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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized, Open-label, Safety and Efficacy Study of Ibrutinib in Pediatric and Young Adult Patients With Relapsed or Refractory Mature B-cell Non-Hodgkin Lymphoma

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Rituximab
* Drug: Ifosfamide
* Drug: Carboplatin
* Drug: Etoposide
* Drug: Vincristine
* Drug: Idarubicin
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Ibrutinib<br>The first 2 participants enrolled in each age group (1-5 years, 6-11 years and 12-17 years) will receive starting dose of Ibrutinib 240 milligram per square meter (mg/m^2) for the first cycle, followed by dose escalation at the start of Cycle 2 as long as all pharmacokinetic assessments are within the expected range and there are no safety concerns. For participants being treated at 240 mg/m^2 dose level during the first cycle, the maximum dose should not exceed a total of 420 mg/day. All participants will receive rituximab, ifosfamide, carboplatin, etoposide and dexamethasone (RICE) or ituximab, vincristine, ifosfamide, carboplatin, idarubicin and dexamethasone (RVICI) background therapy (investigator's choice), during treatment phase. Participants with PR or better only will receive Ibrutinib for 3 cycles or until PD, unacceptable toxicity or until initiating antilymphoma therapy or a conditioning regimen for stem cell transplantation during post-treatment phase. | Drug: Ibrutinib<br>* Participants will receive Ibrutinib (dose 240 mg/m^2 /329 mg/m^2 per day) during part 1 and part 2.<br>Drug: Rituximab<br>* 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.<br>Drug: Ifosfamide<br>* 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.<br>Drug: Carboplatin<br>* 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.<br>Drug: Etoposide<br>* 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.<br>Drug: Vincristine<br>* 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.<br>Drug: Idarubicin<br>* 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.<br>Drug: Dexamethasone<br>* 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.<br>|
| Experimental: Part 2: Ibrutinib<br>Participants will either receive ibrutinib and RICE/RVICI background therapy or RICE/RVICI background therapy alone, until 3 cycles are completed or until PD or unacceptable toxicity during the treatment phase. Participants who received ibrutinib and RICE/RVICI background therapy and with PR or better only will receive ibrutinib alone for 3 cycles during post-treatment phase. | Drug: Ibrutinib<br>* Participants will receive Ibrutinib (dose 240 mg/m^2 /329 mg/m^2 per day) during part 1 and part 2.<br>Drug: Rituximab<br>* 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.<br>Drug: Ifosfamide<br>* 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.<br>Drug: Carboplatin<br>* 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.<br>Drug: Etoposide<br>* 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.<br>Drug: Vincristine<br>* 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.<br>Drug: Idarubicin<br>* 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.<br>Drug: Dexamethasone<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to Cycle 3 (each cycle of 21 or 28 days) | 
| 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. | Up to Cycle 3 (each cycle of 21 or 28 days) | 
| 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. | Up to Cycle 3 (each cycle of 21 or 28 days) | 
| 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. | Up to Cycle 3 (each cycle of 21 or 28 days) | 
| 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. | Up to Cycle 3 (each cycle of 28 days) | 
| 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 from Randomization to death, disease progression, or lack of CR or PR after 3 cycles of treatment (up to 4 year and 4 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 4 year and 4 months | 
| 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. | Up to 4 year and 4 months | 
| 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. | Baseline | 
| 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. | At baseline (Cycle 1 Day 1) of Part 1 and 2 | 
| 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. | Up to 3 months | 
| 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. | Day 1 of Cycle 1 and Cycle 3 | 
| Part 1: Number of Participants With CD79B, CARD11, and MYD Mutations | Number of Participants with CD79B, CARD11, and MYD Mutations were reported. | Up to 4 years and 4 months | 
| 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. | Up to 4 year and 4 months | 
| Part 1: Number of Participants With c-MYC Gene Rearrangement | Number of participants with c-MYC gene rearrangement were reported. | At baseline (Cycle 1 Day 1) | 
| 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. | At baseline (Cycle 1 Day 1) | 
| 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. | Up to 4 year and 4 months | 
| 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. | Up to 4 year and 4 months | 
| 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. | At Day 14 | 
| Part 2: Number of Participants Who Proceeded to Stem Cell Transplantation | Number of participants who proceeded to stem cell transplantation were reported. | Up to end of the study (Up to 4 year and 4 months) | 
| 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. | Up to 4 Years and 4 months | 
| 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. | Up to 4 year and 4 months | 
| 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. | At 2 years | 
| 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. | At 3 years | 
| Part 2: Overall Survival | Overall survival was defined as duration from the date of randomization to the date of the participant's death. | Up to 4 year and 4 months | 
| 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. | Up to Cycle 3 (each cycle of 21 or 28 days) | 
| 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. | Up to Cycle 3 (each cycle of 21 or 28 days) | 
| 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. | Up to Cycle 3 (each cycle of 21 or 28 days) | 
| 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. | Up to Cycle 3 (each cycle of 21 or 28 days) | 
| 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. | Up to Cycle 3 (each cycle of 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, Non-Hodgkin, Ibrutinib, JNJ-54179060