Methods of using anti-CD79B immunoconjugates to treat diffuse large B-cell lymphoma - Patents.com

Abstract

Methods are provided for treating B cell proliferative disorders (such as diffuse large B cell lymphoma "DLBCL") using immunoconjugates comprising anti-CD79b antibodies in combination with anti-CD20 antibodies, chemotherapy and corticosteroids.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 282,002, filed November 22, 2021, U.S. Provisional Patent Application No. 63 / 230,735, filed August 7, 2021, and U.S. Provisional Patent Application No. 63 / 230,725, filed August 7, 2021, each of which is incorporated by reference herein in its entirety.

[0002] Electronic Sequence Listing Reference The contents of the electronic sequence listing (146392054640 SEQLIST.xml; size: 75,734 bytes; created: August 4, 2022) are incorporated herein by reference in their entirety.

[0003] FIELD OF THE INVENTION The present disclosure relates to methods of treating B-cell proliferative disorders, such as diffuse large B-cell lymphoma (DLBCL), by administering an immunoconjugate comprising an anti-CD79b antibody in combination with an anti-CD20 antibody, one or more chemotherapeutic agents, and a corticosteroid. [Background technology]

[0004] Background of the Invention Non-Hodgkin's lymphoma (NHL) is the most common hematologic malignancy worldwide and the 13th most common cancer overall (Bray et al., (2018) CA Cancer J Clin, 68:394-424). Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of NHL, accounting for approximately 32.5% of all NHL cases. Patients with DLBCL present with a rapidly expanding mass, often accompanied by local and systemic symptoms of fever, recurrent night sweats, and / or weight loss. Approximately 45% to 60% of patients present with advanced-stage disease (Ann Arbor stage III or IV). The incidence of DLBCL increases with age, with the median age at onset being 64 years (Armitage and Weisenburger, J Clin Oncol (1998) 6:2780-95). If left untreated, patients with DLBCL have a median survival of approximately 6 months.

[0005] Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was established as the standard of care (SoC) therapy for DLBCL over 20 years ago. Approaches to improve the current SoC therapy for DLBCL have met with little success. This includes attempts to maximize the dose density of R-CHOP (Cunningham et al., Lancet (2013) 381:1817-26; Delarue et al., Lancet Oncol (2013) 14:525-33), as well as experimental treatments such as those tested in large studies in DLBCL, including BO 21005 / GOYA (Vitolo et al., Blood (2016) 128:470), DA-EPOCH-R (Wilson et al., Blood (2016) 128:469), and REMARC (Thieblemont et al., Blood (2016) 128:471). Overall, since R-CHOP was established as a SoC therapy for DLBCL, 11 randomized phase III trials have not shown any benefit in first-line DLBCL compared with R-CHOP.

[0006] For patients not cured by previously untreated DLBCL treatment, high-dose chemotherapy followed by autologous stem cell transplantation offers a second chance for cure. However, approximately half of these patients do not respond to subsequent therapy due to refractory disease (Gisselbrecht et al., J Clin Oncol (2010) 28:4184-90), and a significant number are ineligible for this aggressive treatment due to age or comorbidities. Patients who relapse after stem cell transplantation or are ineligible for stem cell transplantation due to refractory disease or frailty have poor outcomes. Response to subsequent therapy is mostly in the 10%-35% range (Seyfarth et al., Br J Haematol (2006) 133(1):3-18), with only occasional durable responses. The fact that most patients not cured by standard frontline R-CHOP or equivalent chemoimmunotherapy treatment die of lymphoma highlights the need for novel approaches in frontline treatment of this aggressive disease.

[0007] Therefore, there is a need in the art for new therapeutic approaches in patients with DLBCL, such as previously untreated DLBCL.

[0008] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety. Summary of the Invention

[0009] In some embodiments, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need of such treatment comprises administering to the human patient (a) a compound of the formula: TIFF2024530189000002.tif22170, wherein Ab is an anti-CD79b antibody comprising (i) a hypervariable region H1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and p is between 1 and 8. (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients results in improved progression-free survival (PFS) for the plurality of human patients as compared to a reference PFS, wherein the reference PFS is the PFS of the plurality of human patients who received a control treatment comprising (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone, in the absence of the immunoconjugate. In some embodiments, PFS or baseline PFS is measured from (a) the start of the corresponding treatment to the first occurrence of disease progression, recurrence, or death; or (b) up to 7 days before the start of the corresponding treatment to the first occurrence of disease progression, recurrence, or death; or (c) from the time of randomization to the first occurrence of disease progression, recurrence, or death. In some embodiments, PFS or baseline PFS is the median PFS of multiple human patients receiving the corresponding treatment. In some embodiments, the improvement in PFS is statistically significant. In some embodiments, the improvement in PFS is statistically significant at a hazard ratio of 0.75 or less (95% confidence interval: 0.57, 0.97). In some embodiments, the improvement in PFS is statistically significant at a hazard ratio of 0.78 or less (95% confidence interval: 0.60, 1.00). In some embodiments, the improvement in PFS is statistically significant at a hazard ratio of 0.79 or less (95% confidence interval: 0.61, 1.02).

[0010] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the method comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to the plurality of human patients results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, wherein the reference PFS is the PFS of the plurality of human patients who received a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone, in the absence of polatuzumab vedotin.

[0011] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof comprises administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient is greater than 60 years of age, and wherein a plurality of the human patients greater than 60 years of age are administered the same or similar combination of polatuzumab vedotin and rituximab. Provided herein are methods, wherein administering such a treatment results in an improvement in progression-free survival (PFS) of a plurality of human patients as compared to a baseline PFS, where the baseline PFS is the PFS of a plurality of human patients over 60 years of age who received a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone, in the absence of polatuzumab vedotin.

[0012] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need of such treatment comprises administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient is greater than 65 years of age, and wherein a plurality of the human patients greater than 65 years of age are administered the same or similar combination of polatuzumab vedotin and rituximab. Provided herein are methods, wherein administering such a treatment results in an improvement in progression-free survival (PFS) of a plurality of human patients as compared to a baseline PFS, where the baseline PFS is the PFS of a plurality of human patients over 65 years of age who received a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone, in the absence of polatuzumab vedotin.

[0013] In certain embodiments, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need of such treatment comprises administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient has an International Prognostic Index (IPI) score between 3 and 5, and wherein the human patient has a plurality of human patients with IPI scores between 3 and 5. Provided herein are methods, wherein administering such a treatment to a human patient results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a baseline PFS, where the baseline PFS is the PFS of a plurality of human patients with an IPI score between 3 and 5 who received a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone, in the absence of polatuzumab vedotin.

[0014] In certain embodiments, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need of such treatment comprises administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient is greater than 60 years of age and has an International Prognostic Index (IPI) score between 3 and 5, and wherein the human patient is greater than 60 years of age and has an IPI score between 3 and 5. Provided herein are methods, wherein administering such treatment to a plurality of human patients results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a baseline PFS, where the baseline PFS is the PFS of a plurality of human patients with an age greater than 60 years and an IPI score between 3 and 5 who received a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone, in the absence of polatuzumab vedotin.

[0015] In certain embodiments, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need of such treatment comprises administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient is greater than 65 years of age and has an International Prognostic Index (IPI) score between 3 and 5, and wherein the human patient is greater than 65 years of age and has an IPI score between 3 and 5. Provided herein are methods, wherein administering such treatment to a plurality of human patients results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a baseline PFS, where the baseline PFS is the PFS of a plurality of human patients with an age greater than 65 years and an IPI score between 3 and 5 who received a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone, in the absence of polatuzumab vedotin.

[0016] In certain embodiments, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof comprises administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient has activated B-cell (ABC) DLBCL, and a plurality of human patients with ABC DLBCL are administered. Provided herein are methods, wherein administering such a treatment to a subject results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a baseline PFS, where the baseline PFS is the PFS of the plurality of human patients with ABC DLBCL who received a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone, in the absence of polatuzumab vedotin.

[0017] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof comprises administering to the human patient (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient has double expresser lymphoma (DEL)-type DLBCL, and a plurality of human patients with DEL-type DLBCL are administered. Provided herein are methods, wherein administering such a treatment to a patient results in an improvement in progression-free survival (PFS) of a plurality of human patients as compared to a baseline PFS, where the baseline PFS is the PFS of a plurality of human patients with DEL DLBCL who received a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone, in the absence of polatuzumab vedotin.

[0018] In some embodiments that can be combined with any of the above aspects or embodiments, the PFS or reference PFS is measured (a) from the start of the corresponding treatment to the first occurrence of disease progression, recurrence, or death; or (b) from a maximum of 7 days before the start of the corresponding treatment to the first occurrence of disease progression, recurrence, or death; or (c) from the time of randomization to the first occurrence of disease progression, recurrence, or death. In some embodiments that can be combined with any of the above aspects or embodiments, the PFS or reference PFS is the median PFS of multiple human patients receiving the corresponding treatment. In some embodiments that can be combined with any of the above aspects or embodiments, the improvement in PFS is statistically significant.

[0019] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients results in at least a 25% reduction in the risk of disease progression, recurrence, or death in the plurality of human patients when compared to a control treatment comprising (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone in the absence of polatuzumab vedotin.

[0020] In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients results in at least a 20%, 21%, 22%, 23%, or 24% reduction in the risk of disease progression, recurrence, or death in the plurality of human patients when compared to a control treatment comprising (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone in the absence of polatuzumab vedotin.

[0021] In some embodiments, the disease progression, recurrence, or death is measured from (a) the start of the corresponding treatment to the first occurrence of disease progression, recurrence, or death; or (b) up to 7 days before the start of the corresponding treatment to the first occurrence of disease progression, recurrence, or death; or (c) from the time of randomization to the first occurrence of disease progression, recurrence, or death. In some embodiments, the reduction in risk of disease progression, recurrence, or death is calculated at 12 months, 24 months, or more, measured from the following starting points: (a) the start of the corresponding treatment; or (b) up to 7 days before the start of the corresponding treatment; or (c) the time of randomization to the first occurrence of disease progression, recurrence, or death.

[0022] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients results in a stratified hazard ratio of 0.75 or less in progression-free survival (PFS) for the plurality of human patients when compared to a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone in the absence of polatuzumab vedotin.

[0023] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the method comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients results in a stratified hazard ratio of 0.78 or less in progression-free survival (PFS) for the plurality of human patients when compared to a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone in the absence of polatuzumab vedotin.

[0024] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients results in an unstratified hazard ratio of 0.79 or less for progression-free survival (PFS) for the plurality of human patients when compared to a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone in the absence of polatuzumab vedotin.

[0025] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone; wherein (i) the human patient is greater than 60 years of age, and administering such treatment to a plurality of human patients greater than 60 years of age improves progression-free survival (PFS) of the plurality of human patients compared to a control treatment. or (ii) the human patients are greater than 65 years of age, and administering such treatment to a plurality of human patients greater than 65 years of age results in a stratified hazard ratio of 0.79 or less in PFS for the plurality of human patients when compared to a control treatment, wherein the control treatment comprises, in the absence of polatuzumab vedotin, (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone.

[0026] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need of such treatment comprises administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient has an International Prognostic Index (IPI) score between 3 and 5, and Provided herein are methods, wherein administering such a treatment to a plurality of human patients having an IPI score between 5 and 5 results in a stratified hazard ratio of 0.68 or less in progression-free survival (PFS) for the plurality of human patients when compared to a control treatment comprising, in the absence of polatuzumab vedotin, (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone.

[0027] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof comprises administering to the human patient (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein (i) the human patient has activated B-cell (ABC) DLBCL and multiple myeloma with ABC DLBCL is described. or (ii) the human patient has double expressing lymphoma (DEL) subtype DLBCL, and administering such a treatment to a plurality of human patients having DEL subtype DLBCL results in a stratified hazard ratio of 0.62 or less in PFS for the plurality of human patients compared to a control treatment, wherein the control treatment is a treatment for a disease that affects the progression of the disease.

[0028] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein (i) the human patient is greater than 60 years of age, and wherein administering such treatment to a plurality of human patients greater than 60 years of age results in an unstratified hazard ratio of 0.72 or less in progression-free survival (PFS) for the plurality of human patients when compared to a control treatment, or (ii) the human patient is greater than 65 years of age, and wherein administering such treatment to a plurality of human patients greater than 65 years of age results in an unstratified hazard ratio of 0.77 or less in PFS for the plurality of human patients when compared to a control treatment, wherein the control treatment is

[0029] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein (i) the human patient is greater than 60 years of age, and wherein administering such treatment to a plurality of human patients greater than 60 years of age results in an unstratified hazard ratio of 0.76 or less in progression-free survival (PFS) for the plurality of human patients when compared to a control treatment, or (ii) the human patient is greater than 65 years of age, and wherein administering such treatment to a plurality of human patients greater than 65 years of age results in an unstratified hazard ratio of 0.78 or less in PFS for the plurality of human patients when compared to a control treatment, wherein the control treatment is

[0030] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need of such treatment comprises administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient has an International Prognostic Index (IPI) score between 3 and 5, and Provided herein are methods, wherein administering such a treatment to a plurality of human patients having an IPI score between 5 and 5 results in an unstratified hazard ratio of 0.71 or less for progression-free survival (PFS) of the plurality of human patients, in the absence of polatuzumab vedotin, when compared to a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone.

[0031] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need of such treatment comprises administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient has an International Prognostic Index (IPI) score between 3 and 5, and Provided herein are methods, wherein administering such a treatment to a plurality of human patients having an IPI score between 5 and 5 results in an unstratified hazard ratio of 0.75 or less for progression-free survival (PFS) of the plurality of human patients, in the absence of polatuzumab vedotin, when compared to a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone.

[0032] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof comprises administering to the human patient (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein (i) the human patient has activated B-cell (ABC) DLBCL and multiple myeloma with ABC DLBCL is described. Methods are provided herein, wherein (ii) administering such a treatment to a human patient results in an unstratified hazard ratio of 0.36 or less in progression-free survival (PFS) for the plurality of human patients when compared to a control treatment, or (iii) the human patient has dual expression lymphoma (DEL)-type DLBCL, and administering such a treatment to a plurality of human patients with DEL-type DLBCL results in an unstratified hazard ratio of 0.67 or less in PFS for the plurality of human patients when compared to a control treatment, wherein the control treatment is.

[0033] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof comprises administering to the human patient (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein (i) the human patient has activated B-cell (ABC) DLBCL and multiple myeloma with ABC DLBCL is described. Methods are provided herein, wherein (ii) administering such a treatment to a human patient results in an unstratified hazard ratio of 0.39 or less in progression-free survival (PFS) for a plurality of human patients when compared to a control treatment, or (iii) the human patient has dual expression lymphoma (DEL)-type DLBCL, and administering such a treatment to a plurality of human patients with DEL-type DLBCL results in an unstratified hazard ratio of 0.65 or less in PFS for a plurality of human patients when compared to a control treatment, wherein the control treatment is a

[0034] In some embodiments that may be combined with any of the preceding aspects or embodiments, PFS is measured (a) from the start of the corresponding treatment to the first occurrence of disease progression, recurrence, or death; or (b) from up to 7 days before the start of the corresponding treatment to the first occurrence of disease progression, recurrence, or death; or (c) from the time of randomization to the first occurrence of disease progression, recurrence, or death. In some embodiments that may be combined with any of the preceding aspects or embodiments, the stratified hazard ratio is stratified by: (a) geographic region selected from the group consisting of: (i) Asia, (ii) Western Europe, the United States, Canada, or Australia, and (iii) the rest of the world excluding (i)-(ii); (b) an International Prognostic Index (IPI) score of 2, or between 3 and 5; and / or (c) the presence or absence of bulky disease. In some embodiments that may be combined with any of the preceding aspects or embodiments, administration of such a treatment results in a statistically significant improvement in PFS compared to the control treatment, with a stratified hazard ratio of 0.75 or less (95% confidence interval: 0.57, 0.97). In some embodiments that may be combined with any of the preceding aspects or embodiments, administration of such a treatment results in a statistically significant improvement in PFS compared to the control treatment, with a stratified hazard ratio of 0.78 or less (95% confidence interval: 0.60, 1.00). In some embodiments that may be combined with any of the preceding aspects or embodiments, administration of such a treatment results in a statistically significant improvement in PFS compared to the control treatment, with an unstratified hazard ratio of 0.79 or less (95% confidence interval: 0.61, 1.02). In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) administering such a treatment to a plurality of human patients aged greater than 60 years results in an improvement in PFS when compared to a control treatment, wherein the stratified hazard ratio is 0.72 or less (95% confidence interval: 0.52, 0.99), or (b) administering such a treatment to a plurality of human patients aged greater than 65 years results in an improvement in PFS when compared to a control treatment, wherein the stratified hazard ratio is 0.79 or less (95% confidence interval: 0.54, 1.14).In some embodiments that may be combined with any of the preceding aspects or embodiments, administering such a treatment to a plurality of human patients with an IPI score between 3 and 5 results in an improvement in PFS compared to the control treatment with a stratified hazard ratio of 0.68 or less (95% confidence interval: 0.50, 0.94). In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) administering such a treatment to a plurality of human patients with ABC DLBCL results in an improvement in PFS compared to the control treatment with a stratified hazard ratio of 0.31 or less (95% confidence interval: 0.17, 0.56), or (b) administering such a treatment to a plurality of human patients with DEL DLBCL results in an improvement in PFS compared to the control treatment with a stratified hazard ratio of 0.62 or less (95% confidence interval: 0.40, 0.97). In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) administering such a treatment to a plurality of human patients aged greater than 60 years results in an improvement in PFS when compared to a control treatment, wherein the unstratified hazard ratio is 0.72 or less (95% confidence interval: 0.53, 0.99), or (b) administering such a treatment to a plurality of human patients aged greater than 65 years results in an improvement in PFS when compared to a control treatment, wherein the unstratified hazard ratio is 0.77 or less (95% confidence interval: 0.54, 1.10). In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) administering such a treatment to a plurality of human patients aged greater than 60 years results in an improvement in PFS when compared to a control treatment, wherein the unstratified hazard ratio is 0.76 or less (95% confidence interval: 0.56, 1.02), or (b) administering such a treatment to a plurality of human patients aged greater than 65 years results in an improvement in PFS when compared to a control treatment, wherein the unstratified hazard ratio is 0.78 or less (95% confidence interval: 0.56, 1.10).In some embodiments that may be combined with any of the preceding aspects or embodiments, administering such a treatment to a plurality of human patients with IPI scores between 3 and 5 results in improved PFS compared to the control treatment, with an unstratified hazard ratio of 0.71 or less (95% confidence interval: 0.51, 0.97). In some embodiments that may be combined with any of the preceding aspects or embodiments, administering such a treatment to a plurality of human patients with IPI scores between 3 and 5 results in improved PFS compared to the control treatment, with an unstratified hazard ratio of 0.75 or less (95% confidence interval: 0.55, 1.01). In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) administering such a treatment to a plurality of human patients with ABC DLBCL results in an improvement in PFS when compared to a control treatment, wherein the unstratified hazard ratio is 0.36 or less (95% confidence interval: 0.21, 0.62), or (b) administering such a treatment to a plurality of human patients with DEL DLBCL results in an improvement in PFS when compared to a control treatment, wherein the unstratified hazard ratio is 0.67 or less (95% confidence interval: 0.44, 1.02). In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) administering such a treatment to a plurality of human patients with ABC DLBCL results in an improvement in PFS when compared to a control treatment, wherein the unstratified hazard ratio is 0.39 or less (95% confidence interval: 0.23, 0.65), or (b) administering such a treatment to a plurality of human patients with DEL DLBCL results in an improvement in PFS when compared to a control treatment, wherein the unstratified hazard ratio is 0.65 or less (95% confidence interval: 0.43, 0.98). In some embodiments that may be combined with any of the preceding aspects or embodiments, the stratified or unstratified hazard ratio is calculated at 12 months, 24 months, or more, measured from the following starting points: (a) at the start of the corresponding treatment; or (b) up to 7 days before the start of the corresponding treatment; or (c) at 12 months, 24 months, or more, measured from the time of randomization to the first occurrence of disease progression, relapse, or death.

