	Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).
Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using AUClast	Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose	Phase I: Age-based determination of RP2D in Groups 2 and 3 and was based on observed PK parameters in Groups 1-3 * Group 2: age ≥ 6 to \< 12 years * Group 3: age ≥ 2 to \< 6 years AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).
Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using Cmax	Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose	Phase I: Age-based determination of RP2D in Groups 2 and 3 and was based on observed PK parameters in Groups 1-3 * Group 2: age ≥ 6 to \< 12 years * Group 3: age ≥ 2 to \< 6 years Cmax: The maximum (peak) observed plasma drug concentration.
Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using Ctrough	Day 7 at pre-dose	Phase I: Age-based determination of RP2D in Groups 2 and 3 and was based on observed PK parameters in Groups 1-3 * Group 2: age ≥ 6 to \< 12 years * Group 3: age ≥ 2 to \< 6 years Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).
Phase II: Overall Response Rate (ORR)	Day 28	Phase II: ORR is defined as the percentage of patients demonstrating a complete response (CR) or partial response (PR) without requirement for additional systemic therapies for an earlier progression, mixed response or non-response. Scoring of response was relative to the organ stage at the start of the study treatment. Complete response (CR) is defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapy for any earlier progression, mixed response or non-response of aGvHD. Partial response (PR) is defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapy for an earlier progression, mixed response or non-response of aGvHD.

Secondary Outcome Measures

Name	Time	Method
Area Under the Curve (AUClast) Versus Efficacy: Impact of AUClast on Overall Response Rate (ORR) at Day 28	Day 28	To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUClast with ORR at day 28). ORR is the percentage of patients with a complete response (CR) or partial response (PR) without additional systemic therapies. Given age group did not have a significant effect on the model fit, the comparison is made indirectly through the odds ratio across exposure levels in each group. A high response rate may prevent model convergence. Results are shown only upon successful convergence.
Percentage of All Patients Who Achieved a Complete Response (CR) or Partial Response (PR) (Durable Overall Response Rate (ORR))	Day 56	Durable ORR at Day 56 was defined as the percentage of all subjects who achieved a complete response (CR) or partial response (PR) at Day 28 and maintained a CR or PR at Day 56. Complete-response was defined as a score of 0 for the acute GvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of acute GvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of acute GvHD. Partial response was defined as improvement of 1 stage in 1 or more organs involved with acute GvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of acute GvHD.
Percentage of Patients Who Achieved OR (CR+PR) at Day 14	Day 14	ORR at Day 14 was defined as the percentage of participants with complete response (CR) or partial response (PR ) at Day 14 according to standard criteria. Complete response (CR) is defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapy for any earlier progression, mixed response or non-response of aGvHD. Partial response (PR) is defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapy for an earlier progression, mixed response or non-response of aGvHD.
Area Under the Curve (AUClast) Versus Efficacy: Impact of AUClast on Durable Response Rate (DRR) at Day 56	Day 56	To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUClast with DRR at day 56). Durable ORR at Day 56 was defined as the percentage of all participants who achieved a complete response (CR) or partial response (PR) at Day 28 and maintained a CR or PR at Day 56. Given age group did not have a significant effect on the model fit, the comparison is made indirectly through the odds ratio across exposure levels in each group. A high response rate may prevent model convergence. Results are shown only upon successful convergence.
Area Under the Curve (AUClast) Versus Safety: Impact of AUClast on Bleeding	24 weeks	To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUClast with safety - bleeding). Bleeding was reported as an adverse event and the AE severity grade was assessed according to CTCAE grading. Given age group did not have a significant effect on the model fit, the comparison is made indirectly through the hazard ratio across exposure levels in each group. A high response rate may prevent model convergence. Results are shown only upon successful convergence.
Area Under the Curve (AUClast) Versus Safety: Impact of AUClast on Infection	24 weeks	To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUClast with safety - infection). This analysis includes subjects from F12201 (pediatric and adolescent participants) study. Infections were reported as adverse events and the AE severity grade was assessed according to CTCAE grading. Given age group did not have a significant effect on the model fit, the comparison is made indirectly throughs the hazard ratio across exposure levels in each group. A high response rate may prevent model convergence. Results are shown only upon successful convergence
Duration of Response (DOR)	Months 1, 2 & 6	Duration of response was defined as the time from first response (PR or CR) until acute GvHD progression, or the date of additional systemic therapy for acute GvHD. Death without prior observation of acute GvHD progression, and onset of chronic GvHD are considered to be competing risks. Duration of response will be censored at the last response assessment prior to or at the analysis cut-off date, if no events/competing risks occurred on or before 4 weeks (28 days) after the last GvHD assessment. The estimated probability of loss of response at 1, 2 and 6 months after participant's first achievement of CR or PR has been reported. Due to the presence of competing risk, the DOR results are being presented in the form of the probability of loss of response at different time points. As planned in the Statistical Analysis Plan (SAP), this outcome measure is provided for all subjects instead of per age groups.
Weekly Cumulative Steroid Dose for Each Patient up to Day 56	up to 56 days (Week 1 - Week 8)	The weekly cumulative steroid dose was calculated for each subject up to Day 56 and the overall cumulative steroid dose was calculated for each subject at Day 56.
Overall Survival (OS) Per Kaplan Meier	1 Month (M), 2 M, 6M, 12M, 18M	OS is defined as the time from the start of treatment to the date of death due to any cause. If a subject was not known to have died, then OS was censored at the latest date the subject was known to be alive. The estimated survival probability at 1,2,6,12,18 months after start of treatment has been reported. (on or before the cut-off date). As planned in the SAP, this outcome measure is provided for all subjects instead of per age groups.
Event-Free Survival (EFS) Per Kaplan-Meier Estimates	1 Month (M), 2 M, 6M, 12M, 18M	EFS is defined as the time from start of treatment to the date of hematologic disease relapse/progression, graft failure, or death due to any cause. If a subject was not known to have any event, then EFS was censored at the latest date the subject was known to be alive (on or before the cut-off date).The estimated probability of event free at 1,2,6,12,18 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all subjects instead of per age groups.
Failure-Free Survival (FFS)	1 Month (M), 2M, 6M, 12M, 18M, 24M	Failure-free (FF) survival was defined as the time from start date of treatment to any of the following: hematologic relapse/progression, non-relapse mortality (NRM) or addition of new systemic acute GvHD treatment. The cumulative incidence (CI) of the onset of failure event at 1,2,6,12,18,24 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all subjects instead of per age groups.
Non Relapse Mortality (NRM)	Month (M)1, M2, M6, M12, M18, M24	NRM is defined as the time from start of treatment to date of death not preceded by hematologic disease relapse/progression. The cumulative incidence (CI) of non-relapse mortality at 1,2,6,12,18,24 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all subjects instead of per age groups.
Incidence of Malignancy Relapse (MR)/Progression	Month (M) 1, M2, M6, M12, M18, M24,	MR was defined as the time from start of treatment to hematologic malignancy relapse/progression. Calculated for patients with underlying hematologic malignant disease. The cumulative incidence (CI) of malignancy relapse/progression at 1,2,6,12,18,24 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all subjects instead of per age groups.
Cumulative Incidence (CI) of cGvHD	Month (M) 1, M2, M6, M12, M18, M24	cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe. Incidence of chronic GvHD was the time from the start of treatment to onset of chronic GvHD. Cumulative incidence of chronic GvHD was estimated, accounting for deaths without prior onset of chronic GvHD and hematologic disease relapse/progression as the competing risks. The cumulative incidence (CI) of cGvHD at 1, 2, 6, 12, 18 and 24 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all subjects instead of per age groups.
Graft Failure	2 years	This 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.
Questionnaire on Acceptability and Palatability	Day 1, Week 4 (1 month), Week 24 (6 months)	Responses from the acceptability and palatability of the study drug (only for subjects administered with oral pediatric formulation starting treatment Day 1) were evaluated from a questionnaire completed by subjects, with the help from parents or caregivers as needed at the following visits: Day 1 (after first dose), Week 4 (1 month) ((after either morning or evening dose of that visit date), Week 24 (6 months) (after either morning or evening dose of that visit date). The choices for taste of the medication were, 'Very good', 'good', 'not good or bad', 'Bad', very bad. The choices for aftertaste of the medication were, 'Very good', 'Good', 'Not good or bad' , 'Bad', Very bad'. The choices for the smell of the medication were, 'Not good or bad' or 'Bad'.
PK Parameter - Maximum Serum Concentration (Cmax) Versus Efficacy	24 weeks	To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with efficacy). Cmax: The maximum (peak) observed plasma drug concentration.
PK Parameter: Minimum Serum Concentration (Ctrough) Versus Safety	24 weeks	To assess pharmacokinetic/pharmacodynamic relationships (comparison of Ctrough with safety). Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).
PK Parameter: Cmax Versus Safety	24 weeks	To assess pharmacokinetic/pharmacodynamics relationship (comparison of Cmax with safety). Cmax: The maximum (peak) observed plasma drug concentration.
PK Parameter: Ctrough Versus Efficacy	24 weeks	To assess pharmacokinetic/pharmacodynamics relationship (comparison of Ctrough with efficacy). Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).
PK Parameter: Profile of Biomarker Concentration Changes Across Different AUC Quantile Groups	Week 4	Describe the relationship between AUC and PD biomarkers. Provide profile of biomarker concentration changes across different AUC quantile groups from baseline. This analysis includes subjects from F12201 study. Population was divided by four level of exposure using AUClast Day 1 quartiles. As planned in SAP, this outcome measure is provided for all subjects instead of per age groups.
PK Parameter: Cmax Versus PD Biomarkers	24 weeks	To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with PD biomarkers). Cmax: The maximum (peak) observed plasma drug concentration.
PK Parameter: Ctrough Versus PD Biomarkers	24 weeks	To assess pharmacokinetic/pharmacodynamics relationship (Ctrough with PD biomarkers). Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).
Percentage of Patients Who Achieved Best Overall Response (BOR) up to Day 28	Up to 28 days and before start of additional aGvHD therapy	The best overall response (BOR) was defined as percentage of participants with (complete response (CR) or partial response (PR) at any time point and up to and including Day 28 and before the start of additional systemic therapy for acute GvHD (aGvHD).