| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language | |
| 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 | HLGT | | E.1.2 | Classification code | 10025320 | | E.1.2 | Term | Lymphomas non-Hodgkin's B-cell | | E.1.2 | System Organ Class | 10005329 - Blood and lymphatic 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 1:
Confirm that the pharmacokinetics in pediatric subjects is consistent with that in adults
Part 2:
Assess efficacy (EFS) of ibrutinib in combination with RICE or RVICI background therapy compared to RICE or RVICI background therapy alone | |
| E.2.2 | Secondary objectives of the trial | Part 1:
-Evaluate the safety and tolerability of ibrutinib in combination with RICE or RVICI background therapy in pediatric subjects with B-cell malignancies
-Assess anti-tumor activity of ibrutinib as add-on to RICE or RVICI regimens
-Assess disease-specific biomarkers
-Assess the pharmacodynamic response
-Acceptability and palatability assessment of all ibrutinib formulations
Part 2:
-Evaluate the safety and tolerability of ibrutinib in combination with RICE or RVICI background therapy in pediatric subjects and young adults with B-cell malignancies
-Determine the ORR
-Evaluate tumor volume reduction at Day 14
-Determine the number and proportion of subjects who proceed to stem cell transplantation
-Evaluate the time to response
-Measure the duration of response
-Evaluate long-term survival (EFS at 2 and 3 years)
-Evaluate overall survival
-Assess disease-specific biomarkers
For the remaining secondary objectives, please refer to protocol page 44. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | -Participants with 1 to less than (<) 18 years of age (Part 1 only), or 1 to 30 years of age, inclusive, if initial diagnosis of mature B-cell non-Hodgkin lymphoma (NHL) occurred at <18 years of age (Part 2 only)
NOTE: Must have pathology report for the original NHL diagnosis or from the time of relapse (if available). If these pathology reports are not available, the pathology results of a fresh biopsy will be required for enrollment into the study.
-Participants must be in first recurrence or have received only one prior line of therapy or have disease that is primarily refractory to conventional therapy
-Participants must have at least 1 of the following: 1 site of measurable disease greater than (>) 1 centimeter (cm) in the longest diameter and >1 cm in the shortest diameter by radiological imaging; bone marrow involvement; cerebrospinal fluid with blasts present
-Participants with lansky-Karnofsky score of greater than or equal to (>=) 50
-ICF must be signed by legally authorized representative or by the subject if at legal age of consent indicating understanding of the purpose of, and procedures required for, the study and willingness to participate in the study. Assent is also required of children capable of understanding the nature of the study per country-specific or site-specific standards as described in Section 16.2.3, Informed Consent and Assent Form.
- Adolescent women/young women of childbearing potential must have a negative highly sensitive serum or urine beta-human chorionic gonadotropin (beta-hCG) pregnancy test at Screening before enrollment/randomization. Adolescent/young women who are pregnant or breastfeeding are ineligible for this study
- Adolescents/young women of childbearing potential must be practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) and agree to remain on a highly effective method throughout the study and for at least 3 months after the last dose of ibrutinib and 1 year after the last dose of the background CIT whichever is later. | |
| E.4 | Principal exclusion criteria | - Participants with ongoing anticoagulation treatment with warfarin or equivalent vitamin K antagonists (example phenprocoumon), or ongoing treatment with agents known to be strong CYP3A4/5 inhibitors, or has taken any disallowed therapies as noted in Section 8.2, Prohibited Medications, before the planned first dose of study drug
- Participants with inherited or acquired bleeding disorders
- Participants with clinically significant arrhythmias, complex congenital heart disease, or left ventricular ejection fraction (LVEF) <50 percent (%) or shortening fraction (SF) <=28%
- Participants with known history of human immunodeficiency virus (HIV) or active Hepatitis B or C virus
- Participants with any condition that could interfere with the absorption or metabolism of ibrutinib including malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel
- Participants with known allergies, hypersensitivity, or intolerance to ibrutinib or its excipients (refer to Investigator's Brochure)
- Participants who are pregnant, or breastfeeding, or planning to become pregnant while enrolled in this study or within at least 3 months after the last dose of ibrutinib or 1 year after the last dose of the background CIT, whichever is later
- A diagnosis of post-transplant lymphoproliferative disease (PTLD)
- Patients who are within 6 months of an allogeneic bone marrow transplant
- Subjects who have had prior exposure to ibrutinib | |
| E.5 End points |
| E.5.1 | Primary end point(s) | 1/ Part 1: Area Under The Plasma Concentration-Time Curve (AUC) of Ibrutinib
2/ Part 1: Apparent (oral) Plasma Clearance (CL/F) of Ibrutinib
3/ Part 1: Apparent (oral) Volume of Distribution (Vd/F) of Ibrutinib
4/ Part 1: Maximum Observed Plasma Concentration (Cmax)
5/ Part 1: Relationship Between Pharmacokinetic Parameters and Age or Measure of Body Size
6/ Part 2: Event-free Survival [EFS]) of Ibrutinib | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | 1-4 /Predose and at 1, 2, 4, and 6 hours postdose on Day 1 and on Day 7 or 8 of cycle 1; predose, 1, 2, 4, and 6 hours postdose on Day 1 of Cycle 2 or Cycle 3.
