Trial Outcomes & Findings for A Safety and Efficacy Study of Ibrutinib in Pediatric and Young Adult Participants With Relapsed or Refractory Mature B-cell Non-Hodgkin Lymphoma (NCT NCT02703272)

Last Updated: 2022-12-02

Results Overview

AUC is defined as area under the plasma concentration-time curve. As per planned analyses, pharmacokinetic (PK) parameters for Part 1 were presented per dose group (240 milligrams per meter square \[mg/m\^2\], 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

72 participants

Primary outcome timeframe

Up to Cycle 3 (each cycle of 21 or 28 days)

Results posted on

2022-12-02

Participant Flow

Participant milestones

Participant milestones
Measure	Part 1: Ibrutinib+RICE Participants received ibrutinib based on age group and body surface area (BSA) in combination with chemoimmunotherapy (CIT) (investigator choice of RICE \[rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone\]). For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. Ibrutinib suspension or capsule was administered once daily starting Day 1 Cycle 1. The first 2 participants enrolled in each age group (1-5 years, 6-11 years, and 12-17 years) received Ibrutinib at a lower starting dose of 240 milligram per meter square (mg/m\^2) (not to exceed 420 mg per day) for the first cycle (older children \[6-17 years\] were enrolled first before enrolling younger children \[1-5 years\]), followed by dose escalation to 329 mg/m\^2 (not to exceed 560 mg per day) at the start of Cycle 2 based on the safety assessments. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 grams per meter square (g/m\^2), carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. Study treatment continued for 3 cycles (each cycle of 28 or 21 days), unless the participants experienced unacceptable toxicity or disease progression.	Part 1: Ibrutinib+RVICI Participants received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RVICI \[rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone\]). dexamethasone\]). For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. The first 2 participants enrolled in each age group (1-5 years, 6-11 years, and 12-17 years) received Ibrutinib at a lower starting dose of 240 mg/m2 (not to exceed 420 mg per day) for the first cycle (older children \[6-17 years\] were enrolled first before enrolling younger children \[1-5 years\]), followed by dose escalation to 329 mg/m2 (not to exceed 560 mg per day) at the start of Cycle 2 based on the safety assessments. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, ifosfamide 10 g/m\^2, carboplatin 800 mg/m\^2, idarubicin 20 mg/m\^2, and dexamethasone 100 mg/m\^2. Study treatment continued for 3 cycles (each cycle of 28 or 21 days), unless the participants experienced unacceptable toxicity or disease progression.	Part 2: Ibrutinib+CIT (RICE or RVICI) Participants received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RICE or RVICI) until 3 treatment cycles, transplantation if indicated, or until progressive disease (PD) or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. Participants of age groups 1-5 years and 6-11 years received ibrutinib 440 mg/m\^2, and age group 12-17 years received Ibrutinib 329 mg/m\^2 (dose selected from Part 1).	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Overall Study STARTED	11	10	35	16
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	11	10	35	16

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1: Ibrutinib+RICE Participants received ibrutinib based on age group and body surface area (BSA) in combination with chemoimmunotherapy (CIT) (investigator choice of RICE \[rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone\]). For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. Ibrutinib suspension or capsule was administered once daily starting Day 1 Cycle 1. The first 2 participants enrolled in each age group (1-5 years, 6-11 years, and 12-17 years) received Ibrutinib at a lower starting dose of 240 milligram per meter square (mg/m\^2) (not to exceed 420 mg per day) for the first cycle (older children \[6-17 years\] were enrolled first before enrolling younger children \[1-5 years\]), followed by dose escalation to 329 mg/m\^2 (not to exceed 560 mg per day) at the start of Cycle 2 based on the safety assessments. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 grams per meter square (g/m\^2), carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. Study treatment continued for 3 cycles (each cycle of 28 or 21 days), unless the participants experienced unacceptable toxicity or disease progression.	Part 1: Ibrutinib+RVICI Participants received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RVICI \[rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone\]). dexamethasone\]). For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. The first 2 participants enrolled in each age group (1-5 years, 6-11 years, and 12-17 years) received Ibrutinib at a lower starting dose of 240 mg/m2 (not to exceed 420 mg per day) for the first cycle (older children \[6-17 years\] were enrolled first before enrolling younger children \[1-5 years\]), followed by dose escalation to 329 mg/m2 (not to exceed 560 mg per day) at the start of Cycle 2 based on the safety assessments. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, ifosfamide 10 g/m\^2, carboplatin 800 mg/m\^2, idarubicin 20 mg/m\^2, and dexamethasone 100 mg/m\^2. Study treatment continued for 3 cycles (each cycle of 28 or 21 days), unless the participants experienced unacceptable toxicity or disease progression.	Part 2: Ibrutinib+CIT (RICE or RVICI) Participants received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RICE or RVICI) until 3 treatment cycles, transplantation if indicated, or until progressive disease (PD) or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. Participants of age groups 1-5 years and 6-11 years received ibrutinib 440 mg/m\^2, and age group 12-17 years received Ibrutinib 329 mg/m\^2 (dose selected from Part 1).	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Overall Study Death	4	9	19	10
Overall Study Withdrawal by Subject	0	0	4	2
Overall Study Study Terminated by Sponsor	6	1	12	4
Overall Study Other	1	0	0	0

