Clinical trial NCT03774082: Activity, Safety and Pharmacokinetics in Pediatric Subjects With Moderate and Severe Chronic Graft vs. Host Disease After Allogeneic Stem Cell Transplant
Official title: A Phase II Open-label, Single-arm, Multi-center Study of Ruxolitinib Added to Corticosteroids in Pediatric Subjects With Moderate and Severe Chronic Graft vs. Host Disease After Allogeneic Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Graft vs Host Disease
Keywords: GvHD
INC424
pediatric
Chronic Graft versus Host Disease
moderate and severe chronic graft vs. host disease
allogeneic stem cell transplant
ruxolitinib
corticosteroids
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-12-12
Enrollment: 46
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: This open-label, single-arm, Phase II multi-center study enrolled 46 participants and investigated the activity, pharmacokinetics and safety of ruxolitinib added to the subject's immunosuppressive regimen among infants, children, and adolescents aged ≥28 days to \<18 years old with either moderate to severe treatment-naive cGvHD or SR-cGvHD.

Although 46 participants were enrolled,1 participant (enrolled in the ≥6y to \<12y age group) received study treatment beyond protocol requirements and was excluded from analyses.

Detailed description: Subjects were grouped according to their age as follows:

* Group 1 included subjects ≥12y to \<18y
* Group 2 included subjects ≥6y to \<12y
* Group 3 included subjects ≥2y to \<6y and
* Group 4 included subjects ≥28days to \<2y. Enrollment initiation into the youngest age group, Group 4, was subject to the availability of data in this age group from another study, as well as a review of available PK, safety, and activity data generated from Groups 1 to 3 in the current study. At least 5 evaluable participants per group were needed for the primary analysis in Groups 1, 2 and 3. No minimum number of evaluable participants were needed in Group 4. Enrollment was completed prior to the availability of the data and so no subjects were enrolled in Group 4.

After a screening period of Day -28 to Day -1: eligible subjects started study treatment on Cycle

1 Day 1 and were treated for up to a maximum of 3 years (39 cycles/156 weeks) or until early discontinuation. Subjects who discontinued study treatment for any reason earlier than 39 cycles were followed every 6 months until 3 years from their first dose of study treatment was reached.

Eligibility criteria: Inclusion Criteria:

* Male or female subjects age ≥28 days and \<18 years at the time of informed consent.
* Subjects who have undergone a successful 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.
* Subjects with diagnosed moderate to severe cGvHD according to NIH 2014 Consensus Criteria prior to Cycle 1 Day 1. Other possible diagnoses for clinical symptoms supporting cGvHD diagnoses must be excluded (e.g., infection, drug side effects, malignancy). Subjects must be either:

  * Treatment-naive cGvHD subjects that have not received any prior systemic treatment for cGvHD except for a maximum 72h of prior systemic corticosteroid therapy of methylprednisolone or equivalent after the onset of chronic GvHD. Subjects are allowed to have received prior systemic treatment for cGvHD prophylaxis (as long as the prophylaxis was started prior to the diagnosis of cGvHD).

OR o Steroid-refractory moderate to severe cGvHD as per institutional criteria, or per physician decision in case institutional criteria are not available, and still receiving systemic corticosteroids for the treatment of cGvHD for a duration of \<18 months prior to Cycle 1 Day 1. In case the corticosteroids were previously interrupted due to response, the duration of \< 18 months applies to the last period of corticosteroid use.

Exclusion Criteria:

* SR-cGvHD subjects with a prior cGvHD treatment with a JAK1- or a JAK2- or a JAK1/2-inhibitor, except when the subject achieved complete or partial response and has been off JAK inhibitor treatment for at least 4 weeks prior to Cycle Day 1 or up to 5 times the half-life of the prior JAK inhibitor, whichever is longer.

