E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
chronic graft versus host disease |
|
E.1.1.1 | Medical condition in easily understood language |
graft versus host disease |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064677 |
E.1.2 | Term | Graft versus host disease in intestine |
E.1.2 | System Organ Class | 100000004870 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10075161 |
E.1.2 | Term | Graft versus host disease in GI tract |
E.1.2 | System Organ Class | 100000004870 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the activity of ruxolitinib added to standard dose corticosteroids +/- CNI in pediatric subjects with moderate or severe treatment naivecGvHD or SR-cGvHD measured by overall response rate (ORR) at Cycle 7 Day 1 based on all subjects in the study |
|
E.2.2 | Secondary objectives of the trial |
- To assess pharmacokinetics (PK) of ruxolitinib in treatment-naïve cGvHD and SR-cGvHD pediatric subjects - To evaluate the safety of ruxolitinib - To assess duration of response (DOR) - To estimate ORR at end of Cycle 3 - To assess best overall response (BOR) - To estimate the failure free survival (FFS) - To assess cumulative incidence of malignancy relapse/recurrence (MR) - To assess non-relapse mortality (NRM) - To assess overall survival (OS) - To assess a reduction of at least ≥ 50% in daily corticosteroid use at Cycle 7 Day 1 - To assess a reduction to a low dose corticosteroid dose at Cycle 7 Day 1 - To assess graft failure |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male or female subjects age ≥28 days and <18 years at the time of informed consent. • Subjects who have undergone alloSCT from any donor source (matched unrelated donor, sibling, haploidentical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of myeloablative or reduced intensity conditioning are eligible. • Subjects with diagnosed moderate to severe cGvHD according to NIH 2014 Consensus Criteria (Section 16.2) prior to Cycle 1 Day 1. Other possible diagnoses for clinical symptoms supporting cGvHD diagnoses must be excluded (e.g., infection, drug side effects, malignancy). Subjects must be either: o 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 interrupted due to response, the duration of < 18 months applies to the last period of corticosteroid use.
Additional inclusion criteria as per fulll protocol may apply. |
|
E.4 | Principal 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/day methylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days of the screening visit. • History of progressive multifocal leukoencephalopathy (PML). • Presence of severely impaired renal function
Other protocol-defined inclusion/exclusion criteria may apply. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overall Response Rate ORR defined as the proportion of subjects demonstrating a complete response (CR) or partial response (PR) without the requirement of additional systemic therapies for an earlier progression, mixed response or non-response |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1. Ruxolitinib concentrations by timepoint 2. Duration of response (DOR) assessed for responders only. DOR is defined as the time from first response until cGvHD progression, death, or the date of addition of systemic therapies for cGvHD 3. Proportion of subjects who achieve OR (CR+PR) at Cycle 4 Day 1 4. Proportion of subjects who achieved OR (CR+PR) at any time point 5. Composite time to event endpoint incorporating the following FFS events: i) relapse or recurrence of underlying disease or death due to underlying disease, ii) non-relapse mortality, or iii) addition or initiation of another systemic therapy for cGvHD 6. Malignancy relapse/recurrence (MR) is defined as the time from date of treatment assignment to hematologic malignancy relapse/recurrence. Calculated for subjects with underlying hematologic malignant disease 7. Non-relapse mortality (NRM), defined as the time from date of treatment assignment to date of death not preceded by underlying disease relapse/recurrence. 8. Overall survival, defined as the time from the date of treatment assignment to the date of death due to any cause 9. Proportion of subjects with ≥ 50% reduction from baseline in daily corticosteroid dose at Cycle 7 Day 1 10. Proportion of subjects with reduction from baseline in daily corticosteroid dose to ≤ 0.2 mg/kg/day methylprednisolone (or equivalent dose of ≤ 0.25 mg/kg/day prednisone or prednisolone) at Cycle 7 Day 1 11. Proportion of subjects with reduction from baseline in daily corticosteroid dose to ≤ 0.2 mg/kg/day methylprednisolone (or equivalent dose of ≤ 0.25 mg/kg/day prednisone or prednisolone) at Cycle 7 Day 1 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Cycle 7 Day 1 (from baseline to Day 168) 2. From baseline up to endof study treatment, up to 36 months 3. Cycle 4 Day 1 (Day 84) 4. Until Cycle 7 Day 1 (Day 168) or the start of additional systemic therapy for cGvHD 5. From baseline up to 35 days after end of study treatment, up to 37 months 6. From baseline up to 35 days after end of study treatment, up to 37 months 7. From baseline up to 35 days after end of study treatment, up to 37 months 8. From baseline up to 35 days after end of study treatment, up to 37 months 9. Cycle 7 Day 1 (Day 168) 10. Cycle 7 Day 1 (Day 168) 11. From baseline up to 35 days after end of study treatment, up to 37 months |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Chile |
Saudi Arabia |
Thailand |
Turkey |
Argentina |
Brazil |
Canada |
Czechia |
Germany |
Greece |
India |
Italy |
Japan |
Korea, Republic of |
Lithuania |
Russian Federation |
Slovakia |
Slovenia |
Spain |
Switzerland |
Taiwan |
|
E.8.7 | Trial 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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 9 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 3 |