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

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).

Time frame: From first dose of study drug to 30 days after last dose. Maximum time on treatment in Part 1 was 1260 days.

Population: The safety analysis set was defined as all participants who received at least one dose of any medication within the combination therapy.

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.

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.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL. Participants with no post-baseline response assessments were treated as non-responders.~Overall response rate was a prespecified primary endpoint in Part 2 only; results are also presented for all participants (Part 1 + Part 2) who received the recommended phase 2 dose (RP2D) of lenalidomide (25 mg).

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).

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK.~The analysis includes participants with available AUCt data at both Day 1 and Day 21.

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).

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK. Per the prespecified analysis of zanubrutinib PK parameters, participants were analyzed in one group since there was only one dose level for zanubrutinib, regardless of dose of lenalidomide they received. The analysis includes participants with available AUCt data at both Day 1 and Day 21.

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).

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK.~The analysis includes participants with available Cmax data at both Day 1 and Day 21.

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).

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK. Per the prespecified analysis of zanubrutinib PK parameters, participants were analyzed in one group since there was only one dose level for zanubrutinib, regardless of dose of lenalidomide they received. The analysis includes participants with available Cmax data at both Day 1 and Day 21.

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.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK. Per the prespecified analysis of zanubrutinib PK parameters, participants were analyzed in one group since there was only one dose level for zanubrutinib, regardless of dose of lenalidomide they received.~The analysis includes participants with available PK parameter data at each time point.

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.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK. Per the prespecified analysis of zanubrutinib PK parameters, participants were analyzed in one group since there was only one dose level for zanubrutinib, regardless of dose of lenalidomide they received.~The analysis includes participants with available PK parameter data at each time point.

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.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK. Per the prespecified analysis of zanubrutinib PK parameters, participants were analyzed in one group since there was only one dose level for zanubrutinib, regardless of dose of lenalidomide they received.~The analysis includes participants with available PK parameter data at each time point.

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.

Time frame: Cycle 1 Day 1, 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK. Per the prespecified analysis of zanubrutinib PK parameters, participants were analyzed in one group since there was only one dose level for zanubrutinib, regardless of dose of lenalidomide they received.~The analysis includes participants with available AUCinf data.

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 frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK. Per the prespecified analysis of zanubrutinib PK parameters, participants were analyzed in one group since there was only one dose level for zanubrutinib, regardless of dose of lenalidomide they received.~The analysis includes participants with available PK parameter data at each time point.

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.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK.~The analysis includes participants with available PK parameter data at each time point.

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.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK. Per the prespecified analysis of zanubrutinib PK parameters, participants were analyzed in one group since there was only one dose level for zanubrutinib, regardless of dose of lenalidomide they received.~The analysis includes participants with available PK parameter data at each time point.

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.

Time frame: Cycle 1 Day 1 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK.~The analysis includes participants with available PK parameter data at each time point.

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.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK.~The analysis includes participants with available PK parameter data at each time point.

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.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK.~The analysis includes participants with available PK parameter data at each time point.

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.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK.~The analysis includes participants with available PK parameter data at each time point.

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 frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK. Per the prespecified analysis of zanubrutinib PK parameters, participants were analyzed in one group since there was only one dose level for zanubrutinib, regardless of dose of lenalidomide they received.~The analysis includes participants with available PK parameter data at each time point.

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.

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 in Part 1 was 42 months.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL. Participants with no post-baseline response assessments were treated as non-responders. Four participants in the Zanubrutinib + Lenalidomide 15 mg group had a missing or unclassified GEP-subtype and are not included in the analysis.

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.

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 in Part 1 was 42 months.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL. Participants with no post-baseline response assessments were treated as non-responders.

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.

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 in Part 1 was 42 months.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL. Participants with no post-baseline response assessments were treated as non-responders.

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.

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 31 months in the RP2D group.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL. Participants with no post-baseline response assessments were treated as non-responders.~CRR by GEP subtype was a prespecified secondary endpoint in Part 2 only. For Part 2 clinical outcomes analyzed by subtype, results include all participants who received the RP2D of lenalidomide (25 mg) with non-missing subtype.

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.

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 31 months in the RP2D group.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL. Participants with no post-baseline response assessments were treated as non-responders.~CRR by IHC subtype was a prespecified secondary endpoint in Part 2 only. For Part 2 clinical outcomes analyzed by subtype, results include all participants who received the RP2D of lenalidomide (25 mg) with non-missing subtype.

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).

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.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL. Participants with no post-baseline response assessments were treated as non-responders.~Complete response rate was a prespecified secondary endpoint in Part 2 only; results are also presented for all participants who received the RP2D of lenalidomide (25 mg).