5/ up to three 28-day cycles
6/ Randomization to death, disease progression, or lack of CR or PR after 3 cycles of treatment (approximately 4.2 years) | |
| E.5.2 | Secondary end point(s) | 1/ Part 1: Number of Participants with Adverse Events
2/ Part 1: Percentage of Participants Who Achieve Complete Response (CR) and Partial Response (PR)
3/ Part 1: Disease-specific Biomarkers Assessment
4/ Part 1: Bruton’s tyrosine kinase (BTK) Percent Occupancy
5/ Part 1: Visual analog Scale Score for Palatability
6/ Part 2: Number of Participants with Adverse Events
7/ Part 2: Percentage of Participants Who Achieve Complete Response (CR) and Partial Response (PR)
8/ Part 2: Tumor Volume Reduction
9/ Part 2: Percentage of Participants who Proceed to Stem Cell Transplantation
10/ Part 2: Time to Response
11/ Part 2: Duration of Response
12/ Part 2: Percentage of Participants with Long-term Survival
13/ Part 2: Overall Survival
14/ Part 2: Disease-specific Biomarkers Assessment
15/ Part 2: Bruton’s tyrosine kinase (BTK) Percent Occupancy
16/ Part 2: Visual analog Scale Score for Palatability
17/ Part 2: Area under the plasma concentration-time curve (AUC) | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | 1/Throughout the study
2&7/Treatment Phase:D14 (Cy1),end of Cy2,EOT visit;Post treatment phase: 6,12,24,36 mth post C1D1/clinical cutoff for primary endpoint/or up to 3yrs after the date of C1D1, whichever occurs first
3/Predose on C1D1, C1D7 or 8, C1D14, C2D1 or C3D1 & EOT visit
4/Predose &4hrs postdose on D1 & D7 or 8 of C1, predose on C2D1 or C3D1 & at PD or EOT visit
5/Cy1D1& Cy3D1
6/Throughout the study
8/D14
9/Cy2 (D28)
10-11/Up to 4.2yrs
12/2, 3yrs
13/Randomization to till death
14/Predose on Cy1 D1, Cy1 D7 or 8, Cy1 D14, Cy2 D1 or Cy3 D1 & EOT visit
15/Predose and 4hrs postdose on C1D1 and Predose and 4hrs postdose on C1D14 or Cy2 D1, Predose on Cy3 D1, & at PD or EOT visit
16/Cy1 D1 & Cy3 D1
17/Predose, 1, 2, 4 hrs postdose, either on D14 of Cy1 or on D1 of Cy2 | |
| 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 | No |
| 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 | |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description | | Background Chemoimmunotherapy | |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 54 |
| 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 | | Brazil | | Bulgaria | | Canada | | Czech Republic | | France | | Germany | | Hungary | | Italy | | Japan | | Korea, Republic of | | Netherlands | | Poland | | Romania | | Russian Federation | | Spain | | Taiwan | | Turkey | | Ukraine | | United Kingdom | | United States | |
| 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 | | LVLS or when the sponsor decides to terminate the study | |
| 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 | 6 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