  \* Subjects who initiated systemic calcineurin inhibitors (CNI; cyclosporine or tacrolimus) within 3 weeks prior to start of ruxolitinib on Cycle 1 Day 1. Note: systemic CNI are allowed when initiated \> 3 weeks from start of ruxolitinib.
* Failed prior alloSCT within the past 6 months
* Significant respiratory disease including subjects who are on mechanical ventilation or who have a resting oxygen saturation \< 90% by pulse-oximetry on room-air.
* Impairment of gastrointestinal (GI) function (unrelated to GvHD) or GI disease (unrelated to GvHD) that may significantly alter the absorption of oral ruxolitinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection),
* Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to cGvHD and ongoing organ dysfunction)
* Presence of clinically active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment.
* Known human immunodeficiency virus (HIV) infection.
* Evidence of uncontrolled hepatitis B virus (HBV) or hepatitis C virus (HCV) based on assessment done by Investigator or delegate.
* Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds.
* History of bone disorders such as osteogenesis imperfecta, rickets, renal osteodystrophy, osteomyelitis, osteopenia, fibrous dysplasia, osteomalacia etc. prior to the underlying diagnosis which resulted in the alloSCT.
* History of endocrine or kidney related growth retardation prior to the underlying diagnosis which resulted in the alloSCT.
* Evidence of clinically active tuberculosis (clinical diagnosis per local practice)
* Any corticosteroid therapy for indications other than cGvHD at doses \> 1 mg/kg/daymethylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days of the screening visit.
* History of progressive multifocal leuko-encephalopathy (PML).
* Presence of severely impaired renal function

Primary outcomes:
measure: Overall Response Rate (ORR) at Cycle 7 Day 1
timeFrame: At Cycle 7 Day 1 (Day 168); Cycle = 28 Days
Secondary outcomes:
measure: Ruxolitinib Concentrations by Timepoint
timeFrame: Cycle 1 Day 1: 0.5, 2 and 6 hours post-dose; Pre-dose on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 3 Day 1, Cycle 5 Day 1 and Cycle 7 Day 1; Cycle = 28 Days
measure: Duration of Response (DOR)
timeFrame: From baseline up to 39 cycles; Cycle = 28 Days
measure: Overall Response Rate (ORR) at Cycle 4 Day 1
timeFrame: At Cycle 4 Day 1 (Day 84); Cycle = 28 Days
measure: Best Overall Response (BOR)
timeFrame: Until Cycle 7 Day 1 (Day 168) or the start of additional systemic therapy for cGvHD; Cycle = 28 Days
measure: Failure Free Survival (FFS)
timeFrame: From baseline up to 39 cycles; Cycle = 28 Days
measure: Cumulative Incidence of Malignancy Relapse/Recurrence (MR)
timeFrame: From baseline up to 39 cycles; Cycle = 28 Days
measure: Non-relapse Mortality (NRM)
timeFrame: From baseline up to 39 cycles; Cycle = 28 Days
measure: Overall Survival (OS)
timeFrame: From baseline up to 39 cycles; Cycle = 28 Days
measure: Percentage of Participants With ≥50% Reduction From Baseline in Daily Corticosteroid Dose
timeFrame: Baseline to Cycle 7 Day 1 (Day 168); Cycle = 28 Days
measure: Percentage of Participants With a Reduction to a Low Dose Corticosteriod
timeFrame: Baseline to Cycle 7 Day 1 (Day 168); Cycle = 28 Days
measure: Graft Failure
timeFrame: From baseline up to 39 cycles; Cycle = 28 Days
Other outcomes:
Locations:
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Praha 5
country: Czechia
facility: Novartis Investigative Site
city: Tamil Nadu
country: India
facility: Novartis Investigative Site
state: Chennai
city: Pune
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Bangalore
country: India
facility: Novartis Investigative Site
city: Delhi
country: India
facility: Novartis Investigative Site
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: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Antalya
country: Turkey
facility: Novartis Investigative Site
city: Antalya
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: