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

Phase 3TerminatedNCT02703272

Janssen Research & Development, LLC72 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Conditions

Lymphoma, Non-Hodgkin

Interventions

IbrutinibDRUG

Participants will receive Ibrutinib (dose 240 mg/m\^2 /329 mg/m\^2 per day) during part 1 and part 2.

RituximabDRUG

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.

IfosfamideDRUG

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.

Eligibility

Sex: ALLMin age: 1 YearMax age: 30 Years

Medical Language ↔ Plain English

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

Locations (76)

Outcomes

Primary Outcomes

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)

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)

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)

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)

Part 1: Relationship Between AUC and Body Size

Data from ClinicalTrials.gov

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Secondary Outcomes

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

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

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

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

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

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

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

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

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)

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)

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

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

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

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)

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

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

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

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

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

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)

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)

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)

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)

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)