[0035] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the methods comprising administering to the human patient (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients results in a 24-month progression-free survival rate (PFS24) of at least 75%. In some embodiments, PFS24 is calculated at 24 months, measured from the following starting points: (a) the start of treatment; or (b) up to 7 days before the start of treatment; or (c) the time of randomization to the first occurrence of disease progression, recurrence, or death.

[0036] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof comprises administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients is Provided herein are methods for improving 24-month progression-free survival (PFS24) of a plurality of human patients compared to a PFS24 of a control treatment comprising (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone, in the absence of polatuzumab vedotin.

[0037] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of the human patients results in an improvement in PFS24 or higher by baseline. Provided herein are methods that result in at least about a 6% improvement in 24-month progression-free survival (PFS24) of a plurality of human patients compared to polatuzumab vedotin, where the reference PFS24 is the 24-month progression-free survival of a plurality of human patients who received a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone, in the absence of polatuzumab vedotin.

[0038] In some embodiments that may be combined with any of the preceding aspects or embodiments, PFS24 or baseline PFS24 is calculated at 24 months, measured from the following starting points: (a) initiation of corresponding treatment; or (b) up to 7 days before initiation of corresponding treatment; or (c) the time between randomization and the first occurrence of disease progression, recurrence, or death. In some embodiments that may be combined with any of the preceding aspects or embodiments, PFS24 or baseline PFS24 is a progression-free survival (PFS) rate calculated using the Kaplan-Meier method.

[0039] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the methods comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients results in a 12-month progression-free survival (PFS) rate of at least 83%. In some embodiments, the 12-month PFS is calculated at 12 months, measured from the following starting points: (a) the start of treatment; or (b) up to 7 days before the start of treatment; or (c) the time of randomization to the first occurrence of disease progression, recurrence, or death.

[0040] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof comprises administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients meets one or more of the criteria. Provided herein are methods that result in an improvement in a 12-month progression-free survival (PFS) rate for a plurality of human patients compared to a 2-month PFS rate, wherein the reference 12-month PFS rate is the 12-month PFS rate for a plurality of human patients that received a control treatment that included (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone, in the absence of polatuzumab vedotin.

[0041] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients results in a baseline 12-month progression-free survival. Provided herein are methods that result in at least about a 3% improvement in a 12-month progression-free survival (PFS) rate for a plurality of human patients compared to a baseline 12-month PFS rate, where the baseline 12-month PFS rate is the 12-month PFS rate for a plurality of human patients who received a control treatment comprising: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone, in the absence of polatuzumab vedotin.

[0042] In some embodiments that may be combined with any of the preceding aspects or embodiments, the 12-month PFS rate or reference 12-month PFS rate is calculated at 12 months, measured from the following starting points: (a) the start of the corresponding treatment; or (b) up to 7 days before the start of the corresponding treatment; or (c) the time between the time of randomization and the first occurrence of disease progression, recurrence, or death. In some embodiments that may be combined with any of the preceding aspects or embodiments, the 12-month PFS rate or reference 12-month PFS rate is a progression-free survival (PFS) rate calculated using the Kaplan-Meier method.

[0043] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients meets or exceeds a baseline EFS. eff Event-free survival (EFS) in multiple human patients compared with eff) and the standard EFS eff

[0043] The EFS of multiple human patients who received control treatments including (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone in the absence of polatuzumab vedotin. eff In some embodiments, the EFS eff or standard EFS eff (a) EFEFS from the start of the corresponding treatment eff (b) from the start of the corresponding treatment to the time of the first occurrence of the event; or (c) from the start of the corresponding treatment to the time of the first occurrence of the event; or (d) from the start of the corresponding treatment to the time of the first occurrence of the event. eff (c) from randomization to the time of the first occurrence of an event; or (d) from randomization to the time of EF eff In some embodiments, the EFS is measured from the time of the first occurrence of an event. eff The improvement in EFS is statistically significant. eff Improvement in EFS was measured from the start of: (a) the start of corresponding treatment; or (b) up to 7 days before the start of corresponding treatment; or (c) from the time of randomization. eff It is calculated at 12 months, 24 months or more, measured from the time of the event.

[0044] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need of such treatment comprises administering to the human patient (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients results in an improvement in event-free survival (EFS) of the plurality of human patients compared to a control treatment comprising (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone in the absence of polatuzumab vedotin. eff ) that results in a stratified hazard ratio of 0.77 or less.

[0045] In certain aspects, a method for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need of such treatment comprises administering to the human patient (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients results in an improvement in event-free survival (EFS) of the plurality of human patients compared to a control treatment comprising (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone in the absence of polatuzumab vedotin. eff ) that results in a stratified hazard ratio of 0.81 or less.

[0046] In some embodiments, EFS eff (a) EFEFS from the start of the corresponding treatment eff (b) from the start of the corresponding treatment to the time of the first occurrence of the event; or (c) from the start of the corresponding treatment to the time of the first occurrence of the event; or (d) from the start of the corresponding treatment to the time of the first occurrence of the event. eff (c) from randomization to the time of the first occurrence of an event; or (d) from randomization to the time of EF eff In some embodiments, administering such a treatment increases EFS compared to a control treatment. eff In some embodiments, administering such a treatment results in a statistically significant improvement in EFS compared to a control treatment, with a stratified hazard ratio of 0.77 or less (95% confidence interval: 0.59, 1.00). eff In some embodiments, the hazard ratio is calculated based on the EFS data from the following starting points: (a) at the start of the corresponding treatment; or (b) up to 7 days before the start of the corresponding treatment; or (c) from the time of randomization. eff It is calculated at 12 months, 24 months or more, measured from the time of the event.

[0047] In some embodiments, which may be combined with any of the preceding aspects or embodiments, EFS eff An event is (a) disease progression; (b) disease recurrence; (c) death; (d) a primary reason for efficacy that results in initiation of non-protocol-specified antilymphoma treatment (NALT) and is not disease progression or recurrence; or (e) biopsy positive for residual disease. In some embodiments that may be combined with any of the preceding aspects or embodiments, the stratified hazard ratio is stratified by: (a) geographic region selected from the group consisting of: (i) Asia, (ii) Western Europe, the United States, Canada, or Australia, and (iii) the rest of the world excluding (i)-(ii); (b) an International Prognostic Index (IPI) score of 2, or between 3 and 5; and / or (c) the presence or absence of bulky disease.

[0048] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the method comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the method results in a complete response (CR) rate of at least about 77% at end of treatment (EOT)s in a plurality of human patients, wherein the CR rate is assessed by positron emission tomography-computed tomography (PET-CT). In some embodiments, CR is assessed by an investigator or by blinded independent central review (BICR). In some embodiments, administering such a treatment to a plurality of human patients results in an improvement in CR rate of at least about 3% in the plurality of human patients as compared to the plurality of human patients who received a control treatment comprising (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone in the absence of polatuzumab vedotin.

[0049] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the method comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients results in an objective response rate (ORR) at end of treatment (EOT) of at least about 85% in the plurality of human patients, wherein the ORR is assessed by positron emission tomography-computed tomography (PET-CT).

[0050] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the method comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein administering such treatment to a plurality of human patients results in an objective response rate (ORR) at end of treatment (EOT) of at least about 84% in the plurality of human patients, wherein the ORR is assessed by positron emission tomography-computed tomography (PET-CT).

[0051] In some embodiments, the ORR is assessed by an investigator or by blinded independent central review (BICR). In some embodiments, administering such a treatment to a plurality of human patients results in an improvement in ORR rate of at least about 2% in the plurality of human patients when compared to the plurality of human patients who received a control treatment comprising (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone in the absence of polatuzumab vedotin.

[0052] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the method comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient is greater than 60 years of age.

[0053] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the method comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient is greater than 65 years of age.

[0054] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the method comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient has an International Prognostic Index (IPI) score between 3 and 5.

[0055] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the method comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient is greater than 60 years of age and has an International Prognostic Index (IPI) score between 3 and 5.

[0056] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the method comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient is greater than 65 years of age and has an International Prognostic Index (IPI) score between 3 and 5.

[0057] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the method comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient has activated B-cell (ABC) DLBCL.

[0058] In certain aspects, provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, the method comprising administering to the human patient: (a) polatuzumab vedotin, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone, wherein the human patient has double expressing lymphoma (DEL)-type DLBCL.

[0059] In some embodiments that may be combined with any of the preceding aspects or embodiments, polatuzumab vedotin is administered at a dose of about 1.8 mg / kg. In some embodiments that may be combined with any of the preceding aspects or embodiments, rituximab is administered at a dose of about 375 mg / m 2 In some embodiments that may be combined with any of the preceding aspects or embodiments, cyclophosphamide is administered at a dose of about 750 mg / m 2In some embodiments that may be combined with any of the preceding aspects or embodiments, doxorubicin is administered at a dose of about 50 mg / m 2 In some embodiments that may be combined with any of the preceding aspects or embodiments, vincristine is administered at a dose of about 1.4 mg / m 2 and up to 2 mg at each dose. In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) prednisone is administered at a dose of about 100 mg; (b) prednisolone is administered at a dose of about 100 mg; or (c) methylprednisolone is administered at a dose of about 80 mg.

[0060] In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) polatuzumab vedotin is administered to a human patient at a dose of about 1.8 mg / kg; (b) rituximab is administered to a human patient at a dose of about 375 mg / m 2 (c) cyclophosphamide is administered to a human patient at a dose of about 750 mg / m 2 (d) doxorubicin is administered to a human patient at a dose of about 50 mg / m 2 (e) prednisone is administered to a human patient at a dose of about 100 mg; prednisolone is administered to a human patient at a dose of about 100 mg; or methylprednisolone is administered to a human patient at a dose of about 80 mg.

[0061] In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) polatuzumab vedotin is administered intravenously to a human patient at a dose of about 1.8 mg / kg; (b) rituximab is administered intravenously to a human patient at a dose of about 375 mg / m 2 (c) cyclophosphamide is administered intravenously to a human patient at a dose of about 750 mg / m 2 (d) doxorubicin is administered intravenously to human patients at a dose of about 50 mg / m 2(e) prednisone is administered orally to a human patient at a dose of about 100 mg; prednisolone is administered orally to a human patient at a dose of about 100 mg; or methylprednisolone is administered intravenously to a human patient at a dose of about 80 mg.

[0062] In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) polatuzumab vedotin is administered to a human patient at a dose of about 1.0 mg / kg to about 1.8 mg / kg; (b) rituximab is administered to a human patient at a dose of about 375 mg / m 2 (c) cyclophosphamide is administered to a human patient at a dose of about 375 mg / m 2 ~about 750mg / m 2 (d) doxorubicin is administered to a human patient at a dose of about 25 mg / m 2 ~about 50mg / m 2 (e) prednisone is administered to a human patient at a dose of about 100 mg; prednisolone is administered to a human patient at a dose of about 100 mg; or methylprednisolone is administered to a human patient at a dose of about 80 mg.

[0063] In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) polatuzumab vedotin is administered intravenously to a human patient at a dose of about 1.0 mg / kg to about 1.8 mg / kg; (b) rituximab is administered intravenously to a human patient at a dose of about 375 mg / m 2 (c) cyclophosphamide is administered intravenously to a human patient at a dose of about 375 mg / m 2 ~about 750mg / m 2 (d) doxorubicin is administered intravenously to human patients at a dose of about 25 mg / m 2 ~about 50mg / m 2 (e) prednisone is administered orally to a human patient at a dose of about 100 mg; prednisolone is administered orally to a human patient at a dose of about 100 mg; or methylprednisolone is administered intravenously to a human patient at a dose of about 80 mg.

[0064] In some embodiments that may be combined with any of the preceding aspects or embodiments, polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone are administered to a human patient in each 21-day cycle. In some embodiments, polatuzumab vedotin, rituximab, cyclophosphamide, and doxorubicin are administered on day 1 of each 21-day cycle, and prednisone, prednisolone, or methylprednisolone is administered on days 1-5 of each 21-day cycle. In some embodiments, (a) polatuzumab vedotin is administered intravenously to a human patient at a dose of about 1.8 mg / kg on day 1 of each 21-day cycle; (b) rituximab is administered intravenously to a human patient at a dose of 375 mg / m on day 1 of each 21-day cycle. 2 (c) cyclophosphamide is administered intravenously to human patients at a dose of about 750 mg / m on day 1 of each 21-day cycle. 2 (d) doxorubicin is administered intravenously to human patients at a dose of about 50 mg / m on day 1 of each 21-day cycle. 2 (e) prednisone is administered orally to a human patient at a dose of about 100 mg / day on each of days 1-5 of each 21-day cycle; prednisolone is administered orally at a dose of about 100 mg / day on each of days 1-5 of each 21-day cycle; or methylprednisolone is administered intravenously at a dose of about 80 mg / day on each of days 1-5 of each 21-day cycle.

[0065] In some embodiments that may be combined with any of the preceding aspects or embodiments, polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone are administered for one, two, three, four, five, or six 21-day cycles. In some embodiments that may be combined with any of the preceding aspects or embodiments, polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone are administered for at least six 21-day cycles. In some embodiments that may be combined with any of the preceding aspects or embodiments, polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone are administered for six 21-day cycles.

[0066] In some embodiments that may be combined with any of the preceding aspects or embodiments, the control treatments rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone, or methylprednisolone are administered in 21-day cycles. In some embodiments that may be combined with any of the preceding aspects or embodiments, rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 of each 21-day cycle, and prednisone, prednisolone, or methylprednisolone is administered on days 1-5 of each 21-day cycle. In some embodiments, (a) rituximab is administered at about 375 mg / m on day 1 of each 21-day cycle. 2 (b) Cyclophosphamide is administered intravenously at a dose of approximately 750 mg / m on day 1 of each 21-day cycle. 2 (c) doxorubicin is administered intravenously at a dose of approximately 50 mg / m on day 1 of each 21-day cycle. 2 (d) vincristine is administered intravenously at a dose of approximately 1.4 mg / m on day 1 of each 21-day cycle. 2and up to 2 mg at each dose; (e) prednisone is administered orally at a dose of about 100 mg / day on each of days 1-5 of each 21-day cycle; prednisolone is administered orally at a dose of about 100 mg / day on each of days 1-5 of each 21-day cycle; or methylprednisolone is administered intravenously at a dose of about 80 mg / day on each of days 1-5 of each 21-day cycle. In some embodiments that may be combined with any of the preceding aspects or embodiments, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, prednisolone, or methylprednisolone are administered for one, two, three, four, five, or six 21-day cycles. In some embodiments that may be combined with any of the preceding aspects or embodiments, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone, or methylprednisolone are administered for at least six 21-day cycles. In some embodiments that may be combined with any of the preceding aspects or embodiments, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone, or methylprednisolone are administered for six 21-day cycles.

[0067] In some embodiments that may be combined with any of the preceding aspects or embodiments, polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone are administered to a human patient. In some embodiments that may be combined with any of the preceding aspects or embodiments, polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisolone are administered to a human patient. In some embodiments that may be combined with any of the preceding aspects or embodiments, polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisolone are administered to a human patient.

[0068] In some embodiments that may be combined with any of the preceding aspects or embodiments, polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone are administered sequentially to a human patient on day 1 of each 21-day cycle. In some embodiments, (a) prednisone, prednisolone, or methylprednisolone is administered before rituximab, which is administered before polatuzumab vedotin, which is administered before cyclophosphamide and doxorubicin, or (b) rituximab, polatuzumab vedotin, cyclophosphamide, and doxorubicin are administered in any order after administration of prednisone, prednisolone, or methylprednisolone.

[0069] In some embodiments that may be combined with any of the preceding aspects or embodiments, the method further comprises (a) administering rituximab monotherapy to the human patient during cycles 7 and 8 of a 21-day cycle following cycle 6 of the 21-day cycle, or (b) administering rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone to the human patient during cycles 7 and 8 of a 21-day cycle following cycle 6 of the 21-day cycle. In some embodiments, the rituximab monotherapy is about 375 mg / m on day 1 of each of cycles 7 and 8 of the 21-day cycle. 2 In some embodiments, the method comprises administering rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone to a human patient, wherein (a) rituximab is administered intravenously at a dose of about 375 mg / m on day 1 of each of cycles 7 and 8 of a 21-day cycle. 2 (b) cyclophosphamide is administered intravenously at a dose of about 750 mg / m on Day 1 of each of Cycles 7 and 8 of a 21-day cycle. 2(c) doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each of cycles 7 and 8 of a 21-day cycle. 2 (d) prednisone is administered orally at a dose of about 100 mg / day on each of days 1-5 of each of cycles 7 and 8 of a 21-day cycle; prednisolone is administered orally at a dose of about 100 mg / day on each of days 1-5 of each of cycles 7 and 8 of a 21-day cycle; or methylprednisolone is administered intravenously at a dose of about 80 mg / day on each of days 1-5 of cycles 7 and 8 of a 21-day cycle.

[0070] In some embodiments that may be combined with any of the preceding aspects or embodiments, the control treatments rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, prednisolone, or methylprednisolone are administered sequentially on day 1 of each 21-day cycle. In some embodiments, (a) prednisone, prednisolone, or methylprednisolone is administered before rituximab, which is administered before cyclophosphamide, doxorubicin, and vincristine, or (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered in any order after administration of prednisone, prednisolone, or methylprednisolone. In some embodiments that may be combined with any of the preceding aspects or embodiments, the control treatment further comprises (a) rituximab monotherapy during cycles 7 and 8 of a 21-day cycle following cycle 6 of the 21-day cycle; or (b) rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone, or methylprednisolone during cycles 7 and 8 of a 21-day cycle following cycle 6 of the 21-day cycle. In some embodiments, the control treatment is about 375 mg / m on day 1 of each of cycles 7 and 8 of the 21-day cycle. 2In some embodiments, the control treatment further comprises rituximab monotherapy administered intravenously at a dose of 0.05 mg / kg or more. In some embodiments, the control treatment further comprises rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone, or methylprednisolone during cycles 7 and 8 of a 21-day cycle after cycle 6 of a 21-day cycle. (a) rituximab is administered at about 375 mg / m on day 1 of each of cycles 7 and 8 of a 21-day cycle. 2 (b) cyclophosphamide is administered intravenously at a dose of about 750 mg / m on Day 1 of each of Cycles 7 and 8 of a 21-day cycle. 2 (c) doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each of cycles 7 and 8 of a 21-day cycle. 2 (d) vincristine is administered intravenously at a dose of about 1.4 mg / m on day 1 of each of cycles 7 and 8 of a 21-day cycle. 2 and up to 2 mg at each dose; (e) prednisone is administered orally at a dose of about 100 mg / day on each of days 1-5 of each of cycles 7 and 8 of a 21-day cycle; prednisolone is administered orally at a dose of about 100 mg / day on each of days 1-5 of each of cycles 7 and 8 of a 21-day cycle; or methylprednisolone is administered intravenously at a dose of about 80 mg / day on each of days 1-5 of cycles 7 and 8 of a 21-day cycle.

[0071] In some embodiments that may be combined with any of the preceding aspects or embodiments, the method further comprises administering an antihistamine, an analgesic, and / or an antipyretic to the human patient. In some embodiments that may be combined with any of the preceding aspects or embodiments, the method further comprises administering a prophylactic therapy for neutropenia to the human patient. In some embodiments, the method comprises administering granulocyte colony-stimulating factor (G-CSF) to the human patient. In some embodiments, the G-CSF is filgrastim, or lenograstim, or pegfilgrastim.

[0072] In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient has a high tumor burden. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient has at least about 25×10 9 / L. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient has bulky lymphadenopathy. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient is at risk of developing tumor lysis syndrome. In some embodiments that may be combined with any of the preceding aspects or embodiments, the method further comprises administering to the human patient a prophylactic therapy against tumor lysis syndrome. In some embodiments, the prophylactic therapy against tumor lysis syndrome comprises administering allopurinol or rasburicase to the human patient. In some embodiments, the prophylactic therapy against tumor lysis syndrome comprises a hydration regimen. In some embodiments, the hydration regimen comprises administering about 3 liters of fluid per day to the human patient starting 1-2 days before the initiation of treatment for DLBCL.

[0073] In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient had previously untreated DLBCL.

[0074] In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is CD20 positive. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is a not-of-specialty (NOS) DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is a germinal center B-cell DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is an activated B-cell (ABC) DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is a double-expressing (DEL) DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is (a) T-cell / histiocyte-rich large B-cell lymphoma; (b) Epstein-Barr virus-positive DLBCL, NOS; (c) ALK-positive large B-cell lymphoma; (d) HHV8-positive DLBCL, NOS; (e) high-grade B-cell lymphoma containing MYC, BCL2, and / or BCL6 rearrangements (double-hit lymphoma or triple-hit lymphoma); or (h) high-grade B-cell lymphoma, NOS.

[0075] In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient has an International Prognostic Index (IPI) score of between 2 and 5. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient has an IPI score of 2. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient has an IPI score of between 3 and 5.

[0076] In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient is an adult. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient has at least one two-dimensionally measurable lesion. In some embodiments, the at least one two-dimensionally measurable lesion has a size of greater than 1.5 cm in its longest dimension as measured by computed tomography (CT) or magnetic resonance imaging (MRI).

[0077] In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient does not have peripheral neuropathy greater than Grade 1 before initiation of treatment for DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient does not have demyelinating Charcot-Marie-Tooth disease before initiation of treatment for DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient does not have a history of low-grade lymphoma before initiation of treatment for DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient does not have (a) follicular lymphoma grade 3B, (b) unclassifiable B-cell lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma, (c) gray zone lymphoma, (d) primary mediastinal (thymic) large B-cell lymphoma, (e) Burkitt lymphoma, (f) central nervous system (CNS) lymphoma, primary or secondary lesions, (g) primary effusion DLBCL, or (h) primary cutaneous DLBCL prior to initiation of treatment for DLBCL.

[0078] In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient has not been previously treated for DLBCL.

[0079] In some embodiments that may be combined with any of the preceding aspects or embodiments, disease progression or recurrence is assessed using the 2014 Lugano Classification of Malignant Lymphoma and death is from any cause.

[0080] In certain aspects, provided herein are kits comprising polatuzumab vedotin for use in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone for treating a human patient having and in need of treatment for diffuse large B-cell lymphoma (DLBCL) according to any of the methods provided herein. In some embodiments, the DLBCL is previously untreated DLBCL.

[0081] In certain aspects, provided herein is polatuzumab vedotin for use in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone to treat a human patient having diffuse large B-cell lymphoma (DLBCL) and in need of treatment therefor, according to any of the methods provided herein. In some embodiments, the DLBCL is previously untreated DLBCL.

[0082] It should be understood that one, some, or all of the features of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the present invention will be apparent to those skilled in the art. These and other embodiments of the present invention are further described in the detailed description that follows. [Brief explanation of the drawings]

[0083] [Figure 1]Figure 1 is a design diagram of the study described in Example 1. DLBCL = diffuse large B-cell lymphoma; ECOG PS = Eastern Cooperative Oncology Group performance status; IPI = International Prognostic Index; Q21D = every 21 days; R = randomized; R-CHOP = rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHP = rituximab plus cyclophosphamide, doxorubicin, and prednisone.

[0084] [Figure 2] FIG. 2 is a diagram of the treatment regimen used in the study described in the Example(s).

[0085] [Figure 3] Figure 3 is a Kaplan-Meier plot of investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) population of patients described in the Example(s).

[0086] [Figure 4] Figures 4A and 4B provide a between-event summary of investigator-assessed PFS for the ITT population of patients as described in the Example(s). [Figure 5] Figures 5A and 5B provide a summary of the time to event for investigator-assessed PFS for the ITT population of patients as described in the Example(s).

[0087] [Figure 6] Figure 6 provides a forest plot of stratified hazard ratios for PFS by biomarker subgroups, as assessed by the investigator in the ITT population of patients, as described in the Example(s).

[0088] [Figure 7]Figure 7 provides a forest plot of stratified hazard ratios for PFS by baseline characteristic subgroups, as assessed by the investigator for the ITT population of patients, as described in the Example(s). [Figure 8] Figure 8 provides a forest plot of stratified hazard ratios for PFS by baseline characteristic subgroups, as assessed by the investigator for the ITT population of patients, as described in the Example(s).

[0089] [Figure 9] Figures 9A and 9B provide an overview of the overall AE profile in the safety-evaluable patient population described in the Example(s).

[0090] [Figure 10] Figures 10A and 10B provide forest plots of unstratified hazard ratios for PFS by baseline characteristic subgroups, as assessed by the investigator for the ITT population of patients, as described in the Example(s).

[0091] [Figure 11] Figure 11 provides a forest plot of unstratified hazard ratios for PFS by biomarker subgroups, as assessed by the investigator in the ITT population of patients, as described in the Example(s).

[0092] [Figure 12]Figures 12A-12E provide a summary of the demographics and baseline characteristics of patients in the ITT population as described in the Example(s). Figure 12A provides the age, sex, and race of patients in the ITT population. Figure 12B provides the ethnicity, baseline weight, baseline height, baseline Eastern Cooperative Oncology Group (ECOG) status, and Ann Arbor severity score of patients in the ITT population. Figure 12C provides the stratified International Prognostic Index (IPI) score, screening IPI score, stratified bulk status, baseline bulk status, and stratified geographic region of patients in the ITT population. Figure 12D provides the baseline lactate dehydrogenase (LDH) status, bone marrow involvement status at diagnosis, number of extranodal sites, time from diagnosis to administration of study treatment, and non-Hodgkin's lymphoma (NHL) histological diagnosis of patients in the ITT population. Figure 12E provides the cell of origin (COO), double expression lymphoma status (by immunohistochemistry [IHC]), and double / triple hit (DH / TH) lymphoma status of patients in the ITT population.

[0093] [Figure 13] Figure 13 provides a summary of best overall response (BOR) assessed by the investigator (INV) in the intention-to-treat (ITT) population of patients, as described in the Example(s). Stratification factors included International Prognostic Index (IPI) score, bulky disease status, and geographic region. 95% confidence intervals (CIs) for rates were constructed using the Clopper-Pearson method. 95% CIs for differences in response rates were constructed using the Wilson method.

[0094] [Figure 14]Figures 14A-14C provide time-to-event summaries of disease-free survival (DFS; assessed by INV) for best overall response (BOR) complete responders in the intention-to-treat (ITT) population of patients as described in the Example(s). Figure 14A provides the percent of patients with or without a DFS event, the time to event (in months), and stratified and unstratified hazard ratios. Figures 14B-14C provide the number of patients remaining at risk, event-free rates and 95% confidence intervals (CIs), and differences in event-free rates and 95% CIs at 6-, 12-, 18-, and 24-month durations (Figure 14B) and 30- and 36-month durations (Figure 14C). In Figures 14A-14C, DFS summaries by INV (median, percentile) are Kaplan-Meier estimates. The 95% CIs for the medians were calculated using the method of Brookmeyer and Crowley. Hazard ratios were estimated by Cox regression. Stratification factors were geographic region, International Prognostic Index (IPI) score, and bulky disease (defined as a single lesion ≥7.5 cm). Asterisks (*) indicate censoring.

[0095] [Figure 15]Figures 15A-15C provide time-to-event summaries for duration of response (DOR; assessed by INV) for best overall response (BOR) complete responders in the intention-to-treat (ITT) population of patients as described in the Example(s). Figure 15A provides the percent of patients with or without a DOR event, the time to event (in months), and stratified and unstratified hazard ratios. Figures 15B-15C provide the number of patients remaining at risk, event-free rates and 95% confidence intervals (CIs), and differences in event-free rates and 95% CIs at 6-, 12-, 18-, and 24-month durations (Figure 15B) and 30- and 36-month durations (Figure 15C). In Figures 15A-15C, the DOR summaries by INV (median, percentiles) are Kaplan-Meier estimates. The 95% CIs for the medians were calculated using the method of Brookmeyer and Crowley. Hazard ratios were estimated by Cox regression. Stratification factors were geographic region, International Prognostic Index (IPI) score, and bulky disease (defined as a single lesion ≥7.5 cm). Asterisks (*) indicate censoring.

[0096] [Figure 16]Figures 16A-16C provide time-to-event summaries for overall survival (OS) in the intention-to-treat (ITT) population of patients as described in the Example(s). Figure 16A provides the percentage of patients with and without an OS event, the time to event (in months), and stratified and unstratified p-values ​​and hazard ratios. Figures 16B-16C provide the number of patients remaining at risk, event-free rates and 95% CIs, and differences in event-free rates and 95% CIs at 6-, 12-, 18-, and 24-month durations (Figure 16B) and 30- and 36-month durations (Figure 16C). In Figures 16A-16C, OS (median, percentile) summaries are Kaplan-Meier estimates. The 95% CIs for the medians were calculated using the method of Brookmeyer and Crowley. Hazard ratios were estimated by Cox regression. Stratification factors were geographic region, International Prognostic Index (IPI) score, and bulky disease (defined as a single lesion ≥7.5 cm). An asterisk (*) indicates censoring.

[0097] [Figure 17] Figure 17 provides a forest plot of unstratified hazard ratios for PFS by biomarker subgroups, as assessed by the investigator in the intent-to-treat (ITT) population of patients, as described in the Example(s).

[0098] [Figure 18] Figures 18A and 18B provide forest plots of unstratified hazard ratios for PFS by baseline characteristic subgroups, as assessed by the investigator in the intent-to-treat (ITT) population of patients, as described in the Example(s).

[0099] [Figure 19] FIG. 19 is a Kaplan-Meier plot of investigator-assessed event-free survival (EFS) in the intent-to-treat (ITT) population of patients described in the example(s).

[0100] [Figure 20] FIG. 20 is a Kaplan-Meier plot of investigator-assessed overall survival (OS) in the intent-to-treat (ITT) population of patients described in the example(s).

[0101] [Figure 21] Figure 21 is a Kaplan-Meier plot of investigator-assessed progression-free survival (PFS) in the intent-to-treat (ITT) population of patients described in the example(s).

[0102] [Figure 22] Figures 22A and 22B provide a summary of time to event for investigator-assessed event-free survival (EFS) in the intent-to-treat (ITT) population of patients, as described in the Example(s).

[0103] [Figure 23] 23A-23B provide a summary of time to event for overall survival (OS) in the intent-to-treat (ITT) population of patients as described in the Example(s).

[0104] [Figure 24] Figures 24A and 24B provide a summary of time to event for investigator-assessed progression-free survival (PFS) in the intent-to-treat (ITT) population of patients, as described in the Example(s).

[0105] [Figure 25] Figure 25 provides a summary of the best overall response (BOR) assessed by the investigator (INV) in the intention-to-treat (ITT) population of patients, as described in the Example(s).

[0106] [Figure 26]Figures 26A and 26B provide a summary of time to event for investigator-assessed disease-free survival (DFS) for BOR complete responders in the intent-to-treat (ITT) population of patients as described in the Example(s).

[0107] [Figure 27] Figures 27A and 27B provide a summary of time to event for investigator-assessed duration of response (DOR) for BOR responders in the intent-to-treat (ITT) population of patients as described in the Example(s).

[0108] [Figure 28] FIG. 28 provides a summary of novel anti-lymphoma therapies (NALT) administered to the intent-to-treat (ITT) population of patients described in the Example(s).

[0109] [Figure 29] FIG. 29 provides a summary of the overall adverse event (AE) profile in the safety-evaluable patient population described in the Example(s).

[0110] [Figure 30] Figure 30 provides a summary of peripheral neuropathy, AEs of particular interest (AEPIs), in the safety-evaluable patient population described in the Examples. DETAILED DESCRIPTION OF THE INVENTION

[0111] As used herein, the term "polatuzumab vedotin" refers to an anti-CD79b immunoconjugate having IUPHAR / BPS number 8404, KEGG number D10761, or CAS registry number 1313206-42-6. Polatuzumab vedotin is also referred to interchangeably as "polatuzumab vedotin-piiq," "huMA79bv28-MC-vc-PAB-MMAE," "DCDS4501A," or "RG7596." The term "polatuzumab vedotin" also refers to any corresponding anti-CD79b immunoconjugate that meets the requirements necessary to obtain marketing authorization as an identical or biosimilar product in a country or region selected from the group consisting of the United States, Europe, and Japan.

[0112] Provided herein are methods for treating or delaying the progression of lymphoma (such as diffuse large B-cell lymphoma (DLBCL)) in an individual (e.g., a human patient), the methods comprising administering to the individual effective amounts of an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE (also known as polatuzumab vedotin)), an anti-CD20 agent (e.g., an anti-CD20 antibody such as obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). In some embodiments, the method comprises administering to the individual an effective amount of an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE (also known as polatuzumab vedotin)), an anti-CD20 agent (e.g., an anti-CD20 antibody such as obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). In some embodiments, the method comprises administering to the individual an anti-CD79b immunoconjugate of the formula: TIFF2024530189000003.tif22170 (wherein Ab is an anti-CD79b antibody comprising: (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and p is between 1 and 8 (e.g., between 2 and 5, or between 3 and 4). (b) an anti-CD20 antibody (e.g., obinutuzumab or rituximab), (c) one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and (d) a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). In some embodiments, the immunoconjugate is administered at a dose of between about 1.0 mg / kg and about 1.8 mg / kg (e.g., 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg). In some embodiments, the immunoconjugate is administered at a dose of about 1.8 mg / kg. In some embodiments, the anti-CD20 antibody (e.g., rituximab) is administered at a dose of about 375 mg / m 2 In some embodiments, the anti-CD20 antibody (e.g., obinutuzumab) is administered at a dose of about 1000 mg. In some embodiments, the one or more chemotherapeutic agents comprise cyclophosphamide and doxorubicin. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m 2 and approximately 750 mg / m 2 Between (e.g., 375 mg / m 2 , 563 mg / m 2 , or 750 mg / m 2 In some embodiments, cyclophosphamide is administered at a dose of about 750 mg / m 2 In some embodiments, doxorubicin is administered at a dose of about 25 mg / m 2 and approximately 50 mg / m 2 Between (e.g., 25 mg / m 2 , 37.5 mg / m 2 , or 50 mg / m 2 In some embodiments, doxorubicin is administered at a dose of about 50 mg / m 2In some embodiments, the corticosteroid is prednisone, prednisolone, or methylprednisolone. In some embodiments, the corticosteroid is prednisone administered at a dose of about 100 mg. In some embodiments, the corticosteroid is prednisolone administered at a dose of about 100 mg. In some embodiments, the corticosteroid is methylprednisolone administered intravenously at a dose of about 80 mg.

[0113] I. General Techniques The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the skill of those in the art. Such techniques are fully explained in such publications as "Molecular Cloning: A Laboratory Manual", second edition (Sambrook et al., 1989); "Oligonucleotide Synthesis" (M.J. Gait, ed., 1984); "Animal Cell Culture" (R.I. Freshney, ed., 1987); "Methods in Enzymology" (Academic Press, Inc.); "Current Protocols in Molecular Biology" (F.M. Usubel et al., eds., 1987, and periodic updates); "PCR: The Polymerase Chain Reaction" (Mullis et al., ed., 1994); "A Practical Guide to Molecular Cloning" (Perbal Bernard V., 1988); "Phage Display: A Laboratory Manual" (Barbas et al., 2001).

[0114] II. Definition Before describing the present invention in detail, it is to be understood that this invention is not limited to particular compositions or biological systems, which can, of course, vary widely. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0115] As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a molecule" includes any combination of two or more such molecules.

[0116] As used herein, the term "about" refers to a normal range of error for the respective value, which would be readily understood by one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself.

[0117] It is understood that aspects and embodiments of the invention described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0118] As used herein, the term "CD79b," unless otherwise indicated, refers to any native CD79b from any vertebrate source, including mammals such as primates (e.g., humans, cynomolgus monkeys (cyno)), and rodents (e.g., mice and rats). Human CD79b is also referred to herein as "Igβ," "B29," "DNA225786," ​​or "PRO36249." An exemplary CD79b sequence, including the signal sequence, is set forth in SEQ ID NO: 1. An exemplary CD79b sequence, excluding the signal sequence, is set forth in SEQ ID NO: 2. The term "CD79b" encompasses "full-length," unprocessed CD79b, as well as any form of CD79b resulting from processing within a cell. The term also encompasses naturally occurring variants of CD79b, such as splice variants, allelic variants, and isoforms. The CD79b polypeptides described herein can be isolated from a variety of sources, such as human tissue types or another source, or prepared by recombinant or synthetic methods. A "native sequence CD79b polypeptide" includes a polypeptide having the same amino acid sequence as a corresponding CD79b polypeptide derived from nature. Such native sequence CD79b polypeptides can be isolated from nature or can be produced by recombinant or synthetic methods. The term "native sequence CD79b polypeptide" specifically encompasses naturally occurring truncated or secreted forms of a particular CD79b polypeptide (e.g., an extracellular domain sequence), naturally occurring variant forms (e.g., alternatively spliced ​​forms), and naturally occurring allelic variants of the polypeptide.

[0119] As used herein, "CD20" refers to the human B lymphocyte antigen CD20 (also known as CD20, B lymphocyte surface antigen B1, Leu-16, Bp35, BM5, and LF5; its sequence is characterized by SwissProt database entry P11836), a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B lymphocytes and mature B lymphocytes. (Valentine,MA,et al.,J.Biol.Chem.264(19)(1989 11282-11287;Tedder,TF,et al,Proc.Natl.Acad.Sci.USA85(1988)208-12;Stamenkovic,I.,et al.,J.Exp.Med.167(1988)1975-80;Einfeld,DAet al.,EMBO J.7(1988)711-7;Tedder,TF,et al., J. Immunol. 142 (1989) 2560-8). The corresponding human gene is transmembrane 4 domain subfamily A member 1, also known as MS4A1. This gene encodes a member of the transmembrane 4A gene family. Members of this emerging protein family are characterized by common structural features and similar intron / exon splice boundaries and show unique expression patterns between hematopoietic cells and non-lymphoid tissues. This gene encodes a B lymphocyte surface molecule that plays a role in the development and differentiation of B cells into plasma cells. This family member is localized to 11q12 within a cluster of family members. Alternative splicing of this gene results in two transcript variants encoding the same protein.

[0120] The terms "CD20" and "CD20 antigen" are used interchangeably herein and include any variant, isoform, and species homolog of human CD20 naturally expressed by cells or expressed on cells transfected with the CD20 gene. Binding of the antibodies of the invention to the CD20 antigen mediates the killing of cells expressing CD20 (e.g., tumor cells) by inactivating CD20. Killing of cells expressing CD20 can occur by one or more of the following mechanisms: cell death / apoptosis induction, ADCC, and CDC. Art-recognized synonyms for CD20 include B-lymphocyte antigen CD20, B-lymphocyte surface antigen B1, Leu-16, Bp35, BM5, and LF5.

[0121] The term "CD20 antigen expression" is intended to refer to a significant level of expression of the CD20 antigen on a cell, e.g., a T cell or a B cell. In one embodiment, a patient treated according to the methods of the present invention expresses a significant level of CD20 on a B cell tumor or cancer. Patients with a "CD20-expressing cancer" can be determined by standard assays known in the art. For example, CD20 antigen expression is measured using immunohistochemistry (IHC) detection, FACS, or via PCR-based detection of the corresponding mRNA.

[0122] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by methods common in the art, including those described herein. Specific illustrative explanations and exemplary embodiments for measuring binding affinity are described below.

[0123] An "affinity matured" antibody contains one or more alterations in one or more hypervariable regions (HVRs) compared to a parent antibody that does not possess those alterations, which alterations result in an improvement in the affinity of the antibody for antigen.

[0124] The term "antibody" as used herein is used in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0125] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of the intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab'), diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments.

[0126] An "antibody that binds to the same epitope" as a reference antibody refers to an antibody that blocks the binding of the reference antibody to its antigen by 50% or more in a competition assay; conversely, the reference antibody blocks the binding of the antibody to its antigen by 50% or more in a competition assay. Exemplary competition assays are provided herein.

[0127] The term "epitope" refers to the specific site on an antigen molecule to which an antibody binds.

[0128] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0129] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, several of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0130] The terms "anti-CD79b antibody" or "antibody that binds to CD79b" refer to an antibody that can bind to CD79b with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD79b. Preferably, the binding of an anti-CD79b antibody to an unrelated, non-CD79b protein is less than about 10% of the binding of the antibody to CD79b, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the dissociation constant (Kd value) of an antibody that binds to CD79b is 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In certain embodiments, the anti-CD79b antibody binds to an epitope of CD79b that is conserved among CD79b from different species.

[0131] The term "anti-CD20 antibody" according to the present invention refers to an antibody that can bind to CD20 with sufficient affinity so that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD20. Preferably, the binding of the anti-CD20 antibody to an unrelated, non-CD20 protein is less than about 10% of the binding of the antibody to CD20 as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the dissociation constant (Kd value) of the antibody that binds to CD20 is 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In certain embodiments, the anti-CD20 antibody binds to an epitope of CD20 that is conserved among CD20 from different species.

[0132] An "isolated" antibody is one that is separated from components of its natural environment. In some embodiments, antibodies are purified to greater than 95% or 99% purity, for example, as determined by electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse-phase HPLC) methods. For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007). The "variable region" or "variable domain" of an antibody refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domain of a heavy chain may be referred to as "VH." The variable domain of a light chain may be referred to as "VL." These domains are generally the most variable parts of an antibody and contain the antigen-binding sites.

[0133] An "isolated nucleic acid encoding an anti-CD79b antibody" refers to one or more nucleic acid molecules encoding the antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present in one or more locations within a host cell.

[0134] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical and / or bind to the same epitope, except for variant antibodies containing, for example, naturally occurring mutations or mutations that arise during production of the monoclonal antibody preparation, such variants usually being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci; such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0135] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical formulation.

[0136] "Native antibodies" refer to naturally occurring immunoglobulin molecules with diverse structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (κ) or lambda (λ), based on the amino acid sequence of its constant domain.

[0137] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of the constant region. This term includes native-sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues within the Fc region or constant region is according to the EU numbering system, also referred to as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., or the EU numbering system, also referred to as the EU index, as described in the Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0138] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain typically consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences typically appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0139] For purposes herein, an "acceptor human framework" is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence, or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0140] The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a heavy chain that has a structure substantially similar to a native antibody structure or that contains an Fc region as defined herein.

[0141] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," including the primary transformed cell and its progeny regardless of the number of passages. The progeny may not be exactly identical in nucleic acid content as the parent cell and may contain mutations. As used herein, included are mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell.

[0142] A "human antibody" is an antibody having an amino acid sequence corresponding to an antibody produced by a human or human cell, or an antibody derived from a non-human source that utilizes the human antibody repertoire or other human antibody-encoding sequences. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0143] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda, MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I in Kabat et al. (supra). In one embodiment, for VH, the subgroup is subgroup III in Kabat et al. (supra).

[0144] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and human FRs. In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0145] As used herein, the term "hypervariable region" or "HVR" refers to each of the regions of an antibody variable domain that are hypervariable in sequence and / or form structurally defined loops ("hypervariable loops"). Generally, naturally occurring four-chain antibodies comprise six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). HVRs usually comprise amino acid residues from the hypervariable loops and / or from the "complementarity-determining regions" (CDRs), the latter having the highest sequence variability and / or involved in antigen recognition. Exemplary hypervariable loops occur at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). Exemplary CDRs (CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3) occur at amino acid residues 24-34 of L1, 50-56 of L2, 89-97 of L3, 31-35B of H1, 50-65 of H2, and 95-102 of H3 (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health) Health, Bethesda, MD (1991). Except for CDR1 in VH, CDRs generally comprise amino acid residues that form hypervariable loops. CDRs also comprise "specificity-determining regions," or "SDRs," which are residues that contact the antigen. SDRs are contained within regions of CDRs referred to as abbreviated CDRs, or a-CDRs. Exemplary a-CDRs (a-CDR-L1, a-CDR-L2, a-CDR-L3, a-CDR-H1, a-CDR-H2, and a-CDR-H3) are located at amino acid residues 31-34 of L1, 50-55 of L2, 89-96 of L3, 31-35B of H1, 50-58 of H2, and 95-102 of H3. (See Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)).Unless otherwise indicated, HVR residues and other residues of the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.

[0146] The term "variable region" or "variable domain" refers to the domain of an antibody heavy chain or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of a natural antibody generally have a similar structure, each containing four conserved framework regions (FR) and three hypervariable regions (HVR) (see, for example, Kindt et al., Kuby Immunology, 6 th (See, e.g., W.H. Freeman and Co., page 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Moreover, antibodies that bind to a specific antigen may be isolated by using the VH or VL domain of an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0147] "Effector functions" refer to biological activities attributable to the Fc region of an antibody and vary depending on the antibody isotype. Examples of antibody effector functions include C1q binding and complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

[0148] "Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximum alignment over the full length of the sequences being compared. However, for purposes herein, percent amino acid sequence identity values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and the source code, together with user documentation, has been filed with the U.S. Copyright Office, Washington, DC 20559, and is hereby registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California), or can be compiled from its source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0149] In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (alternatively, it may be written as a given amino acid sequence A having or comprising a particular % amino acid sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y In this case, X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A differs from the length of amino acid sequence B, the % amino acid sequence identity of A to B will differ from the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values ​​used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0150] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. This term includes vectors as autonomously replicating nucleic acid structures and vectors that integrate into the genome of a host cell into which they are introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors."

[0151] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecule(s), including, but not limited to, a cytotoxic agent.

[0152] In the context of the formulas provided herein, "p" refers to the average number of drug moieties per antibody, ranging, for example, from about 1 to about 20 drug moieties per antibody, and in certain embodiments, from 1 to about 8 drug moieties per antibody. The invention includes compositions comprising mixtures of antibody-drug compounds of Formula I having an average drug loading per antibody of from about 2 to about 5, or from about 3 to about 4 (e.g., about 3.4 or about 3.5).

[0153] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents the function of cells and / or causes cell death or destruction. Cytotoxic agents include radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, e.g., nucleases; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin (including fragments and / or variants thereof); and various anti-tumor or anti-cancer agents disclosed below.

[0154] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, B-cell lymphoma (including low-grade / follicular non-Hodgkin's lymphoma (NHL), small lymphocytic (SL) NHL, intermediate-grade / follicular NHL, intermediate-grade diffuse NHL, high-grade immunoblastic NHL, high-grade lymphoblastic NHL, high-grade small non-cleaved cell NHL, bulky disease NHL, mantle cell lymphoma, AIDS-related lymphoma, and Waldenstrom's macroglobulinemia), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, chronic myeloblastic leukemia, and post-transplant lymphoproliferative disorder (PTLD), as well as phacomatosis, edema (e.g., associated with brain tumors), and abnormal blood vessel growth associated with Meigs' syndrome.More specific examples include, but are not limited to, relapsed or refractory NHL, frontline line) low-grade NHL, stage III / IV NHL, chemotherapy-resistant NHL, precursor B-lymphoblastic leukemia and / or lymphoma, small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia and / or prolymphocytic leukemia and / or small lymphocytic lymphoma, B-cell prolymphocytic lymphoma, immunocytoma and / or lymphoplasmacytic lymphoma, lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, splenic marginal zone lymphoma, extranodal marginal zone-MALT lymphoma, nodal marginal zone lymphoma, hairy cell leukemia, plasmacytoma and / or plasma cell myeloma, low-grade / follicular lymphoma, intermediate-grade / follicular NHL, mantle cell lymphoma, follicle center lymphoma (follicular), follicular lymphoma (e.g., relapsed) relapsed / refractory follicular lymphoma), intermediate-grade diffuse NHL, diffuse large B-cell lymphoma (DLBCL: e.g., relapsed / refractory DLBCL), invasive NHL (including invasive first-line NHL and invasive relapsed NHL), NHL that relapses after or is refractory to autologous stem cell transplant, primary mediastinal large B-cell lymphoma, primary effusion lymphoma, high-grade immunoblastic NHL, high-grade lymphoblastic NHL, high-grade small non-cleaved cell NHL, bulky disease NHL, Burkitt's lymphoma, precursor (peripheral) large granular lymphocytic leukemia, mycosis fungoides and / or Sézary syndrome, cutaneous (cutaneous) lymphoma, anaplastic large cell lymphoma, angiocentric lymphoma.

[0155] An "individual" or "subject" is a mammal. Mammals include, but are not limited to, livestock animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans (e.g., human patients with DLBCL) and non-human primates, e.g., monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is human.

[0156] An "effective amount" of an agent, e.g., a pharmaceutical formulation, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic or prophylactic result.

[0157] The term "pharmaceutical formulation" refers to a preparation that is in a form that allows the biological activity of the active ingredient contained therein to be effective and that does not contain additional ingredients that have unacceptable toxicity to the subject to which the formulation is administered.

[0158] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0159] As used herein, "treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to a clinical intervention that attempts to alter the natural course of the individual being treated and can be performed prophylactically or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, reduction of free light chains, prevention of disease onset or recurrence, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, slowing of disease progression, amelioration or palliation of disease symptoms, and remission or improved prognosis. In some embodiments, the methods described herein are used to delay disease onset or slow disease progression.

[0160] The term "CD79b-positive cancer" refers to a cancer comprising cells that express CD79b on their surface. In some embodiments, cell surface expression of CD79b is determined using an antibody to CD79b, e.g., by immunohistochemistry, FACS, or the like. Alternatively, CD79b mRNA expression, which is believed to correlate with cell surface CD79b expression, can be determined by a method selected from in situ hybridization and RT-PCR (including quantitative RT-PCR).

[0161] As used herein, "in conjunction with" refers to the administration of one treatment modality in addition to another treatment modality. Thus, "in conjunction with" refers to the administration of one treatment modality before, during, or after the administration of another treatment modality to an individual.

[0162] Chemotherapeutic agents are chemical compounds useful in the treatment of cancer.

[0163] The term "package insert" is used to refer to instructions typically included in commercial packaging for a therapeutic product, and includes information regarding the indications, uses, dosage, administration, concomitant therapy, contraindications and / or warnings regarding such therapeutic product.

[0164] "Alkyl" refers to a C1-C alkyl group containing normal, secondary, tertiary or cyclic carbon atoms. 18 It is a hydrocarbon. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl ( t -Bu, t -butyl, -C(CH3)3), 1-pentyl ( n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH (CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3), C(CH3)3).

[0165] As used herein, the term "C1-C8 alkyl" refers to a straight or branched, saturated or unsaturated hydrocarbon having 1 to 8 carbon atoms. Representative "C1-C8 alkyl" groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl; branched C1-C8 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl; and unsaturated C1-C8 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl. Examples of alkyl groups include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexyl, 2-hexyl, 3-hexyl, acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, and 3-methyl-1 butynyl. The C1-C8 alkyl group can be unsubstituted or substituted with one or more groups including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S3R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2 and -CN, where each R' is independently selected from H, -C1-C8 alkyl and aryl.

[0166] As used herein, "C1-C 12 The term "alkyl" refers to a straight or branched chain, saturated or unsaturated hydrocarbon having 1 to 12 carbon atoms. 12Alkyl groups can be unsubstituted or substituted with one or more groups including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S3R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2 and -CN, where each R' is independently selected from H, -C1-C8 alkyl and aryl.

[0167] As used herein, the term "C1-C6 alkyl" refers to a straight-chain or branched, saturated or unsaturated hydrocarbon having 1 to 6 carbon atoms. Representative "C1-C6 alkyl" groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and n-hexyl; branched C1-C6 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and 2-methylbutyl; unsaturated C1-C6 alkyls include, but are not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, and -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, 1-hexyl, 2-hexyl, and 3-hexyl. The C1-C6 alkyl group may be unsubstituted or substituted with one or more groups as described above for the C1-C8 alkyl group.

[0168] As used herein, the term "C1-C4 alkyl" refers to a straight-chain or branched, saturated or unsaturated hydrocarbon having from 1 to 4 carbon atoms. Representative "C1-C4 alkyl" groups include, but are not limited to, -methyl, -ethyl, -n-propyl, and -n-butyl; branched C1-C4 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, and -tert-butyl; and unsaturated C1-C4 alkyls include, but are not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, and -isobutylenyl. C1-C4 alkyl groups can be unsubstituted or substituted with one or more groups as described above for C1-C8 alkyl groups.

[0169] An "alkoxy" is an alkyl group singly bonded to oxygen. Exemplary alkoxy groups include, but are not limited to, methoxy (-OCH3) and ethoxy (-OCH2CH3). A "C1-C5 alkoxy" is an alkoxy group having from 1 to 5 carbon atoms. An alkoxy group can be unsubstituted or substituted with one or more groups, as described above for alkyl groups.

[0170] "Alkenyl" means an alkyl group having at least one site of unsaturation, i.e., a carbon-carbon sp 2 It is a C2-C18 hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms with a double bond. Examples include, but are not limited to: ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2). "C2-C8 alkenyl" refers to an alkyl group having at least one unsaturated site, i.e., a carbon-carbon, sp 2 It is a hydrocarbon containing 2 to 8 normal, secondary, tertiary or cyclic carbon atoms with a double bond.

[0171] An "alkynyl" is a C2-C18 hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. Examples include, but are not limited to, acetylene (-C≡CH) and propargyl (-CH2C≡CH). A "C2-C8 alkynyl" is a hydrocarbon containing from 2 to 8 normal, secondary, tertiary, or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond.

[0172] "Alkylene" refers to a saturated, branched or straight-chain or cyclic hydrocarbon radical of 1 to 18 carbon atoms and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to, methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.

[0173] "C1~C 10 "Alkylene" is a group of the formula -(CH2) 1~10 - is a straight chain saturated hydrocarbon group of C1 to C 10 Examples of alkylene include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, and decalene.

[0174] "Alkenylene" refers to an unsaturated, branched or straight-chain or cyclic hydrocarbon radical of 2 to 18 carbon atoms and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH=CH-).

[0175] "Alkynylene" refers to an unsaturated, branched or straight-chain or cyclic hydrocarbon radical of 2 to 18 carbon atoms and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. Typical alkynylene radicals include, but are not limited to, acetylene (-C≡C-), propargyl (-CHC≡C-), and 4-pentynyl (-CHCHCHC≡C-).

[0176] "Aryl" refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. A carbocyclic aromatic or heterocyclic aromatic group can be unsubstituted or substituted with one or more groups including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2, and -CN, where each R' is independently selected from H, -C1-C8 alkyl, and aryl.

[0177] "C5~C 20 "Aryl" is an aryl group having 5 to 20 carbon atoms in a carbocyclic aromatic ring. C5-C 20 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. 20 The aryl group can be substituted or unsubstituted as described above for the aryl group. 14 "Aryl" is an aryl group having 5 to 14 carbon atoms in a carbocyclic aromatic ring. C5-C 14 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. 14 The aryl group can be substituted or unsubstituted as described above for aryl groups.

[0178] An "arylene" has two covalent bonds and is: TIFF2024530189000004.tif22170, wherein the phenyl group is unsubstituted or optionally substituted with up to four groups including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2, and -CN, where each R' is independently selected from H, -C1-C8 alkyl, and aryl. The aryl group may be in the ortho, meta or para configuration as shown in the structure:

[0179] "Arylalkyl" refers to an alkyl group consisting of a carbon atom, typically a terminal or sp 3 "(Aryl)" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, and 2-naphthophenylethan-1-yl. Arylalkyl groups contain 6 to 20 carbon atoms; for example, the alkyl portion of the arylalkyl group, including the alkanyl, alkenyl, or alkynyl group, is 1 to 6 carbon atoms, and the aryl portion is 5 to 14 carbon atoms.

[0180] "Heteroarylalkyl" refers to a heteroaryl group consisting of a carbon atom, typically a terminal or sp 3This refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom has been replaced with a heteroaryl radical. Typical heteroarylalkyl groups include, but are not limited to, 2-benzimidazolylmethyl and 2-furylethyl. The heteroarylalkyl group contains 6 to 20 carbon atoms; for example, the alkyl portion of the heteroarylalkyl group, including the alkanyl, alkenyl, or alkynyl group, is 1 to 6 carbon atoms, and the heteroaryl portion is 5 to 14 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. The heteroaryl portion of the heteroarylalkyl group can be a 3- to 7-membered monocyclic ring (2 to 6 carbon atoms) or a 7- to 10-membered bicyclic ring (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), e.g., a bicyclo[4,5], [5,5], [5,6], or [6,6] system.

[0181] "Substituted alkyl," "substituted aryl," and "substituted arylalkyl" refer to alkyl, aryl, and arylalkyl, respectively, in which one or more hydrogen atoms are each independently replaced with a substituent. Exemplary substituents include, but are not limited to, -X, -R, -O, - , -OR, -SR, -S - , -NR2, -NR3, =NR, -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N2, -N3, NC(=O)R, -C(=O)R, -C(=O)NR2, -SO3 - , -SO3H, -S(=O)2R, -OS(=O)2OR, -S(=O)2NR, -S(=O)R, -OP(=O)(OR)2, -P(=O)(OR)2, -PO - 3, -PO3H2, -C(=O)R, -C(=O)X, -C(=S)R, -CO2R, -CO2 - , —C(═S)OR, —C(═O)SR, —C(═S)SR, —C(═O)NR, —C(═S)NR, —C(═NR)NR, where each X is independently a halogen: F, Cl, Br, or I; each R is independently —H, C2-C 18 Alkyl, C6-C 20 Aryl, C3-C 14The alkylene, alkenylene and alkynylene groups mentioned above may also be similarly substituted.

[0182] "Heteroaryl" and "heterocycle" refer to a ring system in which one or more ring atoms is a heteroatom, such as nitrogen, oxygen, and sulfur. The heterocycle radical contains 3 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. The heterocycle can be a 3- to 7-membered monocycle (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a 7- to 10-membered bicycle (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), such as a bicyclo[4,5], [5,5], [5,6], or [6,6] system.

[0183] Heterocycles are described, for example, in Paquette, Leo A., "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), especially Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.

[0184] Examples of heterocycles include, by way of example and not limitation, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidyl, and the like. nyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuran, bis-tetrahydrofuran, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuran nyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl nyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.

[0185] By way of example and not limitation, carbon-bonded heterocycles are bonded at the 2-, 3-, 4-, 5-, or 6-position of pyridine, the 3-, 4-, 5-, or 6-position of pyridazine, the 2-, 4-, 5-, or 6-position of pyrimidine, the 2-, 3-, 5-, or 6-position of pyrazine, the 2-, 3-, 4-, or 5-position of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, the 2-, 4-, or 5-position of oxazole, imidazole, or thiazole, the 3-, 4-, or 5-position of isoxazole, pyrazole, or isothiazole, the 2- or 3-position of aziridine, the 2-, 3-, or 4-position of azetidine, the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position of quinoline, or the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position of isoquinoline. Even more typically, the carbon-linked heterocycle includes 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

[0186] By way of example and not limitation, nitrogen-linked heterocycles are linked at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, 2-position of isoindole or isoindoline, 4-position of morpholine, and 9-position of carbazole or β-carboline. Even more typically, nitrogen-linked heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0187] A "C3-C8 heterocycle" refers to an aromatic or non-aromatic C3-C8 carbocycle in which one to four ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S, and N. Representative examples of C3-C8 heterocycles include, but are not limited to, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, coumarinyl, isoquinolinyl, pyrrolyl, thiophenyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridinyl, pyridonyl, pyrazinyl, pyridazinyl, isothiazolyl, isoxazolyl, and tetrazolyl. A C3-C8 heterocycle can be unsubstituted or substituted with up to seven groups including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2 and -CN, where each R' is independently selected from H, -C1-C8 alkyl and aryl.

[0188] "C-C heterocyclo" refers to a C-C heterocyclic group, as defined above, in which one of the heterocyclic group's hydrogen atoms is replaced with a single bond. The C-C heterocyclyl may be unsubstituted or substituted with up to six groups, including, but not limited to, -C-C alkyl, -O-(C-C alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH, -C(O)NHR', -C(O)N(R')-NHC(O)R', -S(O)R', -S(O)R', -OH, -halogen, -N, -NH, -NH(R'), -N(R') and -CN, where each R' is independently selected from H, -C-C alkyl and aryl.

[0189] "C3~C 20 "Heterocycle" refers to an aromatic or non-aromatic C3-C8 carbocyclic ring in which one to four ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S, and N. 20Heterocycles can be unsubstituted or substituted with up to seven groups including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2 and -CN, where each R' is independently selected from H, -C1-C8 alkyl and aryl.

[0190] "C3~C 20 "Heterocyclo" refers to a C3-C4 heterocyclic ring, as defined above, in which one of the hydrogen atoms of the heterocyclic ring is replaced with a single bond. 20 It refers to a heterocyclic group.

[0191] "Carbocycle" refers to a saturated or unsaturated ring having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle. Monocyclic carbocycles have 3 to 6 ring atoms, and even more typically 5 or 6 ring atoms. Bicyclic carbocycles have, for example, 7 to 12 ring atoms arranged as a bicyclo[4,5], [5,5], [5,6], or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo[5,6] or [6,6] system. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cycloheptyl, and cyclooctyl.

[0192] A "C3-C8 carbocycle" is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or unsaturated non-aromatic carbocyclic ring. Representative C3-C8 carbocycles include, but are not limited to, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclopentadienyl, -cyclohexyl, -cyclohexenyl, -1,3-cyclohexadienyl, -1,4-cyclohexadienyl, -cycloheptyl, -1,3-cycloheptadienyl, -1,3,5-cycloheptatrienyl, -cyclooctyl, and -cyclooctadienyl. A C3-C8 carbocyclic group can be unsubstituted or substituted with one or more groups including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2 and -CN, where each R' is independently selected from H, -C1-C8 alkyl and aryl.

[0193] "C3-C8 carbocyclo" refers to a C3-C8 carbocyclic group, as defined above, in which one of the carbocyclic group's hydrogen atoms is replaced with a single bond.

[0194] "Linker" refers to a chemical moiety comprising a covalent bond or a chain of atoms that covalently attaches an antibody to a drug moiety. In various embodiments, the linker comprises a divalent radical such as alkyldiyl, aryldiyl, heteroaryldiyl, and the like, for example: -(CR2) n O(CR2) n -, alkyloxy (e.g., polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, Jeffamine™) repeating units; and diacid esters and amides, including succinate, succinamide, diglycolate, malonate, and caproamide. In various embodiments, the linker can include one or more amino acid residues, such as valine, phenylalanine, lysine, and homolysine.

[0195] The term "chiral" refers to molecules that have the property of not being superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0196] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0197] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high-resolution analytical procedures such as electrophoresis and chromatography.

[0198] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0199] Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994), John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l, or (+) and (-), are used to denote the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0200] A "leaving group" refers to a functional group that can be displaced by another functional group. Certain leaving groups are well known in the art, and examples include, but are not limited to, halides (e.g., chloride, bromide, iodide), methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), trifluoromethylsulfonyl (triflate), and trifluoromethylsulfonate.

[0201] The term "protecting group" refers to a substituent that is commonly used to block or protect a particular functionality while reacting with other functional groups on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality of the compound. Suitable amino-protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethylenoxycarbonyl (Fmoc). For a general description of protecting groups and their uses, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991, or subsequent editions.

[0202] III. Method Provided herein are methods of treating a B cell proliferative disorder (e.g., diffuse large B cell lymphoma (DLBCL)) in an individual (human patient) in need thereof, the method comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising an antibody that binds CD79b linked to a cytotoxic agent, and (b) at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is a chemotherapeutic agent. In some embodiments, the at least one additional therapeutic agent is a cytotoxic agent. In some embodiments, the at least one additional therapeutic agent is an anti-CD20 agent, e.g., an anti-CD20 antibody. In some embodiments, the method comprises administering to the individual an effective amount of an immunoconjugate comprising: (a) an anti-CD79b antibody linked to a cytotoxic agent (i.e., an anti-CD79b immunoconjugate), (b) an anti-CD20 antibody, (c) one or more chemotherapeutic agents, and (d) a corticosteroid.

[0203] In some embodiments, provided herein are methods of treating a B-cell proliferative disorder in an individual (human patient) in need of treatment for diffuse large B-cell lymphoma (DLBCL), the method comprising administering to the individual an effective amount of: (a) a compound of the formula: TIFF2024530189000005.tif22170 (wherein Ab is an anti-CD79b antibody comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and p is between 1 and 8) (b) an immunoconjugate comprising: (a) an anti-CD20 antibody; (b) an anti-CD20 antibody; (c) one or more chemotherapeutic agents; and (d) a corticosteroid.

[0204] In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 38. In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, p is between 2 and 7, between 2 and 6, between 2 and 5, between 3 and 5, or between 3 and 4. In some embodiments, p is 3.4. In some embodiments, p is 3.5. In some embodiments, the immunoconjugate is polatuzumab vedotin (or huMA79bv28-MC-vc-PAB-MMAE, or CAS Registry Number 1313206-42-6 (e.g., as described in U.S. Pat. No. 8,545,850, which is incorporated by reference in its entirety)).

[0205] In some embodiments, the anti-CD20 antibody is a humanized B-Ly1 antibody. In some embodiments, the humanized B-Ly1 antibody is obinutuzumab. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the anti-CD20 antibody is ofatumumab, ublituximab, and / or ibritumomab tiuxetan.

[0206] In some embodiments, the one or more chemotherapeutic agents comprise cyclophosphamide and / or doxorubicin. In some embodiments, the one or more chemotherapeutic agents comprise cyclophosphamide and doxorubicin.

[0207] In some embodiments, the corticosteroid is prednisone, prednisolone, or methylprednisolone. In some embodiments, the corticosteroid is not hydrocortisone.

[0208] In some embodiments, the therapeutic or clinical response in a human patient or patients treated according to the methods of the present disclosure is compared to a control treatment. In some embodiments, the control treatment comprises rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). In some embodiments, prednisone can be substituted with prednisolone or methylprednisolone. Thus, in some embodiments, R-CHOP refers to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; in some embodiments, R-CHOP refers to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; in some embodiments, R-CHOP refers to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; in some embodiments, R-CHOP refers to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone.

[0209] In some embodiments, administering the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin, etc.), an anti-CD20 antibody (e.g., obinutuzumab or rituximab, etc.), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) to an individual, e.g., a human patient, results in one or more of the following: (a) an improvement in progression-free survival (PFS) of a plurality of human patients compared to a reference PFS, where the reference PFS is the PFS of a plurality of human patients who received a control treatment; (b) an improvement in PFS of a plurality of human patients compared to a control treatment; (c) a hazard ratio of 0.75 (e.g., 0.74, 0.73, 0.72, 0.71, 0.70) or less in PFS for the plurality of human patients when compared to the control treatment; (d) a hazard ratio of 0.78 (e.g., 0.77, 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, 0.70) or less in PFS for the plurality of human patients when compared to the control treatment; (e) a hazard ratio of 0.79 (e.g., 0.78, 0.77, 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, 0.70) or less in PFS for the plurality of human patients when compared to the control treatment;(f) a 24-month progression-free survival (PFS24) rate of at least 75% (e.g., 76%, 77%, 78%, 79%, 80%) in a plurality of human patients; (g) an improvement in 24-month progression-free survival (PFS24) rate of at least about 70% (e.g., 76%, 77%, 78%, 79%, 80%) in a plurality of human patients; (g) an improvement in 24-month progression-free survival (PFS24) rate of at least about 6% (e.g., 7%, 8%, 9%, or 10%) in a plurality of human patients compared to a baseline PFS24, the improvement being the 24-month progression-free survival rate of a plurality of human patients receiving a control treatment; (h) an improvement in PFS24 rate of at least about 6% (e.g., 7%, 8%, 9%, or 10%) in a plurality of human patients compared to a baseline PFS24, the improvement being the 24-month progression-free survival rate of a plurality of human patients receiving a control treatment. (i) an improvement in PFS36 for a plurality of human patients of at least about 6% (e.g., 7%, 8%, 9%, or 10%) as compared to a reference PFS36, where the reference PFS36 is the 36-month progression-free survival rate for a plurality of human patients receiving the control treatment; (j) an improvement in overall survival (OS) for a plurality of human patients as compared to a reference OS, where the reference OS is the OS for a plurality of human patients receiving the control treatment; (k) an improvement in EFS for a plurality of human patients. eff Event-free survival (EFS) in multiple human patients compared with eff ) improvement of the standard EFS eff However, EFS in multiple human patients receiving control treatment eff That is, EFS eff (l) an improvement in 24-month event-free survival efficacy rate (EFS24) in a plurality of human patients compared to a reference EFS24, wherein the EFS24 is improved by at least about 5% (e.g., 6%, 7%, 8%, 9%, or 10%); (m) an improvement in EFS24 in a plurality of human patients compared to a control treatment. eff (n) EFS in multiple human patients when compared to a control treatment; eff(o) an improvement in 24-month event-free survival (EFS24) of a plurality of human patients as compared to a reference EFS24, where the reference EFS24 is the 24-month event-free survival of a plurality of human patients receiving a control treatment, and the improvement is at least about 5% (e.g., 6%, 7%, 8%, 9%, or 10%); (p) a hazard ratio of 0.81 or less (e.g., 0.80, 0.79, 0.78, 0.77, 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, 0.70) in a 24-month event-free survival (EFS24) of a plurality of human patients as compared to a reference EFS24, where the reference EFS24 is the 24-month event-free survival of a plurality of human patients receiving a control treatment, and the improvement is at least about 5% (e.g., 6%, 7%, 8%, 9%, or 10%); (q) a complete response rate (CR) at end of treatment (EOT) in a plurality of human patients of at least about 77% (e.g., 78%, 79%, or 80%), where the CR rate is assessed by positron emission tomography-computed tomography (PET-CT); (r) an EOT of at least about 85% (e.g., 86%, 87%, 88%, 89%, or 90%) in a plurality of human patients. (s) an objective response rate (ORR) of at least about 70% of human patients, wherein the ORR is assessed by PET-CT; (s) an improvement in 36-month event-free survival (EFS36) of at least about 70% of human patients, where ... reference EFS36 is the 36-month event-free survival of at least about 70% of human patients, where the improvement is at least about 6% (e.g., 6.5%, 7%, 8%, 9%, or 10%); (t) an improvement in 36-month event-free survival (EFS36) of at least about 70% of human patients, where the improvement is at least about 7% (e.g., 7.5%, 7%, 8%, 9%, or 10%); 1%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80%); (u) an improvement in 42-month event-free survival (EFS42) of a plurality of human patients as compared to a reference EFS42, where the reference EFS42 is the 42-month event-free survival of a plurality of human patients receiving a control treatment, and the improvement in EFS42 is at least about 5% (e.g., 6%, 7%, 8%, 9%, or 10%); (v) an improvement in 42-month event-free survival of a plurality of human patients of at least about 68% (e.g., 68.(w) an improvement in 42-month progression-free survival (PFS42) of a plurality of human patients of at least about 6% (e.g., 7%, 8%, 9%, or 10%) as compared to a reference PFS42, where the reference PFS42 is the 42-month progression-free survival rate of a plurality of human patients receiving a control treatment. (x) at least a 20% (e.g., 21%, 22%, 23%, or 24%) reduction in the risk of disease progression, relapse, or death in a plurality of human patients compared to a control treatment; or (y) an objective response rate (ORR) of at least about 84% (e.g., 85%, 86%, 87%, 88%, 89%, or 90%) at EOT in a plurality of human patients, wherein the ORR is assessed by PET-CT. In some embodiments, the control treatment comprises rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone, or methylprednisolone in the absence of polatuzumab vedotin (R-CHOP).

[0210] In some embodiments, administration of the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) to a human patient extends the progression-free survival (PFS) or overall survival (OS) of such patient.

[0211] Further details regarding the dosing and administration of the immunoconjugates, anti-CD20 antibodies, one or more chemotherapeutic agents and corticosteroids, treatment regimens, and response to treatment of DLBCL, e.g., progression-free survival, event-free survival, overall survival, complete response, overall response, and other therapeutic responses, are provided herein below.

[0212] A. Medication and Administration The anti-CD79b immunoconjugates and additional therapeutic agents (e.g., anti-CD20 antibodies, one or more chemotherapeutic agents, and corticosteroids) provided herein for use in any of the therapeutic methods described herein are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to medical professionals. The immunoconjugates are optionally, but need not necessarily, formulated with one or more agents currently used to prevent or treat the disorder in question. The amounts of anti-CD79b immunoconjugates and additional therapeutic agents (e.g., anti-CD20 antibodies, one or more chemotherapeutic agents, and corticosteroids) and the timing of co-administration will depend on the type (species, sex, age, weight, etc.) and condition of the patient being treated, and the severity of the disease or condition being treated. The anti-CD79b immunoconjugate and additional therapeutic agent (e.g., an anti-CD20 antibody, one or more chemotherapeutic agents, and a corticosteroid) are suitably co-administered to the patient in a single treatment or over a series of treatments, e.g., according to any of the treatment regimens described below.

[0213] In some embodiments, the dosage of the anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is between 1.0 and 1.8 mg / kg. In some embodiments of any of the methods, the dosage of the anti-CD79b immunoconjugate is about 1.0, 1.4, 1.5, 1.6, 1.7, or 1.8 mg / kg. In some embodiments, the dosage of the anti-CD79b immunoconjugate is about 1.0 mg / kg. In some embodiments, the dosage of the anti-CD79b immunoconjugate is about 1.4 mg / kg. In some embodiments, the dosage of the anti-CD79b immunoconjugate is about 1.8 mg / kg. In some embodiments of any of the methods, the anti-CD79b immunoconjugate is administered q3w (i.e., once every three weeks). In some embodiments of any of the methods, the anti-CD79b immunoconjugate is administered once every 21 days. In some embodiments, the anti-CD79b immunoconjugate is administered via intravenous infusion. In some embodiments, the dosage administered via infusion ranges from about 1 mg to about 1,500 mg per dose. Alternatively, dosage ranges are about 1 mg to about 1,500 mg, about 1 mg to about 1,000 mg, about 400 mg to about 1,200 mg, about 600 mg to about 1,000 mg, about 10 mg to about 500 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, and about 1 mg to about 200 mg. In some embodiments, the dosage administered via infusion is about 1 μg / m per dose. 2 ~Approx. 10,000μg / m 2 Alternatively, the dosage range is about 1 μg / m 2 ~Approx. 1000μg / m2, approx. 1μg / m 2 ~about 800μg / m 2 , about 1μg / m 2 ~about 600μg / m2, about 1μg / m 2 ~about 400μg / m 2 , about 10μg / m 2 ~about 500μg / m 2 , about 10μg / m 2 ~about 300μg / m 2 , about 10μg / m 2~about 200μg / m 2 , and approximately 1 μg / m 2 ~about 200μg / m 2 The dose may be administered once daily, once weekly, multiple times weekly but less than once daily, multiple times monthly but less than once daily, multiple times monthly but less than once weekly, monthly, once every 21 days, or intermittently to reduce or alleviate symptoms of the disease. In some embodiments, the dose of the immunoconjugate is 1.8 mg / kg and is administered in 21-day cycles. In some embodiments, the dose of the immunoconjugate is 1.8 mg / kg and is administered on day 1 of each 21-day cycle. Administration may continue at any of the disclosed intervals until remission of the tumor or symptoms of the B-cell proliferative disorder being treated. Administration may continue after remission or alleviation of symptoms is achieved, if such remission or alleviation is prolonged by such continued administration.

[0214] In some embodiments, the immunoconjugate is polatuzumab vedotin. In some embodiments, polatuzumab vedotin is administered at a dose of about 1.0 to 1.8 mg / kg (e.g., 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg). In some embodiments, polatuzumab vedotin is administered at a dose of about 1.0 mg / kg. In some embodiments, polatuzumab vedotin is administered at a dose of about 1.4 mg / kg. In some embodiments, polatuzumab vedotin is administered at a dose of about 1.8 mg / kg. In some embodiments, polatuzumab vedotin is administered intravenously. In some embodiments, polatuzumab vedotin is administered in a 21-day cycle. In some embodiments, polatuzumab vedotin is administered on day 1 of each 21-day cycle. In some embodiments, polatuzumab vedotin is administered in between 1 and 6 21-day cycles, for example, 1, 2, 3, 4, 5, or 6 21-day cycles. In some embodiments, polatuzumab vedotin is administered in at least 6 21-day cycles. In some embodiments, polatuzumab vedotin is administered in 6 21-day cycles. In some embodiments, polatuzumab vedotin is administered at a dose of about 1.0 to 1.8 mg / kg (e.g., 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg) on ​​day 1 of each 21-day cycle for at least 6 cycles. In some embodiments, polatuzumab vedotin is administered at a dose of about 1.0 to 1.8 mg / kg (e.g., 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg) on ​​day 1 of each of 6 21-day cycles.

[0215] In some embodiments, the dose of an anti-CD20 agent (e.g., an anti-CD20 antibody, e.g., rituximab or obinutuzumab) is between about 300 and 1600 mg / m 2 and / or between 300 and 2000 mg. In some embodiments, the dose of anti-CD20 antibody is about 300, 375, 600, 1000, or 1250 mg / m 2and / or 300, 1000, or 2000 mg. In some embodiments, the anti-CD20 antibody is rituximab and the administered dose is 375 mg / m 2 In some embodiments, the anti-CD20 antibody is obinutuzumab, and the administered dosage is 1000 mg. In some embodiments, the anti-CD20 antibody is administered q3w (i.e., every 3 weeks). In some embodiments, the anti-CD20 antibody is administered once every 21 days. In some embodiments, the dosage of the defucosylated anti-CD20 antibody (preferably, the defucosylated humanized B-Ly1 antibody) can be 800-1600 mg (in one embodiment, 800-1200 mg, e.g., 1000 mg). In some embodiments, the dose is a constant 1000 mg dose. In some embodiments, the dosage of rituximab is 375 mg / m 2 and is administered on day 1 of each 21-day cycle. In some embodiments, the anti-CD20 antibody is administered by intravenous infusion.

[0216] In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, rituximab is administered at a dose of about 375 mg / m 2In some embodiments, rituximab is administered intravenously. In some embodiments, rituximab is administered in 21-day cycles. In some embodiments, rituximab is administered on day 1 of each 21-day cycle. In some embodiments, rituximab is administered in between 1 and 8 21-day cycles, for example, 1, 2, 3, 4, 5, 6, 7, or 8 21-day cycles. In some embodiments, rituximab is administered in between 6 and 8 21-day cycles, for example, 6, 7, or 8 21-day cycles. In some embodiments, rituximab is administered in at least 6 21-day cycles. In some embodiments, rituximab is administered in 6 21-day cycles. In some embodiments, rituximab is administered in 7 21-day cycles. In some embodiments, rituximab is administered in 8 21-day cycles. In some embodiments, rituximab is administered for up to eight 21-day cycles. In some embodiments, rituximab is administered at about 375 mg / m on day 1 of each of at least six 21-day cycles. 2 In some embodiments, rituximab is administered at a dose of about 375 mg / m 2 on day 1 of each of six, seven, or eight 21-day cycles.

[0217] In some embodiments, the one or more chemotherapeutic agents include cyclophosphamide. In some embodiments, the dosage of cyclophosphamide is about 375 mg / m 2 and approximately 750 mg / m 2 Between 2 and approximately 563 mg / m 2 Between 563 mg / m 2 and approximately 750 mg / m 2 In some embodiments, the dose of cyclophosphamide is between about 375 mg / m 2 In some embodiments, the dose of cyclophosphamide is about 563 mg / m 2 In some embodiments, the dose of cyclophosphamide is about 750 mg / m 2In some embodiments, cyclophosphamide is administered q3w (i.e., every 3 weeks). In some embodiments, cyclophosphamide is administered once every 21 days. In some embodiments, cyclophosphamide is administered on day 1 of each 21-day cycle. In some embodiments, cyclophosphamide is administered by intravenous infusion. In some embodiments, cyclophosphamide is administered for between 1 and 8 21-day cycles, e.g., 1, 2, 3, 4, 5, 6, 7, or 8 21-day cycles. In some embodiments, cyclophosphamide is administered for between 6 and 8 21-day cycles, e.g., 6, 7, or 8 21-day cycles. In some embodiments, cyclophosphamide is administered for at least 6 21-day cycles. In some embodiments, cyclophosphamide is administered for 6 21-day cycles. In some embodiments, cyclophosphamide is administered for 7 21-day cycles. In some embodiments, cyclophosphamide is administered in eight 21-day cycles. In some embodiments, cyclophosphamide is administered in up to eight 21-day cycles. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m 2 and approximately 750 mg / m 2 Between (e.g., 375 mg / m 2 , 562.5 mg / m 2 , or 750 mg / m 2 ) on day 1 of each of at least six 21-day cycles. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m 2 and approximately 750 mg / m 2 Between (e.g., 375 mg / m 2 , 562.5 mg / m 2 , or 750 mg / m 2 ) administered on day 1 of six, seven, or eight 21-day cycles.

[0218] In some embodiments, the one or more chemotherapeutic agents include doxorubicin. In some embodiments, the dosage of doxorubicin is about 25 mg / m 2and approximately 50 mg / m 2 Between 2 and approximately 38 mg / m 2 Between 100 mg / m and 150 mg / m² 2 and approximately 50 mg / m 2 In some embodiments, the dose of doxorubicin is between about 25 mg / m 2 In some embodiments, the dose of doxorubicin is about 38 mg / m 2 In some embodiments, the dosage of doxorubicin is about 50 mg / m 2 In some embodiments, doxorubicin is administered q3w (i.e., every 3 weeks). In some embodiments, doxorubicin is administered once every 21 days. In some embodiments, doxorubicin is administered on day 1 of each 21-day cycle. In some embodiments, doxorubicin is administered by intravenous infusion. In some embodiments, doxorubicin is administered in between 1 and 8 21-day cycles, for example, 1, 2, 3, 4, 5, 6, 7, or 8 21-day cycles. In some embodiments, doxorubicin is administered in between 6 and 8 21-day cycles, for example, 6, 7, or 8 21-day cycles. In some embodiments, doxorubicin is administered in at least 6 21-day cycles. In some embodiments, doxorubicin is administered in 6 21-day cycles. In some embodiments, doxorubicin is administered in 7 21-day cycles. In some embodiments, doxorubicin is administered in eight 21-day cycles. In some embodiments, doxorubicin is administered in up to eight 21-day cycles. In some embodiments, doxorubicin is administered at a dose of about 25 mg / m 2 and approximately 50 mg / m 2 Between (e.g., 25 mg / m 2 , 37.5 mg / m 2 , or 50 mg / m 2 ) on day 1 of each of at least six 21-day cycles. In some embodiments, doxorubicin is administered at a dose of about 25 mg / m 2 and approximately 50 mg / m 2Between (e.g., 25 mg / m 2 , 37.5 mg / m 2 , or 50 mg / m 2 ) administered on day 1 of six, seven, or eight 21-day cycles.

[0219] In some embodiments, the corticosteroid dosage is between about 50 mg and about 100 mg, between about 50 mg and about 80 mg, or between about 80 mg and about 100 mg. In some embodiments, the corticosteroid dosage is about 50 mg. In some embodiments, the corticosteroid dosage is about 80 mg. In some embodiments, the corticosteroid dosage is about 100 mg. In some embodiments, the corticosteroid is administered in 21-day cycles. In some embodiments, the corticosteroid is administered on days 1, 2, 3, 4, and 5 of each 21-day cycle. In some embodiments, the corticosteroid is administered by intravenous infusion or orally. In some embodiments, the corticosteroid is prednisone. In some embodiments, the prednisone dosage is about 100 mg. In some embodiments, prednisone is administered at a dose of about 100 mg / day on days 1, 2, 3, 4, and 5 of each 21-day cycle. In some embodiments, prednisone is administered orally. In some embodiments, the corticosteroid is prednisolone. In some embodiments, the dosage of prednisolone is about 100 mg. In some embodiments, prednisolone is administered at a dose of about 100 mg / day on days 1, 2, 3, 4, and 5 of each 21-day cycle. In some embodiments, prednisolone is administered orally. In some embodiments, the corticosteroid is methylprednisolone. In some embodiments, the dosage of methylprednisolone is about 80 mg. In some embodiments, methylprednisolone is administered at a dose of about 80 mg / day on days 1, 2, 3, 4, and 5 of each 21-day cycle. In some embodiments, methylprednisolone is administered intravenously. In some embodiments, the corticosteroid (eg, prednisone, prednisolone, or methylprednisolone) is administered in between 1 and 8 21-day cycles, for example, any of 1, 2, 3, 4, 5, 6, 7, or 8 21-day cycles.In some embodiments, the corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) is administered for between six and eight 21-day cycles, for example, six, seven, or eight 21-day cycles. In some embodiments, the corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) is administered for at least six 21-day cycles. In some embodiments, the corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) is administered for six 21-day cycles. In some embodiments, the corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) is administered for seven 21-day cycles. In some embodiments, the corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) is administered for eight 21-day cycles. In some embodiments, prednisone is administered at a dose of about 100 mg / day on days 1, 2, 3, 4, and 5 of at least six 21-day cycles. In some embodiments, prednisone is administered at a dose of about 100 mg / day on days 1, 2, 3, 4, and 5 of six, seven, or eight 21-day cycles. In some embodiments, prednisolone is administered at a dose of about 100 mg / day on days 1, 2, 3, 4, and 5 of at least six 21-day cycles. In some embodiments, prednisolone is administered at a dose of about 100 mg / day on days 1, 2, 3, 4, and 5 of six, seven, or eight 21-day cycles. In some embodiments, methylprednisolone is administered at a dose of about 80 mg / day on days 1, 2, 3, 4, and 5 of at least six 21-day cycles. In some embodiments, methylprednisolone is administered at a dose of about 80 mg / day on days 1, 2, 3, 4, and 5 of each of six, seven, or eight 21-day cycles.

[0220] Exemplary dosing regimens for combination therapy of an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) with one or more additional therapeutic agents include an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) administered at a dose of about 1.0 to 1.8 mg / kg (e.g., 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg) once every 21 days, e.g., on day 1 of each 21-day cycle; an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) administered at a dose of about 375 mg / kg once every 21 days, e.g., on day 1 of each 21-day cycle; 2 once every 21 days, e.g., about 375 mg / m on day 1 of each 21-day cycle 2 and approximately 750 mg / m 2 Between (e.g., 375 mg / m 2 , 562.5 mg / m 2 , or 750 mg / m 2 cyclophosphamide at a dose of about 25 mg / m on day 1 of each 21-day cycle; 2 and approximately 50 mg / m 2 Between (e.g., 25 mg / m 2 , 37.5 mg / m 2 , or 50 mg / m 2 ) doxorubicin; and a corticosteroid (e.g., prednisone at a dose of about 100 mg, prednisolone at a dose of about 100 mg, or methylprednisolone at a dose of about 80 mg) on ​​days 1-5 of each 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.4 mg / kg. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered at a dose of about 750 mg / m 2 In some embodiments, doxorubicin is administered at a dose of about 50 mg / m2 In some embodiments, the corticosteroid is prednisone administered at a dose of about 100 mg. In some embodiments, the corticosteroid is prednisolone administered at a dose of about 100 mg. In some embodiments, the corticosteroid is methylprednisolone administered at a dose of about 80 mg.

[0221] Other exemplary dosing regimens for combination therapy of an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) with one or more additional therapeutic agents include an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) administered at a dose of about 1.0 to 1.8 mg / kg (e.g., 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg) once every 21 days, e.g., on day 1 of each 21-day cycle; an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) administered at a dose of about 375 mg / kg once every 21 days, e.g., on day 1 of each 21-day cycle; 2 rituximab at a dose of 0.05 mg / kg; cyclophosphamide once every 21 days, e.g., on day 1 of a 21-day cycle; doxorubicin once every 21 days, e.g., on day 1 of a 21-day cycle; and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) on days 1-5 of a 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg.

[0222] Exemplary dosing regimens for combination therapy of an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) with one or more additional therapeutic agents include an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) administered at a dose of about 1.0 to 1.8 mg / kg (e.g., 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg) once every 21 days, e.g., on day 1 of each 21-day cycle; obinutuzumab at a dose of about 1000 mg once every 21 days, e.g., on day 1 of each 21-day cycle; or obinutuzumab at a dose of about 375 mg / m once every 21 days, e.g., on day 1 of each 21-day cycle. 2 and approximately 750 mg / m 2 Between (e.g., 375 mg / m 2 , 562.5 mg / m 2 , or 750 mg / m 2 cyclophosphamide at a dose of about 25 mg / m on day 1 of each 21-day cycle; 2 and approximately 50 mg / m 2 Between (e.g., 25 mg / m 2 , 37.5 mg / m 2 , or 50 mg / m 2 ) doxorubicin; and a corticosteroid (e.g., prednisone at a dose of about 100 mg, prednisolone at a dose of about 100 mg, or methylprednisolone at a dose of about 80 mg) on ​​days 1-5 of each 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.4 mg / kg. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered at a dose of about 750 mg / m 2 In some embodiments, doxorubicin is administered at a dose of about 50 mg / m 2In some embodiments, the corticosteroid is prednisone administered at a dose of about 100 mg. In some embodiments, the corticosteroid is prednisolone administered at a dose of about 100 mg. In some embodiments, the corticosteroid is methylprednisolone administered at a dose of about 80 mg.

[0223] Another exemplary dosing regimen for combination therapy of an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) with one or more additional therapeutic agents includes administration of an anti-CD79b immunoconjugate (huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) at a dose of about 1.0 to 1.8 mg / kg (e.g., 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg) once every 21 days, e.g., on day 1 of each 21-day cycle. 8-MC-vc-PAB-MMAE or polatuzumab vedotin); obinutuzumab at a dose of about 1000 mg once every 21 days, e.g., on day 1 of each 21-day cycle; cyclophosphamide once every 21 days, e.g., on day 1 of a 21-day cycle; doxorubicin once every 21 days, e.g., on day 1 of a 21-day cycle; and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) on days 1-5 of a 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg.

[0224] The terms "co-administration," "co-administering," "combination," or "in combination," with respect to the administration of two or more therapeutic agents, such as an anti-CD79b immunoconjugate and at least one additional therapeutic agent (e.g., an anti-CD20 antibody, one or more chemotherapeutic agents, and a corticosteroid), refer to the administration of the two or more therapeutic agents as two (or more) separate formulations or as one single formulation containing the two or more therapeutic agents. When separate formulations are used, the co-administration can occur simultaneously (i.e., at the same time) or sequentially in any order, preferably with a period of time during which all active agents simultaneously exert their biological activity. In some embodiments, the two or more therapeutic agents are co-administered simultaneously or sequentially. In some embodiments, when all therapeutic agents are co-administered sequentially, e.g., according to any of the treatment regimens described herein, doses of each agent are administered on the same day in two or more separate administrations, or one of the agents is administered on day 1 and one or more other agent(s) is co-administered the following day.

[0225] The immunoconjugates provided herein (and any additional therapeutic agents, e.g., anti-CD20 antibodies, one or more chemotherapeutic agents, and corticosteroids) for use in any of the methods of treatment described herein can be administered by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if desired for localized treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing can be by any suitable route, e.g., injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. Various dosing schedules are contemplated herein, including, but not limited to, single or multiple doses at various time points, bolus administration, and pulse infusion. The anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) can be administered by the same or different routes of administration. In some embodiments, the anti-CD79b immunoconjugate is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intracerebroventricularly, or intranasally. In some embodiments, the anti-CD20 antibody (e.g., obinutuzumab or rituximab, etc.) is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intracerebroventricularly, or intranasally. In some embodiments, one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intracerebroventricularly, or intranasally. In some embodiments, the corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intracerebroventricularly, or intranasally.In some embodiments, the anti-CD79b immunoconjugate, the anti-CD20 antibody (e.g., obinutuzumab or rituximab), and the one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) are each administered by intravenous infusion, and the corticosteroid (e.g., prednisone or prednisolone) is administered orally. In some embodiments, the anti-CD79b immunoconjugate, the anti-CD20 antibody (e.g., obinutuzumab or rituximab), the one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and the corticosteroid (e.g., methylprednisolone) are each administered by intravenous infusion. Effective amounts of an anti-CD79b immunoconjugate, an anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) may be administered for the prevention or treatment of a disease, e.g., DLBCL.

[0226] B. Exemplary Treatment Regimens In some embodiments, the method for treating diffuse large B-cell lymphoma (DLBCL) in an individual in need thereof, e.g., a human patient, comprises administering to the individual a dose of a compound of the following formula: TIFF2024530189000006.tif22170 (wherein Ab is an anti-CD79b antibody comprising: (i) a hypervariable region H1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and p is between 1 and 8.) an anti-CD79b immunoconjugate comprising: an anti-CD20 antibody (e.g., obinutuzumab or rituximab); one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin); and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). In some embodiments, p is between 2 and 5. In some embodiments, p is between 3 and 4. In some embodiments, p is 3.4. In some embodiments, p is 3.5. In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate is polatuzumab vedotin. In some embodiments, the anti-CD79b immunoconjugate, an anti-CD20 antibody (such as, for example, obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) are administered to an individual, e.g., a human patient, in 21-day cycles. In some embodiments, the anti-CD20 antibody is rituximab; see, e.g., section (i) below. In some embodiments, the anti-CD20 antibody is obinutuzumab; see, e.g., section (ii) below.

[0227] In some embodiments of any of the methods provided herein, the treatment for DLBCL by any of the disclosed methods is a first-line treatment for DLBCL, i.e., treating a human patient with previously untreated DLBCL.

[0228] (i) a treatment regimen containing rituximab In some embodiments of any of the methods provided herein, the anti-CD20 antibody is rituximab.

[0229] In some embodiments, the corticosteroid is prednisone.

[0230] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose between about 1.0 mg / kg and about 1.8 mg / kg on day 1 of each 21-day cycle, and the anti-CD20 antibody is administered at a dose of about 375 mg / m on day 1 of each 21-day cycle. 2 and the one or more chemotherapy agents is rituximab administered intravenously at a dose of about 375 mg / m on day 1 of each 21-day cycle. 2 and approximately 750 mg / m 2 Cyclophosphamide given intravenously at a dose between 25 mg / m on day 1 of each 21-day cycle 2 and approximately 50 mg / m 2 and doxorubicin administered intravenously at a dose between 0.1 mg / kg and 1.0 mg / kg, and the corticosteroid is prednisone administered orally at a dose of about 100 mg per day on each of days 1-5 of each 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.4 mg / kg. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously on day 1 of each 21-day cycle at a dose of about 563 mg / m 2In some embodiments, cyclophosphamide is administered intravenously at a dose of about 750 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each 21-day cycle. 2 will be administered intravenously on day 1 of each 21-day cycle at a dose of

[0231] In some embodiments of any of the methods for treating diffuse large B-cell lymphoma (DLBCL) provided herein, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of between about 1.0 mg / kg and about 1.8 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle, and the anti-CD20 antibody is administered intravenously at a dose of about 375 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and the one or more chemotherapy agents are administered intravenously at a dose of about 375 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and approximately 750 mg / m 2 and cyclophosphamide administered intravenously at a dose between about 25 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and approximately 50 mg / m 2and doxorubicin administered intravenously at a dose between 0.05 and 0.15 mg / kg, and the corticosteroid is prednisone administered orally at a dose of about 100 mg per day on each of days 1-5 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.0 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered intravenously at a dose of about 375 mg / m 2 is administered intravenously on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 563 mg / m 2 is administered intravenously on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 750 mg / m 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 It is administered intravenously at a dose of

[0232] In some embodiments, the corticosteroid is prednisolone.

[0233] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose between about 1.0 mg / kg and about 1.8 mg / kg on day 1 of each 21-day cycle, and the anti-CD20 antibody is administered at a dose of about 375 mg / m on day 1 of each 21-day cycle. 2 and the one or more chemotherapy agents is rituximab administered intravenously at a dose of about 375 mg / m on day 1 of each 21-day cycle. 2 and approximately 750 mg / m 2 Cyclophosphamide given intravenously at a dose between 25 mg / m on day 1 of each 21-day cycle 2 and approximately 50 mg / m 2and doxorubicin administered intravenously at a dose between 0.1 mg / kg and 1.0 mg / kg, and the corticosteroid is prednisolone administered orally at a dose of about 100 mg per day on each of days 1-5 of each 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.4 mg / kg. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously on day 1 of each 21-day cycle at a dose of about 563 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 750 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each 21-day cycle. 2 will be administered intravenously on day 1 of each 21-day cycle at a dose of

[0234] In some embodiments of any of the methods for treating diffuse large B-cell lymphoma (DLBCL) provided herein, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of between about 1.0 mg / kg and about 1.8 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle, and the anti-CD20 antibody is administered intravenously at a dose of about 375 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and the one or more chemotherapy agents are administered intravenously at a dose of about 375 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and approximately 750 mg / m 2 and cyclophosphamide administered intravenously at a dose between about 25 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and approximately 50 mg / m 2and doxorubicin administered intravenously at a dose between 0.05 and 1.0 mg / kg, and the corticosteroid is prednisolone administered orally at a dose of about 100 mg per day on each of days 1-5 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.0 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered intravenously at a dose of about 375 mg / m 2 is administered intravenously on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 563 mg / m 2 is administered intravenously on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 750 mg / m 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 will be administered intravenously on day 1 of each of the first, second, third, fourth, fifth and sixth cycles of a 21-day cycle.

[0235] In some embodiments, the corticosteroid is methylprednisolone.

[0236] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose between about 1.0 mg / kg and about 1.8 mg / kg on day 1 of each 21-day cycle, and the anti-CD20 antibody is administered at a dose of about 375 mg / m on day 1 of each 21-day cycle. 2 and the one or more chemotherapy agents is rituximab administered intravenously at a dose of about 375 mg / m on day 1 of each 21-day cycle. 2 and approximately 750 mg / m 2 Cyclophosphamide given intravenously at a dose between 25 mg / m on day 1 of each 21-day cycle 2 and approximately 50 mg / m 2and doxorubicin administered intravenously at a dose between 0.1 mg / kg and 1 mg / kg, and the corticosteroid is methylprednisolone administered intravenously at a dose of about 80 mg per day on each of days 1-5 of each 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.4 mg / kg. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously on day 1 of each 21-day cycle at a dose of about 563 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 750 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each 21-day cycle. 2 will be administered intravenously on day 1 of each 21-day cycle at a dose of

[0237] In some embodiments of any of the methods for treating diffuse large B-cell lymphoma (DLBCL) provided herein, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of between about 1.0 mg / kg and about 1.8 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle, and the anti-CD20 antibody is administered intravenously at a dose of about 375 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and the one or more chemotherapy agents are administered intravenously at a dose of about 375 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and approximately 750 mg / m 2 and cyclophosphamide administered intravenously at a dose between about 25 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and approximately 50 mg / m 2and doxorubicin administered intravenously at a dose between 0.05 and 1.0 mg / kg, and the corticosteroid is methylprednisolone administered intravenously at a dose of about 80 mg per day on each of days 1-5 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.0 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered intravenously at a dose of about 375 mg / m 2 is administered intravenously on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 563 mg / m 2 is administered intravenously on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 750 mg / m 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 will be administered intravenously on day 1 of each of the first, second, third, fourth, fifth and sixth cycles of a 21-day cycle.

[0238] (ii) a treatment regimen containing obinutuzumab In some embodiments of any of the methods provided herein, the anti-CD20 antibody is obinutuzumab.

[0239] In some embodiments, the corticosteroid is prednisone.

[0240] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of between about 1.0 mg / kg and about 1.8 mg / kg on day 1 of each 21-day cycle, the anti-CD20 antibody is obinutuzumab administered intravenously at a dose of about 1000 mg on day 1 of each 21-day cycle, and the one or more chemotherapeutic agents are administered intravenously at a dose of about 375 mg / m on each day 1 of each 21-day cycle. 2 and approximately 750 mg / m 2 Cyclophosphamide given intravenously at a dose between 25 mg / m on day 1 of each 21-day cycle 2 and approximately 50 mg / m 2and doxorubicin administered intravenously at a dose between 0.1 mg / kg and 1.0 mg / kg, and the corticosteroid is prednisone administered orally at a dose of about 100 mg per day on each of days 1-5 of each 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.4 mg / kg. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously on day 1 of each 21-day cycle at a dose of about 563 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 750 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each 21-day cycle. 2 will be administered intravenously on day 1 of each 21-day cycle at a dose of

[0241] In some embodiments of any of the methods for treating diffuse large B-cell lymphoma (DLBCL) provided herein, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of between about 1.0 mg / kg and about 1.8 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle; the anti-CD20 antibody is obinutuzumab administered intravenously at a dose of about 1000 mg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle; and the one or more chemotherapeutic agents are administered intravenously at a dose of about 375 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and approximately 750 mg / m 2 and cyclophosphamide administered intravenously at a dose between about 25 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and approximately 50 mg / m 2and doxorubicin administered intravenously at a dose between 0.05 and 0.15 mg / kg, and the corticosteroid is prednisone administered orally at a dose of about 100 mg per day on each of days 1-5 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.0 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered intravenously at a dose of about 375 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 563 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 750 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 It is administered intravenously at a dose of

[0242] In some embodiments, the corticosteroid is prednisolone.

[0243] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously on day 1 of each 21-day cycle at a dose between about 1.0 mg / kg and about 1.8 mg / kg, the anti-CD20 antibody is obinutuzumab administered intravenously on day 1 of each 21-day cycle at a dose of about 1000 mg, and the one or more chemotherapeutic agents are administered intravenously at a dose of about 375 mg / m on each day 1 of each 21-day cycle. 2 and approximately 750 mg / m 2 Cyclophosphamide given intravenously at a dose between 25 mg / m on day 1 of each 21-day cycle 2 and approximately 50 mg / m 2and doxorubicin administered intravenously at a dose between 0.1 mg / kg and 1.0 mg / kg, and the corticosteroid is prednisolone administered orally at a dose of about 100 mg per day on each of days 1-5 of each 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.0 mg / kg on day 1 of each 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 21-day cycle. In some embodiments, cyclophosphamide is administered intravenously at a dose of about 375 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously on day 1 of each 21-day cycle at a dose of about 563 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 750 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each 21-day cycle. 2 will be administered intravenously on day 1 of each 21-day cycle at a dose of

[0244] In some embodiments of any of the methods for treating diffuse large B-cell lymphoma (DLBCL) provided herein, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of between about 1.0 mg / kg and about 1.8 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle; the anti-CD20 antibody is obinutuzumab administered intravenously at a dose of about 1000 mg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle; and the one or more chemotherapeutic agents are administered intravenously at a dose of about 375 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and approximately 750 mg / m 2 and cyclophosphamide administered intravenously at a dose between about 25 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and approximately 50 mg / m 2and doxorubicin administered intravenously at a dose between 0.05 and 1.0 mg / kg, and the corticosteroid is prednisolone administered orally at a dose of about 100 mg per day on each of days 1-5 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.0 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered intravenously at a dose of about 375 mg / m 2 is administered intravenously on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 563 mg / m 2 is administered intravenously on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 750 mg / m 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 will be administered intravenously on day 1 of each of the first, second, third, fourth, fifth and sixth cycles of a 21-day cycle.

