Acute Graft Versus Host DiseasePhase 1/2NCT03491215
Study of Pharmacokinetics, Activity and Safety of Ruxolitinib in Pediatric Patients With Grade II-IV Acute Graft vs. Host Disease
A Phase 1/2 study testing Ruxolitinib in people with Acute Graft Versus Host Disease, run by Novartis Pharmaceuticals at 19 sites in 8 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 28 days to 17 years
- Conditions the study is for
- Acute Graft Versus Host Disease
- What is being tested?
- Ruxolitinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 45 participants
- Where
- 19 sitesin 8 countries
- Study dates
- 21 Feb 2019to 2 Feb 2023
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 28 days to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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.)
Who cannot join
- 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.
Trial locations and contacts
19 sites in 8 countries.
19 sites in 8 countries
France6 sites
Novartis Investigative Site
Lille, 59000
Novartis Investigative Site
Nantes, 44093
Novartis Investigative Site
Paris, 75015
Novartis Investigative Site
Paris, 75019
Novartis Investigative Site
Rennes, 35022
Novartis Investigative Site
Vandœuvre-lès-Nancy, 54511
Spain4 sites
Novartis Investigative Site
Barcelona, Catalonia, 08035
Novartis Investigative Site
Barcelona, 08041
Novartis Investigative Site
Madrid, 28009
Novartis Investigative Site
Madrid, 28046
Belgium2 sites
Novartis Investigative Site
Ghent, 9000
Novartis Investigative Site
Laken, 1020
Italy2 sites
Novartis Investigative Site
Genova, GE, 16147
Novartis Investigative Site
Roma, RM, 00165
Japan2 sites
Novartis Investigative Site
Nagoya, Aichi-ken, 466 8560
Novartis Investigative Site
Saitama, 330 8777
About this study
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
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.
Read the 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.
- Conditions
- Acute Graft Versus Host Disease
- Being tested
- Ruxolitinib
- 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
- Medical subject headings
- Graft vs Host Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RuxolitinibDrug
Also called INC424
All enrolled pediatric participants received ruxolitinib as a 5 mg tablet (adult and adolescent formulation) or an oral pediatric formulation (administered as oral solution or capsule dispersed in liquid).
| Study group | Role | What they receive |
|---|---|---|
| Ruxolitinib | Experimental | All pediatric participants received ruxolitinib twice a day (BID) for a planned duration of 24 weeks in either tablet, capsule or oral solution (liquid), depending on the group they were in. Receives: Drug: Ruxolitinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase I: Measurement of Pharmacokinetic (PK) Parameter, AUClast, in aGvHD and SR-aGvHD Patients
Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 sparse sampling in Group 4.
AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).
Measured: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
Phase I: Measurement of PK Parameter, Cmax, in aGvHD and SR-aGvHD Patients
Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
Cmax: The maximum (peak) observed plasma drug concentration
Measured: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
Phase I: Measurement of PK Parameter, T1/2, in aGvHD and SR-aGvHD Patients
Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4.
T1/2: The elimination half-life associated with the terminal slope (Lambda_z ) of a semi logarithmic concentration-time curve
Measured: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
Phase I: Measurement of PK Parameter, Ctrough, in aGvHD and SR-aGvHD Patients
Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).
Measured: Day 7 at pre-dose
Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using AUClast
Phase I: Age-based determination of RP2D in Groups 2 and 3 and was based on observed PK parameters in Groups 1-3
- Group 2: age ≥ 6 to < 12 years
- Group 3: age ≥ 2 to < 6 years AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).
Measured: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using Cmax
Phase I: Age-based determination of RP2D in Groups 2 and 3 and was based on observed PK parameters in Groups 1-3
- Group 2: age ≥ 6 to < 12 years
- Group 3: age ≥ 2 to < 6 years Cmax: The maximum (peak) observed plasma drug concentration.
Measured: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using Ctrough
Phase I: Age-based determination of RP2D in Groups 2 and 3 and was based on observed PK parameters in Groups 1-3
- Group 2: age ≥ 6 to < 12 years
- Group 3: age ≥ 2 to < 6 years Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).
Measured: Day 7 at pre-dose
Phase II: Overall Response Rate (ORR)
Phase II: ORR is defined as the percentage 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 was relative to the organ stage at the start of the study treatment.
Complete response (CR) is defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapy for any earlier progression, mixed response or non-response of aGvHD.
Partial response (PR) is defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapy for an earlier progression, mixed response or non-response of aGvHD.
Measured: Day 28
Secondary outcomes (24)
Percentage of All Patients Who Achieved a Complete Response (CR) or Partial Response (PR) (Durable Overall Response Rate (ORR))
Durable ORR at Day 56 was defined as the percentage of all subjects who achieved a complete response (CR) or partial response (PR) at Day 28 and maintained a CR or PR at Day 56.
Complete-response was defined as a score of 0 for the acute GvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of acute GvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of acute GvHD.
Partial response was defined as improvement of 1 stage in 1 or more organs involved with acute GvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of acute GvHD.
Measured: Day 56
Percentage of Patients Who Achieved OR (CR+PR) at Day 14
ORR at Day 14 was defined as the percentage of participants with complete response (CR) or partial response (PR ) at Day 14 according to standard criteria.
Complete response (CR) is defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapy for any earlier progression, mixed response or non-response of aGvHD.
Partial response (PR) is defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapy for an earlier progression, mixed response or non-response of aGvHD.
Measured: Day 14
Area Under the Curve (AUClast) Versus Efficacy: Impact of AUClast on Overall Response Rate (ORR) at Day 28
To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUClast with ORR at day 28). ORR is the percentage of patients with a complete response (CR) or partial response (PR) without additional systemic therapies. Given age group did not have a significant effect on the model fit, the comparison is made indirectly through the odds ratio across exposure levels in each group. A high response rate may prevent model convergence. Results are shown only upon successful convergence.
Measured: Day 28
Area Under the Curve (AUClast) Versus Efficacy: Impact of AUClast on Durable Response Rate (DRR) at Day 56
To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUClast with DRR at day 56). Durable ORR at Day 56 was defined as the percentage of all participants who achieved a complete response (CR) or partial response (PR) at Day 28 and maintained a CR or PR at Day 56. Given age group did not have a significant effect on the model fit, the comparison is made indirectly through the odds ratio across exposure levels in each group. A high response rate may prevent model convergence. Results are shown only upon successful convergence.
Measured: Day 56
Area Under the Curve (AUClast) Versus Safety: Impact of AUClast on Bleeding
To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUClast with safety - bleeding). Bleeding was reported as an adverse event and the AE severity grade was assessed according to CTCAE grading. Given age group did not have a significant effect on the model fit, the comparison is made indirectly through the hazard ratio across exposure levels in each group. A high response rate may prevent model convergence. Results are shown only upon successful convergence.
Measured: 24 weeks
Area Under the Curve (AUClast) Versus Safety: Impact of AUClast on Infection
To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUClast with safety - infection). This analysis includes subjects from F12201 (pediatric and adolescent participants) study. Infections were reported as adverse events and the AE severity grade was assessed according to CTCAE grading. Given age group did not have a significant effect on the model fit, the comparison is made indirectly throughs the hazard ratio across exposure levels in each group. A high response rate may prevent model convergence. Results are shown only upon successful convergence
Measured: 24 weeks
Duration of Response (DOR)
Duration of response was defined as the time from first response (PR or CR) until acute GvHD progression, or the date of additional systemic therapy for acute GvHD. Death without prior observation of acute GvHD progression, and onset of chronic GvHD are considered to be competing risks. Duration of response will be censored at the last response assessment prior to or at the analysis cut-off date, if no events/competing risks occurred on or before 4 weeks (28 days) after the last GvHD assessment. The estimated probability of loss of response at 1, 2 and 6 months after participant's first achievement of CR or PR has been reported. Due to the presence of competing risk, the DOR results are being presented in the form of the probability of loss of response at different time points. As planned in the Statistical Analysis Plan (SAP), this outcome measure is provided for all subjects instead of per age groups.
Measured: Months 1, 2 & 6
Weekly Cumulative Steroid Dose for Each Patient up to Day 56
The weekly cumulative steroid dose was calculated for each subject up to Day 56 and the overall cumulative steroid dose was calculated for each subject at Day 56.
Measured: up to 56 days (Week 1 - Week 8)
Overall Survival (OS) Per Kaplan Meier
OS is defined as the time from the start of treatment to the date of death due to any cause. If a subject was not known to have died, then OS was censored at the latest date the subject was known to be alive. The estimated survival probability at 1,2,6,12,18 months after start of treatment has been reported. (on or before the cut-off date). As planned in the SAP, this outcome measure is provided for all subjects instead of per age groups.