Baseline Characteristics

A Safety and Efficacy Study of Ibrutinib in Pediatric and Young Adult Participants With Relapsed or Refractory Mature B-cell Non-Hodgkin Lymphoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1: Ibrutinib+RICE n=11 Participants Participants received ibrutinib based on age group and body surface area (BSA) in combination with chemoimmunotherapy (CIT) (investigator choice of RICE \[rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone\]). For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. Ibrutinib suspension or capsule was administered once daily starting Day 1 Cycle 1. The first 2 participants enrolled in each age group (1-5 years, 6-11 years, and 12-17 years) received Ibrutinib at a lower starting dose of 240 milligram per meter square (mg/m\^2) (not to exceed 420 mg per day) for the first cycle (older children \[6-17 years\] were enrolled first before enrolling younger children \[1-5 years\]), followed by dose escalation to 329 mg/m\^2 (not to exceed 560 mg per day) at the start of Cycle 2 based on the safety assessments. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 grams per meter square (g/m\^2), carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. Study treatment continued for 3 cycles (each cycle of 28 or 21 days), unless the participants experienced unacceptable toxicity or disease progression.	Part 1: Ibrutinib+RVICI n=10 Participants Participants received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RVICI \[rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone\]). dexamethasone\]). For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. The first 2 participants enrolled in each age group (1-5 years, 6-11 years, and 12-17 years) received Ibrutinib at a lower starting dose of 240 mg/m2 (not to exceed 420 mg per day) for the first cycle (older children \[6-17 years\] were enrolled first before enrolling younger children \[1-5 years\]), followed by dose escalation to 329 mg/m2 (not to exceed 560 mg per day) at the start of Cycle 2 based on the safety assessments. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, ifosfamide 10 g/m\^2, carboplatin 800 mg/m\^2, idarubicin 20 mg/m\^2, and dexamethasone 100 mg/m\^2. Study treatment continued for 3 cycles (each cycle of 28 or 21 days), unless the participants experienced unacceptable toxicity or disease progression.	Part 2: Ibrutinib+CIT (RICE or RVICI) n=35 Participants Participants received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RICE or RVICI) until 3 treatment cycles, transplantation if indicated, or until progressive disease (PD) or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. Participants of age groups 1-5 years and 6-11 years received ibrutinib 440 mg/m\^2, and age group 12-17 years received Ibrutinib 329 mg/m\^2 (dose selected from Part 1).	Part 2: Chemoimmunotherapy n=16 Participants Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).	Total n=72 Participants Total of all reporting groups
Age, Continuous	10.5 years STANDARD_DEVIATION 4.91 • n=5 Participants	8.3 years STANDARD_DEVIATION 3.43 • n=7 Participants	13.9 years STANDARD_DEVIATION 3.94 • n=5 Participants	13.2 years STANDARD_DEVIATION 4.37 • n=4 Participants	12.4 years STANDARD_DEVIATION 4.54 • n=21 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	1 Participants n=7 Participants	12 Participants n=5 Participants	3 Participants n=4 Participants	19 Participants n=21 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	9 Participants n=7 Participants	23 Participants n=5 Participants	13 Participants n=4 Participants	53 Participants n=21 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	8 Participants n=5 Participants	6 Participants n=4 Participants	15 Participants n=21 Participants
Race/Ethnicity, Customized Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race/Ethnicity, Customized White	9 Participants n=5 Participants	10 Participants n=7 Participants	22 Participants n=5 Participants	8 Participants n=4 Participants	49 Participants n=21 Participants
Race/Ethnicity, Customized More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race/Ethnicity, Customized Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	0 Participants n=4 Participants	4 Participants n=21 Participants
Race/Ethnicity, Customized Other	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants
Region of Enrollment BELGIUM	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Region of Enrollment BRAZIL	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	4 Participants n=21 Participants
Region of Enrollment BULGARIA	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Region of Enrollment CANADA	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Region of Enrollment CZECH REPUBLIC	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	4 Participants n=21 Participants
Region of Enrollment FRANCE	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	1 Participants n=4 Participants	7 Participants n=21 Participants
Region of Enrollment GERMANY	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	0 Participants n=4 Participants	6 Participants n=21 Participants
Region of Enrollment ITALY	2 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants	2 Participants n=4 Participants	9 Participants n=21 Participants
Region of Enrollment NETHERLANDS	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants
Region of Enrollment POLAND	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants	3 Participants n=21 Participants
Region of Enrollment ROMANIA	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Region of Enrollment RUSSIAN FEDERATION	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Region of Enrollment SOUTH KOREA	1 Participants n=5 Participants	0 Participants n=7 Participants	5 Participants n=5 Participants	4 Participants n=4 Participants	10 Participants n=21 Participants
Region of Enrollment SPAIN	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Region of Enrollment SWEDEN	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Region of Enrollment TAIWAN	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants
Region of Enrollment TURKEY	1 Participants n=5 Participants	4 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	8 Participants n=21 Participants
Region of Enrollment UKRAINE	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Region of Enrollment UNITED KINGDOM	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants
Region of Enrollment UNITED STATES	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants

PRIMARY outcome

Timeframe: Up to Cycle 3 (each cycle of 21 or 28 days)

Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. Here, "n (number analyzed)" is defined as number of participants analyzed for specified category.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=3 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=10 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 n=7 Participants Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib 6-11 years	145 hoursnanogram per milliliter (hng/mL) Interval 140.0 to 233.0	349 hoursnanogram per milliliter (hng/mL) Interval 238.0 to 562.0	324 hoursnanogram per milliliter (hng/mL) Interval 185.0 to 538.0	—
Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib 1-5 years	143 hoursnanogram per milliliter (hng/mL) Interval 116.0 to 170.0	386 hoursnanogram per milliliter (hng/mL) Interval 386.0 to 386.0	310 hoursnanogram per milliliter (hng/mL) Interval 230.0 to 543.0	—
Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib 12-17 years	1210 hoursnanogram per milliliter (hng/mL) Interval 939.0 to 1450.0	661 hoursnanogram per milliliter (hng/mL) Interval 394.0 to 778.0	—	—

PRIMARY outcome

Timeframe: Up to Cycle 3 (each cycle of 21 or 28 days)

CL/F is defined as apparent plasma clearance of ibrutinib. As per planned analyses, PK parameters for Part 1 were presented per dose group (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=3 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=10 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 n=7 Participants Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib 1-5 years	1220 milliliter per hour (mL/h) Interval 1000.0 to 1430.0	508 milliliter per hour (mL/h) Interval 508.0 to 508.0	1200 milliliter per hour (mL/h) Interval 838.0 to 1550.0	—
Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib 6-11 years	1450 milliliter per hour (mL/h) Interval 1080.0 to 1500.0	805 milliliter per hour (mL/h) Interval 664.0 to 1100.0	1300 milliliter per hour (mL/h) Interval 910.0 to 2460.0	—
Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib 12-17 years	348 milliliter per hour (mL/h) Interval 340.0 to 433.0	729 milliliter per hour (mL/h) Interval 568.0 to 1330.0	—	—

PRIMARY outcome

Timeframe: Up to Cycle 3 (each cycle of 21 or 28 days)

Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. Here, n (number analyzed)" is defined as number of participants analyzed for specified category.

