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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02703272
Recruitment Status : Terminated (IDMC recommended that enrolment be stoped, as the EFS hazard ratio and associated p-value crossed the futility boundary specified in protocol (July 2020).)
First Posted : March 9, 2016
Results First Posted : December 2, 2022
Last Update Posted : December 2, 2022
Sponsor:
Collaborator:
Pharmacyclics LLC.
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Lymphoma, Non-Hodgkin
Interventions Drug: Ibrutinib
Drug: Rituximab
Drug: Ifosfamide
Drug: Carboplatin
Drug: Etoposide
Drug: Vincristine
Drug: Idarubicin
Drug: Dexamethasone
Enrollment 72
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description 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. 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. 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). 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).
Period Title: Overall Study
Started 11 10 35 16
Completed 0 0 0 0
Not Completed 11 10 35 16
Reason Not Completed
Death             4             9             19             10
Withdrawal by Subject             0             0             4             2
Study Terminated by Sponsor             6             1             12             4
Other             1             0             0             0
Arm/Group Title Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy Total
Hide Arm/Group Description 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. 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. 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). 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 of all reporting groups
Overall Number of Baseline Participants 11 10 35 16 72
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 11 participants 10 participants 35 participants 16 participants 72 participants
10.5  (4.91) 8.3  (3.43) 13.9  (3.94) 13.2  (4.37) 12.4  (4.54)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 11 participants 10 participants 35 participants 16 participants 72 participants
Female
3
  27.3%
1
  10.0%
12
  34.3%
3
  18.8%
19
  26.4%
Male
8
  72.7%
9
  90.0%
23
  65.7%
13
  81.3%
53
  73.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 11 participants 10 participants 35 participants 16 participants 72 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   9.1%
0
   0.0%
8
  22.9%
6
  37.5%
15
  20.8%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
1
   6.3%
1
   1.4%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
White
9
  81.8%
10
 100.0%
22
  62.9%
8
  50.0%
49
  68.1%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
1
   9.1%
0
   0.0%
3
   8.6%
0
   0.0%
4
   5.6%
Other
0
   0.0%
0
   0.0%
2
   5.7%
1
   6.3%
3
   4.2%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 11 participants 10 participants 35 participants 16 participants 72 participants
BELGIUM
0
   0.0%
0
   0.0%
2
   5.7%
0
   0.0%
2
   2.8%
BRAZIL
1
   9.1%
0
   0.0%
1
   2.9%
2
  12.5%
4
   5.6%
BULGARIA
0
   0.0%
0
   0.0%
2
   5.7%
0
   0.0%
2
   2.8%
CANADA
0
   0.0%
0
   0.0%
1
   2.9%
0
   0.0%
1
   1.4%
CZECH REPUBLIC
0
   0.0%
2
  20.0%
2
   5.7%
0
   0.0%
4
   5.6%
FRANCE
2
  18.2%
1
  10.0%
3
   8.6%
1
   6.3%
7
   9.7%
GERMANY
2
  18.2%
1
  10.0%
3
   8.6%
0
   0.0%
6
   8.3%
ITALY
2
  18.2%
1
  10.0%
4
  11.4%
2
  12.5%
9
  12.5%
NETHERLANDS
0
   0.0%
0
   0.0%
1
   2.9%
1
   6.3%
2
   2.8%
POLAND
0
   0.0%
1
  10.0%
0
   0.0%
2
  12.5%
3
   4.2%
ROMANIA
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.4%
RUSSIAN FEDERATION
0
   0.0%
0
   0.0%
2
   5.7%
0
   0.0%
2
   2.8%
SOUTH KOREA
1
   9.1%
0
   0.0%
5
  14.3%
4
  25.0%
10
  13.9%
SPAIN
0
   0.0%
0
   0.0%
2
   5.7%
0
   0.0%
2
   2.8%
SWEDEN
0
   0.0%
0
   0.0%
1
   2.9%
0
   0.0%
1
   1.4%
TAIWAN
0
   0.0%
0
   0.0%
2
   5.7%
1
   6.3%
3
   4.2%
TURKEY
1
   9.1%
4
  40.0%
1
   2.9%
2
  12.5%
8
  11.1%
UKRAINE
0
   0.0%
0
   0.0%
1
   2.9%
0
   0.0%
1
   1.4%
UNITED KINGDOM
0
   0.0%
0
   0.0%
1
   2.9%
1
   6.3%
2
   2.8%
UNITED STATES
1
   9.1%
0
   0.0%
1
   2.9%
0
   0.0%
2
   2.8%
1.Primary Outcome
Title Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib
Hide Description 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.
Time Frame Up to Cycle 3 (each cycle of 21 or 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 1: Ibrutinib: 240 mg/m^2 Part 1: Ibrutinib: 329 mg/m^2 Part 1: Ibrutinib: 440 mg/m^2
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 3 10 7
Median (Full Range)
Unit of Measure: hours*nanogram per milliliter (h*ng/mL)
1-5 years Number Analyzed 2 participants 1 participants 3 participants
143
(116 to 170)
386
(386 to 386)
310
(230 to 543)
6-11 years Number Analyzed 3 participants 10 participants 7 participants
145
(140 to 233)
349
(238 to 562)
324
(185 to 538)
12-17 years Number Analyzed 3 participants 8 participants 0 participants
1210
(939 to 1450)
661
(394 to 778)
18+ years Number Analyzed 0 participants 0 participants 0 participants
2.Primary Outcome
Title Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib
Hide Description 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.
