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NCT02703272 · OUTCOME

Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline

A Safety and Efficacy Study of Ibrutinib in Pediatric and Young Adult Participants With Relapsed or Refractory Mature B-cell Non-Hodgkin Lymphoma · Source last updated 2022-12-02

Results reported by the registry submitting party. Population, time horizon, units and missing values must be read together.

Measure
MEAN
Unit
Transcripts per million
Interval / dispersion
Standard Deviation
Time frame
Baseline

What was measured

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.

Analysis 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.

Groups in this outcome

Part 1: Ibrutinib+RICE

Participants received ibrutinib based on age group and body surface area (BSA) in combination with chemoimmunotherapy (CIT) (investigator choice of RICE \[rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone\]). For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. Ibrutinib suspension or capsule was administered once daily starting Day 1 Cycle 1. The first 2 participants enrolled in each age group (1-5 years, 6-11 years, and 12-17 years) received Ibrutinib at a lower starting dose of 240 milligram per meter square (mg/m\^2) (not to exceed 420 mg per day) for the first cycle (older children \[6-17 years\] were enrolled first before enrolling younger children \[1-5 years\]), followed by dose escalation to 329 mg/m\^2 (not to exceed 560 mg per day) at the start of Cycle 2 based on the safety assessments. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 grams per meter square (g/m\^2), carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. Study treatment continued for 3 cycles (each cycle of 28 or 21 days), unless the participants experienced unacceptable toxicity or disease progression.

Part 1: Ibrutinib+RVICI

Participants received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RVICI \[rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone\]). dexamethasone\]). For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. The first 2 participants enrolled in each age group (1-5 years, 6-11 years, and 12-17 years) received Ibrutinib at a lower starting dose of 240 mg/m2 (not to exceed 420 mg per day) for the first cycle (older children \[6-17 years\] were enrolled first before enrolling younger children \[1-5 years\]), followed by dose escalation to 329 mg/m2 (not to exceed 560 mg per day) at the start of Cycle 2 based on the safety assessments. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, ifosfamide 10 g/m\^2, carboplatin 800 mg/m\^2, idarubicin 20 mg/m\^2, and dexamethasone 100 mg/m\^2. Study treatment continued for 3 cycles (each cycle of 28 or 21 days), unless the participants experienced unacceptable toxicity or disease progression.

Part 2: Ibrutinib+CIT (RICE or RVICI)

Participants received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RICE or RVICI) until 3 treatment cycles, transplantation if indicated, or until progressive disease (PD) or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. Participants of age groups 1-5 years and 6-11 years received ibrutinib 440 mg/m\^2, and age group 12-17 years received Ibrutinib 329 mg/m\^2 (dose selected from Part 1).

Part 2: Chemoimmunotherapy

Participants received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until PD or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 g/m2, carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. The RVICI regimen was composed of rituximab 750 mg/m\^2, vincristine 1.6 mg/m\^2, idarubicin 20 mg/m\^2, carboplatin 800 mg/m\^2, ifosfamide 10 g/m\^2, and dexamethasone 100 mg/m\^2 (all doses represented as cumulative administered in 1 cycle).

Group identifiers and denominators belong to this outcome only. They may differ in another outcome or in safety reporting.

Analysis denominator · Participants

GroupSource count
Part 1: Ibrutinib+RICE0
Part 1: Ibrutinib+RVICI0
Part 2: Ibrutinib+CIT (RICE or RVICI)18
Part 2: Chemoimmunotherapy9

Reported measurements

BCL-2L1 (BCL-xl)
Values in Transcripts per million · Interval/dispersion: Standard Deviation
GroupValueSpreadLowerUpperComment
Part 2: Ibrutinib+CIT (RICE or RVICI)58.0934638.75996Not reportedNot reportedNot reported
Part 2: Chemoimmunotherapy74.3079075.82331Not reportedNot reportedNot reported
BIRC2 (cIAP1)
Values in Transcripts per million · Interval/dispersion: Standard Deviation
GroupValueSpreadLowerUpperComment
Part 2: Ibrutinib+CIT (RICE or RVICI)47.2078716.26430Not reportedNot reportedNot reported
Part 2: Chemoimmunotherapy40.017169.28104Not reportedNot reportedNot reported
Caspase 3 (CASP3)
Values in Transcripts per million · Interval/dispersion: Standard Deviation
GroupValueSpreadLowerUpperComment
Part 2: Ibrutinib+CIT (RICE or RVICI)51.1471121.44109Not reportedNot reportedNot reported
Part 2: Chemoimmunotherapy47.6141232.12666Not reportedNot reportedNot reported
STAT3
Values in Transcripts per million · Interval/dispersion: Standard Deviation
GroupValueSpreadLowerUpperComment
Part 2: Ibrutinib+CIT (RICE or RVICI)540.02256363.75256Not reportedNot reportedNot reported
Part 2: Chemoimmunotherapy526.35308473.08255Not reportedNot reportedNot reported
SYK
Values in Transcripts per million · Interval/dispersion: Standard Deviation
GroupValueSpreadLowerUpperComment
Part 2: Ibrutinib+CIT (RICE or RVICI)705.29909503.07085Not reportedNot reportedNot reported
Part 2: Chemoimmunotherapy618.36324144.72067Not reportedNot reportedNot reported
Complete source fields
classes
  1. categories
    1. measurements
      1. group Id
        OG002
        spread
        38.75996
        value
        58.09346
      2. group Id
        OG003
        spread
        75.82331
        value
        74.30790
    title
    BCL-2L1 (BCL-xl)
  2. categories
    1. measurements
      1. group Id
        OG002
        spread
        16.26430
        value
        47.20787
      2. group Id
        OG003
        spread
        9.28104
        value
        40.01716
    title
    BIRC2 (cIAP1)
  3. categories
    1. measurements
      1. group Id
        OG002
        spread
        21.44109
        value
        51.14711
      2. group Id
        OG003
        spread
        32.12666
        value
        47.61412
    title
    Caspase 3 (CASP3)
  4. categories
    1. measurements
      1. group Id
        OG002
        spread
        363.75256
        value
        540.02256
      2. group Id
        OG003
        spread
        473.08255
        value
        526.35308
    title
    STAT3
  5. categories
    1. measurements
      1. group Id
        OG002
        spread
        503.07085
        value
        705.29909
      2. group Id
        OG003
        spread
        144.72067
        value
        618.36324
    title
    SYK
denoms
  1. counts
    1. group Id
      OG000
      value
      0
    2. group Id
      OG001
      value
      0
    3. group Id
      OG002
      value
      18
    4. group Id
      OG003
      value
      9
    units
    Participants
description
Tumor formalin-fixed paraffin-embedded (FFPE) samples were taken to evaluate the baseline gene expression by disease-specific biomarkers such as BCL-2L1 (BCL-xl), BIRC2 (cIAP1), Caspase 3 (CASP3), STAT3, and SYK. Transcripts per million (TPM) is a normalization method for RNA-sequencing, which means "for every 1,000,000 RNA molecules in the RNA-sequencing tumor FFPE sample, x came from this gene/transcript.
dispersion Type
Standard Deviation
groups
  1. description
    Participants received ibrutinib based on age group and body surface area (BSA) in combination with chemoimmunotherapy (CIT) (investigator choice of RICE \[rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone\]). For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. Ibrutinib suspension or capsule was administered once daily starting Day 1 Cycle 1. The first 2 participants enrolled in each age group (1-5 years, 6-11 years, and 12-17 years) received Ibrutinib at a lower starting dose of 240 milligram per meter square (mg/m\^2) (not to exceed 420 mg per day) for the first cycle (older children \[6-17 years\] were enrolled first before enrolling younger children \[1-5 years\]), followed by dose escalation to 329 mg/m\^2 (not to exceed 560 mg per day) at the start of Cycle 2 based on the safety assessments. The RICE regimen was composed of rituximab 750 mg/m\^2, ifosfamide 9 grams per meter square (g/m\^2), carboplatin 635 mg/m\^2, etoposide 300 mg/m\^2, and dexamethasone 100 mg/m\^2. Study treatment continued for 3 cycles (each cycle of 28 or 21 days), unless the participants experienced unacceptable toxicity or disease progression.
    id
    OG000
    title
    Part 1: Ibrutinib+RICE
  2. description
    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.
    id
    OG001
    title
    Part 1: Ibrutinib+RVICI
  3. description
    Participants received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RICE or RVICI) until 3 treatment cycles, transplantation if indicated, or until progressive disease (PD) or unacceptable toxicity. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system (CNS) prophylaxis in age-appropriate dosing. Participants of age groups 1-5 years and 6-11 years received ibrutinib 440 mg/m\^2, and age group 12-17 years received Ibrutinib 329 mg/m\^2 (dose selected from Part 1).
    id
    OG002
    title
    Part 2: Ibrutinib+CIT (RICE or RVICI)
  4. description
    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).
    id
    OG003
    title
    Part 2: Chemoimmunotherapy
param Type
MEAN
population Description
Biomarker analyses were conducted on the ITT population. As per change in planned analysis, genetic analysis was not performed for Part 1. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
reporting Status
POSTED
time Frame
Baseline
title
Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline
type
SECONDARY
unit Of Measure
Transcripts per million

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Preserved source evidence · Not medical advice