Clinical trial NCT03491215: Study of Pharmacokinetics, Activity and Safety of Ruxolitinib in Pediatric Patients With Grade II-IV Acute Graft vs. Host Disease
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Acute Graft Versus Host Disease
Keywords: Graft versus host disease
GvHD
acute graft versus host disease
aGvHD
Steroid refractory acute graft versus host disease
SR-aGvHD
Ruxolitinib
INC424
allogeneic stem cell transplantation
treatment naive
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-04-09
Enrollment: 45
Sex: ALL
Minimum age (years): 28
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Phase I: Measurement of Pharmacokinetic (PK) Parameter, AUClast, in aGvHD and SR-aGvHD Patients
timeFrame: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
measure: Phase I: Measurement of PK Parameter, Cmax, in aGvHD and SR-aGvHD Patients
timeFrame: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
measure: Phase I: Measurement of PK Parameter, T1/2, in aGvHD and SR-aGvHD Patients
timeFrame: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
measure: Phase I: Measurement of PK Parameter, Ctrough, in aGvHD and SR-aGvHD Patients
timeFrame: Day 7 at pre-dose
measure: Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using AUClast
timeFrame: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
measure: Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using Cmax
timeFrame: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
measure: Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using Ctrough
timeFrame: Day 7 at pre-dose
measure: Phase II: Overall Response Rate (ORR)
timeFrame: Day 28
Secondary outcomes:
measure: Percentage of All Patients Who Achieved a Complete Response (CR) or Partial Response (PR) (Durable Overall Response Rate (ORR))
timeFrame: Day 56
measure: Percentage of Patients Who Achieved OR (CR+PR) at Day 14
timeFrame: Day 14
measure: Area Under the Curve (AUClast) Versus Efficacy: Impact of AUClast on Overall Response Rate (ORR) at Day 28
timeFrame: Day 28
measure: Area Under the Curve (AUClast) Versus Efficacy: Impact of AUClast on Durable Response Rate (DRR) at Day 56
timeFrame: Day 56
measure: Area Under the Curve (AUClast) Versus Safety: Impact of AUClast on Bleeding
timeFrame: 24 weeks
measure: Area Under the Curve (AUClast) Versus Safety: Impact of AUClast on Infection
timeFrame: 24 weeks
measure: Duration of Response (DOR)
timeFrame: Months 1, 2 & 6
measure: Weekly Cumulative Steroid Dose for Each Patient up to Day 56
timeFrame: up to 56 days (Week 1 - Week 8)
measure: Overall Survival (OS) Per Kaplan Meier
timeFrame: 1 Month (M), 2 M, 6M, 12M, 18M
measure: Event-Free Survival (EFS) Per Kaplan-Meier Estimates
timeFrame: 1 Month (M), 2 M, 6M, 12M, 18M
measure: Failure-Free Survival (FFS)
timeFrame: 1 Month (M), 2M, 6M, 12M, 18M, 24M
measure: Non Relapse Mortality (NRM)
timeFrame: Month (M)1, M2, M6, M12, M18, M24
measure: Incidence of Malignancy Relapse (MR)/Progression
timeFrame: Month (M) 1, M2, M6, M12, M18, M24,
measure: Cumulative Incidence (CI) of cGvHD
timeFrame: Month (M) 1, M2, M6, M12, M18, M24
measure: Graft Failure
timeFrame: 2 years
measure: Questionnaire on Acceptability and Palatability
timeFrame: Day 1, Week 4 (1 month), Week 24 (6 months)
measure: PK Parameter - Maximum Serum Concentration (Cmax) Versus Efficacy
timeFrame: 24 weeks
measure: PK Parameter: Minimum Serum Concentration (Ctrough) Versus Safety
timeFrame: 24 weeks
measure: PK Parameter: Cmax Versus Safety
timeFrame: 24 weeks
measure: PK Parameter: Ctrough Versus Efficacy
timeFrame: 24 weeks
measure: PK Parameter: Profile of Biomarker Concentration Changes Across Different AUC Quantile Groups
timeFrame: Week 4
measure: PK Parameter: Cmax Versus PD Biomarkers
timeFrame: 24 weeks
measure: PK Parameter: Ctrough Versus PD Biomarkers
timeFrame: 24 weeks
measure: Percentage of Patients Who Achieved Best Overall Response (BOR) up to Day 28
timeFrame: Up to 28 days and before start of additional aGvHD therapy
Other outcomes:
Locations:
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Laeken
country: Belgium
facility: Novartis Investigative Site
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Copenhagen
country: Denmark
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Nantes Cedex 01
country: France
facility: Novartis Investigative Site
city: Paris 15
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Rennes
country: France
facility: Novartis Investigative Site
city: Vandoeuvre Les Nancy
country: France
facility: Novartis Investigative Site
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Saitama
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: