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

Acute Graft Versus Host Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03491215
• Other study ID #: CINC424F12201
• Secondary ID: 2018-000422-55
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: February 21, 2019
• Est. completion date: February 2, 2023

Study information

• Verified date: June 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: February 2, 2023
• Est. primary completion date: March 11, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 28 Days to 17 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Graft Versus Host Disease
• Graft vs Host Disease

Intervention

Drug:
• Ruxolitinib
Ruxolitinib taken orally (5mg tablets) or oral pediatric formulation and dosage based on age group

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Laeken
Canada	Novartis Investigative Site	Montreal	Quebec
Denmark	Novartis Investigative Site	Copenhagen
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Nantes Cedex 01
France	Novartis Investigative Site	Paris Cedex
France	Novartis Investigative Site	Paris cedex 15
France	Novartis Investigative Site	Rennes Cedex
France	Novartis Investigative Site	Vandoeuvre Les Nancy
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	Roma	RM
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Saitama
Korea, Republic of	Novartis Investigative Site	Seoul
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Belgium,  Canada,  Denmark,  France,  Italy,  Japan,  Korea, Republic of,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	Percentage of patients who achieved OR (CR+PR)	14 days	To estimate ORR at Day 14.
Secondary	PK parameter: Area under the curve (AUC) versus safety	To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUC with safety)	24 weeks
Secondary	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
Secondary	Weekly cumulative steroid dose for each patient	To assess the cumulative steroid dose until Day 56	up to 56 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Incidence of cGvHD	cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe	2 years
Secondary	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
Secondary	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
Secondary	PK parameter - maximum serum concentration (Cmax) versus efficacy	To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with efficacy)	24 weeks
Secondary	PK parameter: Minimum serum concentration (Ctrough) versus safety	To assess pharmacokinetic/pharmacodynamic relationships (comparison of Ctrough with safety)	24 weeks
Secondary	PK parameter: Cmax versus safety	To assess pharmacokinetic/pharmacodynamics relationship (comparison of Cmax with safety)	24 weeks
Secondary	PK parameter: Ctrough versus efficacy	To assess pharmacokinetic/pharmacodynamics relationship (comparison of Ctrough with efficacy)	24 weeks
Secondary	PK parameter: AUC versus efficacy	To assess pharmacokinetic/pharmacodynamics relationship (comparison of AUC with efficacy)	24 weeks
Secondary	PK parameter: AUC versus PD biomarkers	To assess pharmacokinetics/pharmacodynamics relationship (Comparison of AUC with PD biomarkers)	24 weeks
Secondary	PK parameter: Cmax versus PD biomarkers	To assess pharmacokinetic/pharmocodynamic relationship (comparison of Cmax with PD biomarkers)	24 weeks
Secondary	PK parameter: Ctrough versus PD biomarkers	To assess pharmacokinetic/pharmacodynamics relationship (Ctrough with PD biomarkers)	24 weeks
Secondary	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