A Phase 1, Open Label, Multiple Dose, Dose Escalation and Expansion Study of Bruton Tyrosine Kinase (BTK) Inhibitor, Zanubrutinib, in Combination With Lenalidomide, With or Without Rituximab in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Zanubrutinib
- Conditions
- Relapsed/Refractory Diffuse Large B-Cell Lymphoma
- Sponsor
- BeiGene
- Enrollment
- 66
- Locations
- 10
- Primary Endpoint
- Part 1: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)
- Status
- Completed
- Last Updated
- 11 months ago
Overview
Brief Summary
The primary objective of this study is to determine the maximum tolerated doses (MTD) and the recommended Phase 2 dose (RP2D), and safety, tolerability, and efficacy of zanubrutinib in combination with lenalidomide in participants with R/R DLBCL
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed DLBCL, all participants must provide sufficient archival or fresh tumor tissue samples for evaluation by immunohistochemistry (IHC) and Gene Expression Profiling (GEP).
- •Relapsed or refractory disease, defined as either: 1) progression of disease after having achieved disease remission (complete response \[CR\] or partial response \[PR\]) , or 2) stable disease (SD), or progressive disease (PD) at completion of the treatment regimen preceding entry to the study.
- •Participants who have not received high dose therapy/stem cell transplantation (HDT/SCT) must be ineligible for HDT/SCT.
- •Measurable disease as defined by at least 1 lymph node \>1.5 cm in longest diameter, or at least 1 extra-nodal lesion \>1.0 cm in longest diameter, and measurable in 2 perpendicular dimensions.
- •Received an appropriate first-line therapy for DLBCL,defined as an anti CD20 antibody and an appropriate anthracycline-based combination therapy for at least 2 cycles, unless the patient is intolerant or had disease progression before Cycle 2..
Exclusion Criteria
- •Current or history of central nervous system (CNS) lymphoma.
- •Histologically transformed lymphoma.
- •History of allogeneic stem-cell transplantation.
- •Prior exposure to a BTK inhibitor.
- •Prior exposure to lenalidomide or thalidomide.
- •NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
Arms & Interventions
Part 1: Zanubrutinib + Lenalidomide 15 mg
Participants received zanubrutinib 160 mg orally twice a day (BID) and lenalidomide 15 mg orally once a day (QD) on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity.
Intervention: Zanubrutinib
Part 1: Zanubrutinib + Lenalidomide 15 mg
Participants received zanubrutinib 160 mg orally twice a day (BID) and lenalidomide 15 mg orally once a day (QD) on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity.
Intervention: Lenalidomide
Part 1: Zanubrutinib + Lenalidomide 20 mg
Participants received zanubrutinib 160 mg orally BID and lenalidomide 20 mg orally QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity.
Intervention: Zanubrutinib
Part 1: Zanubrutinib + Lenalidomide 20 mg
Participants received zanubrutinib 160 mg orally BID and lenalidomide 20 mg orally QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity.
Intervention: Lenalidomide
Part 1: Zanubrutinib + Lenalidomide 25 mg
Participants received zanubrutinib 160 mg orally BID and lenalidomide 25 mg orally QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity.
Intervention: Zanubrutinib
Part 1: Zanubrutinib + Lenalidomide 25 mg
Participants received zanubrutinib 160 mg orally BID and lenalidomide 25 mg orally QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity.
Intervention: Lenalidomide
Part 2: Zanubrutinib + Lenalidomide 25 mg
Participants received zanubrutinib 160 mg orally BID and lenalidomide 25 mg orally QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity.
Intervention: Zanubrutinib
Part 2: Zanubrutinib + Lenalidomide 25 mg
Participants received zanubrutinib 160 mg orally BID and lenalidomide 25 mg orally QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity.
Intervention: Lenalidomide
Outcomes
Primary Outcomes
Part 1: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)
Time Frame: From first dose of study drug to 30 days after last dose. Maximum time on treatment in Part 1 was 1260 days.
An adverse event (AE) is defined as any untoward medical occurrence in a patient temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product (zanubrutinib in combination with lenalidomide). A serious adverse event (SAE) is any untoward medical occurrence that, at any dose: * Resulted in death. * Was life threatening. * Required hospitalization or prolongation of existing hospitalization. * Resulted in disability/incapacity. * Was a congenital anomaly/birth defect. * Was considered a significant medical AE by the investigator based on medical judgement (eg, may have jeopardized the patient or may have required medical/surgical intervention to prevent one of the outcomes listed above).
Part 2: Overall Response Rate (ORR)
Time Frame: Response was assessed every 12 weeks for the first 48 weeks and every 16 weeks for the next 48 weeks and every 24 weeks thereafter; maximum time on follow-up was 24 months in Part 2 and 31 months in the RP2D group.
ORR is defined as the percentage of participants who achieved a best overall response of partial response (PR) or complete response (CR) based on the Lugano classification as assessed by the investigator. Response was evaluated using computed tomography (CT) and metabolic imaging (fluorodeoxyglucose-positron emission tomography (FDG-PET)). CR: complete metabolic (no/minimal FDG uptake and no evidence of FDG-avid disease in bone marrow) and radiologic response (target lesions regressed to ≤ 1.5 cm in longest diameter with no extra-lymphatic sites of disease, no organ enlargement and normal bone marrow morphology), no new lesions, and no bone marrow involvement confirmed by bone marrow biopsies (if bone marrow was involved at baseline). PR is partial metabolic (reduced FDG uptake from Baseline) and radiologic response (≥ 50% decrease in size of measurable nodes and extranodal sites, no increase in lesions, and spleen regressed by \> 50% in length beyond normal) and no new lesions.
Secondary Outcomes
- Part 1: Overall Response Rate (ORR)(Response was assessed every 12 weeks for the first 48 weeks and every 16 weeks for the next 48 weeks and every 24 weeks thereafter; maximum time on follow-up in Part 1 was 42 months.)
- Area Under the Plasma Concentration-time Curve From Zero to 8 Hours Postdose (AUCt) of Zanubrutinib After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Area Under the Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of Zanubrutinib After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) of Zanubrutinib After a Single Dose(Cycle 1 Day 1, 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Maximum Plasma Concentration (Cmax) of Zanubrutinib After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Time to Maximum Plasma Concentration (Tmax) of Zanubrutinib After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Time to the Last Quantifiable Concentration (Tlast) of Zanubrutinib After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Apparent Terminal Elimination Half-life (T1/2) of Zanubrutinib After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Apparent Volume (CL/F) of Zanubrutinib After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Apparent Clearance (Vz/F) of Zanubrutinib After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Part 2: Time to Response (TTR)(Response was assessed every 12 weeks for the first 48 weeks and every 16 weeks for the next 48 weeks and every 24 weeks thereafter; maximum time on follow-up was 24 months in Part 2 and 31 months in the RP2D group.)
- Accumulation Ratio of AUCt for Zanubrutinib(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Accumulation Ratio of Cmax for Zanubrutinib(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Area Under the Plasma Concentration-time Curve From Zero to 8 Hours Postdose (AUCt) of Lenalidomide After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- AUClast of Lenalidomide After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- AUCinf of Lenalidomide After a Single Dose(Cycle 1 Day 1 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Cmax of Lenalidomide After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Tmax of Lenalidomide After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Tlast of Lenalidomide After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- T1/2 of Lenalidomide After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- CL/F of Lenalidomide After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Vz/F of Lenalidomide After a Single Dose and at Steady State(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Part 2: Time to Response by Immunohistochemistry Subtypes(Response was assessed every 12 weeks for the first 48 weeks and every 16 weeks for the next 48 weeks and every 24 weeks thereafter; maximum time on follow-up was 31 months in the RP2D group.)
- Accumulation Ratio of AUCt for Lenalidomide(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Accumulation Ratio of Cmax for Lenalidomide(Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose)
- Part 1: Overall Response Rate by Immunohistochemistry Subtypes(Response was assessed every 12 weeks for the first 48 weeks and every 16 weeks for the next 48 weeks and every 24 weeks thereafter; maximum time on follow-up in Part 1 was 42 months.)
- Part 1: Overall Response Rate by Gene Expression Profiling (GEP) Subtypes(Response was assessed every 12 weeks for the first 48 weeks and every 16 weeks for the next 48 weeks and every 24 weeks thereafter; maximum time on follow-up in Part 1 was 42 months.)
- Part 2: Overall Response Rate by Immunohistochemistry Subtypes(Response was assessed every 12 weeks for the first 48 weeks and every 16 weeks for the next 48 weeks and every 24 weeks thereafter; maximum time on follow-up was 31 months in the RP2D group.)
- Part 2: Overall Response Rate by Gene Expression Profiling Subtypes(Response was assessed every 12 weeks for the first 48 weeks and every 16 weeks for the next 48 weeks and every 24 weeks thereafter; maximum time on follow-up was 31 months in the RP2D group.)
- Part 2: Complete Response Rate (CRR)(Response was assessed every 12 weeks for the first 48 weeks and every 16 weeks for the next 48 weeks and every 24 weeks thereafter; maximum time on follow-up was 24 months in Part 2 and 31 months in the RP2D group.)
- Part 2: Complete Response Rate by Immunohistochemistry Subtypes(Response was assessed every 12 weeks for the first 48 weeks and every 16 weeks for the next 48 weeks and every 24 weeks thereafter; maximum time on follow-up was 31 months in the RP2D group.)
- Part 2: Complete Response Rate by Gene Expression Profiling Subtypes(Response was assessed every 12 weeks for the first 48 weeks and every 16 weeks for the next 48 weeks and every 24 weeks thereafter; maximum time on follow-up was 31 months in the RP2D group.)
- Part 2: Duration of Response (DOR)(From first dose to the end of study; maximum time on follow-up was 24 months in Part 2 and 31 months in the RP2D group.)
- Part 2: Duration of Response by Immunohistochemistry Subtypes(From first dose to the end of study; maximum time on follow-up was 31 months in the RP2D group.)
- Part 2: Duration of Response by Gene Expression Profiling Subtypes(From first dose to the end of study; maximum time on follow-up was 31 months in the RP2D group.)
- Part 2: Progression-free Survival (PFS)(From first dose to the end of study; maximum time on follow-up was 24 months in Part 2 and 31 months in the RP2D group.)
- Part 2: Progression-Free Survival by Immunohistochemistry Subtypes(From first dose to the end of study; maximum time on follow-up was 31 months in the RP2D group.)
- Part 2: Progression-Free Survival by Gene Expression Profiling Subtypes(From first dose to the end of study; maximum time on follow-up was 31 months in the RP2D group.)
- Part 2: Time to Response by Gene Expression Profiling Subtypes(From first dose to the end of study; maximum time on follow-up was 31 months in the RP2D group.)
- Part 2: Number of Participants With Treatment-emergent Adverse Events(From first dose of study drug to 30 days after last dose. Maximum time on treatment in Part 2 was 701 days.)