Graft vs Host Disease
Conditions
Keywords
GvHD, INC424, pediatric, Chronic Graft versus Host Disease, moderate and severe chronic graft vs. host disease, allogeneic stem cell transplant, ruxolitinib, corticosteroids
Brief summary
This open-label, single-arm, Phase II multi-center study enrolled 46 participants and investigated the activity, pharmacokinetics and safety of ruxolitinib added to the subject's immunosuppressive regimen among infants, children, and adolescents aged ≥28 days to \<18 years old with either moderate to severe treatment-naive cGvHD or SR-cGvHD. Although 46 participants were enrolled,1 participant (enrolled in the ≥6y to \<12y age group) received study treatment beyond protocol requirements and was excluded from analyses.
Detailed description
Subjects were grouped according to their age as follows: * Group 1 included subjects ≥12y to \<18y * Group 2 included subjects ≥6y to \<12y * Group 3 included subjects ≥2y to \<6y and * Group 4 included subjects ≥28days to \<2y. Enrollment initiation into the youngest age group, Group 4, was subject to the availability of data in this age group from another study, as well as a review of available PK, safety, and activity data generated from Groups 1 to 3 in the current study. At least 5 evaluable participants per group were needed for the primary analysis in Groups 1, 2 and 3. No minimum number of evaluable participants were needed in Group 4. Enrollment was completed prior to the availability of the data and so no subjects were enrolled in Group 4. After a screening period of Day -28 to Day -1: eligible subjects started study treatment on Cycle 1 Day 1 and were treated for up to a maximum of 3 years (39 cycles/156 weeks) or until early discontinuation. Subjects who discontinued study treatment for any reason earlier than 39 cycles were followed every 6 months until 3 years from their first dose of study treatment was reached.
Interventions
DRUGINC424
Ruxolitinib was taken orally based on age groups as follows: Group 1 (\>=12y to \<18y): 10mg bid as tablet Group 2 (\>=6y to \<12y): 5mg bid as tablet or liquid Group 3 (\>=2y to \<6y): 4mg/m2 bid as liquid
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
28 Days to 17 Years
Healthy volunteers
No
Inclusion criteria
* Male or female subjects age ≥28 days and \<18 years at the time of informed consent. * Subjects who have undergone a successful alloSCT from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of myeloablative or reduced intensity conditioning are eligible. * Subjects with diagnosed moderate to severe cGvHD according to NIH 2014 Consensus Criteria prior to Cycle 1 Day 1. Other possible diagnoses for clinical symptoms supporting cGvHD diagnoses must be excluded (e.g., infection, drug side effects, malignancy). Subjects must be either: * Treatment-naive cGvHD subjects that have not received any prior systemic treatment for cGvHD except for a maximum 72h of prior systemic corticosteroid therapy of methylprednisolone or equivalent after the onset of chronic GvHD. Subjects are allowed to have received prior systemic treatment for cGvHD prophylaxis (as long as the prophylaxis was started prior to the diagnosis of cGvHD). OR o Steroid-refractory moderate to severe cGvHD as per institutional criteria, or per physician decision in case institutional criteria are not available, and still receiving systemic corticosteroids for the treatment of cGvHD for a duration of \<18 months prior to Cycle 1 Day 1. In case the corticosteroids were previously interrupted due to response, the duration of \< 18 months applies to the last period of corticosteroid use.
