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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 )

Tracking Information
First Submitted Date  ICMJE December 11, 2018
First Posted Date  ICMJE December 12, 2018
Last Update Posted Date November 20, 2020
Actual Study Start Date  ICMJE May 20, 2020
Estimated Primary Completion Date December 22, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 11, 2018)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 25, 2019)
  • 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
  • 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
  • Overall Response Rate (ORR) [ Time Frame: Cycle 4 Day 1 (Day 84) ]
    Proportion of subjects who achieve OR (CR+PR)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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)
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: December 11, 2018)
  • Pharmacokinetics (PK) parameter - AUC - of ruxolitinib in treatment-naïve cGvHD and SR-cGvHD pediatric subjects [ Time Frame: Cycle 7 Day 1 (from baseline to Day 168) ]
    Pharmacokinetic parameters derived by population PK analysis from sparse concentration-time data
  • PK parameter - Cmax - of ruxolitinib in treatment-naïve cGvHD and SR-cGvHD pediatric subjects [ Time Frame: Cycle 7 Day 1 (from baseline to Day 168) ]
    Pharmacokinetic parameters derived by population PK analysis from sparse concentration-time data
  • PK parameter - Ctrough - of ruxolitinib in treatment-naïve cGvHD and SR-cGvHD pediatric subjects [ Time Frame: Cycle 7 Day 1 (from baseline to Day 168) ]
    Pharmacokinetic parameters derived by population PK analysis from sparse concentration-time data
  • 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
  • Overall Response Rate (ORR) [ Time Frame: Cycle 4 Day 1 (Day 84) ]
    Proportion of subjects who achieve OR (CR+PR)
  • 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
  • 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
  • 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
  • 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
  • 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
  • Reduction in daily corticosteroid use [ Time Frame: Cycle 7 Day 1 (Day 168) ]
    Proportion of subjects with ≥50% reduction from baseline in daily corticosteroid dose
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Activity, Safety and Pharmacokinetics in Pediatric Subjects With Moderate and Severe Chronic Graft vs. Host Disease After Allogeneic Stem Cell Transplant
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Graft vs Host Disease
Intervention  ICMJE Drug: INC424
Ruxolitinib is taken orally either as 5mg tablets or as pediatric formulation (dosage based on age group)
Other Name: Ruxolitinib
Study Arms  ICMJE Experimental: INC424 (ruxolitinib)
Subjects who will be administered 5mg ruxolitinib tablet or ruxolitinib oral pediatric formulation twice a day.
Intervention: Drug: INC424
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 11, 2018)
42
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 24, 2026
Estimated Primary Completion Date December 22, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +81337978748
Listed Location Countries  ICMJE Brazil,   Czechia,   India,   Italy,   Japan,   Korea, Republic of,   Lithuania,   Russian Federation,   Slovakia,   Spain,   Switzerland,   Taiwan,   Thailand,   Turkey
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03774082
Other Study ID Numbers  ICMJE CINC424G12201
2018-003296-35 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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.

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP