Clinical Trials /

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

NCT02703272

Description:

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).

Related Conditions:
  • Mature B-Cell Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: CR108134
  • SECONDARY ID: 54179060LYM3003
  • SECONDARY ID: 2016-000259-28
  • NCT ID: NCT02703272

Conditions

  • Lymphoma, Non-Hodgkin

Interventions

DrugSynonymsArms
IbrutinibPart 1: Ibrutinib
RituximabPart 1: Ibrutinib
IfosfamidePart 1: Ibrutinib
CarboplatinPart 1: Ibrutinib
EtoposidePart 1: Ibrutinib
VincristinePart 1: Ibrutinib
IdarubicinPart 1: Ibrutinib
DexamethasonePart 1: Ibrutinib

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Part 1: IbrutinibExperimentalThe first 2 participants enrolled in each age group (1-5 years, 6-11 years, and 12-17 years) will be treated at a lower starting dose of Ibrutinib 240 milligram per square meter (mg/m2) for the first cycle, followed by dose escalation to 329 mg/m2 at the start of Cycle 2 as long as all pharmacokinetic assessments are within the expected range and there are no safety concerns. All participants will also 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 up until initiating antilymphoma therapy or a conditioning regimen for stem cell transplantation during post-treatment phase.
  • Ibrutinib
  • Rituximab
  • Ifosfamide
  • Carboplatin
  • Etoposide
  • Vincristine
  • Idarubicin
  • Dexamethasone
Part 2: IbrutinibExperimentalParticipants 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.
  • Ibrutinib
  • Rituximab
  • Ifosfamide
  • Carboplatin
  • Etoposide
  • Vincristine
  • Idarubicin
  • Dexamethasone

Eligibility Criteria

        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 or later recurrence 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 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)
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Area Under The Plasma Concentration-Time Curve (Auc) of Ibrutinib
Time Frame:Predose and at 1, 2, 4, and 6 hours postdose on Day 1 and on Day 7 or 8 of cycle 1; predose, 1, 2, 4, and 6 hours postdose on Day 1 of Cycle 2 or Cycle 3
Safety Issue:
Description:AUC is the under the plasma concentration-time curve.

Secondary Outcome Measures

Measure:Part 1: Number of Participants with Adverse Events
Time Frame:Throughout the study duration (approximately up to 4.2 years)
Safety Issue:
Description:
Measure:Part 1: Percentage of Participants Who Achieve Complete Response (CR) and Partial Response (PR)
Time Frame:Treatment Phase:Day 14 (Cycle 1),end of Cycle 2,End-of-Treatment visit;Post treatment phase:every 12 weeks for first 12 months,every 6 months until PD/clinical cutoff for primary endpoint/or upto 2 years after last subject enrolled,whichever occurs first
Safety Issue:
Description:CR: computed tomography (CT) or magnetic resonance imaging (MRI) reveals no residual disease or new lesions; Resected residual mass that is pathologically negative for disease; bone marrow (BM) and cerebrospinal fluid (CSF) morphologically free of disease with no new lesions by imaging examination. PR: 50 percent (%) decrease in sum of the products of the lesion diameters (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.
Measure:Part 1: Disease-specific Biomarkers Assessment
Time Frame:Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1 and End of treatment visit
Safety Issue:
Description:Blood samples will be taken to evaluate the levels of biomarkers such as Phosphor- Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), p-signal transducer, activator of transcription 3 (STAT3), Caspase-3 and B-cell receptor (BCR)/CD79B, CARD11, and MYD Mutations.
Measure:Part 1: Bruton's tyrosine kinase (BTK) Percent Occupancy
Time Frame:4 hours postdose on Day 1 and Day 7 or 8 of Cycle 1, predose on Cycle 2 Day 1 or Cycle 3 Day 1, and the End-of-Treatment visit
Safety Issue:
Description:The pharmacodynamic activity of ibrutinib in the presence of chemoimmunotherapy (CIT) (RICE or RVICI) will be assessed by determining the percentage of probe occupancy of the BTK receptor. Blood samples will be obtained for pharmacodynamic assessments (BTK occupancy).
Measure:Part 1: Visual analog Scale Score for Palatability
Time Frame:Cycle 1 Day 1 and Cycle 3 Day 1
Safety Issue:
Description:Palatability will be measured using a visual analog scale. The scale is a 5-point visual analog scale incorporating a facial hedonic scale designed to span pediatric ages and levels of participant comprehension.
Measure:Part 2: Number of Participants with Adverse Events
Time Frame:Throughout the study duration (approximately up to 4.2 years)
Safety Issue:
Description:
Measure:Part 2: Percentage of Participants Who Achieve Complete Response (CR) and Partial Response (PR)
Time Frame:Treatment Phase:Day 14 (Cycle 1),end of Cycle 2,End-of-Treatment visit;Post treatment phase:every 12 weeks for first 12 months,every 6 months until PD/clinical cutoff for primary endpoint/or upto 2 years after last subject enrolled,whichever occurs
Safety Issue:
Description:CR: CT or MRI reveals no residual disease or new lesions; Resected residual mass that is pathologically negative for disease; BM and CSF morphologically free of disease with no new lesions by imaging examination. 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.
Measure:Part 2: Tumor Volume Reduction
Time Frame:Day 14
Safety Issue:
Description:Tumor volume reduction will be measured by decrease in the sum of the products of the lesion diameters.
Measure:Part 2: Percentage of Participants who Proceed to Stem Cell Transplantation
Time Frame:Cycle 2 (Day 28)
Safety Issue:
Description:Percentage of participants who proceeded to stem cell transplantation will be calculated.
Measure:Part 2: Time to Response
Time Frame:Up to 4.2 years
Safety Issue:
Description:The time interval from the first dose of ibrutinib to the first documented response for those participants who respond.
Measure:Part 2: Duration of Response
Time Frame:up to 4.2 years
Safety Issue:
Description:Duration calculated from the date of initial documentation of a response (CR or PR) to the date of first documented evidence of PD or death.
Measure:Part 2: Percentage of Participants with Long-term Survival
Time Frame:2, 3 years
Safety Issue:
Description:Participants with event-free survival (EFS) at 2 and 3 years will be assessed.
Measure:Part 2: Overall Survival
Time Frame:Randomization to the date of death (maximum up to 4.2 years)
Safety Issue:
Description:Duration from the date of randomization to the date of the subject's death.
Measure:Part 2: Disease-specific Biomarkers Assessment
Time Frame:Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1 and End of treatment visit
Safety Issue:
Description:Blood samples will be taken to evaluate the levels of biomarkers such as Phosphor- Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), p-signal transducer, activator of transcription 3 (STAT3), Caspase-3 and B-cell receptor (BCR)/CD79B, CARD11, and MYD Mutations.
Measure:Part 2: Bruton's tyrosine kinase (BTK) Percent Occupancy
Time Frame:Cycle 1 Day 1 and Cycle 3 Day 1
Safety Issue:
Description:The pharmacodynamic activity of ibrutinib will be assessed by determining the percentage of probe occupancy of the BTK receptor. Blood samples will be obtained for pharmacodynamic assessments (BTK occupancy).
Measure:Part 2: Visual analog Scale Score for Palatability
Time Frame:Cycle 1 Day 1 and Cycle 3 Day 1
Safety Issue:
Description:Palatability will be measured using a visual analog scale. The scale is a 5-point visual analog scale incorporating a facial hedonic scale designed to span pediatric ages and levels of participant comprehension.
Measure:Part 2: Area under the plasma concentration-time curve (AUC)
Time Frame:Predose; 1, 2, and 4 hours postdose, either on Day 7 or 8 of Cycle 1 or on Day 1 of Cycle 2 (or Cycle 3)
Safety Issue:
Description:AUC is the aea under the plasma concentration-time curve.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Janssen Research & Development, LLC

Trial Keywords

  • Lymphoma, Non-Hodgkin
  • Ibrutinib
  • JNJ-54179060

Last Updated

April 7, 2017