Exclusion criteria
* SR-cGvHD subjects with a prior cGvHD treatment with a JAK1- or a JAK2- or a JAK1/2-inhibitor, except when the subject achieved complete or partial response and has been off JAK inhibitor treatment for at least 4 weeks prior to Cycle Day 1 or up to 5 times the half-life of the prior JAK inhibitor, whichever is longer. \* Subjects who initiated systemic calcineurin inhibitors (CNI; cyclosporine or tacrolimus) within 3 weeks prior to start of ruxolitinib on Cycle 1 Day 1. Note: systemic CNI are allowed when initiated \> 3 weeks from start of ruxolitinib. * Failed prior alloSCT within the past 6 months * Significant respiratory disease including subjects who are on mechanical ventilation or who have a resting oxygen saturation \< 90% by pulse-oximetry on room-air. * Impairment of gastrointestinal (GI) function (unrelated to GvHD) or GI disease (unrelated to GvHD) that may significantly alter the absorption of oral ruxolitinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection), * Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to cGvHD and ongoing organ dysfunction) * Presence of clinically active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. * Known human immunodeficiency virus (HIV) infection. * Evidence of uncontrolled hepatitis B virus (HBV) or hepatitis C virus (HCV) based on assessment done by Investigator or delegate. * Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds. * History of bone disorders such as osteogenesis imperfecta, rickets, renal osteodystrophy, osteomyelitis, osteopenia, fibrous dysplasia, osteomalacia etc. prior to the underlying diagnosis which resulted in the alloSCT. * History of endocrine or kidney related growth retardation prior to the underlying diagnosis which resulted in the alloSCT. * Evidence of clinically active tuberculosis (clinical diagnosis per local practice) * Any corticosteroid therapy for indications other than cGvHD at doses \> 1 mg/kg/daymethylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days of the screening visit. * History of progressive multifocal leuko-encephalopathy (PML). * Presence of severely impaired renal function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) at Cycle 7 Day 1 | At Cycle 7 Day 1 (Day 168); Cycle = 28 Days | ORR is defined as the percentage of participants 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 National Institute of Health (NIH) consensus criteria and scoring of response was relative to the organ stage at the start of study treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | From baseline up to 39 cycles; Cycle = 28 Days | Time from first response until chronic Graft vs. host disease (cGvHD) progression, death, or the date of addition of systemic therapies for cGvHD assessed for responders only based on BOR up to Cycle 7 Day 1. Presented as percentage of participants to still be in response at different time points in months (per Kaplan-Meier estimates). Participants without event will be censored at the date of their last response assessment prior to or at the analysis cut-off date if no events occurred on or before 12 weeks (84 days) after the last GvHD assessment. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups. |
| Overall Response Rate (ORR) at Cycle 4 Day 1 | At Cycle 4 Day 1 (Day 84); Cycle = 28 Days | ORR is defined as the percentage of participants 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 National Institute of Health (NIH) consensus criteria and scoring of response will be relative to the organ stage at the start of study treatment at Cycle 4 Day 1. |
| Best Overall Response (BOR) | Until Cycle 7 Day 1 (Day 168) or the start of additional systemic therapy for cGvHD; Cycle = 28 Days | Percentage of participants who achieved overall response (complete response (CR) or partial response (PR)) at any time point until Cycle 7 Day 1 or the start of additional systemic therapy for chronic GvHD. |
| Failure Free Survival (FFS) | From baseline up to 39 cycles; Cycle = 28 Days | Failure-free survival was defined as the time from date of treatment to any of the following 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 per Kaplan-Meier estimates. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups. |
| Cumulative Incidence of Malignancy Relapse/Recurrence (MR) | From baseline up to 39 cycles; Cycle = 28 Days | MR was defined as the time from date of treatment assignment to the date of hematologic malignancy relapse/recurrence. Calculated for subjects with underlying hematologic malignant disease. The cumulative incidence (CI) of malignancy relapse/recurrence at 1, 2, 6, 12, 18, 24, 30 and 36 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups. |
| Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 1: 0.5, 2 and 6 hours post-dose; Pre-dose on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 3 Day 1, Cycle 5 Day 1 and Cycle 7 Day 1; Cycle = 28 Days | Pharmacokinetics (PK) of ruxolitinib by age groups (and formulation tablet vs liquid). |
| Overall Survival (OS) | From baseline up to 39 cycles; Cycle = 28 Days | OS is defined as the time from the date of treatment assignment to the date of death due to any cause. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups. |
| Percentage of Participants With ≥50% Reduction From Baseline in Daily Corticosteroid Dose | Baseline to Cycle 7 Day 1 (Day 168); Cycle = 28 Days | Reduction of at least ≥50% from baseline in daily corticosteroid use by Cycle 7 Day 1 (regardless of reason). As planned in the SAP, this outcome measure is provided for all participants instead of per age groups, for those who received corticosteroids at baseline. |
| Percentage of Participants With a Reduction to a Low Dose Corticosteriod | Baseline to Cycle 7 Day 1 (Day 168); Cycle = 28 Days | Reduction to low dose corticosteroids, is defined as the percentage of participants with reduction from baseline in daily corticosteroid dose to methylprednisolone-equivalent steroid dose of ≤ 0.2 mg/kg/day (or equivalent dose of ≤ 0.25 mg/kg/day prednisone or prednisolone). As planned in the SAP, this outcome measure is provided for all participants instead of per age groups, for those who received corticosteroids at baseline. |
| Graft Failure | From baseline up to 39 cycles; Cycle = 28 Days | Reported are the number of participants with graft failure from all age groups together. Graft failure 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. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups. |
| Non-relapse Mortality (NRM) | From baseline up to 39 cycles; Cycle = 28 Days | NRM is defined as the time from date of treatment assignment to date of death not preceded by underlying disease relapse/recurrence calculated for all participants. The cumulative incidence (CI) of non-relapse mortality at 1, 2, 6, 12, 18, 24, 30 and 36 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups. |
Countries
Brazil, Canada, Czechia, India, Italy, Japan, Russia, Slovakia, South Korea, Spain, Switzerland, Taiwan, Thailand, Turkey (Türkiye)
Participant flow
Recruitment details
At least 5 evaluable participants per group were needed for the primary analysis in Groups 1, 2 and 3. No minimum number of evaluable participants were needed in Group 4. Disposition and Demographics are presented by age group.
Pre-assignment details
Enrollment initiation into the youngest age group, Group 4, was subject to the availability of data in this age group from study CINC424F12201. However, no participants were enrolled in group 4 (aged ≥ 28 days to \< 2y) due to the completion of the overall study enrolment with participants in the older age groups (groups 1, 2, & 3).
Participants by arm
| Arm | Count |
|---|---|
| ≥ 12y - < 18y RUX 10mg BID (Group 1) Participants received ruxolitinib 10mg orally twice a day (BID). | 22 |
| ≥ 6y - < 12y RUX 5mg BID (Group 2) Participants received ruxolitinib 5mg orally twice a day (BID). | 16 |
| ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) Participants received ruxolitinib 4mg/m2 orally twice a day (BID). | 7 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 6 | 3 | 2 |
| Overall Study | Enrolled but received treatment beyond protocol requirement | 0 | 1 | 0 |
| Overall Study | Guardian decision | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 0 | 0 |
| Overall Study | Subject decision | 0 | 3 | 0 |
Baseline characteristics
| Characteristic | ≥ 12y - < 18y RUX 10mg BID (Group 1) | ≥ 6y - < 12y RUX 5mg BID (Group 2) | ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) | Total |
|---|---|---|---|---|
| Age, Continuous | 175.2 months STANDARD_DEVIATION 20.05 | 99.3 months STANDARD_DEVIATION 18.39 | 47.1 months STANDARD_DEVIATION 15.08 | 128.3 months STANDARD_DEVIATION 52.86 |
| Race/Ethnicity, Customized Asian | 14 Participants | 5 Participants | 4 Participants | 23 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 10 Participants | 3 Participants | 21 Participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 2 Participants | 16 Participants |
| Sex: Female, Male Male | 15 Participants | 9 Participants | 5 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 2 / 16 | 1 / 7 | 3 / 45 | 6 / 22 | 1 / 16 | 1 / 7 | 8 / 45 |
| other Total, other adverse events | 22 / 22 | 15 / 16 | 7 / 7 | 44 / 45 | 4 / 22 | 2 / 16 | 0 / 7 | 6 / 45 |
| serious Total, serious adverse events | 15 / 22 | 7 / 16 | 4 / 7 | 26 / 45 | 3 / 22 | 0 / 16 | 0 / 7 | 3 / 45 |
Outcome results
Primary
Overall Response Rate (ORR) at Cycle 7 Day 1
ORR is defined as the percentage of participants 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 National Institute of Health (NIH) consensus criteria and scoring of response was relative to the organ stage at the start of study treatment.
