| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Graft Versus Host Disease (cGVHD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| After HCT, the donor’s immune system senses and attacks the recipient’s normal tissues, resulting in graft versus host disease (GVHD) |
|
| 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 | 10066261 |
| E.1.2 | Term | Chronic graft versus host disease |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| 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 |
Part A - Dose Finding Study
Primary Objective: To determine the RPED (based on PK and, if applicable, pharmacodynamic data) for use in pediatric subjects (age ≥1 to <12 years) with cGVHD as
defined by the 2014 NIH Consensus Development Project Criteria.
Part B - Pharmacokinetics and Safety Study
Primary Objective: To assess the PK and safety of ibrutinib in pediatric subjects (age ≥ 1 to < 22 years) with cGVHD. |
|
| E.2.2 | Secondary objectives of the trial |
Part A - Dose Finding Study
• To determine the safety of ibrutinib in pediatric subjects with cGVHD
• To assess pharmacodynamics (BTK occupancy) of ibrutinib in pediatric subjects with cGVHD
• For those subjects continuing therapy after dose escalation (Part A Continuation Cohort), secondary endpoints will be the same as those outlined under Part B below and will include safety and efficacy
Part B - Pharmacokinetics, Safety, and Efficacy Study
• To evaluate the efficacy of ibrutinib treatment at 24 weeks in pediatric subjects with cGVHD using the 2014 NIH Consensus Development Project Criteria
• To evaluate the duration of response to ibrutinib treatment in pediatric subjects with cGVHD
• To evaluate the overall survival rate in pediatric subjects with cGVHD treated with ibrutinib
• To evaluate safety by assessing the potential impact of ibrutinib on late effects (including effects on growth and development and immune reconstitution) in pediatric subjects with cGVHD |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Part A: Subjects with moderate or severe cGVHD after failure of 1 or more lines of systemic
therapy
2. Part B: Subjects with moderate or severe cGVHD after failure of 1 or more lines of systemic therapy, or subjects with new onset moderate or severe cGVHD and in need of systemic immunosuppression.
a. Subjects with new onset moderate or severe cGVHD must not have received previous systemic therapy for cGVHD with the exception of corticosteroids received within
72 hours prior to signing the informed consent form.
b. Subjects with newly diagnosed cGVHD may be receiving other immunosuppressants for the prophylaxis or treatment of acute GVHD, but if the subject is receiving prednisone for prophylaxis or treatment of acute GVHD it must be at or below 0.5 mg/kg/d at the time of enrollment.
3. History of allogeneic stem cell transplantation
4. Age
• Part A: ≥1 to <12 years of age at the time of enrollment
• Part B: ≥1 to <22 years of age at the time of enrollment
5. Written informed consent or parental or guardian permission and assent of children capable of understanding the nature of the study, per country specific or site-specific standards.
6. Ability of subject or, if a minor, parent/guardian to understand the purpose and risks of the study and to provide a signed and dated parental permission and authorization to use protected health information (in accordance with national and local subject privacy
regulations); willingness of child to provide an assent, if developmentally able to do so. |
|
| E.4 | Principal exclusion criteria |
1. Presence of single organ genito-urinary involvement as the only manifestation of cGVHD.
Concurrent Conditions
2. Received an investigational agent within 28 days before enrollment.
3. Received donor lymphocyte infusion (DLI) within 56 days before enrollment.
4. Progressive underlying malignant disease or active post-transplant lymphoproliferative disease.
5. Ongoing anticoagulation treatment with warfarin or equivalent vitamin K antagonist.
6. History of other malignancy (not including the underlying malignancy that was the indication for transplant), with the following exceptions:
• Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to enrollment and felt to be at low risk for recurrence by treating physician
• Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
• Adequately treated cervical carcinoma in situ without current evidence of disease
7. History of major surgery within 28 days before enrollment or lack of full recovery from surgery.
8. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk.
9. Female subject who is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 3 months of the last dose of study drug. Male subject who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug.
10. Unwilling or unable to participate in all required study evaluations and procedures. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A: The primary endpoint is the PK (AUC) to determine the RPED of ibrutinib for use in pediatric subjects (age ≥ 1 to < 12 years) with cGVHD.
Part B: The primary endpoint is the PK (AUC) and safety (treatment-emergent AEs and laboratory abnormalities) of ibrutinib in pediatric subjects (age ≥ 1 to < 22 years) with cGVHD. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis for PK, safety and efficacy will occur after all subjects have had the opportunity to complete 24 weeks of treatment. |
|
| E.5.2 | Secondary end point(s) |
Part A: The secondary endpoints are safety, including treatment-emergent AEs, laboratory abnormalities, and other safety endpoints; pharmacodynamics (BTK occupancy) and for those subjects continuing therapy after dose escalation (Part A Continuation Cohort), secondary
endpoints will be the same as outlined under Part B below.
Part B: The secondary endpoints include cGVHD response rate (i.e. the proportion of responders [CR or PR]) at 24 weeks; duration of response; overall survival rate; growth and development in pediatric subjects (i.e., height, weight, Tanner Stage, and head circumference in subjects < 3 years), and immune reconstitution data |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After all subjects have had the opportunity to complete 24 weeks of treatment. |
|
| 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
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Australia |
| Canada |
| Israel |
| Korea, Republic of |
| Russian Federation |
| Turkey |
| United States |
| Austria |
| France |
| Germany |
| Italy |
| United Kingdom |
| Netherlands |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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