Measured: 1 Month (M), 2 M, 6M, 12M, 18M
Event-Free Survival (EFS) Per Kaplan-Meier Estimates
EFS is defined as the time from start of treatment to the date of hematologic disease relapse/progression, graft failure, or death due to any cause. If a subject was not known to have any event, then EFS was censored at the latest date the subject was known to be alive (on or before the cut-off date).The estimated probability of event free at 1,2,6,12,18 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all subjects instead of per age groups.
Measured: 1 Month (M), 2 M, 6M, 12M, 18M
Failure-Free Survival (FFS)
Failure-free (FF) survival was defined as the time from start date of treatment to any of the following: hematologic relapse/progression, non-relapse mortality (NRM) or addition of new systemic acute GvHD treatment. The cumulative incidence (CI) of the onset of failure event at 1,2,6,12,18,24 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all subjects instead of per age groups.
Measured: 1 Month (M), 2M, 6M, 12M, 18M, 24M
Non Relapse Mortality (NRM)
NRM is defined as the time from start of treatment to date of death not preceded by hematologic disease relapse/progression. The cumulative incidence (CI) of non-relapse mortality at 1,2,6,12,18,24 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all subjects instead of per age groups.
Measured: Month (M)1, M2, M6, M12, M18, M24
Incidence of Malignancy Relapse (MR)/Progression
MR was defined as the time from start of treatment to hematologic malignancy relapse/progression. Calculated for patients with underlying hematologic malignant disease. The cumulative incidence (CI) of malignancy relapse/progression at 1,2,6,12,18,24 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all subjects instead of per age groups.
Measured: Month (M) 1, M2, M6, M12, M18, M24,
Cumulative Incidence (CI) of cGvHD
cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe. Incidence of chronic GvHD was the time from the start of treatment to onset of chronic GvHD. Cumulative incidence of chronic GvHD was estimated, accounting for deaths without prior onset of chronic GvHD and hematologic disease relapse/progression as the competing risks. The cumulative incidence (CI) of cGvHD at 1, 2, 6, 12, 18 and 24 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all subjects instead of per age groups.
Measured: Month (M) 1, M2, M6, M12, M18, M24
Graft Failure
This was assessed by 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 declined to <5% on subsequent measurements, graft failure was declared.
Measured: 2 years
Questionnaire on Acceptability and Palatability
Responses from the acceptability and palatability of the study drug (only for subjects administered with oral pediatric formulation starting treatment Day 1) were evaluated from a questionnaire completed by subjects, with the help from parents or caregivers as needed at the following visits: Day 1 (after first dose), Week 4 (1 month) ((after either morning or evening dose of that visit date), Week 24 (6 months) (after either morning or evening dose of that visit date). The choices for taste of the medication were, 'Very good', 'good', 'not good or bad', 'Bad', very bad. The choices for aftertaste of the medication were, 'Very good', 'Good', 'Not good or bad' , 'Bad', Very bad'. The choices for the smell of the medication were, 'Not good or bad' or 'Bad'.
Measured: Day 1, Week 4 (1 month), Week 24 (6 months)
PK Parameter - Maximum Serum Concentration (Cmax) Versus Efficacy
To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with efficacy). Cmax: The maximum (peak) observed plasma drug concentration.
Measured: 24 weeks
PK Parameter: Minimum Serum Concentration (Ctrough) Versus Safety
To assess pharmacokinetic/pharmacodynamic relationships (comparison of Ctrough with safety). Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).
Measured: 24 weeks
PK Parameter: Cmax Versus Safety
To assess pharmacokinetic/pharmacodynamics relationship (comparison of Cmax with safety). Cmax: The maximum (peak) observed plasma drug concentration.
Measured: 24 weeks
PK Parameter: Ctrough Versus Efficacy
To assess pharmacokinetic/pharmacodynamics relationship (comparison of Ctrough with efficacy). Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).
Measured: 24 weeks
PK Parameter: Profile of Biomarker Concentration Changes Across Different AUC Quantile Groups
Describe the relationship between AUC and PD biomarkers. Provide profile of biomarker concentration changes across different AUC quantile groups from baseline. This analysis includes subjects from F12201 study. Population was divided by four level of exposure using AUClast Day 1 quartiles. As planned in SAP, this outcome measure is provided for all subjects instead of per age groups.