Vd/F is defined as apparent (oral) volume of distribution of ibrutinib. As per planned analyses, pharmacokinetic (PK) parameters for Part 1 were presented per dose group (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=3 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=10 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 n=7 Participants Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib 1-5 years	11.1 liter(s) Interval 8.26 to 13.9	5.18 liter(s) Interval 5.18 to 5.18	7.63 liter(s) Interval 5.34 to 11.1	—
Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib 6-11 years	18 liter(s) Interval 10.8 to 29.9	7.55 liter(s) Interval 2.89 to 15.6	19 liter(s) Interval 6.09 to 55.9	—
Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib 12-17 years	3.63 liter(s) Interval 2.32 to 4.77	11.3 liter(s) Interval 6.34 to 18.5	—	—

PRIMARY outcome

Timeframe: Up to Cycle 3 (each cycle of 21 or 28 days)

Cmax is defined as maximum plasma concentration of ibrutinib. As per planned analyses, pharmacokinetic (PK) parameters for Part 1 were presented per dose group (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=3 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=10 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 n=7 Participants Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib 1-5 years	3.86 nanograms per milliliter (ng/mL) Interval 3.75 to 3.98	4.48 nanograms per milliliter (ng/mL) Interval 4.48 to 4.48	5.07 nanograms per milliliter (ng/mL) Interval 4.5 to 5.14	—
Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib 6-11 years	3.46 nanograms per milliliter (ng/mL) Interval 3.12 to 3.6	3.64 nanograms per milliliter (ng/mL) Interval 3.32 to 4.59	3.88 nanograms per milliliter (ng/mL) Interval 3.2 to 4.44	—
Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib 12-17 years	4.88 nanograms per milliliter (ng/mL) Interval 4.76 to 5.4	4.73 nanograms per milliliter (ng/mL) Interval 4.07 to 5.07	—	—

PRIMARY outcome

Timeframe: Up to Cycle 3 (each cycle of 28 days)

Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib.

The relationship between ibrutinib metrics of systemic exposure (AUC) with body size was assessed to determine the impact on AUC which were presented per dose groups (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age groups (1-5, 6-11, 12-17 and \>18 years). The data could not be analyzed in tabular format for this outcome measure as they correspond to a flat regression line in nonlinear mixed effects modeling.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Time from Randomization to death, disease progression, or lack of CR or PR after 3 cycles of treatment (up to 4 year and 4 months)

Population: The intent-to-treat (ITT) population consisted of all randomized participants; participants analyzed based on randomization, regardless of study drug received. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

EFS was the time interval from randomization to death, disease progression, or lack of complete response (CR) or partial response (PR) after 3 cycles of treatment, whichever occurred first based on blinded independent event review by the Independent Review Committee (IRC). CR was defined as computed tomography (CT) or magnetic resonance imaging (MRI) reveals no residual disease or new lesions, resected residual mass that was pathologically (morphologically) negative for disease, BM and CSF morphologically free of disease with no new lesions by imaging examination. PR was defined as 50 percent (%) decrease in sum of the products of the lesion diameters (SPD) on CT or MRI; fluorodeoxyglucose (FDG)-positron emission tomography (PET) may be positive, no new or progressive disease (PD); morphologic evidence of disease may be present in BM or cerebrospinal fluid (CSF) if present at diagnosis; however, there should be 50% reduction in percentage of lymphoma cells.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=35 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=16 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Event Free Survival (EFS) Between the 2 Treatment Groups	6.05 Months Interval 2.99 to 8.84	6.97 Months Interval 2.6 to 11.07	—	—

SECONDARY outcome

Timeframe: Up to 4 year and 4 months

Population: Safety population consisted of all participants who received at least 1 dose of treatment.

An AE is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=11 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=10 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 n=35 Participants Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy n=15 Participants Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 1 and Part 2: Number of Participants With Adverse Events as Measure of Safety and Tolerability	11 Participants	10 Participants	35 Participants	15 Participants

SECONDARY outcome

Timeframe: Up to 4 year and 4 months

Population: The ITT Population consisted of all randomized participants; participants analyzed based on randomization, regardless of study drug received.