Time Frame Up to Cycle 3 (each cycle of 21 or 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 1: Ibrutinib: 240 mg/m^2 Part 1: Ibrutinib: 329 mg/m^2 Part 1: Ibrutinib: 440 mg/m^2
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 3 10 7
Median (Full Range)
Unit of Measure: milliliter per hour (mL/h)
1-5 years Number Analyzed 2 participants 1 participants 3 participants
1220
(1000 to 1430)
508
(508 to 508)
1200
(838 to 1550)
6-11 years Number Analyzed 3 participants 10 participants 7 participants
1450
(1080 to 1500)
805
(664 to 1100)
1300
(910 to 2460)
12-17 years Number Analyzed 3 participants 8 participants 0 participants
348
(340 to 433)
729
(568 to 1330)
18+ years Number Analyzed 0 participants 0 participants 0 participants
3.Primary Outcome
Title Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib
Hide Description 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.
Time Frame Up to Cycle 3 (each cycle of 21 or 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 1: Ibrutinib: 240 mg/m^2 Part 1: Ibrutinib: 329 mg/m^2 Part 1: Ibrutinib: 440 mg/m^2
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 3 10 7
Median (Full Range)
Unit of Measure: liter(s)
1-5 years Number Analyzed 2 participants 1 participants 3 participants
11.1
(8.26 to 13.9)
5.18
(5.18 to 5.18)
7.63
(5.34 to 11.1)
6-11 years Number Analyzed 3 participants 10 participants 7 participants
18
(10.8 to 29.9)
7.55
(2.89 to 15.6)
19
(6.09 to 55.9)
12-17 years Number Analyzed 3 participants 8 participants 0 participants
3.63
(2.32 to 4.77)
11.3
(6.34 to 18.5)
18+ years Number Analyzed 0 participants 0 participants 0 participants
4.Primary Outcome
Title Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib
Hide Description 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.
Time Frame Up to Cycle 3 (each cycle of 21 or 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 1: Ibrutinib: 240 mg/m^2 Part 1: Ibrutinib: 329 mg/m^2 Part 1: Ibrutinib: 440 mg/m^2
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 3 10 7
Median (Full Range)
Unit of Measure: nanograms per milliliter (ng/mL)
1-5 years Number Analyzed 2 participants 1 participants 3 participants
3.86
(3.75 to 3.98)
4.48
(4.48 to 4.48)
5.07
(4.5 to 5.14)
6-11 years Number Analyzed 3 participants 10 participants 7 participants
3.46
(3.12 to 3.6)
3.64
(3.32 to 4.59)
3.88
(3.2 to 4.44)
12-17 years Number Analyzed 3 participants 8 participants 0 participants
4.88
(4.76 to 5.4)
4.73
(4.07 to 5.07)
18+ years Number Analyzed 0 participants 0 participants 0 participants
5.Primary Outcome
Title Part 1: Relationship Between AUC and Body Size
Hide Description 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.
Time Frame Up to Cycle 3 (each cycle of 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib.
Arm/Group Title Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
6.Primary Outcome
Title Part 2: Event Free Survival (EFS) Between the 2 Treatment Groups
Hide Description 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.
Time Frame 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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).
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 Number of Participants Analyzed 35 16
Median (95% Confidence Interval)
Unit of Measure: Months
6.05
(2.99 to 8.84)
6.97
(2.60 to 11.07)
7.Secondary Outcome
Title Part 1 and Part 2: Number of Participants With Adverse Events as Measure of Safety and Tolerability
Hide Description 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.
Time Frame Up to 4 year and 4 months
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population consisted of all participants who received at least 1 dose of treatment.
Arm/Group Title Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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.
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.
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).
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 Number of Participants Analyzed 11 10 35 15
Measure Type: Count of Participants
Unit of Measure: Participants
11
 100.0%
10
 100.0%
35
 100.0%
15
 100.0%
8.Secondary Outcome
Title Part 1 and Part 2: Overall Response Rate (ORR)
Hide Description 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.
Time Frame Up to 4 year and 4 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT Population consisted of all randomized participants; participants analyzed based on randomization, regardless of study drug received.
Arm/Group Title Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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.
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.
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).
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 Number of Participants Analyzed 11 10 35 16
Measure Type: Number
Unit of Measure: Percentage of participants
81.8 50.0 68.6 81.3
9.Secondary Outcome
Title Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline
Hide Description 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.
Time Frame Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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.
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.
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).
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 Number of Participants Analyzed 0 0 18 9
Mean (Standard Deviation)
Unit of Measure: Transcripts per million
BCL-2L1 (BCL-xl) 58.09346  (38.75996) 74.30790  (75.82331)
BIRC2 (cIAP1) 47.20787  (16.26430) 40.01716  (9.28104)
Caspase 3 (CASP3) 51.14711  (21.44109) 47.61412  (32.12666)
STAT3 540.02256  (363.75256) 526.35308  (473.08255)
SYK 705.29909  (503.07085) 618.36324  (144.72067)
10.Secondary Outcome
Title Part 1 and Part 2: Number of Participants With Immunoglobulin and T-cell Receptor Gene Rearrangements
Hide Description Number of participants with immunoglobulin and T-cell receptor gene rearrangements were reported.
