Lymphoma, Non-Hodgkin
Conditions
Keywords
Lymphoma, Non-Hodgkin, Ibrutinib, JNJ-54179060
Brief summary
The purpose of this study is to confirm that the pharmacokinetics of ibrutinib in pediatric participants is consistent with that in adults (part 1) and to assess efficacy (event-free survival \[EFS\]) of ibrutinib in combination with rituximab, ifosfamide, carboplatin, and etoposide (RICE) or rituximab, vincristine, ifosfamide, carboplatin, and idarubicin (RVICI) background therapy compared to RICE or RVICI background therapy alone (part 2).
Detailed description
This is a Phase 3, randomized (study medication assigned to participants by chance), open-label (identity of study drug will be known to participant and study staff), controlled study which consists of two parts: Part 1 and Part 2. The Part 1 is a pharmacokinetic run-in part, which will be conducted before starting the randomized part (Part 2) of the study and Part 2 is a randomized and open-label study. Part 1 and Part 2 of the study will be conducted in 3 phases: a Pretreatment (Screening) Phase (Up to 14 days before administration of study drug), a Treatment Phase, and a Posttreatment Phase. The Treatment Phase will extend from enrollment (in Part 1) or randomization (in Part 2) until 1 of the following: 1) completion of 3 cycles of therapy, 2) transplantation, if clinically indicated, or 3) progressive disease (PD), whichever comes first. The Posttreatment Phase will continue until death, loss to follow up, consent withdrawal, or study end, whichever occurs first. The end of study is defined as when approximately 60 event-free survival (EFS) events have occurred in Part 2 (death, disease progression, or lack of complete response \[CR\] or partial response \[PR\] after 3 cycles of treatment based on blinded independent event review), or the sponsor terminates the study, whichever comes first. Participants in Part 1 will be 1 to less than (\<) 18 years old. Participants in Part 2 will be 1 to 30 years old. Participants will be primarily evaluated for pharmacokinetics in part 1 and efficacy (EFS) of ibrutinib in combination with RICE or RVICI background therapy compared to RICE or RVICI background therapy alone in part 2. Participants' safety will be monitored throughout the study.
Interventions
DRUGIbrutinib
Participants will receive Ibrutinib (dose 240 mg/m\^2 /329 mg/m\^2 per day) during part 1 and part 2.
DRUGRituximab
Participants will receive a cumulative dose of rituximab 750 mg/m\^2 as a part of RICE/RVICI regimen in part 1 and part 2 per cycle.
DRUGIfosfamide
Participants will receive a cumulative dose of Ifosfamide 9 g/m\^2 and 10 g/m\^2 as a part of RICE and RVICI regimen respectively in part 1 and part 2 per cycle.
DRUGCarboplatin
Participants will receive a cumulative dose of carboplatin 635 mg/m\^2 and 800 mg/m\^2 as a part of RICE and RVICI regimen respectively in part 1 and part 2 per cycle.
DRUGEtoposide
Participants will receive a cumulative dose of etoposide 300 mg/m\^2 in part 1 and part 2 as a part of RICE regimen per cycle.
DRUGVincristine
Participants will receive a cumulative dose of vincristine 1.6 mg/m\^2 in part 1 and part 2 as a part of RVICI regimen per cycle.
DRUGIdarubicin
Participants will receive a cumulative dose of idarubicin 20 mg/m\^2 in part 1 and part 2 as a part of RVICI regimen per cycle.
DRUGDexamethasone
Participants will receive a cumulative dose of dexamethasone 100 mg/m\^2 in part 1 and part 2 as a part of RICE/RVICI regimen per cycle.
Sponsors
Pharmacyclics LLC.
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
* Participants with 1 to less than (\<) 18 years of age (Part 1 only), or 1 to 30 years of age, inclusive, if initial diagnosis of mature B-cell non-Hodgkin lymphoma (NHL) occurred at \<18 years of age (Part 2 only) * Participants must be in first recurrence and have received only one prior line of therapy or have disease that is primarily refractory to conventional therapy * Participants must have at least 1 of the following: 1 site of measurable disease greater than (\>) 1 centimeter (cm) in the longest diameter and \>1 cm in the shortest diameter by radiological imaging; bone marrow involvement; cerebrospinal fluid with blasts present * Participants with lansky-Karnofsky score of greater than or equal to (\>=) 50 * Adolescent women/young women of childbearing potential must have a negative highly sensitive serum or urine beta-human chorionic gonadotropin (beta-hCG) pregnancy test at Screening before enrollment/randomization. Adolescent/young women who are pregnant or breastfeeding are ineligible for this study
Exclusion criteria
* Participants with ongoing anticoagulation treatment with warfarin or equivalent vitamin K antagonists (example phenprocoumon), or ongoing treatment with agents known to be strong CYP3A4/5 inhibitors, or has taken any disallowed therapies as noted in Section 8.2, Prohibited Medications, before the planned first dose of study drug * Participants with inherited or acquired bleeding disorders * Participants with clinically significant arrhythmias, complex congenital heart disease, or left ventricular ejection fraction (LVEF) \<50 percent (%) or shortening fraction (SF) \<=28% * Participants with known history of human immunodeficiency virus (HIV) or active Hepatitis B or C virus * Participants with any condition that could interfere with the absorption or metabolism of ibrutinib including malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel * Participants with known allergies, hypersensitivity, or intolerance to ibrutinib or its excipients (refer to Investigator's Brochure) * A diagnosis of post-transplant lymphoproliferative disease (PTLD) * Participants who are within 6 months of an allogeneic bone marrow transplant * Participants who have had prior exposure to ibrutinib
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | Up to Cycle 3 (each cycle of 21 or 28 days) | AUC is defined as area under the plasma concentration-time curve. As per planned analyses, 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. |
| Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | Up to Cycle 3 (each cycle of 21 or 28 days) | CL/F is defined as apparent plasma clearance of ibrutinib. As per planned analyses, PK parameters for Part 1 were presented per dose group (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age. |
| Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | Up to Cycle 3 (each cycle of 21 or 28 days) | Vd/F is defined as apparent (oral) volume of distribution of ibrutinib. As per planned analyses, 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. |
| Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | Up to Cycle 3 (each cycle of 21 or 28 days) | Cmax is defined as maximum plasma concentration of ibrutinib. As per planned analyses, pharmacokinetic (PK) parameters for Part 1 were presented per dose group (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age. |
| Part 1: Relationship Between AUC and Body Size | Up to Cycle 3 (each cycle of 28 days) | 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. |
| Part 2: Event Free Survival (EFS) Between the 2 Treatment Groups | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants With CD79B, CARD11, and MYD Mutations | Up to 4 years and 4 months | Number of Participants with CD79B, CARD11, and MYD Mutations were reported. |
| Part 2: Number of Participants With CD79B, CARD11, and MYD Mutations | Up to 4 year and 4 months | 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. |
| Part 1: Number of Participants With c-MYC Gene Rearrangement | At baseline (Cycle 1 Day 1) | Number of participants with c-MYC gene rearrangement were reported. |
| Part 2: Number of Participants With c-MYC Gene Rearrangement | At baseline (Cycle 1 Day 1) | 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. |
| Part 2: Percentage of Participants Who Achieved Complete Response (CR) | Up to 4 year and 4 months | 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. |
| Part 2: Percentage of Participants Who Achieved Partial Response (PR) | Up to 4 year and 4 months | 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. |
| Part 2: Tumor Volume Reduction Rate at Day 14 | At Day 14 | 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. |
| Part 2: Number of Participants Who Proceeded to Stem Cell Transplantation | Up to end of the study (Up to 4 year and 4 months) | Number of participants who proceeded to stem cell transplantation were reported. |
| Part 2: Time to Response | Up to 4 Years and 4 months | 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. |
| Part 1 and Part 2: Number of Participants With Adverse Events as Measure of Safety and Tolerability | Up to 4 year and 4 months | 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. |
| Part 2: Percentage of Participants With EFS at 2 Years | At 2 years | 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. |
| Part 2: Percentage of Participants With EFS at 3 Years | At 3 years | 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. |
| Part 2: Overall Survival | Up to 4 year and 4 months | Overall survival was defined as duration from the date of randomization to the date of the participant's death. |
| Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | Up to Cycle 3 (each cycle of 21 or 28 days) | AUC is defined as area under the plasma concentration-time curve. As per planned analyses, PK parameters for Part 2 were presented per dose group (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age. |
| Part 2: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | Up to Cycle 3 (each cycle of 21 or 28 days) | CL/F is defined as apparent plasma clearance of ibrutinib. As per planned analyses, PK parameters for Part 2 were presented per dose group (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age. |
| Part 2: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | Up to Cycle 3 (each cycle of 21 or 28 days) | Vd/F is defined as apparent (oral) volume of distribution of ibrutinib. As per planned analyses, PK parameters for Part 2 were presented per dose group (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age. |
| Part 2: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | Up to Cycle 3 (each cycle of 21 or 28 days) | Cmax is defined as maximum plasma concentration of ibrutinib. As per planned analyses, PK parameters for Part 2 were presented per dose group (240 mg/m\^2, 329 mg/m\^2 and 440 mg/m\^2) and age group (1-5, 6-11, 12-17 and \>18 years). As planned in protocol, the PK parameters were presented per dose group as dosing was dependent on age. |
| Part 2: Relationship Between AUC and Body Size | Up to Cycle 3 (each cycle of 28 days) | 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. |
| Part 2: Duration of Response | Up to 4 year and 4 months | 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. |
| Part 1 and Part 2: Overall Response Rate (ORR) | Up to 4 year and 4 months | 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. |
| Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline | Baseline | 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. |
| Part 1 and Part 2: Number of Participants With Immunoglobulin and T-cell Receptor Gene Rearrangements | At baseline (Cycle 1 Day 1) of Part 1 and 2 | Number of participants with immunoglobulin and T-cell receptor gene rearrangements were reported. |
| Part 1 and Part 2: Number of Participants With Greater Than (>) 90% Bruton's Tyrosine Kinase (BTK) Occupancy | Up to 3 months | Number of participants with \>90% BTK occupancy were reported. Blood samples were collected to assess BTK occupancy. |
| Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability | Day 1 of Cycle 1 and Cycle 3 | 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. |
Countries
Belgium, Brazil, Bulgaria, Canada, Czechia, France, Germany, Hungary, Netherlands, Poland, Romania, Russia, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Ibrutinib+RICE Participants received ibrutinib based on age group and body surface area (BSA) in combination with chemoimmunotherapy (CIT) (investigator choice of RICE \[rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone\]). For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. Ibrutinib suspension or capsule was administered once daily starting Day 1 Cycle 1. The first 2 participants enrolled in each age group (1-5 years, 6-11 years, and 12-17 years) received Ibrutinib at a lower starting dose of 240 milligram per meter square (mg/m\^2) (not to exceed 420 mg per day) for the first cycle (older children \[6-17 years\] were enrolled first before enrolling younger children \[1-5 years\]), followed by dose escalation to 329 mg/m\^2 (not to exceed 560 mg per day) at the start of Cycle 2 based on the safety assessments. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 grams per meter square (g/m\^2), carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. Study treatment continued for 3 cycles (each cycle of 28 or 21 days), unless the participants experienced unacceptable toxicity or disease progression. | 11 |
| Part 1: Ibrutinib+RVICI Participants received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RVICI \[rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone\]). dexamethasone\]). For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. The first 2 participants enrolled in each age group (1-5 years, 6-11 years, and 12-17 years) received Ibrutinib at a lower starting dose of 240 mg/m2 (not to exceed 420 mg per day) for the first cycle (older children \[6-17 years\] were enrolled first before enrolling younger children \[1-5 years\]), followed by dose escalation to 329 mg/m2 (not to exceed 560 mg per day) at the start of Cycle 2 based on the safety assessments. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, ifosfamide 10 g/m\^2, carboplatin 800 mg/m\^2, idarubicin 20 mg/m\^2, and dexamethasone 100 mg/m\^2. Study treatment continued for 3 cycles (each cycle of 28 or 21 days), unless the participants experienced unacceptable toxicity or disease progression. | 10 |
| Part 2: Ibrutinib+CIT (RICE or RVICI) Participants received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RICE or RVICI) until 3 treatment cycles, transplantation if indicated, or until progressive disease (PD) or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. Participants of age groups 1-5 years and 6-11 years received ibrutinib 440 mg/m\^2, and age group 12-17 years received Ibrutinib 329 mg/m\^2 (dose selected from Part 1). | 35 |
| Part 2: Chemoimmunotherapy Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle). | 16 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 4 | 9 | 19 | 10 |
| Overall Study | Other | 1 | 0 | 0 | 0 |
| Overall Study | Study Terminated by Sponsor | 6 | 1 | 12 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 4 | 2 |
Baseline characteristics
| Characteristic | Part 1: Ibrutinib+RICE | Total | Part 2: Chemoimmunotherapy | Part 2: Ibrutinib+CIT (RICE or RVICI) | Part 1: Ibrutinib+RVICI |
|---|---|---|---|---|---|
| Age, Continuous | 10.5 years STANDARD_DEVIATION 4.91 | 12.4 years STANDARD_DEVIATION 4.54 | 13.2 years STANDARD_DEVIATION 4.37 | 13.9 years STANDARD_DEVIATION 3.94 | 8.3 years STANDARD_DEVIATION 3.43 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 15 Participants | 6 Participants | 8 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 3 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 1 Participants | 4 Participants | 0 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 9 Participants | 49 Participants | 8 Participants | 22 Participants | 10 Participants |
| Region of Enrollment BELGIUM | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Region of Enrollment BRAZIL | 1 Participants | 4 Participants | 2 Participants | 1 Participants | 0 Participants |
| Region of Enrollment BULGARIA | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Region of Enrollment CANADA | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Region of Enrollment CZECH REPUBLIC | 0 Participants | 4 Participants | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment FRANCE | 2 Participants | 7 Participants | 1 Participants | 3 Participants | 1 Participants |
| Region of Enrollment GERMANY | 2 Participants | 6 Participants | 0 Participants | 3 Participants | 1 Participants |
| Region of Enrollment ITALY | 2 Participants | 9 Participants | 2 Participants | 4 Participants | 1 Participants |
| Region of Enrollment NETHERLANDS | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment POLAND | 0 Participants | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Region of Enrollment ROMANIA | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Region of Enrollment SOUTH KOREA | 1 Participants | 10 Participants | 4 Participants | 5 Participants | 0 Participants |
| Region of Enrollment SPAIN | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Region of Enrollment SWEDEN | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Region of Enrollment TAIWAN | 0 Participants | 3 Participants | 1 Participants | 2 Participants | 0 Participants |
| Region of Enrollment TURKEY | 1 Participants | 8 Participants | 2 Participants | 1 Participants | 4 Participants |
| Region of Enrollment UKRAINE | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Region of Enrollment UNITED KINGDOM | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment UNITED STATES | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 3 Participants | 19 Participants | 3 Participants | 12 Participants | 1 Participants |
| Sex: Female, Male Male | 8 Participants | 53 Participants | 13 Participants | 23 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 11 | 9 / 10 | 19 / 35 | 10 / 15 |
| other Total, other adverse events | 11 / 11 | 10 / 10 | 35 / 35 | 15 / 15 |
| serious Total, serious adverse events | 10 / 11 | 9 / 10 | 25 / 35 | 11 / 15 |
Outcome results
Primary
Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib
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)
Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. Here, n (number analyzed) is defined as number of participants analyzed for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | 6-11 years | 1450 milliliter per hour (mL/h) |
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | 1-5 years | 1220 milliliter per hour (mL/h) |
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | 12-17 years | 348 milliliter per hour (mL/h) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | 12-17 years | 729 milliliter per hour (mL/h) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | 1-5 years | 508 milliliter per hour (mL/h) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | 6-11 years | 805 milliliter per hour (mL/h) |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | 6-11 years | 1300 milliliter per hour (mL/h) |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | 1-5 years | 1200 milliliter per hour (mL/h) |
Primary
Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib
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)
Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. Here, n (number analyzed) is defined as number of participants analyzed for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | 6-11 years | 18 liter(s) |
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | 1-5 years | 11.1 liter(s) |
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | 12-17 years | 3.63 liter(s) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | 12-17 years | 11.3 liter(s) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | 1-5 years | 5.18 liter(s) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | 6-11 years | 7.55 liter(s) |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | 6-11 years | 19 liter(s) |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | 1-5 years | 7.63 liter(s) |
Primary
Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib
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)
Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. Here, n (number analyzed) is defined as number of participants analyzed for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | 6-11 years | 145 hours*nanogram per milliliter (h*ng/mL) |
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | 1-5 years | 143 hours*nanogram per milliliter (h*ng/mL) |
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | 12-17 years | 1210 hours*nanogram per milliliter (h*ng/mL) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | 12-17 years | 661 hours*nanogram per milliliter (h*ng/mL) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | 1-5 years | 386 hours*nanogram per milliliter (h*ng/mL) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | 6-11 years | 349 hours*nanogram per milliliter (h*ng/mL) |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | 6-11 years | 324 hours*nanogram per milliliter (h*ng/mL) |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | 1-5 years | 310 hours*nanogram per milliliter (h*ng/mL) |
Primary
Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib
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)
Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. Here, n (number analyzed) is defined as number of participants analyzed for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | 6-11 years | 3.46 nanograms per milliliter (ng/mL) |
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | 1-5 years | 3.86 nanograms per milliliter (ng/mL) |
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | 12-17 years | 4.88 nanograms per milliliter (ng/mL) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | 12-17 years | 4.73 nanograms per milliliter (ng/mL) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | 1-5 years | 4.48 nanograms per milliliter (ng/mL) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | 6-11 years | 3.64 nanograms per milliliter (ng/mL) |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | 6-11 years | 3.88 nanograms per milliliter (ng/mL) |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | 1-5 years | 5.07 nanograms per milliliter (ng/mL) |
Primary
Part 1: Relationship Between AUC and Body Size
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)
Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib.
Primary
Part 2: Event Free Survival (EFS) Between the 2 Treatment Groups
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)
Population: The intent-to-treat (ITT) population consisted of all randomized participants; participants analyzed based on randomization, regardless of study drug received. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Event Free Survival (EFS) Between the 2 Treatment Groups | 6.05 Months |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Event Free Survival (EFS) Between the 2 Treatment Groups | 6.97 Months |
Secondary
Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline
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
Population: Biomarker analyses were conducted on the ITT population. As per change in planned analysis, genetic analysis was not performed for Part 1. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline | BCL-2L1 (BCL-xl) | 58.09346 Transcripts per million | Standard Deviation 38.75996 |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline | BIRC2 (cIAP1) | 47.20787 Transcripts per million | Standard Deviation 16.2643 |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline | SYK | 705.29909 Transcripts per million | Standard Deviation 503.07085 |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline | Caspase 3 (CASP3) | 51.14711 Transcripts per million | Standard Deviation 21.44109 |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline | STAT3 | 540.02256 Transcripts per million | Standard Deviation 363.75256 |
| Part 2: Chemoimmunotherapy | Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline | STAT3 | 526.35308 Transcripts per million | Standard Deviation 473.08255 |
| Part 2: Chemoimmunotherapy | Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline | BCL-2L1 (BCL-xl) | 74.30790 Transcripts per million | Standard Deviation 75.82331 |
| Part 2: Chemoimmunotherapy | Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline | Caspase 3 (CASP3) | 47.61412 Transcripts per million | Standard Deviation 32.12666 |
| Part 2: Chemoimmunotherapy | Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline | BIRC2 (cIAP1) | 40.01716 Transcripts per million | Standard Deviation 9.28104 |
| Part 2: Chemoimmunotherapy | Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline | SYK | 618.36324 Transcripts per million | Standard Deviation 144.72067 |
Secondary
Part 1 and Part 2: Number of Participants With Adverse Events as Measure of Safety and Tolerability
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
Population: Safety population consisted of all participants who received at least 1 dose of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1 and Part 2: Number of Participants With Adverse Events as Measure of Safety and Tolerability | 11 Participants |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1 and Part 2: Number of Participants With Adverse Events as Measure of Safety and Tolerability | 10 Participants |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1 and Part 2: Number of Participants With Adverse Events as Measure of Safety and Tolerability | 35 Participants |
| Part 2: Chemoimmunotherapy | Part 1 and Part 2: Number of Participants With Adverse Events as Measure of Safety and Tolerability | 15 Participants |
Secondary
Part 1 and Part 2: Number of Participants With Greater Than (>) 90% Bruton's Tyrosine Kinase (BTK) Occupancy
Number of participants with \>90% BTK occupancy were reported. Blood samples were collected to assess BTK occupancy.
Time frame: Up to 3 months
Population: Biomarker analyses were conducted on the ITT population. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. As planned, BTK occupancy was assessed for ibrutinib only.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1 and Part 2: Number of Participants With Greater Than (>) 90% Bruton's Tyrosine Kinase (BTK) Occupancy | 5 Participants |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1 and Part 2: Number of Participants With Greater Than (>) 90% Bruton's Tyrosine Kinase (BTK) Occupancy | 5 Participants |
Secondary
Part 1 and Part 2: Number of Participants With Immunoglobulin and T-cell Receptor Gene Rearrangements
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
Population: Biomarker analyses were conducted on the ITT population. As per change in planned analysis, immunoglobulin and T-cell receptor gene rearrangements were not performed for Part 1 and Part 2.