Time frame: At Cycle 7 Day 1 (Day 168); Cycle = 28 Days
Population: Full Analysis Set (FAS) comprised all subjects to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Overall Response Rate (ORR) at Cycle 7 Day 1 | 36.4 Percentage of participants |
| ≥ 6y - < 12y RUX 5mg BID (Group 2) | Overall Response Rate (ORR) at Cycle 7 Day 1 | 50.0 Percentage of participants |
| ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) | Overall Response Rate (ORR) at Cycle 7 Day 1 | 28.6 Percentage of participants |
| All Participants | Overall Response Rate (ORR) at Cycle 7 Day 1 | 40.0 Percentage of participants |
Secondary
Best Overall Response (BOR)
Percentage of participants who achieved overall response (complete response (CR) or partial response (PR)) at any time point until Cycle 7 Day 1 or the start of additional systemic therapy for chronic GvHD.
Time frame: Until Cycle 7 Day 1 (Day 168) or the start of additional systemic therapy for cGvHD; Cycle = 28 Days
Population: FAS comprised all subjects to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Best Overall Response (BOR) | 81.8 Percentage of participants |
| ≥ 6y - < 12y RUX 5mg BID (Group 2) | Best Overall Response (BOR) | 81.3 Percentage of participants |
| ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) | Best Overall Response (BOR) | 85.7 Percentage of participants |
| All Participants | Best Overall Response (BOR) | 82.2 Percentage of participants |
Secondary
Cumulative Incidence of Malignancy Relapse/Recurrence (MR)
MR was defined as the time from date of treatment assignment to the date of hematologic malignancy relapse/recurrence. Calculated for subjects with underlying hematologic malignant disease. The cumulative incidence (CI) of malignancy relapse/recurrence at 1, 2, 6, 12, 18, 24, 30 and 36 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups.
Time frame: From baseline up to 39 cycles; Cycle = 28 Days
Population: FAS comprised all subjects to whom study treatment has been assigned and who received at least one dose of study treatment, assessed for subjects with malignancy relapse/occurrence only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Cumulative Incidence of Malignancy Relapse/Recurrence (MR) | Month 1 | 3.33 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Cumulative Incidence of Malignancy Relapse/Recurrence (MR) | Month 2 | 10.00 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Cumulative Incidence of Malignancy Relapse/Recurrence (MR) | Month 6 | 10.00 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Cumulative Incidence of Malignancy Relapse/Recurrence (MR) | Month 12 | 10.00 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Cumulative Incidence of Malignancy Relapse/Recurrence (MR) | Month 18 | 10.00 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Cumulative Incidence of Malignancy Relapse/Recurrence (MR) | Month 24 | 10.00 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Cumulative Incidence of Malignancy Relapse/Recurrence (MR) | Month 30 | 10.00 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Cumulative Incidence of Malignancy Relapse/Recurrence (MR) | Month 36 | 10.00 Percentage of participants |
Secondary
Duration of Response (DOR)
Time from first response until chronic Graft vs. host disease (cGvHD) progression, death, or the date of addition of systemic therapies for cGvHD assessed for responders only based on BOR up to Cycle 7 Day 1. Presented as percentage of participants to still be in response at different time points in months (per Kaplan-Meier estimates). Participants without event will be censored at the date of their last response assessment prior to or at the analysis cut-off date if no events occurred on or before 12 weeks (84 days) after the last GvHD assessment. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups.
Time frame: From baseline up to 39 cycles; Cycle = 28 Days
Population: FAS comprised all subjects to whom study treatment has been assigned and who received at least one dose of study treatment. Duration of response (DOR) is assessed for responders only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Duration of Response (DOR) | Month 1 | 94.59 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Duration of Response (DOR) | Month 2 | 86.23 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Duration of Response (DOR) | Month 6 | 74.24 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Duration of Response (DOR) | Month 12 | 63.10 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Duration of Response (DOR) | Month 18 | 58.89 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Duration of Response (DOR) | Month 24 | 58.89 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Duration of Response (DOR) | Month 30 | 58.89 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Duration of Response (DOR) | Month 36 | 58.89 Percentage of participants |
Secondary
Failure Free Survival (FFS)
Failure-free survival was defined as the time from date of treatment to any of the following 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 per Kaplan-Meier estimates. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups.
