E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Male or female, 28 days to less than 18 years of age, who have received an allogeneic hematopoietic stem cell transplant (allo-HSCT) and have developed Grade II to IV acute GVHD |
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E.1.1.1 | Medical condition in easily understood language |
Acute graft versus host disease after allogeneic stem cell transplantation |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066260 |
E.1.2 | Term | Acute graft versus host disease |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066262 |
E.1.2 | Term | Acute graft versus host disease in skin |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066264 |
E.1.2 | Term | Acute graft versus host disease in intestine |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066263 |
E.1.2 | Term | Acute graft versus host disease in liver |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase 1:
- To assess the safety and tolerability of itacitinib in combination with corticosteroids in pediatric subjects with Grade II-IV steroid-naive (SN) acute graft-versus-host disease (aGVHD).
- To evaluate the pharmacokinetics (PK) of itacitinib when administered in combination with corticosteroids.
Phase 2:
- To assess the efficacy of itacitinib in combination with corticosteroids in terms of overall response rate (ORR) at Day 28 in pediatric subjects with aGVHD. |
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E.2.2 | Secondary objectives of the trial |
Phase 1:
- To assess the efficacy of itacitinib in combination with corticosteroids in terms of ORR at Day 28 in pediatric subjects with aGVHD.
Phase 2:
- To evaluate the PK of itacitinib when administered in combination with corticosteroids.
Phase 1 and 2:
- To evaluate additional efficacy and longer-term efficacy outcomes.
- To assess the incidence and severity of AEs and SAEs.
- To evaluate the incidence of secondary graft failure.
- To evaluate the use and discontinuation of corticosteroids.
- To evaluate the use and discontinuation of immunosuppressive medications.
- To evaluate the incidence of aGVHD flares.
- To evaluate the incidence of cGVHD. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male and female subjects from 28 days to < 18 years old
• Undergone 1 allo-HSCT from any donor and source (ie, unrelated, sibling, haploidentical donors with any matching) using bone marrow, peripheral blood, or cord blood stem cells for hematological malignancies or disorders. Recipients of myeloablative and reduced-intensity conditioning regimens are eligible.
• Clinically suspected Grade II to IV aGVHD as per MAGIC criteria, occurring after allo-HSCT and any GVHD prophylactic medication. Efforts should be made to obtain biopsies to pathologically confirm aGVHD. In cases where a biopsy is negative, unable to be obtained, or clinically contraindicated, clinical suspicion of aGVHD by the treating physician is sufficient, provided that alternative diagnoses of drug effects or infection are adequately ruled out.
• Evidence of myeloid engraftment (eg, absolute neutrophil count [ANC] ≥ 0.5 × 109/L for 3 consecutive assessments if ablative therapy was previously used). Use of growth factor supplementation is allowed.
• Estimated creatinine clearance (for subjects > 12 years old) greater than 50 mL/min (using the Cockcroft-Gault formula and actual body weight); for pediatric subjects (≥ 1 to 12 years old), glomerular filtration rate (GFR) > 70 mL/min/1.73 m2 as estimated using local institutional methods (eg, modified Schwartz formula or other validated methods). |
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E.4 | Principal exclusion criteria |
• More than 1 allo-HSCT.
• Received more than 2 days of systemic corticosteroids for aGVHD before the first study drug administration.
• Presence of GVHD overlap syndrome.
• Presence of an active uncontrolled infection, defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs, or radiographic findings attributable to infection. Persisting fever without signs or symptoms will not be interpreted as an active uncontrolled infection.
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1:
• Frequency, duration, and severity of adverse events (AEs) and serious adverse events (SAEs)
• Changes in vital signs and clinical evaluations.
• Changes in clinical laboratory blood samples.
• Cmax, Cmin, Tmax, AUC, and Cl/F assessed at Day 1, 7, and 28.
Phase 2:
• ORR at Day 28, defined as the proportion of subjects demonstrating a complete response (CR), very good partial response (VGPR), or partial response (PR). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day1 , 7, 14, 21, 28, 35, 42, 49, 56, 100, 180, 365 |
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E.5.2 | Secondary end point(s) |
Phase 1:
• ORR at Day 28, defined as the proportion of subjects demonstrating a CR, VGPR, or PR.
Phase 2:
• Cmax, Cmin, Tmax, AUC, and Cl/F assessed at Day 7.
Phase 1 & 2:
• ORR, defined as the proportion of subjects demonstrating a CR, VGPR, or PR, at Days 14, 56, and 100.
• Nonrelapse mortality (NRM), defined as the proportion of subjects who died due to causes other than underlying hematological disorders at Months 6, 9, 12, and 24.
• Duration of response (DOR) for responders will be calculated. The DOR is defined from the time of the onset of response to loss of response. Subjects who died or discontinued will be censored at the death date or the previous assessment.
• Time to response, defined as the interval from treatment initiation to first response.
• Relapse rate of malignant and non-malignant disorders, defined as the proportion of subjects whose underlying disease relapses.
• Malignant and non-malignant disorders relapse–related mortality rate, defined as the proportion of subjects whose underlying disease relapses and has a fatal outcome.
• Failure-free survival, defined as the proportion of subjects who are still alive, have not relapsed, have not required additional therapy for aGVHD, and have not demonstrated signs or symptoms of chronic graft-versus-host disease (cGVHD), at Month 6.
• Overall survival, defined as the interval from study enrollment to death due to any cause.
• Clinical safety data (eg, AEs, infections) will be tabulated and listed.
• Incidence rate of secondary graft failure, defined as > 95% recipient cells any time after engraftment with no signs of relapse OR retransplantation because of secondary neutropenia (< 0.5 × 109/L) and/or thrombocytopenia (< 20 × 109/L) within 2 months of transplant.
• Average and cumulative corticosteroid dose at Days 28, 56, 100, and 180; proportion of subjects who discontinue corticosteroids at Days 56 and 100.
• Proportion of subjects who discontinue immunosuppressive medication at Days 56 and 100.
• Incidence rate of aGVHD flares through Day 100.
• Incidence rate of cGVHD at Days 180 and 365. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day1 , 7, 14, 21, 28, 35, 42, 49, 56, 100, 180, 365
Months 9 and 24. |
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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 | Yes |
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 | Yes |
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) | 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 |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
staggered approach by age cohort |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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 |
Belgium |
France |
Germany |
Italy |
Spain |
United States |
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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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The study will end once 75% of subjects have died or are lost to follow-up. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |