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

Study Overview
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Brief Summary
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The study is 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 includes four age groups: Group 1 includes patients ≥12y to <18y, Group 2 includes patients ≥6y to <12y, Group 3 includes patients ≥2y to <6y, and Group 4 includes patients ≥28days to <2y.

Detailed Description
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The study is 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 includes four age groups: Group 1 includes patients ≥12y to <18y, Group 2 includes patients ≥6y to <12y, Group 3 includes patients ≥2y to <6y, and Group 4 includes patients ≥28days to <2y.

Official Title
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A Phase I/II Open-label, Single-arm, Multi-center Study of Ruxolitinib Added to Corticosteroids in Pediatric Patients With Grade II-IV Acute Graft vs. Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Acute Graft Versus Host Disease

Intervention / Treatment
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* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 28 Days
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib<br>All patients received ruxolitinib in addition to corticosteroids +/-calcineurin inhibitor (CNI) | Drug: Ruxolitinib<br>* Ruxolitinib taken orally (5mg tablets) or oral pediatric formulation and dosage based on age group<br>* Other names: INC424;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Measurement of pharmacokinetic (PK) parameter, AUC, in aGvHD and SR-aGvHD patients | Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4 | 28 days | 
| Phase I: Measurement of PK parameter, Cmax, in aGvHD and SR-aGvHD patients | Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. | 28 days | 
| Phase I: Measurement of PK parameter, T1/2, in aGvHD and SR-aGvHD patients | Phase I: Measurement will be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. | 28 days | 
| Phase I: Measurement of PK parameter, Ctrough, in aGvHD and SR-aGvHD patients | Phase I: Measurement will use be using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. | 28 days | 
| Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2-4 | Phase I: Age-based determination of RP2D for was be based on observed PK parameters: Group 2: age ≥ 6 to < 12 years Group 3: age ≥ 2 to < 6 years Group 4: age ≥ 28 days to < 2 years | 28 days | 
| Phase II: Overall response rate (ORR) | 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 will be relative to the organ stage at the start of the study treatment. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of all patients who achieved a complete response (CR) or partial response (PR) | To assess the rate of durable ORR at Day 56 | 56 Days | 
| Percentage of patients who achieved OR (CR+PR) | 14 days | To estimate ORR at Day 14. | 
| PK parameter: Area under the curve (AUC) versus safety | To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUC with safety) | 24 weeks | 
| Duration of response (DOR) | DOR is assessed for responders only and is defined as the time from first response until aGvHD progression or the date of additional systemic therapies for aGvHD. Onset of chronic GvHD, or death without prior observation of aGvHD progression are considered as competing risks. | 48 weeks | 
| Weekly cumulative steroid dose for each patient | To assess the cumulative steroid dose until Day 56 | up to 56 days | 
| Overall Survival (OS) | OS is defined as the time from the start of treatment to the date of death due to any cause. | 2 years | 
| Event-Free Survival (EFS) | 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. | 2 years | 
| Failure-Free Survival (FFS) | FFS is defined as the time from the start of treatment to date of hematologic disease relapse/progression, non-relapse mortality, or addition of new systemic aGvHD treatment. | 2 years | 
| Non Relapse Mortality (NRM) | NRM is defined as the time from start of treatment to date of death not preceded by hematologic disease relapse/progression. | 2 years | 
| Incidence of Malignancy Relapse/Progression (MR) | MR is defined as the time from start of treatment to hematologic malignancy relapse/progression. Calculated for patients with underlying hematologic malignant disease. | 2 years | 
| Incidence of cGvHD | cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe | 2 years | 
| Monitoring of donor cell chimerism | Monitoring of donor cell chimerism to assess graft failure is defined as initial whole blood or marrow donor chimerism >5% declining to <5% on subsequent measurements compared to baseline. | 2 years | 
| Questionnaire on acceptability and palatability | Responses from the acceptability and palatability questionnaire for ruxolitinib dose forms used after first dose, 1 month and 6 months. | 24 weeks | 
| PK parameter - maximum serum concentration (Cmax) versus efficacy | To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with efficacy) | 24 weeks | 
| PK parameter: Minimum serum concentration (Ctrough) versus safety | To assess pharmacokinetic/pharmacodynamic relationships (comparison of Ctrough with safety) | 24 weeks | 
| PK parameter: Cmax versus safety | To assess pharmacokinetic/pharmacodynamics relationship (comparison of Cmax with safety) | 24 weeks | 
| PK parameter: Ctrough versus efficacy | To assess pharmacokinetic/pharmacodynamics relationship (comparison of Ctrough with efficacy) | 24 weeks | 
| PK parameter: AUC versus efficacy | To assess pharmacokinetic/pharmacodynamics relationship (comparison of AUC with efficacy) | 24 weeks | 
| PK parameter: AUC versus PD biomarkers | To assess pharmacokinetics/pharmacodynamics relationship (Comparison of AUC with PD biomarkers) | 24 weeks | 
| PK parameter: Cmax versus PD biomarkers | To assess pharmacokinetic/pharmocodynamic relationship (comparison of Cmax with PD biomarkers) | 24 weeks | 
| PK parameter: Ctrough versus PD biomarkers | To assess pharmacokinetic/pharmacodynamics relationship (Ctrough with PD biomarkers) | 24 weeks | 
| Percentage of patients who achieved Overall Response (OR) | Estimation of Best overall response (BOR) - is defined as percentage of patients OR (complete response (CR) + partial response (PR)) at any time and up to Day 28 and before the start of additional systemic aGvHD therapy | Up to 28 days and before start of additional aGvHD therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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INC424, Graft versus host disease, GvHD, acute graft versus host disease, aGvHD, Steroid refractory acute graft versus host disease, SR-aGvHD, Ruxolitinib, allogeneic stem cell transplantation, treatment naive