Time frame: From baseline up to 39 cycles; Cycle = 28 Days
Population: FAS comprised all subjects to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Failure Free Survival (FFS) | Month 1 | 91.11 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Failure Free Survival (FFS) | Month 2 | 84.44 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Failure Free Survival (FFS) | Month 6 | 68.89 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Failure Free Survival (FFS) | Month 12 | 64.44 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Failure Free Survival (FFS) | Month 18 | 57.78 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Failure Free Survival (FFS) | Month 24 | 57.78 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Failure Free Survival (FFS) | Month 30 | 57.78 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Failure Free Survival (FFS) | Month 36 | 57.78 Percentage of participants |
Secondary
Graft Failure
Reported are the number of participants with graft failure from all age groups together. Graft failure 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. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups.
Time frame: From baseline up to 39 cycles; Cycle = 28 Days
Population: FAS comprised all subjects to whom study treatment has been assigned and who received at least one dose of study treatment. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Graft Failure | 2 Participants |
Secondary
Non-relapse Mortality (NRM)
NRM is defined as the time from date of treatment assignment to date of death not preceded by underlying disease relapse/recurrence calculated for all participants. The cumulative incidence (CI) of non-relapse mortality at 1, 2, 6, 12, 18, 24, 30 and 36 months after start of treatment has been reported. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups.
Time frame: From baseline up to 39 cycles; Cycle = 28 Days
Population: FAS comprised all subjects to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Non-relapse Mortality (NRM) | Month 1 | 2.22 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Non-relapse Mortality (NRM) | Month 2 | 2.22 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Non-relapse Mortality (NRM) | Month 6 | 6.67 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Non-relapse Mortality (NRM) | Month 12 | 13.33 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Non-relapse Mortality (NRM) | Month 18 | 17.78 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Non-relapse Mortality (NRM) | Month 24 | 20.07 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Non-relapse Mortality (NRM) | Month 30 | 20.07 Percentage of participants |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Non-relapse Mortality (NRM) | Month 36 | 20.07 Percentage of participants |
Secondary
Overall Response Rate (ORR) at Cycle 4 Day 1
ORR is defined as the percentage of participants 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 National Institute of Health (NIH) consensus criteria and scoring of response will be relative to the organ stage at the start of study treatment at Cycle 4 Day 1.
Time frame: At Cycle 4 Day 1 (Day 84); Cycle = 28 Days
Population: FAS comprised all subjects to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Overall Response Rate (ORR) at Cycle 4 Day 1 | 54.5 Percentage of participants |
| ≥ 6y - < 12y RUX 5mg BID (Group 2) | Overall Response Rate (ORR) at Cycle 4 Day 1 | 62.5 Percentage of participants |
| ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) | Overall Response Rate (ORR) at Cycle 4 Day 1 | 42.9 Percentage of participants |
| All Participants | Overall Response Rate (ORR) at Cycle 4 Day 1 | 55.6 Percentage of participants |
Secondary
Overall Survival (OS)
OS is defined as the time from the date of treatment assignment to the date of death due to any cause. As planned in the SAP, this outcome measure is provided for all participants instead of per age groups.
Time frame: From baseline up to 39 cycles; Cycle = 28 Days
Population: FAS comprised all subjects to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Overall Survival (OS) | Month 1 | 97.78 survival probability in percentage |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Overall Survival (OS) | Month 2 | 97.78 survival probability in percentage |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Overall Survival (OS) | Month 6 | 91.06 survival probability in percentage |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Overall Survival (OS) | Month 12 | 84.23 survival probability in percentage |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Overall Survival (OS) | Month 18 | 79.67 survival probability in percentage |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Overall Survival (OS) | Month 24 | 77.33 survival probability in percentage |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Overall Survival (OS) | Month 30 | 77.33 survival probability in percentage |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Overall Survival (OS) | Month 36 | 74.91 survival probability in percentage |
Secondary
Percentage of Participants With ≥50% Reduction From Baseline in Daily Corticosteroid Dose
Reduction of at least ≥50% from baseline in daily corticosteroid use by Cycle 7 Day 1 (regardless of reason). As planned in the SAP, this outcome measure is provided for all participants instead of per age groups, for those who received corticosteroids at baseline.