ORR was defined as the percentage of participants achieving a best overall response of either complete response (CR) (including CR biopsy-negative \[CRb\] and unconfirmed CR \[CRu\]) or partial response (PR) as evaluated by International Pediatric non-Hodgkin lymphoma (NHL) response criteria. CR=disappearance of all disease; CRb=residual mass has no morphologic evidence of disease from limited or core biopsy, with no new lesions by imaging examination; bone marrow (BM) and CSF morphologically free of disease; no new or PD elsewhere, CRu=Residual mass is negative by FDG-PET; no new lesions by imaging examination; BM and CSF morphologically free of disease; no new or PD elsewhere, PR=50% decrease in SPD on CT or MRI; FDG-PET may be positive (deauville score or 4 or 5 with reduced lesional uptake compared with baseline); no new or PD; morphologic evidence of disease may be present in BM or CSF if present at diagnosis; however, there should be 50% reduction in percentage of lymphoma cells.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=11 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=10 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 n=35 Participants Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy n=16 Participants Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 1 and Part 2: Overall Response Rate (ORR)	81.8 Percentage of participants	50.0 Percentage of participants	68.6 Percentage of participants	81.3 Percentage of participants

SECONDARY outcome

Timeframe: Baseline

Population: Biomarker analyses were conducted on the ITT population. As per change in planned analysis, genetic analysis was not performed for Part 1. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Tumor formalin-fixed paraffin-embedded (FFPE) samples were taken to evaluate the baseline gene expression by disease-specific biomarkers such as BCL-2L1 (BCL-xl), BIRC2 (cIAP1), Caspase 3 (CASP3), STAT3, and SYK. Transcripts per million (TPM) is a normalization method for RNA-sequencing, which means "for every 1,000,000 RNA molecules in the RNA-sequencing tumor FFPE sample, x came from this gene/transcript.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 n=18 Participants Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy n=9 Participants Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline Caspase 3 (CASP3)	—	—	51.14711 Transcripts per million Standard Deviation 21.44109	47.61412 Transcripts per million Standard Deviation 32.12666
Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline BCL-2L1 (BCL-xl)	—	—	58.09346 Transcripts per million Standard Deviation 38.75996	74.30790 Transcripts per million Standard Deviation 75.82331
Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline BIRC2 (cIAP1)	—	—	47.20787 Transcripts per million Standard Deviation 16.26430	40.01716 Transcripts per million Standard Deviation 9.28104
Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline STAT3	—	—	540.02256 Transcripts per million Standard Deviation 363.75256	526.35308 Transcripts per million Standard Deviation 473.08255
Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline SYK	—	—	705.29909 Transcripts per million Standard Deviation 503.07085	618.36324 Transcripts per million Standard Deviation 144.72067

SECONDARY outcome

Timeframe: At baseline (Cycle 1 Day 1) of Part 1 and 2

Population: Biomarker analyses were conducted on the ITT population. As per change in planned analysis, immunoglobulin and T-cell receptor gene rearrangements were not performed for Part 1 and Part 2.

Number of participants with immunoglobulin and T-cell receptor gene rearrangements were reported.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 3 months

Population: Biomarker analyses were conducted on the ITT population. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. As planned, BTK occupancy was assessed for ibrutinib only.

Number of participants with \>90% BTK occupancy were reported. Blood samples were collected to assess BTK occupancy.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=15 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=13 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 1 and Part 2: Number of Participants With Greater Than (>) 90% Bruton's Tyrosine Kinase (BTK) Occupancy	5 Participants	5 Participants	—	—

SECONDARY outcome

Timeframe: Day 1 of Cycle 1 and Cycle 3

Population: Safety population: all participants who received at least 1 dose of treatment. Here 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure (OM) and, n (number analyzed) signifies number of participants analyzed for specified category. Participants in arm 'Part 2: Chemoimmunotherapy' did not receive ibrutinib, and palatability of ibrutinib was measured in this OM. Hence, no data available to report for this arm.

Palatability of ibrutinib was measured by using a VAS. The scale is a 5-point visual analog scale incorporating a facial hedonic scale designed to span pediatric ages and levels of participant comprehension with a score range of 1 to 5, where 1 represents best score and 5 is worst palatability.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=11 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=10 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 n=32 Participants Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability Cycle 1 Day 1	2.6 Units on a scale Standard Deviation 1.21	3.2 Units on a scale Standard Deviation 1.40	2.4 Units on a scale Standard Deviation 1.16	—
Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability Cycle 3 Day 1	3.3 Units on a scale Standard Deviation 1.39	2.3 Units on a scale Standard Deviation 1.15	2.6 Units on a scale Standard Deviation 0.89	—

SECONDARY outcome

Timeframe: Up to 4 years and 4 months

Population: Biomarker analyses were conducted on the ITT population. As per change in planned analysis, genetic analysis was not performed for Part 1.