Time Frame At baseline (Cycle 1 Day 1) of Part 1 and 2
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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.
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.
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).
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 Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
11.Secondary Outcome
Title Part 1 and Part 2: Number of Participants With Greater Than (>) 90% Bruton's Tyrosine Kinase (BTK) Occupancy
Hide Description Number of participants with >90% BTK occupancy were reported. Blood samples were collected to assess BTK occupancy.
Time Frame Up to 3 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 1: Ibrutinib Part 2: Ibrutinib
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 15 13
Measure Type: Count of Participants
Unit of Measure: Participants
5
  33.3%
5
  38.5%
12.Secondary Outcome
Title Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability
Hide Description 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.
Time Frame Day 1 of Cycle 1 and Cycle 3
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT (RICE or RVICI)
Hide Arm/Group Description:
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.
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.
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).
Overall Number of Participants Analyzed 11 10 32
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Cycle 1 Day 1 Number Analyzed 11 participants 10 participants 32 participants
2.6  (1.21) 3.2  (1.40) 2.4  (1.16)
Cycle 3 Day 1 Number Analyzed 8 participants 3 participants 16 participants
3.3  (1.39) 2.3  (1.15) 2.6  (0.89)
13.Secondary Outcome
Title Part 1: Number of Participants With CD79B, CARD11, and MYD Mutations
Hide Description Number of Participants with CD79B, CARD11, and MYD Mutations were reported.
Time Frame Up to 4 years and 4 months
Hide Outcome Measure Data
Hide Analysis Population Description
Biomarker analyses were conducted on the ITT population. As per change in planned analysis, genetic analysis was not performed for Part 1.
Arm/Group Title Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
14.Secondary Outcome
Title Part 2: Number of Participants With CD79B, CARD11, and MYD Mutations
Hide Description 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.
Time Frame Up to 4 year and 4 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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).
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 Number of Participants Analyzed 20 10
Measure Type: Count of Participants
Unit of Measure: Participants
CD79B
1
   5.0%
0
   0.0%
CARD11
1
   5.0%
0
   0.0%
MYD mutation
0
   0.0%
0
   0.0%
15.Secondary Outcome
Title Part 1: Number of Participants With c-MYC Gene Rearrangement
Hide Description Number of participants with c-MYC gene rearrangement were reported.
Time Frame At baseline (Cycle 1 Day 1)
Hide Outcome Measure Data
Hide Analysis Population Description
Biomarker analyses were conducted on the ITT population. As per change in planned analysis, genetic analysis was not performed for Part 1.
Arm/Group Title Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
16.Secondary Outcome
Title Part 2: Number of Participants With c-MYC Gene Rearrangement
Hide Description 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.
Time Frame At baseline (Cycle 1 Day 1)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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).
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 Number of Participants Analyzed 18 9
Measure Type: Count of Participants
Unit of Measure: Participants
1
   5.6%
1
  11.1%
17.Secondary Outcome
Title Part 2: Percentage of Participants Who Achieved Complete Response (CR)
Hide Description 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.
Time Frame Up to 4 year and 4 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT Population consisted of all randomized participants; participants analyzed based on randomization, regardless of study drug received.
Arm/Group Title Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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).
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 Number of Participants Analyzed 35 16
Measure Type: Number
Unit of Measure: Percentage of Participants
17.1 18.8
18.Secondary Outcome
Title Part 2: Percentage of Participants Who Achieved Partial Response (PR)
Hide Description 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.
Time Frame Up to 4 year and 4 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT Population consisted of all randomized participants; participants analyzed based on randomization, regardless of study drug received.
Arm/Group Title Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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).
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/m^2, 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 Number of Participants Analyzed 35 16
Measure Type: Number
Unit of Measure: percentage of participants
51.4 62.5
19.Secondary Outcome
Title Part 2: Tumor Volume Reduction Rate at Day 14
Hide Description 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.
Time Frame At Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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).
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/m^2, 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 Number of Participants Analyzed 30 11
Least Squares Mean (Standard Deviation)
Unit of Measure: Percent change
-49.7  (33.41) -58.60  (34.04)
20.Secondary Outcome
Title Part 2: Number of Participants Who Proceeded to Stem Cell Transplantation
Hide Description Number of participants who proceeded to stem cell transplantation were reported.
Time Frame Up to end of the study (Up to 4 year and 4 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants; participants were analyzed based on randomization, regardless of study drug received.
Arm/Group Title Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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).
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 Number of Participants Analyzed 35 16
Measure Type: Count of Participants
Unit of Measure: Participants
13
  37.1%
7
  43.8%
21.Secondary Outcome
Title Part 2: Time to Response
Hide Description 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.
Time Frame Up to 4 Years and 4 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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).
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 Number of Participants Analyzed 24 13
Median (90% Confidence Interval)
Unit of Measure: Months
0.89
(0.49 to 1.87)
0.82
(0.46 to 1.94)
22.Secondary Outcome
Title Part 2: Duration of Response
Hide Description 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.