Time frame: Baseline to Cycle 7 Day 1 (Day 168); Cycle = 28 Days
Population: FAS comprised all subjects to whom study treatment has been assigned and who received at least one dose of study treatment and received corticosteroids at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Percentage of Participants With ≥50% Reduction From Baseline in Daily Corticosteroid Dose | 75.0 Percentage of participants |
Secondary
Percentage of Participants With a Reduction to a Low Dose Corticosteriod
Reduction to low dose corticosteroids, is defined as the percentage of participants with reduction from baseline in daily corticosteroid dose to methylprednisolone-equivalent steroid dose of ≤ 0.2 mg/kg/day (or equivalent dose of ≤ 0.25 mg/kg/day prednisone or prednisolone). As planned in the SAP, this outcome measure is provided for all participants instead of per age groups, for those who received corticosteroids at baseline.
Time frame: Baseline to Cycle 7 Day 1 (Day 168); Cycle = 28 Days
Population: FAS comprised all subjects to whom study treatment has been assigned and who received at least one dose of study treatment and received corticosteroids at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Percentage of Participants With a Reduction to a Low Dose Corticosteriod | 67.5 Percentage of participants |
Secondary
Ruxolitinib Concentrations by Timepoint
Pharmacokinetics (PK) of ruxolitinib by age groups (and formulation tablet vs liquid).
Time frame: Cycle 1 Day 1: 0.5, 2 and 6 hours post-dose; Pre-dose on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 3 Day 1, Cycle 5 Day 1 and Cycle 7 Day 1; Cycle = 28 Days
Population: The Pharmacokinetic Analysis Set (PAS) included all subjects who provided at least one evaluable PK concentration. Evaluable PK concentration: Participants took the dose of ruxolitinib prior to PK sample; For post-dose samples on Cycle 1 Day 1: participants did not vomit within 2 hours after dosing with ruxolitinib; For pre-dose samples: participant samples were collected before the next dose administration of ruxolitinib.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Ruxolitinib Concentrations by Timepoint | Cycle 3 Day 1: 0 hr (pre-dose | 11.4 ug/ml | Geometric Coefficient of Variation 193.8 |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 22: 0 hr (pre-dose) | 20.8 ug/ml | Geometric Coefficient of Variation 199.5 |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Ruxolitinib Concentrations by Timepoint | Cycle 7 Day 1: 0 hr (pre-dose | 14.3 ug/ml | Geometric Coefficient of Variation 173.7 |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 8: 0 hr (pre-dose) | 16.7 ug/ml | Geometric Coefficient of Variation 208.3 |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 1: 6hr (post-dose) | 56.7 ug/ml | Geometric Coefficient of Variation 73.9 |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 1: 2 hr (post-dose) | 112 ug/ml | Geometric Coefficient of Variation 51.8 |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Ruxolitinib Concentrations by Timepoint | Cycle 5 Day 1: 0 hr (pre-dose | 13.0 ug/ml | Geometric Coefficient of Variation 176.6 |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 15: 0 hr (pre-dose) | 17.8 ug/ml | Geometric Coefficient of Variation 195.5 |
| ≥ 12y - < 18y RUX 10mg BID (Group 1) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 1: 0.5 hour (hr) (post-dose) | 60.0 ug/ml | Geometric Coefficient of Variation 350.7 |
| ≥ 6y - < 12y RUX 5mg BID (Group 2) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 15: 0 hr (pre-dose) | 12.9 ug/ml | Geometric Coefficient of Variation 248.2 |
| ≥ 6y - < 12y RUX 5mg BID (Group 2) | Ruxolitinib Concentrations by Timepoint | Cycle 3 Day 1: 0 hr (pre-dose | 11.3 ug/ml | Geometric Coefficient of Variation 193.1 |