Number of Participants with CD79B, CARD11, and MYD Mutations were reported.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 4 year and 4 months

Population: Biomarker analyses were conducted on the ITT population. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Number of participants with CD79B, CARD11, and MYD mutations were reported. Blood samples were taken to evaluate the levels of biomarkers such as CD79B, CARD11, and MYD mutations.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=20 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=10 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Number of Participants With CD79B, CARD11, and MYD Mutations CD79B	1 Participants	0 Participants	—	—
Part 2: Number of Participants With CD79B, CARD11, and MYD Mutations CARD11	1 Participants	0 Participants	—	—
Part 2: Number of Participants With CD79B, CARD11, and MYD Mutations MYD mutation	0 Participants	0 Participants	—	—

SECONDARY outcome

Timeframe: At baseline (Cycle 1 Day 1)

Population: Biomarker analyses were conducted on the ITT population. As per change in planned analysis, genetic analysis was not performed for Part 1.

Number of participants with c-MYC gene rearrangement were reported.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At baseline (Cycle 1 Day 1)

Population: Biomarker analyses were conducted on the ITT population. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Number of participants with c-MYC gene rearrangement were reported. Blood samples were taken to evaluate the levels of biomarker such as c-MYC Gene rearrangement.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=18 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=9 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Number of Participants With c-MYC Gene Rearrangement	1 Participants	1 Participants	—	—

SECONDARY outcome

Timeframe: Up to 4 year and 4 months

Population: The ITT Population consisted of all randomized participants; participants analyzed based on randomization, regardless of study drug received.

Complete response rate was defined as the percentage of participants who achieved complete response or complete response with an incomplete marrow recovery (CRi) on or prior to initiation of subsequent anti-leukemic therapy per the IRC assessment.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=35 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=16 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Percentage of Participants Who Achieved Complete Response (CR)	17.1 Percentage of Participants	18.8 Percentage of Participants	—	—

SECONDARY outcome

Timeframe: Up to 4 year and 4 months

Population: The ITT Population consisted of all randomized participants; participants analyzed based on randomization, regardless of study drug received.

Percentage of participants who achieved PR were assessed. PR was defined as 50% decrease in SPD on computed tomography (CT) or magnetic resonance imaging (MRI); FDG-PET may be positive; no new or PD; morphologic evidence of disease may be present in BM or cerebrospinal fluid (CSF) if present at diagnosis; however, there should be 50% reduction in percentage of lymphoma cells.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=35 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=16 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Percentage of Participants Who Achieved Partial Response (PR)	51.4 percentage of participants	62.5 percentage of participants	—	—

SECONDARY outcome

Timeframe: At Day 14

Population: The ITT Population consisted of all randomized participants; participants was analyzed based on randomization, regardless of study drug received. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

The tumor volume reduction rate was defined as percent decrease in the sum of the products of the lesion diameters at Day 14. It was measured as the mean change in the sum of the products of the lesion diameters (SPD) at Day 14.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=30 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=11 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Tumor Volume Reduction Rate at Day 14	-49.7 Percent change Standard Deviation 33.41	-58.60 Percent change Standard Deviation 34.04	—	—

SECONDARY outcome

Timeframe: Up to end of the study (Up to 4 year and 4 months)

Population: The ITT population consisted of all randomized participants; participants were analyzed based on randomization, regardless of study drug received.

Number of participants who proceeded to stem cell transplantation were reported.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=35 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=16 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Number of Participants Who Proceeded to Stem Cell Transplantation	13 Participants	7 Participants	—	—

SECONDARY outcome

Timeframe: Up to 4 Years and 4 months

Population: Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. Time to response was summarized for participants who achieved either CR (including CRb and CRu) or PR.

