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    Summary
    EudraCT Number:2018-000422-55
    Sponsor's Protocol Code Number:CINC424F12201
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-03-28
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-000422-55
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of pharmacokinetics, activity and safety of ruxolitinib in pediatric patients with grade II-IV acute graft vs. host disease
    A.4.1Sponsor's protocol code numberCINC424F12201
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/349/2017
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNOVARTIS FARMA S.p.A
    B.5.2Functional name of contact pointDrug Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address: Largo Umberto Boccioni, 1
    B.5.3.2Town/ cityORIGGIO
    B.5.3.3Post code21040
    B.5.3.4CountryItaly
    B.5.4Telephone number00390296541
    B.5.5Fax number0039029659066
    B.5.6E-mailinfo.studiclinici@novartis.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Jakavi
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameruxolitinib
    D.3.2Product code INC424
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNruxolitinib
    D.3.9.1CAS number 1092939-17-7
    D.3.9.2Current sponsor codeINC424
    D.3.9.3Other descriptive nameRUXOLITINIB PHOSPHATE
    D.3.9.4EV Substance CodeSUB32897
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    treatment naïve aGvHD grades II-IV or steroid-refractory aGvHD grades II-IV
    E.1.1.1Medical condition in easily understood language
    acute Graft vs Host Disease
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10064677
    E.1.2Term Graft versus host disease in intestine
    E.1.2System Organ Class 100000004870
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10075161
    E.1.2Term Graft versus host disease in GI tract
    E.1.2System Organ Class 100000004870
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I
    To assess pharmacokinetic (PK) parameters of ruxolitinib for
    patients with aGvHD and SR-aGvHD and define an age appropriate RP2D for each of the groups 2-4
     Group 2: age ≥6y to <12y
     Group 3: age ≥2y to <6y
     Group 4: age ≥28days to < 2y

    Phase II
    To measure the activity of ruxolitinib in patients with aGvHD
    or SR-aGvHD assessed by Overall Response Rate (ORR) at Day 28
    E.2.2Secondary objectives of the trial
    Key secondary:
    To assess the rate of durable ORR at Day 56

    Other secondary:
    - To estimate ORR at Day 14
    - To assess pharmacokinetic/ pharmacodynamic relationships
    - To assess Duration of response
    - To assess the cumulative steroid dose until Day 56
    - To evaluate the safety and tolerability of ruxolitinib
    - To evaluate effect of ruxolitinib on markers of bone development in pediatric patients
    - To assess Overall Survival (OS)
    - To assess Event-Free Survival (EFS)
    - To assess Failure-Free Survival (FFS)
    - To assess Non Relapse Mortality (NRM)
    - To assess incidence of Malignancy Relapse/Progression (MR)
    - To measure the incidence of cGvHD
    - To assess graft failure
    - To describe the acceptability and palatability assessments of the ruxolitinib formulation
    E.2.3Trial contains a sub-study No
    E.3Principal 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 confirmed diagnosis of grades II-IV aGvHD (Harris 2016) within 48 hours prior to study treatment start.
    Biopsy confirmation of aGvHD is recommended but is not required. Enrollment should not be delayed awaiting biopsy or
    athology results. Should the biopsy results not confirm aGvHD, however, the patient must discontinue from the study if
    study treatment has already been started. Patients may have either: Treatment-naïve aGvHD (criteria per Harris et al. 2016)
    OR Steroid refractory aGvHD as per institutional criteria, 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.)

    Other inclusion criteria as per full protocol may apply.
    E.4Principal 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
    rior to the diagnsosis 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 preemptive
    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.

    Additional exclusion criteria as per full protocol may apply.
    E.5 End points
    E.5.1Primary end point(s)
    Phase I:
    - Measurement of PK parameters in aGvHD and SR-aGvHD patients: AUC, Cmax, T1/2, Ctrough using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4

    - Age-based determination of RP2D for each of the groups 2-4, based on observed PK parameters

    Phase II:
    - Overall response rate (ORR) at Day 28, defined as the proportion 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
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I:
    - 28 days
    - 28 days

    Phase II:
    - 28 days
    E.5.2Secondary end point(s)
    Key secondary:
    Proportion of all patients who achieve a CR or PR at Day 28 and maintain a CR or PR at Day 56

    Other secondary:
    - Proportion of patients who achieved ORR (CR+PR) at Day 14
    - PK parameters (such as AUC, Cmax, Ctrough) versus safety, efficacy, and PD biomarkers, as
    appropriate
    - Duration of response (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
    - Weekly cumulative steroid dose for each patient up to Day 56
    - Assess changes in soluble markers for bone resorption and formation, including but not limited to CTX, osteopontin and BALP
    - Overall survival, defined as the time from the start of treatment to the date of death due to any cause
    - Event-free survival, defined as the time from start of treatment to the date of hematologic disease relapse/progression, graft failure, or death due to any cause
    - Failure-free survival, 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
    - Non-relapse mortality (NRM), defined as the time from start of treatment to date of death not
    preceded by hematologic disease relapse/progression
    - Malignancy Relapse/Progression (MR), defined as the time from start of treatment to hematologic malignancy relapse/progression. Calculated for patients with underlying hematologic malignant disease
    - cGvHD, defined as the diagnosis of any cGvHD including mild, moderate, severe
    - Monitoring of donor cell chimerism, defined as initial whole blood or marrow donor chimerism
    >5% declining to <5% on subsequent measurements compared to baseline
    - Questionnaire on acceptability and palatability for dose forms used after first dose, 1 month and 6 months
    E.5.2.1Timepoint(s) of evaluation of this end point
    Key secondary:
    - Day 56

    Other secondary:
    - Day 14
    - 24 weeks
    - 48 weeks
    - up to 56 days
    - 24 weeks
    - 2 years
    - 2 years
    - 2 years
    - 2 years
    - 2 years
    - 2 years
    - 2 years
    - 24 weeks
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    palatability assessment of the oral formulation
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    dose finding in paediatric patients
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA19
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Belgium
    Canada
    Chile
    France
    Germany
    Hong Kong
    Italy
    Japan
    Netherlands
    Slovenia
    Spain
    Turkey
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    last patient last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 39
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 5
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 10
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 24
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 21
    F.4.2.2In the whole clinical trial 43
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None, all patients must discontinue treatment by week 48, as defined in the protocol
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-07-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-16
    P. End of Trial
    P.End of Trial StatusOngoing
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