Zanubrutinib, in Combination With Lenalidomide, With or Without Rituximab in Participants With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Phase 1

Completed

Conditions: Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Interventions: Drug: Zanubrutinib
Drug: Lenalidomide

Registration Number: NCT04436107

Lead Sponsor: BeiGene

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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 66

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..

Key

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 1: Zanubrutinib + Lenalidomide 15 mg	Zanubrutinib	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.
Part 1: Zanubrutinib + Lenalidomide 15 mg	Lenalidomide	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.
Part 1: Zanubrutinib + Lenalidomide 20 mg	Zanubrutinib	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.
Part 1: Zanubrutinib + Lenalidomide 20 mg	Lenalidomide	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.
Part 1: Zanubrutinib + Lenalidomide 25 mg	Zanubrutinib	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.
Part 1: Zanubrutinib + Lenalidomide 25 mg	Lenalidomide	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.
Part 2: Zanubrutinib + Lenalidomide 25 mg	Zanubrutinib	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.
Part 2: Zanubrutinib + Lenalidomide 25 mg	Lenalidomide	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.

Primary Outcome Measures

Name	Time	Method
Part 1: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)	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)	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 Outcome Measures

Name	Time	Method
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.	ORR is defined as the percentage of participants who achieved a best overall response of partial response or complete response based on the Lugano classification as assessed by the investigator. Response was evaluated using CT and metabolic imaging (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.
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation (LLOQ) was 1.00 ng/mL.
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	Blood samples to characterize the PK profile of zanubrutinib and lenalidomide when given in combination were collected after first dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 1.00 ng/mL.
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	Blood samples to characterize the PK profile of zanubrutinib and lenalidomide when given in combination were collected after first dose (Cycle 1 Day 1) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 1.00 ng/mL.
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	Blood samples to characterize the PK profile of zanubrutinib and lenalidomide when given in combination were collected after first dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 1.00 ng/mL.
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	Blood samples to characterize the PK profile of zanubrutinib and lenalidomide when given in combination were collected after first dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 1.00 ng/mL.
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	Blood samples to characterize the PK profile of zanubrutinib and lenalidomide when given in combination were collected after first dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 1.00 ng/mL.
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation (LLOQ) was 1.00 ng/mL.
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation (LLOQ) was 1.00 ng/mL.
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation (LLOQ) was 1.00 ng/mL.
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation (LLOQ) was 1.00 ng/mL. Accumulation ratio is defined as the ratio of AUCt at steady state (Day 21) to the AUCt after the first dose (Day 1).
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation (LLOQ) was 1.00 ng/mL. Accumulation ratio is defined as the ratio of Cmax at steady state (Day 21) to the Cmax after the first dose (Day 1).
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 2.00 ng/mL.
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 2.00 ng/mL.
AUCinf of Lenalidomide After a Single Dose	Cycle 1 Day 1 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 2.00 ng/mL.
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 2.00 ng/mL.
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 2.00 ng/mL.
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 2.00 ng/mL.
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 2.00 ng/mL.
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 2.00 ng/mL.
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 2.00 ng/mL.
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 2.00 ng/mL. Accumulation ratio is defined as the ratio of AUCt at steady state (Day 21) to AUCt after the first dose (Day 1).
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	Blood samples to characterize the pharmacokinetic (PK) profile of zanubrutinib and lenalidomide when given in combination were collected after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21) for participants in Part 1 and for twelve participants from the first stage of enrollment in Part 2. The lower limit of quantitation was 2.00 ng/mL. Accumulation ratio is defined as the ratio of Cmax at steady state (Day 21) to Cmax after the first dose (Day 1).
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.	ORR is defined as the percentage of participants who achieved a best overall response of PR or CR based on the Lugano classification as assessed by the investigator. Response was evaluated using CT and metabolic imaging (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. Immunohistochemistry (IHC) was used to identify germinal B-cell-like (GCB) and non-GCB phenotypes.
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.	The percentage of participants who achieved a best overall response of PR or CR based on the Lugano classification as assessed by the investigator. Response was evaluated using CT and metabolic imaging. 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: 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. Gene expression profiling by HTG EdgeSeq DLBCL cell-of-origin (COO) assay was used to determine activated B-cell like (ABC) and GCB subtypes.
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.	ORR is defined as the percentage of participants who achieved a best overall response of PR or CR based on the Lugano classification as assessed by the investigator. 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 biopsy (if bone marrow was involved at baseline). PR: 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. Immunohistochemistry was used to identify GCB and non-GCB phenotypes.
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.	ORR is defined as the percentage of participants who achieved a best overall response of PR or CR based on the Lugano classification assessed by the investigator. 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 biopsy (if bone marrow was involved at baseline). PR: 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. Gene expression profiling by HTG EdgeSeq DLBCL COO assay was used to determine ABC and GCB subtypes.
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.	CRR is defined as the percentage of participants who achieved a best overall response of complete response (CR) based on the Lugano classification as assessed by the investigator. Response was evaluated using CT and metabolic imaging (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).
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.	CRR is defined as the percentage of participants who achieved a best overall response of complete response (CR) based on the Lugano classification as assessed by the investigator. Response was evaluated using CT and metabolic imaging (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). Immunohistochemistry was used to identify GCB and non-GCB phenotypes.
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.	CRR is defined as the percentage of participants who achieved a best overall response of complete response (CR) based on the Lugano classification as assessed by the investigator. Response was evaluated using CT and metabolic imaging (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). Gene expression profiling by HTG EdgeSeq DLBCL cell-of-origin assay was used to determine ABC and GCB subtypes.
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.	DOR is defined as the time from the date that the response criteria were first met to the date that progressive disease (PD) was objectively documented or death, whichever occurred first. Median DOR was estimated using the Kaplan-Meier method. Participants who did not have disease progression were censored at their last valid assessment. PD: Progressive metabolic disease (increased FDG uptake from Baseline and/or new FDG-avid foci consistent with lymphoma), abnormal node or lesions with longest diameter \> 1.5 cm, an increase of ≥ 50% in the product of the perpendicular diameters, and an increase in the longest diameter of 0.5 cm for lesions ≤ 2 cm or 1.0 cm for lesions \> 2 cm, or any new lesions.
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.	DOR is defined as the time from the date that the response criteria were first met to the date that progressive disease PD was objectively documented or death, whichever occurred first. Median DOR was estimated using the Kaplan-Meier method. Participants who did not have disease progression were censored at their last valid assessment. Immunohistochemistry was used to identify GCB and non-GCB phenotypes.
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.	DOR is defined as the time from the date that the response criteria were first met to the date that progressive disease PD was objectively documented or death, whichever occurred first. Median DOR was estimated using the Kaplan-Meier method. Participants who did not have disease progression were censored at their last valid assessment. Gene expression profiling by HTG EdgeSeq DLBCL cell-of-origin assay was used to determine ABC and GCB subtypes.
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.	PFS is defined as the time from the starting date of the combination therapy to the date of first documentation of disease progression or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Participants who did not have disease progression were censored at their last valid tumor assessment.
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.	PFS is defined as the time from the starting date of the combination therapy to the date of first documentation of disease progression or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Participants who did not have disease progression were censored at their last valid tumor assessment. Immunohistochemistry was used to identify GCB and non-GCB phenotypes.
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.	PFS is defined as the time from the starting date of the combination therapy to the date of first documentation of disease progression or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Participants who did not have disease progression were censored at their last valid tumor assessment. Gene expression profiling by HTG EdgeSeq DLBCL cell-of-origin assay was used to determine ABC and GCB subtypes.
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.	Time to response is defined as time from the starting date of combination therapy to the date the response criteria were first met.
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.	Time to response is defined as time from the starting date of combination therapy to the date the response criteria were first met. Immunohistochemistry was used to identify GCB and non-GCB phenotypes.
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.	Time to response is defined as the time from the starting date of combination therapy to the date objective response criteria were first met. Gene expression profiling by HTG EdgeSeq DLBCL cell-of-origin assay was used to determine ABC and GCB subtypes.
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.	An 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).

Trial Locations

Locations (10): Beijing Friendship Hospital, Capital Medical University
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Beijing, Beijing, China
Sun Yat Sen University Cancer Center
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Guangzhou, Guangdong, China
Henan Cancer Hospital
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Zhengzhou, Henan, China
Union Hospital of Tongji Medical College, Huazhong University of Science and Technology
🇨🇳
Wuhan, Hubei, China
Jilin Cancer Hospital
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Changchun, Jilin, China
Fudan University Shanghai Cancer Center
🇨🇳
Shanghai, Shanghai, China
Shanghai East Hospital
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Shanghai, Shanghai, China
West China Hospital, Sichuan University
🇨🇳
Chengdu, Sichuan, China
Tianjin Medical University Cancer Institute and Hospital
🇨🇳
Tianjin, Tianjin, China
Zhejiang Cancer Hospital
🇨🇳
Hangzhou, Zhejiang, China