Time to response was defined as the time interval from the first dose of ibrutinib to the first documented response for those participants who responded. Time to response was summarized for participants who achieved either CR (including CRb and CRu) or PR. CR=disappearance of all disease; CRb=residual mass has no morphologic evidence of disease from limited or core biopsy, with no new lesions by imaging examination; BM and CSF morphologically free of disease; no new or PD elsewhere, CRu=Residual mass is negative by FDG-PET; no new lesions by imaging examination; BM and CSF morphologically free of disease; no new or PD elsewhere, PR=50% decrease in SPD on CT or MRI; FDG-PET may be positive (deauville score or 4 or 5 with reduced lesional uptake compared with baseline); no new or PD; morphologic evidence of disease may be present in BM or CSF if present at diagnosis; however, there should be 50% reduction in percentage of lymphoma cells.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=24 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=13 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Time to Response	0.89 Months Interval 0.49 to 1.87	0.82 Months Interval 0.46 to 1.94	—	—

SECONDARY outcome

Timeframe: Up to 4 year and 4 months

Population: Duration of response was summarized for participants who achieved either CR (including CRb and CRu) or PR. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Duration of response was defined as the duration from date of initial documentation of a response (CR or PR) to the date of first documented evidence of progressive disease (PD) or death, whichever occurred first. PD: \>25% increase in SPD of residual lesions (calculated from nadir) on CT or MRI; Deauville score 4 or 5 on FDG-PET with increase in lesional uptake from baseline; documentation of new lesions or development of new morphologic evidence of disease in BM or CSF.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=24 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=13 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Duration of Response	6.01 Months Interval 3.06 to Here "NA" indicates that upper limit of 90% confidence interval was not estimable due to insufficient number of events.	6.51 Months Interval 4.53 to 10.64	—	—

SECONDARY outcome

Timeframe: At 2 years

Population: The ITT Population consisted of all randomized participants; participants were analyzed based on randomization, regardless of study drug received.

EFS was the time interval from randomization to death, disease progression, or lack of complete response (CR) or partial response (PR) after 3 cycles of treatment, whichever occurred first based on blinded independent event review by the IRC. CR was defined as CT or MRI reveals no residual disease or new lesions, resected residual mass that is pathologically (morphologically) negative for disease, BM and CSF morphologically free of disease with no new lesions by imaging examination. PR was defined as 50% decrease in um of the products of the SPD on CT or MRI; FDG-PET may be positive, no new or PD; morphologic evidence of disease may be present in BM or CSF if present at diagnosis; however, there should be 50% reduction in percentage of lymphoma cells.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=35 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=16 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Percentage of Participants With EFS at 2 Years	14.3 Percentage of participants	12.5 Percentage of participants	—	—

SECONDARY outcome

Timeframe: At 3 years

Population: The ITT Population consisted of all randomized participants; participants were analyzed based on randomization, regardless of study drug received.

EFS is the time interval from randomization to death, disease progression, or lack of complete response (CR) or partial response (PR) after 3 cycles of treatment, whichever occurs first based on blinded independent event review by the IRC. CR was defined as CT or MRI reveals no residual disease or new lesions, resected residual mass that is pathologically (morphologically) negative for disease, BM and CSF morphologically free of disease with no new lesions by imaging examination. PR was defined as 50% decrease in um of the products of the SPD on CT or MRI; FDG-PET may be positive, no new or PD; morphologic evidence of disease may be present in BM or CSF if present at diagnosis; however, there should be 50% reduction in percentage of lymphoma cells.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=35 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=16 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Percentage of Participants With EFS at 3 Years	8.6 Percentage of participants	12.5 Percentage of participants	—	—

SECONDARY outcome

Timeframe: Up to 4 year and 4 months

Population: The ITT Population consisted of all randomized participants; participants were analyzed based on randomization, regardless of study drug received.