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.

Time frame: From first dose to the end of study; maximum time on follow-up was 31 months in the RP2D group.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL.~DOR by GEP subtype was a prespecified secondary endpoint in Part 2 only. For Part 2 clinical outcomes analyzed by subtype, results include all participants who received the RP2D of lenalidomide (25 mg). Participants with an overall response and non-missing GEP subtype are included in the analysis.

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.

Time frame: From first dose to the end of study; maximum time on follow-up was 31 months in the RP2D group.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL.~DOR by IHC subtype was a prespecified secondary endpoint in Part 2 only. For Part 2 clinical outcomes analyzed by subtype, results include all participants who received the RP2D of lenalidomide (25 mg). Participants with an overall response and non-missing IHC subtype are included in the analysis.

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.

Time frame: 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.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL.~DOR was a prespecified secondary endpoint in Part 2 only; results are also presented for all participants who received the RP2D of lenalidomide (25 mg). Participants with an overall response are included in the analysis.

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).

Time frame: From first dose of study drug to 30 days after last dose. Maximum time on treatment in Part 2 was 701 days.

Population: The safety analysis set was defined as all participants who received at least one dose of any medication within the combination therapy.

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.

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 31 months in the RP2D group.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL. Participants with no post-baseline response assessments were treated as non-responders.~For Part 2 clinical outcomes analyzed by subtype, results include all participants who received the RP2D of lenalidomide (25 mg) with non-missing subtype (four participants had a missing GEP-subtype and are not included).

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.

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 31 months in the RP2D group.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL. Participants with no post-baseline response assessments were treated as non-responders.~For Part 2 clinical outcomes analyzed by subtype, results include all participants who received the RP2D of lenalidomide (25 mg) with non-missing subtype.

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.

Time frame: From first dose to the end of study; maximum time on follow-up was 31 months in the RP2D group.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL.~PFS by GEP subtype was a prespecified secondary endpoint in Part 2 only. For Part 2 clinical outcomes analyzed by subtype, results include all participants who received the RP2D of lenalidomide (25 mg) with non-missing subtype (four participants had a missing GEP-subtype and are not included).

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.

Time frame: From first dose to the end of study; maximum time on follow-up was 31 months in the RP2D group.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL.~PFS by IHC subtype was a prespecified secondary endpoint in Part 2 only. For Part 2 clinical outcomes analyzed by subtype, results include all participants who received the RP2D of lenalidomide (25 mg) with non-missing subtype.

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.

Time frame: 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.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL.~PFS was a prespecified secondary endpoint in Part 2 only; results are also presented for all participants who received the RP2D of lenalidomide.

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.

Time frame: From first dose to the end of study; maximum time on follow-up was 31 months in the RP2D group.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL.~TTR by GEP subtype was a prespecified secondary endpoint in Part 2 only. For Part 2 clinical outcomes analyzed by subtype, results include all participants who received the RP2D of lenalidomide (25 mg). Participants with an overall response and non-missing GEP subtype are included in the analysis.

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.

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 31 months in the RP2D group.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL.~TTR by IHC subtype was a prespecified secondary endpoint in Part 2 only. For Part 2 clinical outcomes analyzed by subtype, results include all participants who received the RP2D of lenalidomide (25 mg). Participants with an overall response and non-missing IHC subtype are included in the analysis.

Time to response is defined as time from the starting date of combination therapy to the date the response criteria were first met.

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.

Population: The efficacy analysis set was defined as all participants who were exposed to at least one dose of medication with confirmed R/R DLBCL.~TTR was a prespecified secondary endpoint in Part 2 only; results are also presented for all participants who received the RP2D of lenalidomide (25 mg). Participants with an overall response are included in the analysis.

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.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK.~The analysis includes participants with available PK parameter data at each time point.

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 frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK. Per the prespecified analysis of zanubrutinib PK parameters, participants were analyzed in one group since there was only one dose level for zanubrutinib, regardless of dose of lenalidomide they received.~The analysis includes participants with available PK parameter data at each time point.

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 frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK. Per the prespecified analysis of zanubrutinib PK parameters, participants were analyzed in one group since there was only one dose level for zanubrutinib, regardless of dose of lenalidomide they received.~The analysis includes participants with available PK parameter data at each time point.

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.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK.~The analysis includes participants with available PK parameter data at each time point.

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.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK.~The analysis includes participants with available PK parameter data at each time point.

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.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 21 at predose and 0.5, 1, 2, 3, 4, and 8 hours postdose

Population: The PK analysis set was defined as all participants who had at least one post-dose plasma concentration collected without a major protocol deviation affecting PK.~The analysis includes participants with available PK parameter data at each time point.