| ≥ 6y - < 12y RUX 5mg BID (Group 2) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 22: 0 hr (pre-dose) | 11.7 ug/ml | Geometric Coefficient of Variation 165.4 |
| ≥ 6y - < 12y RUX 5mg BID (Group 2) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 1: 2 hr (post-dose) | 106 ug/ml | Geometric Coefficient of Variation 39.2 |
| ≥ 6y - < 12y RUX 5mg BID (Group 2) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 1: 0.5 hour (hr) (post-dose) | 32.4 ug/ml | Geometric Coefficient of Variation 471.9 |
| ≥ 6y - < 12y RUX 5mg BID (Group 2) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 1: 6hr (post-dose) | 47.8 ug/ml | Geometric Coefficient of Variation 164.1 |
| ≥ 6y - < 12y RUX 5mg BID (Group 2) | Ruxolitinib Concentrations by Timepoint | Cycle 7 Day 1: 0 hr (pre-dose | 10.7 ug/ml | Geometric Coefficient of Variation 129.9 |
| ≥ 6y - < 12y RUX 5mg BID (Group 2) | Ruxolitinib Concentrations by Timepoint | Cycle 5 Day 1: 0 hr (pre-dose | 16.4 ug/ml | Geometric Coefficient of Variation 470.7 |
| ≥ 6y - < 12y RUX 5mg BID (Group 2) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 8: 0 hr (pre-dose) | 10.9 ug/ml | Geometric Coefficient of Variation 146.5 |
| ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 15: 0 hr (pre-dose) | 4.14 ug/ml | Geometric Coefficient of Variation 399.3 |
| ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 1: 0.5 hour (hr) (post-dose) | 78.6 ug/ml | — |
| ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 1: 2 hr (post-dose) | 77.0 ug/ml | — |
| ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 1: 6hr (post-dose) | 60.0 ug/ml | — |
| ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 8: 0 hr (pre-dose) | 3.47 ug/ml | — |
| ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 22: 0 hr (pre-dose) | 4.89 ug/ml | Geometric Coefficient of Variation 505.2 |
| ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) | Ruxolitinib Concentrations by Timepoint | Cycle 3 Day 1: 0 hr (pre-dose | 2.66 ug/ml | Geometric Coefficient of Variation 587.5 |
| ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) | Ruxolitinib Concentrations by Timepoint | Cycle 5 Day 1: 0 hr (pre-dose | 11.0 ug/ml | Geometric Coefficient of Variation 83.5 |
| ≥ 2y - < 6y RUX 4mg/m2 BID (Group 3) | Ruxolitinib Concentrations by Timepoint | Cycle 7 Day 1: 0 hr (pre-dose | 5.79 ug/ml | Geometric Coefficient of Variation 120.1 |
| All Participants | Ruxolitinib Concentrations by Timepoint | Cycle 3 Day 1: 0 hr (pre-dose | 5.56 ug/ml | Geometric Coefficient of Variation 180.8 |
| All Participants | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 8: 0 hr (pre-dose) | 3.88 ug/ml | Geometric Coefficient of Variation 152.4 |
| All Participants | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 1: 6hr (post-dose) | 15.3 ug/ml | Geometric Coefficient of Variation 66.2 |
| All Participants | Ruxolitinib Concentrations by Timepoint | Cycle 7 Day 1: 0 hr (pre-dose | 4.94 ug/ml | Geometric Coefficient of Variation 165.9 |
| All Participants | Ruxolitinib Concentrations by Timepoint | Cycle 5 Day 1: 0 hr (pre-dose | 7.32 ug/ml | Geometric Coefficient of Variation 102 |
| All Participants | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 1: 2 hr (post-dose) | 49.7 ug/ml | Geometric Coefficient of Variation 30.7 |
| All Participants | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 22: 0 hr (pre-dose) | 10.3 ug/ml | Geometric Coefficient of Variation 150.4 |
| All Participants | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 15: 0 hr (pre-dose) | 9.43 ug/ml | Geometric Coefficient of Variation 121.5 |
| All Participants | Ruxolitinib Concentrations by Timepoint | Cycle 1 Day 1: 0.5 hour (hr) (post-dose) | 60.1 ug/ml | Geometric Coefficient of Variation 98.7 |