Overall survival was defined as duration from the date of randomization to the date of the participant's death.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=35 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=16 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Overall Survival	14.13 Months Interval 5.98 to Here "NA" indicates that upper limit of 90% Confidence interval was not estimable due to insufficient number of participants with events.	11.07 Months Interval 7.39 to Here "NA" indicates that upper limit of 90% Confidence interval was not estimable due to insufficient number of participants with events.	—	—

SECONDARY outcome

Timeframe: Up to Cycle 3 (each cycle of 21 or 28 days)

AUC is defined as area under the plasma concentration-time curve. As per planned analyses, PK parameters for Part 2 were presented per dose group (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=1 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=19 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 n=3 Participants Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib 1-5 years	—	—	298 h*ng/mL Interval 268.0 to 327.0	—
Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib 6-11 years	—	—	655 h*ng/mL Interval 428.0 to 879.0	—
Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib 12-17 years	215 h*ng/mL Interval 215.0 to 215.0	499 h*ng/mL Interval 262.0 to 887.0	—	—
Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib 18+ years	—	423 h*ng/mL Interval 348.0 to 498.0	—	—

SECONDARY outcome

Timeframe: Up to Cycle 3 (each cycle of 21 or 28 days)

CL/F is defined as apparent plasma clearance of ibrutinib. As per planned analyses, PK parameters for Part 2 were presented per dose group (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=1 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=19 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 n=3 Participants Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib 1-5 years	—	—	1110 mL/h Interval 1020.0 to 1200.0	—
Part 2: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib 6-11 years	—	—	856 mL/h Interval 618.0 to 1140.0	—
Part 2: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib 12-17 years	1730 mL/h Interval 1730.0 to 1730.0	982 mL/h Interval 598.0 to 2010.0	—	—
Part 2: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib 18+ years	—	1510 mL/h Interval 1250.0 to 1780.0	—	—

SECONDARY outcome

Timeframe: Up to Cycle 3 (each cycle of 21 or 28 days)

Vd/F is defined as apparent (oral) volume of distribution of ibrutinib. As per planned analyses, PK parameters for Part 2 were presented per dose group (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=1 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=19 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 n=3 Participants Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib 1-5 years	—	—	1.68 liter(s) Interval 1.46 to 1.91	—
Part 2: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib 6-11 years	—	—	6.18 liter(s) Interval 3.67 to 10.01	—
Part 2: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib 12-17 years	9.9 liter(s) Interval 9.9 to 9.9	4.14 liter(s) Interval 1.46 to 8.51	—	—
Part 2: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib 18+ years	—	9.29 liter(s) Interval 7.75 to 10.8	—	—

SECONDARY outcome

Timeframe: Up to Cycle 3 (each cycle of 21 or 28 days)

Cmax is defined as maximum plasma concentration of ibrutinib. As per planned analyses, PK parameters for Part 2 were presented per dose group (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age.

Outcome measures

Outcome measures
Measure	Part 1: Ibrutinib: 240 mg/m^2 n=1 Participants Participants received 240 milligrams per meter square (mg/m\^2) ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 329 mg/m^2 n=19 Participants Participants received 329 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 1: Ibrutinib: 440 mg/m^2 n=3 Participants Participants received 440 mg/m\^2 ibrutinib based on age group for 3 treatment cycles with each cycle of 21 or 28 days long in Part 1.	Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).
Part 2: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib 6-11 years	—	—	4.15 ng/mL Interval 3.44 to 5.01	—
Part 2: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib 12-17 years	2.93 ng/mL Interval 2.93 to 2.93	4.86 ng/mL Interval 3.12 to 5.26	—	—
Part 2: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib 18+ years	—	3.7 ng/mL Interval 3.46 to 3.94	—	—
Part 2: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib 1-5 years	—	—	3.79 ng/mL Interval 3.52 to 4.06	—

SECONDARY outcome

Timeframe: Up to Cycle 3 (each cycle of 28 days)

Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib.

Outcome measures

Outcome data not reported

Adverse Events

Part 1: Ibrutinib+RICE

Serious events: 10 serious events

Other events: 11 other events

Deaths: 4 deaths

Part 1: Ibrutinib+RVICI

Serious events: 9 serious events

Other events: 10 other events

Deaths: 9 deaths

Part 2: Ibrutinib+CIT (RICE or RVICI)

Serious events: 25 serious events

Other events: 35 other events

Deaths: 19 deaths

Part 2: Chemoimmunotherapy

Serious events: 11 serious events

Other events: 15 other events

Deaths: 10 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Scientist

Janssen Research & Development, LLC

Phone: 844-434-4210

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will with hold such publication for up to an additional 60 days.
Publication restrictions are in place

Restriction type: OTHER