Time Frame Up to 4 year and 4 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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).
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 Number of Participants Analyzed 24 13
Median (90% Confidence Interval)
Unit of Measure: Months
6.01 [1] 
(3.06 to NA)
6.51
(4.53 to 10.64)
[1]
Here "NA" indicates that upper limit of 90% confidence interval was not estimable due to insufficient number of events.
23.Secondary Outcome
Title Part 2: Percentage of Participants With EFS at 2 Years
Hide Description 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.
Time Frame At 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT Population consisted of all randomized participants; participants were analyzed based on randomization, regardless of study drug received.
Arm/Group Title Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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).
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 Number of Participants Analyzed 35 16
Measure Type: Number
Unit of Measure: Percentage of participants
14.3 12.5
24.Secondary Outcome
Title Part 2: Percentage of Participants With EFS at 3 Years
Hide Description 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.
Time Frame At 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT Population consisted of all randomized participants; participants were analyzed based on randomization, regardless of study drug received.
Arm/Group Title Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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).
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 Number of Participants Analyzed 35 16
Measure Type: Number
Unit of Measure: Percentage of participants
8.6 12.5
25.Secondary Outcome
Title Part 2: Overall Survival
Hide Description Overall survival was defined as duration from the date of randomization to the date of the participant's death.
Time Frame Up to 4 year and 4 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT Population consisted of all randomized participants; participants were analyzed based on randomization, regardless of study drug received.
Arm/Group Title Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description:
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).
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 Number of Participants Analyzed 35 16
Median (90% Confidence Interval)
Unit of Measure: Months
14.13 [1] 
(5.98 to NA)
11.07 [1] 
(7.39 to NA)
[1]
Here "NA" indicates that upper limit of 90% Confidence interval was not estimable due to insufficient number of participants with events.
26.Secondary Outcome
Title Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib
Hide Description 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.
Time Frame Up to Cycle 3 (each cycle of 21 or 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 2: Ibrutinib: 240 mg/m^2: Part 2: Ibrutinib: 329 mg/m^2 Part 2: Ibrutinib: 440 mg/m^2
Hide Arm/Group Description:
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 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 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 2.
Overall Number of Participants Analyzed 1 19 3
Mean (Full Range)
Unit of Measure: h*ng/mL
1-5 years Number Analyzed 0 participants 0 participants 2 participants
298
(268 to 327)
6-11 years Number Analyzed 0 participants 0 participants 3 participants
655
(428 to 879)
12-17 years Number Analyzed 1 participants 19 participants 0 participants
215
(215 to 215)
499
(262 to 887)
18+ years Number Analyzed 0 participants 2 participants 0 participants
423
(348 to 498)
27.Secondary Outcome
Title Part 2: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib
Hide Description 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.
Time Frame Up to Cycle 3 (each cycle of 21 or 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 2: Ibrutinib: 240 mg/m^2 Part 2: Ibrutinib: 329 mg/m^2 Part 2: Ibrutinib: 440 mg/m^2
Hide Arm/Group Description:
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 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 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 2.
Overall Number of Participants Analyzed 1 19 3
Median (Full Range)
Unit of Measure: mL/h
1-5 years Number Analyzed 0 participants 0 participants 2 participants
1110
(1020 to 1200)
6-11 years Number Analyzed 0 participants 0 participants 3 participants
856
(618 to 1140)
12-17 years Number Analyzed 1 participants 19 participants 0 participants
1730
(1730 to 1730)
982
(598 to 2010)
18+ years Number Analyzed 0 participants 2 participants 0 participants
1510
(1250 to 1780)
28.Secondary Outcome
Title Part 2: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib
Hide Description 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.
Time Frame Up to Cycle 3 (each cycle of 21 or 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 2: Ibrutinib: 240 mg/m^2 Part 2: Ibrutinib: 329 mg/m^2 Part 2: Ibrutinib: 440 mg/m^2
Hide Arm/Group Description:
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 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 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 2.
Overall Number of Participants Analyzed 1 19 3
Median (Full Range)
Unit of Measure: liter(s)
1-5 years Number Analyzed 0 participants 0 participants 2 participants
1.68
(1.46 to 1.91)
6-11 years Number Analyzed 0 participants 0 participants 3 participants
6.18
(3.67 to 10.01)
12-17 years Number Analyzed 1 participants 19 participants 0 participants
9.9
(9.9 to 9.9)
4.14
(1.46 to 8.51)
18+ years Number Analyzed 0 participants 2 participants 0 participants
9.29
(7.75 to 10.8)
29.Secondary Outcome
Title Part 2: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib
Hide Description 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.
Time Frame Up to Cycle 3 (each cycle of 21 or 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Part 2: Ibrutinib: 240 mg/m^2 Part 2: Ibrutinib: 329 mg/m^2 Part 2: Ibrutinib: 440 mg/m^2
Hide Arm/Group Description:
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 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 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 2.
Overall Number of Participants Analyzed 1 19 3
Median (Full Range)
Unit of Measure: ng/mL
1-5 years Number Analyzed 0 participants 0 participants 2 participants
3.79
(3.52 to 4.06)
6-11 years Number Analyzed 0 participants 0 participants 3 participants
4.15
(3.44 to 5.01)
12-17 years Number Analyzed 1 participants 19 participants 0 participants
2.93
(2.93 to 2.93)
4.86
(3.12 to 5.26)
18+ years Number Analyzed 0 participants 2 participants 0 participants
3.7
(3.46 to 3.94)
30.Secondary Outcome
Title Part 2: Relationship Between AUC and Body Size
Hide Description 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. This outcome measure was planned to be analyzed for specified arm only.
Time Frame Up to Cycle 3 (each cycle of 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib.
Arm/Group Title Part 2: Ibrutinib+CIT (RICE or RVICI)
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame Up to 4 year and 4 months
Adverse Event Reporting Description The safety population consisted of all participants who received at least 1 dose of treatment.
 
Arm/Group Title Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Hide Arm/Group Description 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. 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. 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). 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).
All-Cause Mortality
Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   4/11 (36.36%)   9/10 (90.00%)   19/35 (54.29%)   10/15 (66.67%) 
Hide Serious Adverse Events
Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   10/11 (90.91%)   9/10 (90.00%)   25/35 (71.43%)   11/15 (73.33%) 
Blood and lymphatic system disorders         
Anaemia * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  3/15 (20.00%) 
Febrile Bone Marrow Aplasia * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Febrile Neutropenia * 1  4/11 (36.36%)  3/10 (30.00%)  21/35 (60.00%)  6/15 (40.00%) 
Leukopenia * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  3/15 (20.00%) 
Neutropenia * 1  2/11 (18.18%)  1/10 (10.00%)  2/35 (5.71%)  3/15 (20.00%) 
Thrombocytopenia * 1  0/11 (0.00%)  0/10 (0.00%)  3/35 (8.57%)  4/15 (26.67%) 
Cardiac disorders         
Sinus Tachycardia * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Eye disorders         
Optic Atrophy * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Gastrointestinal disorders         
Abdominal Pain * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Colitis * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  1/15 (6.67%) 
Diarrhoea * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Gastric Ulcer * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Gastrointestinal Inflammation * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Lower Gastrointestinal Haemorrhage * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  1/15 (6.67%) 
Nausea * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Stomatitis * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Upper Gastrointestinal Haemorrhage * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
General disorders         
Mucosal Inflammation * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Multiple Organ Dysfunction Syndrome * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Pyrexia * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  1/15 (6.67%) 
Systemic Inflammatory Response Syndrome * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Hepatobiliary disorders         
Hepatic Failure * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Immune system disorders         
Anaphylactic Reaction * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Infusion Related Hypersensitivity Reaction * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Infections and infestations         
Anorectal Infection * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Bronchitis * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Capnocytophaga Infection * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Corynebacterium Infection * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Cryptosporidiosis Infection * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Device Related Infection * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  1/15 (6.67%) 
Escherichia Sepsis * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  2/15 (13.33%) 
Herpes Zoster * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Klebsiella Sepsis * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Meningitis * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Neutropenic Sepsis * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Pneumonia * 1  0/11 (0.00%)  1/10 (10.00%)  3/35 (8.57%)  0/15 (0.00%) 
Pulmonary Mycosis * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Sepsis * 1  1/11 (9.09%)  4/10 (40.00%)  5/35 (14.29%)  3/15 (20.00%) 
Septic Shock * 1  1/11 (9.09%)  0/10 (0.00%)  3/35 (8.57%)  0/15 (0.00%) 
Staphylococcal Infection * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Vascular Device Infection * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Injury, poisoning and procedural complications         
Subdural Haematoma * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Subdural Haemorrhage * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Investigations         
Alanine Aminotransferase Increased * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Aspartate Aminotransferase Increased * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Blood Bilirubin Increased * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Coagulation Test Abnormal * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Neutrophil Count Decreased * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Platelet Count Decreased * 1  1/11 (9.09%)  0/10 (0.00%)  3/35 (8.57%)  1/15 (6.67%) 
White Blood Cell Count Decreased * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Metabolism and nutrition disorders         
Hypernatraemia * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Hypokalaemia * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Hypophosphataemia * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Nervous system disorders         
Altered State of Consciousness * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Encephalopathy * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Haemorrhage Intracranial * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Hepatic Encephalopathy * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Paraplegia * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Seizure * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Spinal Cord Haematoma * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Subarachnoid Haemorrhage * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Tonic Convulsion * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Toxic Encephalopathy * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Psychiatric disorders         
Psychotic Disorder * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Renal and urinary disorders         
Acute Kidney Injury * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Cystitis Haemorrhagic * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Haematuria * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Renal Failure * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Reproductive system and breast disorders         
Menorrhagia * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Pneumomediastinum * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Pulmonary Haemorrhage * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Vascular disorders         
Capillary Leak Syndrome * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Hypotension * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  1/15 (6.67%) 
1
Term from vocabulary, MedDRA Version 23.1
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemoimmunotherapy
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   11/11 (100.00%)   10/10 (100.00%)   35/35 (100.00%)   15/15 (100.00%) 
Blood and lymphatic system disorders         
Anaemia * 1  8/11 (72.73%)  9/10 (90.00%)  29/35 (82.86%)  14/15 (93.33%) 
Coagulopathy * 1  0/11 (0.00%)  1/10 (10.00%)  2/35 (5.71%)  0/15 (0.00%) 
Febrile Bone Marrow Aplasia * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  1/15 (6.67%) 
Febrile Neutropenia * 1  5/11 (45.45%)  2/10 (20.00%)  6/35 (17.14%)  1/15 (6.67%) 
Hypofibrinogenaemia * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Leukopenia * 1  3/11 (27.27%)  1/10 (10.00%)  10/35 (28.57%)  3/15 (20.00%) 
Lymphopenia * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Macrocytosis * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Neutropenia * 1  6/11 (54.55%)  6/10 (60.00%)  14/35 (40.00%)  4/15 (26.67%) 
Thrombocytopenia * 1  6/11 (54.55%)  8/10 (80.00%)  19/35 (54.29%)  4/15 (26.67%) 
Cardiac disorders         
Pericardial Effusion * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Sinus Tachycardia * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Tachycardia * 1  0/11 (0.00%)  1/10 (10.00%)  5/35 (14.29%)  2/15 (13.33%) 
Congenital, familial and genetic disorders         
Aplasia * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Ear and labyrinth disorders         
Ear Pain * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Vertigo * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Eye disorders         
Eye Pain * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Eyelid Oedema * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Eyelid Ptosis * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Keratitis * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Pupils Unequal * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Vision Blurred * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Xerophthalmia * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Gastrointestinal disorders         
Abdominal Distension * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Abdominal Pain * 1  3/11 (27.27%)  5/10 (50.00%)  12/35 (34.29%)  2/15 (13.33%) 
Abdominal Pain Upper * 1  0/11 (0.00%)  0/10 (0.00%)  6/35 (17.14%)  1/15 (6.67%) 
Anal Erythema * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  1/15 (6.67%) 
Anal Inflammation * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Anal Ulcer * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Anorectal Ulcer * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Aphthous Ulcer * 1  1/11 (9.09%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Chapped Lips * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Colitis * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  1/15 (6.67%) 
Constipation * 1  1/11 (9.09%)  3/10 (30.00%)  8/35 (22.86%)  3/15 (20.00%) 
Dental Caries * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Diarrhoea * 1  4/11 (36.36%)  6/10 (60.00%)  10/35 (28.57%)  3/15 (20.00%) 
Dyspepsia * 1  0/11 (0.00%)  0/10 (0.00%)  5/35 (14.29%)  2/15 (13.33%) 
Dysphagia * 1  0/11 (0.00%)  0/10 (0.00%)  3/35 (8.57%)  0/15 (0.00%) 
Enterocolitis * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Flatulence * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Gastrointestinal Inflammation * 1  0/11 (0.00%)  1/10 (10.00%)  2/35 (5.71%)  0/15 (0.00%) 
Gastrointestinal Motility Disorder * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Gingival Bleeding * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Gingival Oedema * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Haematemesis * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Haematochezia * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Ileus * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Intestinal Haemorrhage * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Melaena * 1  1/11 (9.09%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Mouth Haemorrhage * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Mouth Ulceration * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Nausea * 1  7/11 (63.64%)  5/10 (50.00%)  21/35 (60.00%)  2/15 (13.33%) 
Odynophagia * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Oesophageal Pain * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Oesophagitis * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Proctalgia * 1  1/11 (9.09%)  1/10 (10.00%)  2/35 (5.71%)  0/15 (0.00%) 