Measured: Week 4
PK Parameter: Cmax Versus PD Biomarkers
To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with PD biomarkers). Cmax: The maximum (peak) observed plasma drug concentration.
Measured: 24 weeks
PK Parameter: Ctrough Versus PD Biomarkers
To assess pharmacokinetic/pharmacodynamics relationship (Ctrough with PD biomarkers). Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).
Measured: 24 weeks
Percentage of Patients Who Achieved Best Overall Response (BOR) up to Day 28
The best overall response (BOR) was defined as percentage of participants with (complete response (CR) or partial response (PR) at any time point and up to and including Day 28 and before the start of additional systemic therapy for acute GvHD (aGvHD).
Measured: Up to 28 days and before start of additional aGvHD therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Apr 2018
- Study start21 Feb 2019
- Primary completion11 Mar 2021
- Study completion2 Feb 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Acute Graft Versus Host DiseaseStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 45 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03491215
- Sponsor's protocol ID
- CINC424F12201
- Other IDs
- 2018-000422-55, 2018
- Status last verified
- May 2025
- First submitted
- 20 Mar 2018
- Last updated
- 4 May 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
Locatelli F, Kang HJ, Bruno B, Gandemer V, Rialland F, Faraci M, Takahashi Y, Koh K, Bittencourt H, Cleary G, Rosko C, Li X, St Pierre A, Prahallad A, Diaz-de-Heredia C. Ruxolitinib for pediatric patients with treatment-naive and steroid-refractory acute graft-versus-host disease: the REACH4 study. Blood. 2024 Nov 14;144(20):2095-2106. doi: 10.1182/blood.2023022565.
PubMed 39046767
Study at a glance
From the registry record, last updated by the sponsor on 4 May 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03491215
- Acronym / sponsor ID
- CINC424F12201
- 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
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 45 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 21 Feb 2019 (actual)
- Primary completion
- 11 Mar 2021 (actual)
- Study completion
- 2 Feb 2023 (actual)
- First posted
- 9 Apr 2018 (actual)
- Results
- Posted 8 Nov 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Ruxolitinib | Experimental | Drug: RuxolitinibAll pediatric participants received ruxolitinib twice a day (BID) for a planned duration of 24 weeks in either tablet, capsule or oral solution (liquid), depending on the group they were in. |
Who may qualify
- Ages
- 28 days to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- 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.)
Key exclusion criteria (8 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RuxolitinibAlso: INC424All enrolled pediatric participants received ruxolitinib as a 5 mg tablet (adult and adolescent formulation) or an oral pediatric formulation (administered as oral solution or capsule dispersed in liquid). | Drug | Ruxolitinib |
Primary outcome
Phase I: Measurement of Pharmacokinetic (PK) Parameter, AUClast, in aGvHD and SR-aGvHD Patients
Time frame: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 sparse sampling in Group 4. AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).
Phase I: Measurement of PK Parameter, Cmax, in aGvHD and SR-aGvHD Patients
Time frame: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. Cmax: The maximum (peak) observed plasma drug concentration
Phase I: Measurement of PK Parameter, T1/2, in aGvHD and SR-aGvHD Patients
Time frame: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. T1/2: The elimination half-life associated with the terminal slope (Lambda_z ) of a semi logarithmic concentration-time curve
Phase I: Measurement of PK Parameter, Ctrough, in aGvHD and SR-aGvHD Patients
Time frame: Day 7 at pre-dose
Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).
Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using AUClast
Time frame: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
Phase I: Age-based determination of RP2D in Groups 2 and 3 and was based on observed PK parameters in Groups 1-3 * Group 2: age ≥ 6 to < 12 years * Group 3: age ≥ 2 to < 6 years AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).
Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using Cmax
Time frame: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose
Phase I: Age-based determination of RP2D in Groups 2 and 3 and was based on observed PK parameters in Groups 1-3 * Group 2: age ≥ 6 to < 12 years * Group 3: age ≥ 2 to < 6 years Cmax: The maximum (peak) observed plasma drug concentration.
Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using Ctrough
Time frame: Day 7 at pre-dose
Phase I: Age-based determination of RP2D in Groups 2 and 3 and was based on observed PK parameters in Groups 1-3 * Group 2: age ≥ 6 to < 12 years * Group 3: age ≥ 2 to < 6 years Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).
Phase II: Overall Response Rate (ORR)
Time frame: Day 28
Phase II: ORR is defined as the percentage 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 was relative to the organ stage at the start of the study treatment. Complete response (CR) is defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapy for any earlier progression, mixed response or non-response of aGvHD. Partial response (PR) is defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapy for an earlier progression, mixed response or non-response of aGvHD.
24 secondary outcomes
Percentage of All Patients Who Achieved a Complete Response (CR) or Partial Response (PR) (Durable Overall Response Rate (ORR))
Time frame: Day 56
Percentage of Patients Who Achieved OR (CR+PR) at Day 14
Time frame: Day 14
Area Under the Curve (AUClast) Versus Efficacy: Impact of AUClast on Overall Response Rate (ORR) at Day 28
Time frame: Day 28
Area Under the Curve (AUClast) Versus Efficacy: Impact of AUClast on Durable Response Rate (DRR) at Day 56
Time frame: Day 56
Area Under the Curve (AUClast) Versus Safety: Impact of AUClast on Bleeding
Time frame: 24 weeks
Area Under the Curve (AUClast) Versus Safety: Impact of AUClast on Infection
Time frame: 24 weeks
Duration of Response (DOR)
Time frame: Months 1, 2 & 6
Weekly Cumulative Steroid Dose for Each Patient up to Day 56
Time frame: up to 56 days (Week 1 - Week 8)
Overall Survival (OS) Per Kaplan Meier
Time frame: 1 Month (M), 2 M, 6M, 12M, 18M
Event-Free Survival (EFS) Per Kaplan-Meier Estimates
Time frame: 1 Month (M), 2 M, 6M, 12M, 18M
Failure-Free Survival (FFS)
Time frame: 1 Month (M), 2M, 6M, 12M, 18M, 24M
Non Relapse Mortality (NRM)
Time frame: Month (M)1, M2, M6, M12, M18, M24
Incidence of Malignancy Relapse (MR)/Progression
Time frame: Month (M) 1, M2, M6, M12, M18, M24,
Cumulative Incidence (CI) of cGvHD
Time frame: Month (M) 1, M2, M6, M12, M18, M24
Graft Failure
Time frame: 2 years
Questionnaire on Acceptability and Palatability
Time frame: Day 1, Week 4 (1 month), Week 24 (6 months)
PK Parameter - Maximum Serum Concentration (Cmax) Versus Efficacy
Time frame: 24 weeks
PK Parameter: Minimum Serum Concentration (Ctrough) Versus Safety
Time frame: 24 weeks
PK Parameter: Cmax Versus Safety
Time frame: 24 weeks
PK Parameter: Ctrough Versus Efficacy
Time frame: 24 weeks
PK Parameter: Profile of Biomarker Concentration Changes Across Different AUC Quantile Groups
Time frame: Week 4
PK Parameter: Cmax Versus PD Biomarkers
Time frame: 24 weeks
PK Parameter: Ctrough Versus PD Biomarkers
Time frame: 24 weeks
Percentage of Patients Who Achieved Best Overall Response (BOR) up to Day 28
Time frame: Up to 28 days and before start of additional aGvHD therapy
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 May 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 39046767Locatelli F, Kang HJ, Bruno B, Gandemer V, Rialland F, Faraci M, Takahashi Y, Koh K, Bittencourt H, Cleary G, Rosko C, Li X, St Pierre A, Prahallad A, Diaz-de-Heredia C. Ruxolitinib for pediatric patients with treatment-naive and steroid-refractory acute graft-versus-host disease: the REACH4 study. Blood. 2024 Nov 14;144(20):2095-2106. doi: 10.1182/blood.2023022565.
- A Plain Language Trial Summary is available on www.novctrd.comLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. 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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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
19 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Ruxolitinib in people with Acute Graft Versus Host Disease, run by Novartis Pharmaceuticals at 19 sites in 8 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 May 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in France, Spain, Belgium, Italy, Japan and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 8 Nov 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase I: Measurement of Pharmacokinetic (PK) Parameter, AUClast, in aGvHD and SR-aGvHD Patients (time frame: Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03491215, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 May 2025.