| Arm | Measure | Group | Value |
|---|---|---|---|
| Unknown | Part 1 and Part 2: Number of Participants With Immunoglobulin and T-cell Receptor Gene Rearrangements | Immunoglobulin | — |
| Unknown | Part 1 and Part 2: Number of Participants With Immunoglobulin and T-cell Receptor Gene Rearrangements | T-cell Receptor Gene Rearrangements | — |
Secondary
Part 1 and Part 2: Overall Response Rate (ORR)
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
Population: The ITT Population consisted of all randomized participants; participants analyzed based on randomization, regardless of study drug received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1 and Part 2: Overall Response Rate (ORR) | 81.8 Percentage of participants |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1 and Part 2: Overall Response Rate (ORR) | 50.0 Percentage of participants |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1 and Part 2: Overall Response Rate (ORR) | 68.6 Percentage of participants |
| Part 2: Chemoimmunotherapy | Part 1 and Part 2: Overall Response Rate (ORR) | 81.3 Percentage of participants |
Secondary
Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability
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
Population: Safety population: all participants who received at least 1 dose of treatment. Here 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure (OM) and, n (number analyzed) signifies number of participants analyzed for specified category. Participants in arm 'Part 2: Chemoimmunotherapy' did not receive ibrutinib, and palatability of ibrutinib was measured in this OM. Hence, no data available to report for this arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability | Cycle 1 Day 1 | 2.6 Units on a scale | Standard Deviation 1.21 |
| Part 1: Ibrutinib: 240 mg/m^2 | Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability | Cycle 3 Day 1 | 3.3 Units on a scale | Standard Deviation 1.39 |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability | Cycle 1 Day 1 | 3.2 Units on a scale | Standard Deviation 1.4 |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability | Cycle 3 Day 1 | 2.3 Units on a scale | Standard Deviation 1.15 |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability | Cycle 1 Day 1 | 2.4 Units on a scale | Standard Deviation 1.16 |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability | Cycle 3 Day 1 | 2.6 Units on a scale | Standard Deviation 0.89 |
Secondary
Part 1: Number of Participants With CD79B, CARD11, and MYD Mutations
Number of Participants with CD79B, CARD11, and MYD Mutations were reported.
Time frame: Up to 4 years and 4 months
Population: Biomarker analyses were conducted on the ITT population. As per change in planned analysis, genetic analysis was not performed for Part 1.
| Arm | Measure | Group | Value |
|---|---|---|---|
| Unknown | Part 1: Number of Participants With CD79B, CARD11, and MYD Mutations | CD79B | — |
| Unknown | Part 1: Number of Participants With CD79B, CARD11, and MYD Mutations | CARD11 | — |
| Unknown | Part 1: Number of Participants With CD79B, CARD11, and MYD Mutations | MYD Mutations | — |
Secondary
Part 1: Number of Participants With c-MYC Gene Rearrangement
Number of participants with c-MYC gene rearrangement were reported.
Time frame: At baseline (Cycle 1 Day 1)
Population: Biomarker analyses were conducted on the ITT population. As per change in planned analysis, genetic analysis was not performed for Part 1.
Secondary
Part 2: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib
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)
Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. Here, n (number analyzed) is defined as number of participants analyzed for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | 12-17 years | 1730 mL/h |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | 12-17 years | 982 mL/h |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | 18+ years | 1510 mL/h |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 2: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | 1-5 years | 1110 mL/h |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 2: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib | 6-11 years | 856 mL/h |
Secondary
Part 2: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib
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)
Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. Here, n (number analyzed) is defined as number of participants analyzed for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | 12-17 years | 9.9 liter(s) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | 12-17 years | 4.14 liter(s) |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | 18+ years | 9.29 liter(s) |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 2: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | 1-5 years | 1.68 liter(s) |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 2: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib | 6-11 years | 6.18 liter(s) |
Secondary
Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib
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)
Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. Here, n (number analyzed) is defined as number of participants analyzed for specified category.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | 12-17 years | 215 h*ng/mL |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | 12-17 years | 499 h*ng/mL |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | 18+ years | 423 h*ng/mL |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | 1-5 years | 298 h*ng/mL |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib | 6-11 years | 655 h*ng/mL |
Secondary
Part 2: Duration of Response
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
Population: Duration of response was summarized for participants who achieved either CR (including CRb and CRu) or PR. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Duration of Response | 6.01 Months |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Duration of Response | 6.51 Months |
Secondary
Part 2: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib
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)
Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. Here, n (number analyzed) is defined as number of participants analyzed for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | 12-17 years | 2.93 ng/mL |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | 12-17 years | 4.86 ng/mL |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | 18+ years | 3.7 ng/mL |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 2: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | 1-5 years | 3.79 ng/mL |
| Part 1: Ibrutinib: 440 mg/m^2 | Part 2: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib | 6-11 years | 4.15 ng/mL |
Secondary
Part 2: Number of Participants Who Proceeded to Stem Cell Transplantation
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)
Population: The ITT population consisted of all randomized participants; participants were analyzed based on randomization, regardless of study drug received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Number of Participants Who Proceeded to Stem Cell Transplantation | 13 Participants |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Number of Participants Who Proceeded to Stem Cell Transplantation | 7 Participants |
Secondary
Part 2: Number of Participants With CD79B, CARD11, and MYD Mutations
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
Population: Biomarker analyses were conducted on the ITT population. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Number of Participants With CD79B, CARD11, and MYD Mutations | CD79B | 1 Participants |
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Number of Participants With CD79B, CARD11, and MYD Mutations | CARD11 | 1 Participants |
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Number of Participants With CD79B, CARD11, and MYD Mutations | MYD mutation | 0 Participants |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Number of Participants With CD79B, CARD11, and MYD Mutations | CD79B | 0 Participants |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Number of Participants With CD79B, CARD11, and MYD Mutations | CARD11 | 0 Participants |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Number of Participants With CD79B, CARD11, and MYD Mutations | MYD mutation | 0 Participants |
Secondary
Part 2: Number of Participants With c-MYC Gene Rearrangement
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)
Population: Biomarker analyses were conducted on the ITT population. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Number of Participants With c-MYC Gene Rearrangement | 1 Participants |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Number of Participants With c-MYC Gene Rearrangement | 1 Participants |
Secondary
Part 2: Overall Survival
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
Population: The ITT Population consisted of all randomized participants; participants were analyzed based on randomization, regardless of study drug received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Overall Survival | 14.13 Months |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Overall Survival | 11.07 Months |
Secondary
Part 2: Percentage of Participants Who Achieved Complete Response (CR)
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
Population: The ITT Population consisted of all randomized participants; participants analyzed based on randomization, regardless of study drug received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Percentage of Participants Who Achieved Complete Response (CR) | 17.1 Percentage of Participants |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Percentage of Participants Who Achieved Complete Response (CR) | 18.8 Percentage of Participants |
Secondary
Part 2: Percentage of Participants Who Achieved Partial Response (PR)
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
Population: The ITT Population consisted of all randomized participants; participants analyzed based on randomization, regardless of study drug received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Percentage of Participants Who Achieved Partial Response (PR) | 51.4 percentage of participants |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Percentage of Participants Who Achieved Partial Response (PR) | 62.5 percentage of participants |
Secondary
Part 2: Percentage of Participants With EFS at 2 Years
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
Population: The ITT Population consisted of all randomized participants; participants were analyzed based on randomization, regardless of study drug received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Percentage of Participants With EFS at 2 Years | 14.3 Percentage of participants |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Percentage of Participants With EFS at 2 Years | 12.5 Percentage of participants |
Secondary
Part 2: Percentage of Participants With EFS at 3 Years
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
Population: The ITT Population consisted of all randomized participants; participants were analyzed based on randomization, regardless of study drug received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Percentage of Participants With EFS at 3 Years | 8.6 Percentage of participants |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Percentage of Participants With EFS at 3 Years | 12.5 Percentage of participants |
Secondary
Part 2: Relationship Between AUC and Body Size
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)
Population: PK analysis set included participants in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib.
Secondary
Part 2: Time to Response
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
Population: Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure. Time to response was summarized for participants who achieved either CR (including CRb and CRu) or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Time to Response | 0.89 Months |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Time to Response | 0.82 Months |
Secondary
Part 2: Tumor Volume Reduction Rate at Day 14
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
Population: The ITT Population consisted of all randomized participants; participants was analyzed based on randomization, regardless of study drug received. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Ibrutinib: 240 mg/m^2 | Part 2: Tumor Volume Reduction Rate at Day 14 | -49.7 Percent change | Standard Deviation 33.41 |
| Part 1: Ibrutinib: 329 mg/m^2 | Part 2: Tumor Volume Reduction Rate at Day 14 | -58.60 Percent change | Standard Deviation 34.04 |