Rectal Haemorrhage * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Stomatitis * 1  0/11 (0.00%)  1/10 (10.00%)  7/35 (20.00%)  3/15 (20.00%) 
Toothache * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  1/15 (6.67%) 
Vomiting * 1  5/11 (45.45%)  5/10 (50.00%)  25/35 (71.43%)  4/15 (26.67%) 
General disorders         
Asthenia * 1  1/11 (9.09%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Catheter Site Granuloma * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Catheter Site Pain * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Chest Pain * 1  0/11 (0.00%)  0/10 (0.00%)  3/35 (8.57%)  2/15 (13.33%) 
Chills * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Device Related Thrombosis * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Face Oedema * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Fatigue * 1  1/11 (9.09%)  1/10 (10.00%)  5/35 (14.29%)  0/15 (0.00%) 
Generalised Oedema * 1  1/11 (9.09%)  0/10 (0.00%)  2/35 (5.71%)  1/15 (6.67%) 
Hypothermia * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Mucosal Inflammation * 1  2/11 (18.18%)  4/10 (40.00%)  9/35 (25.71%)  3/15 (20.00%) 
Mucosal Ulceration * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Pain * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Pyrexia * 1  3/11 (27.27%)  3/10 (30.00%)  14/35 (40.00%)  5/15 (33.33%) 
Swelling * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Swelling Face * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Hepatobiliary disorders         
Hepatic Failure * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Hypertransaminasaemia * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Immune system disorders         
Drug Hypersensitivity * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Hypersensitivity * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Hypogammaglobulinaemia * 1  1/11 (9.09%)  1/10 (10.00%)  0/35 (0.00%)  1/15 (6.67%) 
Infections and infestations         
Anal Abscess * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  1/15 (6.67%) 
Aspergillus Infection * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Bacteraemia * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Bk Virus Infection * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Conjunctivitis * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Device Related Infection * 1  2/11 (18.18%)  0/10 (0.00%)  3/35 (8.57%)  1/15 (6.67%) 
Escherichia Infection * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Fungal Infection * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Fusarium Infection * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Geotrichum Infection * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Herpes Zoster * 1  0/11 (0.00%)  2/10 (20.00%)  0/35 (0.00%)  0/15 (0.00%) 
Klebsiella Infection * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Nasopharyngitis * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Oral Herpes * 1  0/11 (0.00%)  1/10 (10.00%)  2/35 (5.71%)  1/15 (6.67%) 
Pneumonia * 1  0/11 (0.00%)  2/10 (20.00%)  1/35 (2.86%)  0/15 (0.00%) 
Pseudomonal Bacteraemia * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Rhinitis * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  2/15 (13.33%) 
Rhinovirus Infection * 1  0/11 (0.00%)  1/10 (10.00%)  2/35 (5.71%)  0/15 (0.00%) 
Sepsis * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Sinusitis * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Upper Respiratory Tract Infection * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  1/15 (6.67%) 
Urinary Tract Infection * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Urinary Tract Infection Pseudomonal * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Vascular Device Infection * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Viral Upper Respiratory Tract Infection * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Injury, poisoning and procedural complications         
Buttock Injury * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Contusion * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Fall * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Fractured Sacrum * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Infusion Related Reaction * 1  1/11 (9.09%)  1/10 (10.00%)  4/35 (11.43%)  1/15 (6.67%) 
Procedural Pain * 1  0/11 (0.00%)  0/10 (0.00%)  4/35 (11.43%)  0/15 (0.00%) 
Transfusion Reaction * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Traumatic Haematoma * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Investigations         
Alanine Aminotransferase Increased * 1  4/11 (36.36%)  0/10 (0.00%)  7/35 (20.00%)  6/15 (40.00%) 
Amylase Increased * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  1/15 (6.67%) 
Antithrombin Iii Decreased * 1  1/11 (9.09%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Aspartate Aminotransferase Increased * 1  5/11 (45.45%)  0/10 (0.00%)  6/35 (17.14%)  5/15 (33.33%) 
Blood Bilirubin Increased * 1  3/11 (27.27%)  1/10 (10.00%)  2/35 (5.71%)  0/15 (0.00%) 
Blood Lactate Dehydrogenase Increased * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
C-Reactive Protein Increased * 1  1/11 (9.09%)  1/10 (10.00%)  3/35 (8.57%)  0/15 (0.00%) 
Gamma-Glutamyltransferase Increased * 1  2/11 (18.18%)  1/10 (10.00%)  2/35 (5.71%)  0/15 (0.00%) 
Haemoglobin Decreased * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
International Normalised Ratio Increased * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  2/15 (13.33%) 
Lipase Increased * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Lymphocyte Count Decreased * 1  1/11 (9.09%)  0/10 (0.00%)  4/35 (11.43%)  2/15 (13.33%) 
Neutrophil Count Decreased * 1  1/11 (9.09%)  2/10 (20.00%)  12/35 (34.29%)  9/15 (60.00%) 
Pancreatic Enzymes Decreased * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Platelet Count Decreased * 1  5/11 (45.45%)  2/10 (20.00%)  12/35 (34.29%)  8/15 (53.33%) 
Staphylococcus Test Positive * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Weight Decreased * 1  0/11 (0.00%)  1/10 (10.00%)  3/35 (8.57%)  0/15 (0.00%) 
Weight Increased * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  1/15 (6.67%) 
White Blood Cell Count Decreased * 1  1/11 (9.09%)  2/10 (20.00%)  8/35 (22.86%)  6/15 (40.00%) 
Metabolism and nutrition disorders         
Decreased Appetite * 1  0/11 (0.00%)  3/10 (30.00%)  3/35 (8.57%)  0/15 (0.00%) 
Fluid Retention * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Hyperglycaemia * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  1/15 (6.67%) 
Hyperkalaemia * 1  0/11 (0.00%)  1/10 (10.00%)  2/35 (5.71%)  0/15 (0.00%) 
Hypernatraemia * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Hyperphosphataemia * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Hypoalbuminaemia * 1  3/11 (27.27%)  5/10 (50.00%)  7/35 (20.00%)  2/15 (13.33%) 
Hypocalcaemia * 1  1/11 (9.09%)  3/10 (30.00%)  2/35 (5.71%)  0/15 (0.00%) 
Hypoglycaemia * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Hypokalaemia * 1  2/11 (18.18%)  6/10 (60.00%)  12/35 (34.29%)  6/15 (40.00%) 
Hypomagnesaemia * 1  0/11 (0.00%)  2/10 (20.00%)  6/35 (17.14%)  5/15 (33.33%) 
Hyponatraemia * 1  2/11 (18.18%)  1/10 (10.00%)  4/35 (11.43%)  2/15 (13.33%) 
Hypophosphataemia * 1  1/11 (9.09%)  2/10 (20.00%)  5/35 (14.29%)  0/15 (0.00%) 
Musculoskeletal and connective tissue disorders         
Arthralgia * 1  1/11 (9.09%)  0/10 (0.00%)  5/35 (14.29%)  0/15 (0.00%) 
Back Pain * 1  1/11 (9.09%)  0/10 (0.00%)  5/35 (14.29%)  0/15 (0.00%) 
Bone Pain * 1  1/11 (9.09%)  1/10 (10.00%)  4/35 (11.43%)  1/15 (6.67%) 
Musculoskeletal Chest Pain * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Musculoskeletal Pain * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Myalgia * 1  2/11 (18.18%)  1/10 (10.00%)  4/35 (11.43%)  0/15 (0.00%) 
Neck Pain * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Pain in Extremity * 1  2/11 (18.18%)  0/10 (0.00%)  7/35 (20.00%)  1/15 (6.67%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Skin Papilloma * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Nervous system disorders         
Aphasia * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Depressed Level of Consciousness * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Encephalopathy * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  1/15 (6.67%) 
Headache * 1  1/11 (9.09%)  1/10 (10.00%)  16/35 (45.71%)  3/15 (20.00%) 
Hypersomnia * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Muscle Spasticity * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Myoclonus * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Neuralgia * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Seizure * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  1/15 (6.67%) 
Somnolence * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Spinal Cord Haematoma * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Toxic Encephalopathy * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Tremor * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Psychiatric disorders         
Agitation * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  1/15 (6.67%) 
Anxiety * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Confusional State * 1  0/11 (0.00%)  0/10 (0.00%)  1/35 (2.86%)  2/15 (13.33%) 
Depression * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  2/15 (13.33%) 
Hallucination * 1  0/11 (0.00%)  1/10 (10.00%)  1/35 (2.86%)  1/15 (6.67%) 
Insomnia * 1  0/11 (0.00%)  0/10 (0.00%)  4/35 (11.43%)  0/15 (0.00%) 
Irritability * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Post-Traumatic Stress Disorder * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Renal and urinary disorders         
Haematuria * 1  0/11 (0.00%)  0/10 (0.00%)  5/35 (14.29%)  0/15 (0.00%) 
Hypotonic Urinary Bladder * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Renal Impairment * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  1/15 (6.67%) 
Renal Tubular Injury * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Urinary Retention * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Reproductive system and breast disorders         
Penile Swelling * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Cough * 1  1/11 (9.09%)  1/10 (10.00%)  2/35 (5.71%)  4/15 (26.67%) 
Dyspnoea * 1  1/11 (9.09%)  1/10 (10.00%)  2/35 (5.71%)  0/15 (0.00%) 
Epistaxis * 1  2/11 (18.18%)  1/10 (10.00%)  8/35 (22.86%)  1/15 (6.67%) 
Hypoxia * 1  0/11 (0.00%)  1/10 (10.00%)  2/35 (5.71%)  0/15 (0.00%) 
Laryngospasm * 1  0/11 (0.00%)  1/10 (10.00%)  0/35 (0.00%)  0/15 (0.00%) 
Nasal Congestion * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Oropharyngeal Pain * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  1/15 (6.67%) 
Respiratory Alkalosis * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Rhinorrhoea * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  2/15 (13.33%) 
Skin and subcutaneous tissue disorders         
Alopecia * 1  1/11 (9.09%)  0/10 (0.00%)  1/35 (2.86%)  0/15 (0.00%) 
Decubitus Ulcer * 1  0/11 (0.00%)  0/10 (0.00%)  2/35 (5.71%)  0/15 (0.00%) 
Ecchymosis * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Petechiae * 1  0/11 (0.00%)  0/10 (0.00%)  3/35 (8.57%)  0/15 (0.00%) 
Pruritus * 1  2/11 (18.18%)  1/10 (10.00%)  1/35 (2.86%)  0/15 (0.00%) 
Rash * 1  1/11 (9.09%)  1/10 (10.00%)  4/35 (11.43%)  0/15 (0.00%) 
Rash Maculo-Papular * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Skin Lesion * 1  0/11 (0.00%)  0/10 (0.00%)  0/35 (0.00%)  1/15 (6.67%) 
Urticaria * 1  1/11 (9.09%)  0/10 (0.00%)  0/35 (0.00%)  0/15 (0.00%) 
Vascular disorders         
Hypertension * 1  1/11 (9.09%)  4/10 (40.00%)  2/35 (5.71%)  1/15 (6.67%) 
Hypotension * 1  0/11 (0.00%)  2/10 (20.00%)  5/35 (14.29%)  2/15 (13.33%) 
1
Term from vocabulary, MedDRA Version 23.1
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Clinical Scientist
Organization: Janssen Research & Development, LLC
Phone: 844-434-4210
EMail: ClinicalTrialDisclosure@its.jnj.com
Layout table for additonal information
Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT02703272    
Other Study ID Numbers: CR108134
54179060LYM3003 ( Other Identifier: Janssen Research & Development, LLC )
2016-000259-28 ( EudraCT Number )
First Submitted: March 3, 2016
First Posted: March 9, 2016
Results First Submitted: June 10, 2022
Results First Posted: December 2, 2022
Last Update Posted: December 2, 2022