E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
treatment naïve aGvHD grades II-IV or steroid-refractory aGvHD grades II-IV |
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E.1.1.1 | Medical condition in easily understood language |
acute Graft vs Host Disease |
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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 |
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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 |
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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 |
Phase I To assess pharmacokinetic (PK) parameters of ruxolitinib for patients with aGvHD and SR-aGvHD and define an age appropriate RP2D for each of the groups 2-4 Group 2: age ≥6y to <12y Group 3: age ≥2y to <6y Group 4: age ≥28days to < 2y
Phase II To measure the activity of ruxolitinib in patients with aGvHD or SR-aGvHD assessed by Overall Response Rate (ORR) at Day 28 |
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E.2.2 | Secondary objectives of the trial |
Key secondary: To assess the rate of durable ORR at Day 56
Other secondary: - To estimate ORR at Day 14 - To assess pharmacokinetic/ pharmacodynamic relationships - To assess Duration of response - To assess the cumulative steroid dose until Day 56 - To evaluate the safety and tolerability of ruxolitinib - To assess Overall Survival (OS) - To assess Event-Free Survival (EFS) - To assess Failure-Free Survival (FFS) - To assess Non Relapse Mortality (NRM) - To assess incidence of Malignancy Relapse/Progression (MR) - To measure the incidence of cGvHD - To estimate the rate of Best Overall Response (BOR) - To assess graft failure - To describe the acceptability and palatability assessments of the ruxolitinib formulation |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male or female patients age ≥28 days and <18 years at the time of informed consent. • Patients who have undergone alloSCT from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of myeloablative or reduced intensity conditioning are eligible. • Patients with clinically confirmed diagnosis of grades II-IV aGvHD (Harris 2016) 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.)
Other inclusion criteria as per full protocol may apply. |
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E.4 | Principal exclusion criteria |
• Has received the following systemic therapy for aGvHD: a) Treatment-naïve aGvHD patients have received any prior systemic treatment of aGvHD except for a maximum 72h of prior systemic corticosteroid therapy of methylprednisolone or equivalent after the onset of acute GvHD. Patients are allowed to have received prior GvHD prophylaxis which is not counted as systemic treatment (as long as the prophylaxis was started rior to the diagnsosis of aGvHD); OR b) SR-aGvHD patients have received two or more prior systemic treatments for aGvHD in addition to corticosteroids • Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features (as defined by Jagasia et al 2015). • Failed prior alloSCT within the past 6 months. • Presence of relapsed primary malignancy, or who have been treated for relapse after the alloSCT was performed, or who may require rapid immune suppression withdrawal of immune suppression as pre-emergent treatment of early malignancy relapse. • Acute GvHD occurring after non-scheduled donor leukocyte infusion (DLI) administered for preemptive treatment of malignancy recurrence. Note: Patients who have received a scheduled DLI as part of their transplant procedure and not for management of malignancy relapse are eligible. • Any corticosteroid therapy for indications other than aGvHD at doses > 1 mg/kg/day methylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days of Screening. Routine corticosteroids administered during conditioning or cell infusion is allowed. • Patients who received JAK inhibitor therapy for any indication after initiation of current alloSCT conditioning.
Additional exclusion criteria as per full protocol may apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase I: - Measurement of PK parameters in aGvHD and SR-aGvHD patients: AUC, Cmax, T1/2, Ctrough using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4
- Age-based determination of RP2D for each of the groups 2-4, based on observed PK parameters
Phase II: - Overall response rate (ORR) at Day 28, defined as the proportion of patients demonstrating a complete response (CR) or partial response (PR) without requirement for additional systemic therapies for an earlier progression, mixed response or non-response. Scoring of response will be relative to the organ stage at the start of the study treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I: - 28 days - 28 days
Phase II: - 28 days |
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E.5.2 | Secondary end point(s) |
Key secondary: Proportion of all patients who achieve a CR or PR at Day 28 and maintain a CR or PR at Day 56
Other secondary: - Proportion of patients who achieved OR (CR+PR) at Day 14 - PK parameters (such as AUC, Cmax, Ctrough) versus safety, efficacy, and PD biomarkers, as appropriate - Duration of response (DOR) is assessed for responders only and is defined as the time from first response until aGvHD progression or the date of additional systemic therapies for aGvHD. Onset of chronic GvHD, or death without prior observation of aGvHD progression are considered as competing risks - Weekly cumulative steroid dose for each patient up to Day 56 - Overall survival, defined as the time from the start of treatment to the date of death due to any cause - Event-free survival, defined as the time from start of treatment to the date of hematologic disease relapse/progression, graft failure, or death due to any cause - Failure-free survival, defined as the time from the start of treatment to date of hematologic disease relapse/progression, non-relapse mortality, or addition of new systemic aGvHD treatment - Non-relapse mortality (NRM), defined as the time from start of treatment to date of death not preceded by hematologic disease relapse/progression - Malignancy Relapse/Progression (MR), defined as the time from start of treatment to hematologic malignancy relapse/progression. Calculated for patients with underlying hematologic malignant disease - cGvHD, defined as the diagnosis of any cGvHD including mild, moderate, severe - Proportion of patients who achieved OR (CR+PR) at any time point up to and including Day 28 and before the start of additional systemic therapy for aGvHD - Monitoring of donor cell chimerism, defined as initial whole blood or marrow donor chimerism >5% declining to <5% on subsequent measurements compared to baseline - Questionnaire on acceptability and palatability for dose forms used after first dose, 1 month and 6 months |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key secondary: - Day 56
Other secondary: - Day 14 - 24 weeks - 48 weeks - up to 56 days - 2 years - 2 years - 2 years - 2 years - 2 years - 2 years - 2 years - 2 years - 2 years - 2 years - 2 years - 2 years - 2 years - 2 years - 24 weeks |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
palatability assessment of the oral formulation |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
dose finding in paediatric patients |
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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.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
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 |
Argentina |
Australia |
Canada |
Chile |
Hong Kong |
Japan |
Korea, Republic of |
France |
Netherlands |
Spain |
Czechia |
Germany |
Italy |
Belgium |
Denmark |
Slovenia |
Turkey |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 26 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |