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Activity, Safety and Pharmacokinetics in Pediatric Subjects With Moderate and Severe Chronic Graft vs. Host Disease After Allogeneic Stem Cell Transplant

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ClinicalTrials.gov Identifier: NCT03774082
Recruitment Status : Recruiting
First Posted : December 12, 2018
Last Update Posted : November 20, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This open-label, single-arm, Phase II multi-center study will enroll approximately 42 subjects and investigate 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. Subjects will be grouped according to their age as follows: Group 1 includes subjects ≥12y to <18y, Group 2 includes subjects ≥6y to <12y, Group 3 includes subjects ≥2y to <6y, and Group 4 includes subjects ≥28days to <2y.

Condition or disease Intervention/treatment Phase
Graft vs Host Disease Drug: INC424 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 20, 2020
Estimated Primary Completion Date : December 22, 2023
Estimated Study Completion Date : August 24, 2026


Arm Intervention/treatment
Experimental: INC424 (ruxolitinib)
Subjects who will be administered 5mg ruxolitinib tablet or ruxolitinib oral pediatric formulation twice a day.
Drug: INC424
Ruxolitinib is taken orally either as 5mg tablets or as pediatric formulation (dosage based on age group)
Other Name: Ruxolitinib




Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Cycle 7 Day 1 (Day 168) ]
    ORR is defined as the proportion of subjects demonstrating a complete response (CR) or partial response (PR) without the requirement of additional systemic therapies for an earlier progression, mixed response or non-response. The response is assessed per NIH consensus criteria (Lee et al 2015) and scoring of response will be relative to the organ stage at the start of study treatment.


Secondary Outcome Measures :
  1. Ruxolitinib concentrations by timepoint [ Time Frame: Cycle 7 Day 1 (from baseline to Day 168) ]
    PK of ruxolitinib in treatment-naïve cGvHD and SR-cGvHD pediatric subjects

  2. Duration of response (DOR) [ Time Frame: From baseline up to end of study treatment, up to 36 months ]
    Time from first response until cGvHD progression, death, or the date of addition of systemic therapies for cGvHD

  3. Overall Response Rate (ORR) [ Time Frame: Cycle 4 Day 1 (Day 84) ]
    Proportion of subjects who achieve OR (CR+PR)

  4. Best overall response (BOR) [ Time Frame: Until Cycle 7 Day 1 (Day 168) or the start of additional systemic therapy for cGvHD ]
    Proportion of subjects who achieved OR (CR+PR) at any time point

  5. Failure free survival (FFS) [ Time Frame: From baseline up to 35 days after end of study treatment, up to 37 months ]
    Composite time to event endpoint incorporating the following FFS events: i) relapse or recurrence of underlying disease or death due to underlying disease, ii) non-relapse mortality, or iii) addition or initiation of another systemic therapy for cGvHD

  6. Cumulative incidence of malignancy relapse/recurrence (MR) [ Time Frame: From baseline up to 35 days after end of study treatment, up to 37 months ]
    Defined as the time from date of treatment assignment to hematologic malignancy relapse/recurrence. Calculated for subjects with underlying hematologic malignant disease

  7. Non-relapse mortality (NRM) [ Time Frame: From baseline up to 35 days after end of study treatment, up to 37 months ]
    Defined as the time from date of treatment assignment to date of death not preceded by underlying disease relapse/recurrence

  8. Overall survival (OS) [ Time Frame: From baseline up to 35 days after end of study treatment, up to 37 months ]
    Defined as the time from the date of treatment assignment to the date of death due to any cause

  9. Percentage of participants with ≥50% reduction from baseline in daily corticosteroid dose [ Time Frame: Cycle 7 Day 1 (Day 168) ]
    Reduction of at least ≥50% in daily corticosteroid use

  10. Percentage of participants with a reduction to a low dose corticosteriod [ Time Frame: Cycle 7 Day 1 (Day 168) ]
    Reduction in daily corticosteroid dose to ≤0.2mg/kg/day methylprednisolone(or equivalent dose of ≤0.25mg/kg/day prednisone or prednisolone)

  11. Graft failure [ Time Frame: From baseline up to 35 days after end of study treatment, up to 37 months ]
    Assess using 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 declines to <5% on subsequent measurements, the graft failure is declared



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female subjects age ≥28 days and <18 years at the time of informed consent.
  • Subjects 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.
  • Subjects with diagnosed moderate to severe cGvHD according to NIH 2014 Consensus Criteria (Section 16.2) 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, 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 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

Other protocol-defined inclusion/exclusion criteria may apply


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03774082


Contacts
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Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +81337978748

Locations
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Brazil
Novartis Investigative Site Recruiting
Sao Paulo, Brazil, 04039 001
Czechia
Novartis Investigative Site Recruiting
Praha 5, Czechia, 150 06
India
Novartis Investigative Site Recruiting
Tamil Nadu, Chennai, India, 600035
Novartis Investigative Site Recruiting
Bangalore, Karnataka, India, 560099
Novartis Investigative Site Recruiting
Pune, Maharashtra, India, 411004
Novartis Investigative Site Recruiting
Delhi, India, 110 085
Italy
Novartis Investigative Site Recruiting
Roma, ITA, Italy, 00165
Japan
Novartis Investigative Site Recruiting
Nagoya, Aichi, Japan, 466 8560
Novartis Investigative Site Recruiting
Saitama, Japan, 330 8777
Korea, Republic of
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 03080
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 05505
Lithuania
Novartis Investigative Site Recruiting
Vilnius, Lithuania, LT 08661
Russian Federation
Novartis Investigative Site Recruiting
Moscow, Russian Federation, 117997
Novartis Investigative Site Recruiting
Sain Petersburg, Russian Federation, 197022
Slovakia
Novartis Investigative Site Recruiting
Bratislava, Slovakia, 833 40
Spain
Novartis Investigative Site Recruiting
Malaga, Andalucia, Spain, 29010
Novartis Investigative Site Recruiting
Salamanca, Castilla Y Leon, Spain, 37007
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Recruiting
Valencia, Comunidad Valenciana, Spain, 46026
Novartis Investigative Site Recruiting
Madrid, Spain, 28009
Novartis Investigative Site Recruiting
Madrid, Spain, 28046
Switzerland
Novartis Investigative Site Recruiting
Zuerich, Switzerland, 8032
Taiwan
Novartis Investigative Site Recruiting
Taichung, Taiwan, 40447
Novartis Investigative Site Recruiting
Taipei, Taiwan, 10002
Thailand
Novartis Investigative Site Recruiting
Bangkok noi, Bangkok, Thailand, 10700
Novartis Investigative Site Recruiting
Bangkok, Thailand, 10330
Turkey
Novartis Investigative Site Recruiting
Adana, Turkey
Novartis Investigative Site Recruiting
Antalya, Turkey, 07000
Novartis Investigative Site Recruiting
Antalya, Turkey, 07070
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03774082    
Other Study ID Numbers: CINC424G12201
2018-003296-35 ( EudraCT Number )
First Posted: December 12, 2018    Key Record Dates
Last Update Posted: November 20, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.


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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
INC424
pediatric
Chronic Graft versus Host Disease
moderate and severe chronic graft vs. host disease
allogeneic stem cell transplant
ruxolitinib
corticosteroids
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases