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
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 72
- 主要终点
- Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 30 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Ibrutinib (Drug)
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.
干预措施: Rituximab (Drug)
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.
干预措施: Ifosfamide (Drug)
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.
干预措施: Carboplatin (Drug)
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.
干预措施: Etoposide (Drug)
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.
干预措施: Vincristine (Drug)
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.
干预措施: Idarubicin (Drug)
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.
干预措施: Dexamethasone (Drug)
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.
干预措施: Ibrutinib (Drug)
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.
干预措施: Rituximab (Drug)
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.
干预措施: Ifosfamide (Drug)
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.
干预措施: Carboplatin (Drug)
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.
干预措施: Etoposide (Drug)
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.
干预措施: Vincristine (Drug)
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.
干预措施: Idarubicin (Drug)
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.
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib
时间窗: Up to Cycle 3 (each cycle of 21 or 28 days)
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.
Part 1: Relationship Between AUC and Body Size
时间窗: Up to Cycle 3 (each cycle of 28 days)
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.
Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib
时间窗: Up to Cycle 3 (each cycle of 21 or 28 days)
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.
Part 2: Event Free Survival (EFS) Between the 2 Treatment Groups
时间窗: 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)
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.
Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib
时间窗: Up to Cycle 3 (each cycle of 21 or 28 days)
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.
Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib
时间窗: Up to Cycle 3 (each cycle of 21 or 28 days)
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.
次要结局
- Part 1 and Part 2: Number of Participants With Adverse Events as Measure of Safety and Tolerability(Up to 4 year and 4 months)
- Part 1: Number of Participants With CD79B, CARD11, and MYD Mutations(Up to 4 years and 4 months)
- Part 2: Percentage of Participants With EFS at 2 Years(At 2 years)
- Part 1 and Part 2: Gene Expression Evaluated by Disease-specific Biomarkers at Baseline(Baseline)
- Part 2: Percentage of Participants Who Achieved Complete Response (CR)(Up to 4 year and 4 months)
- Part 2: Duration of Response(Up to 4 year and 4 months)
- Part 2: Number of Participants With CD79B, CARD11, and MYD Mutations(Up to 4 year and 4 months)
- Part 1: Number of Participants With c-MYC Gene Rearrangement(At baseline (Cycle 1 Day 1))
- Part 2: Number of Participants With c-MYC Gene Rearrangement(At baseline (Cycle 1 Day 1))
- Part 2: Time to Response(Up to 4 Years and 4 months)
- Part 1 and Part 2: Overall Response Rate (ORR)(Up to 4 year and 4 months)
- Part 1 and Part 2: Number of Participants With Immunoglobulin and T-cell Receptor Gene Rearrangements(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(Up to 3 months)
- Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability(Day 1 of Cycle 1 and Cycle 3)
- Part 2: Tumor Volume Reduction Rate at Day 14(At Day 14)
- Part 2: Percentage of Participants Who Achieved Partial Response (PR)(Up to 4 year and 4 months)
- Part 2: Overall Survival(Up to 4 year and 4 months)
- Part 2: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib(Up to Cycle 3 (each cycle of 21 or 28 days))
- Part 2: Relationship Between AUC and Body Size(Up to Cycle 3 (each cycle of 28 days))
- Part 2: Number of Participants Who Proceeded to Stem Cell Transplantation(Up to end of the study (Up to 4 year and 4 months))
- Part 2: Percentage of Participants With EFS at 3 Years(At 3 years)
- Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib(Up to Cycle 3 (each cycle of 21 or 28 days))
- Part 2: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib(Up to Cycle 3 (each cycle of 21 or 28 days))
- Part 2: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib(Up to Cycle 3 (each cycle of 21 or 28 days))