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

Sponsor

Janssen Research & Development, LLC (Industry)

Overall Status

Completed

CT.gov ID

NCT02703272

Collaborator

Pharmacyclics LLC. (Industry)

Enrollment

Locations

Arms

59.3

Actual Duration (Months)

0.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Non-Hodgkin	Drug: Ibrutinib Drug: Rituximab Drug: Ifosfamide Drug: Carboplatin Drug: Etoposide Drug: Vincristine Drug: Idarubicin Drug: Dexamethasone	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

72 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jul 1, 2016

Actual Primary Completion Date :

Jun 11, 2021

Actual Study Completion Date :

Jun 11, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1: Ibrutinib 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 Participants will receive Ibrutinib (dose 240 mg/m^2 /329 mg/m^2 per day) during part 1 and part 2. Drug: Rituximab 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. Drug: Ifosfamide 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. Drug: Carboplatin 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. Drug: Etoposide 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. Drug: Vincristine 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. Drug: Idarubicin 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. Drug: Dexamethasone 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.
Experimental: Part 2: Ibrutinib 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 Participants will receive Ibrutinib (dose 240 mg/m^2 /329 mg/m^2 per day) during part 1 and part 2. Drug: Rituximab 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. Drug: Ifosfamide 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. Drug: Carboplatin 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. Drug: Etoposide 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. Drug: Vincristine 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. Drug: Idarubicin 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. Drug: Dexamethasone 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.

Arm

Intervention/Treatment

Experimental: Part 1: Ibrutinib

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

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

Drug: Rituximab

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.

Drug: Ifosfamide

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.

Drug: Carboplatin

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.

Drug: Etoposide

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.

Drug: Vincristine

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.

Drug: Idarubicin

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.

Drug: Dexamethasone

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.

Experimental: Part 2: Ibrutinib

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

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

Drug: Rituximab

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.

Drug: Ifosfamide

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.

Drug: Carboplatin

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.

Drug: Etoposide

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.

Drug: Vincristine

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.

Drug: Idarubicin

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.

Drug: Dexamethasone

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.

Outcome Measures

Primary Outcome Measures

Part 1: Area Under The Plasma Concentration-Time Curve (AUC) of Ibrutinib [Predose, at 1, 2, 4, and 6 hours postdose on Day 1, and Day 7 or 8 of cycle 1; predose, 1, 2, 4, and 6 hours postdose on Day 1 of Cycle 2 or Cycle 3 (each cycle of 28 days)]
AUC is the under the plasma concentration-time curve.
Part 1: Apparent (oral) Plasma Clearance (CL/F) of Ibrutinib [Predose, at 1, 2, 4, and 6 hours postdose on Day 1, and Day 7 or 8 of Cycle 1; predose, 1, 2, 4, and 6 hours postdose on Day 1 of Cycle 2 or Cycle 3 (each cycle of 28 days)]
CL/F is the apparent (oral) Plasma Clearance.
Part 1: Apparent (oral) Volume of Distribution (Vd/F) of Ibrutinib [Predose, at 1, 2, 4, and 6 hours postdose on Day 1, and Day 7 or 8 of cycle 1; predose, 1, 2, 4, and 6 hours postdose on Day 1 of Cycle 2 or Cycle 3 (each cycle of 28 days)]
Vd/F is the apparent (oral) Volume of Distribution.
Part 1: Maximum Observed Plasma Concentration (Cmax) [Predose, at 1, 2, 4, and 6 hours postdose on Day 1, and Day 7 or 8 of cycle 1; predose, 1, 2, 4, and 6 hours postdose on Day 1 of Cycle 2 or Cycle 3 (each cycle of 28 days)]
Cmax is the maximum observed plasma concentration.
Part 1: Relationship Between Pharmacokinetic Parameters and Age or Measure of Body Size [up to three 28-day cycles]
The impact of age or body size on the pharmacokinetic parameters will also be investigated.
Part 2: Event-free Survival [EFS]) of Ibrutinib [Randomization to death, disease progression, or lack of CR or PR after 3 cycles of treatment (approximately 4.2 years)]
EFS is the time interval from randomization to death, disease progression, or lack of CR or PR after 3 cycles of treatment, whichever occurs first based on blinded independent event review by the Independent Review Committee (IRC).

Secondary Outcome Measures

Part 1: Number of Participants with Adverse Events [Throughout the study duration (approximately up to 4.2 years)]
Part 1: Percentage of Participants Who Achieve Complete Response (CR) and Partial Response (PR) [Approximately up to 4.2 years]
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.
Part 1: Disease-specific Biomarkers Assessment [Cycle 1: Days 1, and 7 or 8, Cycle 2: Day 1, and Cycle 3: Day 1 (each cycle of 28 days) and End of treatment visit (30 days after last dose)]
Blood samples will be taken to evaluate the levels of biomarkers such as Phospho- 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.
Part 1: Bruton's tyrosine kinase (BTK) Percent Occupancy [Predose and 4 hours postdose on Day 1, Day 7 or 8 of Cycle 1, predose on Cycle 2 Day 1 or Cycle 3 Day 1 (each cycle of 28 days), and the End-of-Treatment visit (30 days after last dose)]
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).
Part 1: Visual analog Scale Score for Palatability [Cycle 1 Day 1 and Cycle 3 Day 1 (each cycle of 28 days)]
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.
Part 2: Number of Participants with Adverse Events [Throughout the study duration (approximately up to 4.2 years)]
Part 2: Percentage of Participants Who Achieve Complete Response (CR) and Partial Response (PR) [Approximately up to 4.2 years]
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.
Part 2: Tumor Volume Reduction [Day 14]
Tumor volume reduction will be measured by decrease in the sum of the products of the lesion diameters.
Part 2: Percentage of Participants who Proceed to Stem Cell Transplantation [Cycle 2 (Day 28)]
Percentage of participants who proceeded to stem cell transplantation will be calculated.
Part 2: Time to Response [Up to 4.2 years]
The time interval from the first dose of ibrutinib to the first documented response for those participants who respond.
Part 2: Duration of Response [Up to 4.2 years]
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.
Part 2: Percentage of Participants with Long-term Survival [2, 3 years]
Participants with event-free survival (EFS) at 2 and 3 years will be assessed.
Part 2: Overall Survival [Randomization to the date of death (maximum up to 4.2 years)]
Duration from the date of randomization to the date of the subject's death.
Part 2: Disease-specific Biomarkers Assessment [Cycle 1: Days 1 and 14, Cycle 2: Day 1, Cycle 3: Day 1 (each cycle of 28 days) and End of treatment visit (30 days after last dose)]
Blood samples will be taken to evaluate the levels of biomarkers such as Phospho- 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.
Part 2: Bruton's tyrosine kinase (BTK) Percent Occupancy [Predose and 4 hours postdose on Cycle 1 Day 1, predose and 4 hours post dose on Cycle 1 Day 14 or Cycle 2 Day 1, predose on Cycle 3 Day 1 (each cycle of 28 days), and End-of-Treatment visit (30 days after last dose)]
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).
Part 2: Visual analog Scale Score for Palatability [Cycle 1 Day 1 and Cycle 3 Day 1 (each cycle of 28 days)]
Palatability of ibrutinib 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.
Part 2: Area under the plasma concentration-time curve (AUC) [Predose, 1, 2, and 4 hours postdose, either on Cycle 1 Day 14 or Cycle 2 Day 1 (each cycle of 28 days)]
AUC is the area under the plasma concentration-time curve.

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	City	State	Country
1	Los Angeles	California	United States
2	Orange	California	United States
3	Palo Alto	California	United States
4	Aurora	Colorado	United States
5	Washington	District of Columbia	United States
6	Atlanta	Georgia	United States
7	Baltimore	Maryland	United States
8	Boston	Massachusetts	United States
9	New York	New York	United States
10	Valhalla	New York	United States
11	Charlotte	North Carolina	United States
12	Cincinnati	Ohio	United States
13	Columbus	Ohio	United States
14	Philadelphia	Pennsylvania	United States
15	Dallas	Texas	United States
16	Salt Lake City	Utah	United States
17	Milwaukee	Wisconsin	United States
18	Brussel		Belgium
19	Leuven		Belgium
20	Barretos		Brazil
21	Curitiba		Brazil
22	Sao Paulo		Brazil
23	São Paulo		Brazil
24	Plovdiv		Bulgaria
25	Sofia		Bulgaria
26	Halifax	Nova Scotia	Canada
27	Toronto	Ontario	Canada
28	Brno		Czechia
29	Praha		Czechia
30	Bordeaux		France
31	Lille		France
32	Lyon		France
33	Marseille		France
34	Nantes		France
35	Toulouse		France
36	Vandoeuvre les Nancy		France
37	Villejuif		France
38	Berlin		Germany
39	Freiburg		Germany
40	Kiel		Germany
41	München		Germany
42	Münster		Germany
43	Budapest		Hungary
44	Debrecen		Hungary
45	Seoul		Korea, Republic of
46	Rotterdam		Netherlands
47	Utrecht		Netherlands
48	Krakow		Poland
49	Warszawa		Poland
50	Wroclaw		Poland
51	Bucuresti		Romania
52	Cluj-Napoca		Romania
53	Oradea		Romania
54	Timisoara		Romania
55	Ekaterinburg		Russian Federation
56	Moscow		Russian Federation
57	St. Petersburg		Russian Federation
58	Barcelona		Spain
59	Esplugues de Llobregat		Spain
60	Madrid		Spain
61	Valencia		Spain
62	Gothenburg		Sweden
63	Kaohsiung		Taiwan
64	Taipei		Taiwan
65	Taoyuan		Taiwan
66	Ankara		Turkey
67	Izmir		Turkey
68	Kiev		Ukraine
69	Birmingham		United Kingdom
70	Cambridge		United Kingdom
71	Leeds		United Kingdom
72	Liverpool		United Kingdom
73	London		United Kingdom
74	Manchester		United Kingdom
75	Newcastle		United Kingdom
76	Sheffield		United Kingdom
77	Surrey		United Kingdom