[0245] In some embodiments, the corticosteroid is methylprednisolone.

[0246] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously on day 1 of each 21-day cycle at a dose between about 1.0 mg / kg and about 1.8 mg / kg, the anti-CD20 antibody is obinutuzumab administered intravenously on day 1 of each 21-day cycle at a dose of about 1000 mg, and the one or more chemotherapeutic agents are administered intravenously at a dose of about 375 mg / m on each day 1 of each 21-day cycle. 2 and approximately 750 mg / m 2 Cyclophosphamide given intravenously at a dose between 25 mg / m on day 1 of each 21-day cycle 2 and approximately 50 mg / m 2and doxorubicin administered intravenously at a dose between 0.1 mg / kg and 1.0 mg / kg, and the corticosteroid is methylprednisolone administered intravenously at a dose of about 80 mg per day on each of days 1-5 of each 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.0 mg / kg on day 1 of each 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 21-day cycle. In some embodiments, cyclophosphamide is administered intravenously at a dose of about 375 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously on day 1 of each 21-day cycle at a dose of about 563 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 750 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on day 1 of each 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each 21-day cycle. 2 will be administered intravenously on day 1 of each 21-day cycle at a dose of

[0247] In some embodiments of any of the methods for treating diffuse large B-cell lymphoma (DLBCL) provided herein, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of between about 1.0 mg / kg and about 1.8 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle; the anti-CD20 antibody is obinutuzumab administered intravenously at a dose of about 1000 mg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle; and the one or more chemotherapeutic agents are administered intravenously at a dose of about 375 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and approximately 750 mg / m 2 and cyclophosphamide administered intravenously at a dose between about 25 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 and approximately 50 mg / m 2and doxorubicin administered intravenously at a dose between 0.05 and 1.0 mg / kg, and the corticosteroid is methylprednisolone administered intravenously at a dose of about 80 mg per day on each of days 1-5 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.0 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered intravenously at a dose of about 375 mg / m 2 is administered intravenously on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 563 mg / m 2 is administered intravenously on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, cyclophosphamide is administered at a dose of about 750 mg / m 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. 2 will be administered intravenously on day 1 of each of the first, second, third, fourth, fifth and sixth cycles of a 21-day cycle.

[0248] (iii) length of treatment regimen In some embodiments of any of the methods for treating diffuse large B-cell lymphoma (DLBCL) provided herein, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (e.g., obinutuzumab or rituximab, etc.), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) are administered to an individual, e.g., a human patient, in 21-day cycles. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) are administered in less than one 21-day cycle. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) are administered to an individual, e.g., a human patient, in at least one, at least two, at least three, at least four, at least five, or at least six 21-day cycles. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin, etc.), an anti-CD20 antibody (e.g., obinutuzumab or rituximab, etc.), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) are administered to an individual, e.g., a human patient, in between one and six 21-day cycles.In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin, etc.), an anti-CD20 antibody (e.g., obinutuzumab or rituximab, etc.), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) are administered to an individual, e.g., a human patient, in six 21-day cycles.

[0249] In some embodiments of any of the methods for treating diffuse large B-cell lymphoma (DLBCL) provided herein, the anti-CD20 antibody (e.g., obinutuzumab or rituximab) is administered as monotherapy following a sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). In some embodiments, the method comprises administering the anti-CD20 antibody (e.g., obinutuzumab or rituximab) as monotherapy for one or two additional 21-day cycles after a sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). In some embodiments, the method comprises administering the anti-CD20 antibody (e.g., obinutuzumab or rituximab) as monotherapy in a seventh 21-day cycle following a sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone).In some embodiments, the method comprises administering the anti-CD20 antibody (e.g., obinutuzumab or rituximab) as monotherapy on cycles 7 and 8 of a 21-day cycle following cycle 6 of a 21-day cycle of treatment with an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). In some embodiments, the method comprises administering the anti-CD20 antibody (e.g., obinutuzumab or rituximab) on day 1 of each cycle after cycle 6 of a 21-day cycle of treatment with an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone), e.g., during cycle 7 of the 21-day cycle, and optionally during cycle 8 of the 21-day cycle. In some embodiments, the method comprises administering an anti-CD20 antibody (e.g., obinutuzumab or rituximab) on days 1 of cycles 7 and 8 of a 21-day cycle following cycle 6 of a 21-day cycle of treatment with an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone).

[0250] In some embodiments of any of the methods for treating DLBCL provided herein, the method includes administering about 375 mg / m rituximab to patients receiving anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin, etc.) after a sixth 21-day cycle of treatment with rituximab, cyclophosphamide, doxorubicin, and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). 2 In some embodiments, the method further comprises administering an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin, etc.), rituximab, cyclophosphamide, doxorubicin, and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) for six 21-day cycles (i.e., cycles 1-6), followed by administration of rituximab monotherapy at a dose of about 375 mg / m 2 for one or two additional 21-day cycles after cycle 6 (i.e., cycle 7 and optionally cycle 8). In some embodiments, rituximab is administered on day 1 of each 21-day cycle.

[0251] In some embodiments of any of the methods for treating diffuse large B-cell lymphoma (DLBCL) provided herein, the anti-CD20 antibody (such as obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) are administered for one or two additional 21-day cycles after a sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (such as obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). In some embodiments, the method comprises administering an anti-CD20 antibody (such as, for example, obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) in a seventh 21-day cycle followed by a sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as, for example, huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (such as, for example, obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone).In some embodiments, the method comprises administering an anti-CD20 antibody (such as, for example, obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) for cycles seven and eight of a 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as, for example, huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (such as, for example, obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). In some embodiments, the method comprises administering an anti-CD20 antibody (e.g., obinutuzumab or rituximab) and one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) on day 1 and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) on days 1-5 of each 21-day cycle after cycle 6 of treatment with an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone).In some embodiments, the method comprises administering the anti-CD20 antibody (e.g., obinutuzumab or rituximab) and one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) on day 1 and the corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) on days 1-5 of cycles 7 and 8 of a 21-day cycle of treatment with an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone).

[0252] In some embodiments of any of the methods for treating DLBCL provided herein, the method includes administering rituximab, cyclophosphamide, doxorubicin, and a corticosteroid (e.g., prednisone at a dose of about 100 mg, prednisolone at a dose of about 100 mg, or methylprednisolone at a dose of about 80 mg) at a dose of about 375 mg / m 2 for one or two additional 21-day cycles after a sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), rituximab, cyclophosphamide, doxorubicin, and a corticosteroid (e.g., prednisone at a dose of about 100 mg, prednisolone at a dose of about 100 mg, or methylprednisolone at a dose of about 80 mg). 2 Rituximab at a dose of approximately 375 mg / m 2 and approximately 750 mg / m 2 Cyclophosphamide at a dose between about 25 mg / m 2 and approximately 50 mg / m 2In some embodiments, the method comprises administering an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin, etc.), rituximab, cyclophosphamide, doxorubicin, and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) at a dose between about 375 mg / m and about 500 mg / m. ... 2 Rituximab at a dose of approximately 375 mg / m 2 and approximately 750 mg / m 2 Cyclophosphamide at a dose between about 25 mg / m 2 and approximately 50 mg / m 2 and a corticosteroid (e.g., prednisone at a dose of about 100 mg, prednisolone at a dose of about 100 mg, or methylprednisolone at a dose of about 80 mg) administered in one or two additional 21-day cycles (i.e., cycle 7 and optionally cycle 8) after cycle 6 of the 21-day cycle. In some embodiments, rituximab, cyclophosphamide, and doxorubicin are each administered on day 1 of each 21-day cycle, and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) is administered on days 1-5 of each 21-day cycle.

[0253] In some embodiments of any of the methods provided herein, rituximab is replaced with obinutuzumab administered at a dose of 1000 mg.

[0254] (iv) Administration sequence and timing In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) are administered sequentially, e.g., on day 1 of each of cycles 1, 2, 3, 4, 5, and 6 of a 21-day cycle. In some embodiments, the corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) is administered before the anti-CD20 antibody (e.g., obinutuzumab or rituximab), the anti-CD20 antibody (e.g., obinutuzumab or rituximab) is administered before the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), and the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered before the one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), e.g., on day 1 of each of the first, second, third, fourth, fifth, and sixth cycles of a 21-day cycle. In some embodiments, the anti-CD20 antibody (e.g., obinutuzumab or rituximab), the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), and one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) are administered in any order following administration of a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone).In some embodiments, the anti-CD20 antibody (e.g., obinutuzumab or rituximab), anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), and one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) are administered in any order following administration of a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone), e.g., on day 1 of each of the first, second, third, fourth, fifth, and sixth cycles of a 21-day cycle.

[0255] In some embodiments of any of the methods for treating DLBCL provided herein, a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) is administered at least about 1 hour before each administration of an anti-CD20 antibody (e.g., obinutuzumab or rituximab) and / or at least about 1 hour before each administration of an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin). In some embodiments, when an anti-CD20 antibody (e.g., obinutuzumab or rituximab) is administered as monotherapy (e.g., on days 1 of cycles 7 and 8 of a 21-day cycle), the corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) is administered to the individual prior to administration of the anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0256] (v) Premedication and prophylaxis In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises administering a premedication to the individual (e.g., a human patient) prior to the initiation of treatment. In some embodiments, the method comprises administering to the individual an antihistamine (e.g., 50-100 mg diphenhydramine), an analgesic, and / or an antipyretic (e.g., 650-1000 mg acetaminophen / paracetamol) prior to the initiation of treatment, e.g., at least about 30 minutes prior to each administration of an anti-CD20 antibody (e.g., obinutuzumab or rituximab) and / or prior to each administration of an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin). In some embodiments, the method comprises administering to the individual an antihistamine and an analgesic and / or antipyretic (e.g., 500-1000 mg oral acetaminophen or paracetamol and 50-100 mg diphenhydramine) prior to each administration of the anti-CD20 antibody (e.g., obinutuzumab or rituximab) and / or prior to each administration of the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin). In some embodiments, the method comprises administering to the individual an antihistamine and an analgesic and / or antipyretic (e.g., 650-1000 mg oral acetaminophen or paracetamol and 50-100 mg diphenhydramine) prior to each administration of the anti-CD20 antibody (e.g., obinutuzumab or rituximab) and / or prior to each administration of the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin).

[0257] In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises administering a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) to the individual prior to initiation of treatment, e.g., up to 7 days prior to treatment with a corticosteroid (e.g., up to 100 mg of oral prednisone per day, or equivalent oral prednisone) prior to initiation of treatment.

[0258] In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises administering to the individual a prophylactic therapy against neutropenia. In some embodiments, the prophylactic therapy against neutropenia is administered as outlined in the American Society of Clinical Oncology (ASCO) recommended guidelines (see, e.g., Smith et al., J Clin Oncol (2015) 33:3199-212). In some embodiments, the prophylactic therapy against neutropenia comprises administering to the individual a granulocyte colony-stimulating factor (G-CSF, e.g., filgrastim or lenograstim or pegfilgrastim), e.g., about 1 to about 3 days prior to each administration of one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) and / or immunoconjugates (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin).

[0259] In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises administering central nervous system prophylaxis (e.g., intrathecal chemotherapy, etc.) to the individual. In some embodiments, the administered central nervous system prophylaxis is high-dose IV methotrexate (e.g., 1 g / m per cycle). 2 )isn't it.

[0260] In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises administering prophylactic treatment for hemorrhagic cystitis to the individual, e.g., adequate hydration and / or mesna.

[0261] In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises administering anti-infective prophylaxis to the individual (e.g., in the case of a viral, fungal, bacterial, or Pneumocystis infection). In some embodiments, the anti-infective prophylaxis is administered as described in Flowers et al., J Clin Oncol (2013) 31:794-810; National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®): Prevention and treatment of cancer-related infections, version 2 [Internet resource]. 2017 [June 9, 2017]. Available at www[dot]nccn[dot]org / professionals / physician_gls / f_guidelines.asp; and Reddy et al., Gastroenterology (2015) 148:215-19. In some embodiments, antiviral prophylaxis is administered, for example, as described in American Gastroenterology Association guidelines (see, e.g., Reddy et al., Gastroenterology (2015) 148:215-19).

[0262] In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises administering to the individual a prophylactic therapy against tumor lysis syndrome. In some embodiments, the prophylactic therapy against tumor lysis syndrome is administered to an individual at risk of developing tumor lysis syndrome. In some embodiments, the prophylactic therapy against tumor lysis syndrome is administered to an individual with a high tumor burden (e.g., lymphocyte count of 25×10 9 / L or greater or bulky lymphadenopathy). In some embodiments, prophylactic therapy against tumor lysis syndrome involves administering a suitable alternative treatment, such as allopurinol (e.g., 300 mg / day or greater or or rasburicase orally), prior to administration of treatment according to the methods provided herein, e.g., administered about 48-72 hours prior to administration of treatment according to the methods provided herein. In some embodiments, prophylactic therapy against tumor lysis syndrome involves adequate hydration, e.g., fluid intake of approximately 3 L / day, beginning one or two days prior to initiation of treatment according to the methods provided herein.

[0263] (vi) Adjustment and modification of procedures In some embodiments of any of the methods for treating DLBCL provided herein, the method comprises adjusting the dose of the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) after initiation of treatment if the individual experiences infusion-related symptoms, infusion-related reactions, or adverse events, e.g., as described in Example 1 herein. In some embodiments of any of the methods provided herein, the dose of the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) administered to the individual is reduced from about 1.8 mg / kg to about 1.4 mg / kg. In some embodiments, the dose of the immunoconjugate administered to the individual is reduced from about 1.4 mg / kg to about 1.0 mg / kg.

[0264] In some embodiments of any of the methods for treating DLBCL provided herein, the method includes adjusting the dose of cyclophosphamide after initiation of treatment if the individual experiences infusion-related symptoms, infusion-related reactions, or adverse events, e.g., as described in Example 1 herein. In some embodiments of any of the methods provided herein, the dose of cyclophosphamide administered to the individual is adjusted to 100% of the starting dose (e.g., 750 mg / m 2 ) to about 75% of the starting dose, e.g., about 563 mg / m 2In some embodiments of any of the methods provided herein, the dose of cyclophosphamide administered to the individual is reduced to about 75% of the starting dose (e.g., 750 mg / m 2 ) to about 50% of the starting dose, e.g., about 375 mg / m 2 Reduce to.

[0265] In some embodiments of any of the methods for treating DLBCL provided herein, the method includes adjusting the dose of doxorubicin after initiation of treatment if the individual experiences infusion-related symptoms, infusion-related reactions, or adverse events, e.g., as described in Example 1 herein. In some embodiments of any of the methods provided herein, the dose of doxorubicin administered to the individual is adjusted to 100% of the starting dose (e.g., 50 mg / m 2 ) to about 75% of the starting dose, e.g., about 37.5 mg / m 2 In some embodiments of any of the methods provided herein, the dose of doxorubicin administered to the individual is reduced to 75% of the starting dose (e.g., 50 mg / m 2 ) to about 50% of the starting dose, e.g., about 25 mg / m 2 Reduce to.

[0266] In some embodiments, treatment with R-CHOP (eg, control treatment) can be adjusted as described above.

[0267] In some embodiments, the dose of cyclophosphamide in R-CHOP treatment may be adjusted, e.g., in the event of infusion-related symptoms, infusion-related reactions, or adverse events, e.g., as described in Example 1 herein. In some embodiments, the dose of cyclophosphamide may be adjusted to 100% of the starting dose (e.g., 750 mg / m 2 ) to about 75% of the starting dose, e.g., about 563 mg / m 2 In some embodiments, the cyclophosphamide dose is reduced to about 75% of the starting dose (e.g., 750 mg / m 2 ) to about 50% of the starting dose, e.g., about 375 mg / m2 Reduce to.

[0268] In some embodiments, the dose of doxorubicin in R-CHOP treatment may be adjusted, e.g., in the event of infusion-related symptoms, infusion-related reactions, or adverse events, e.g., as described in Example 1 herein. In some embodiments, the dose of doxorubicin may be adjusted to 100% of the starting dose (e.g., 50 mg / m 2 ) to about 75% of the starting dose, e.g., about 37.5 mg / m 2 In some embodiments, the dose of doxorubicin is reduced to 75% of the starting dose (e.g., 50 mg / m 2 ) to about 50% of the starting dose, e.g., about 25 mg / m 2 Reduce to.

[0269] In some embodiments, the dose of vincristine in R-CHOP treatment may be adjusted, e.g., in the event of infusion-related symptoms, infusion-related reactions, or adverse events, e.g., as described in Example 1 herein. In some embodiments, the dose of vincristine (also known as Oncovin) may be adjusted to 100% of the starting dose (e.g., 1.4 mg / m 2 ) to about 75% of the starting dose, e.g., about 1.05 mg / m 2 In some embodiments, the dose of vincristine is reduced to 75% of the starting dose (e.g., 1.4 mg / m 2 ) to about 50% of the starting dose, e.g., about 0.7 mg / m 2 In some embodiments of any of the methods provided herein, the dose of vincristine is reduced to about 1.4 mg / m 2 and approximately 0.5 mg / m 2 Between 1.4 mg / m and 1.4 mg / m 2 and approximately 0.7 mg / m 2 In some embodiments of any of the methods provided herein, the dose of vincristine is between about 0.5 mg / m and about 10 mg / m, but up to 2 mg per dose. 2 , 0.55 mg / m 2 , 0.6 mg / m 2 , 0.65 mg / m 2, 0.7 mg / m 2 , 0.75 mg / m 2 , 0.8 mg / m 2 , 0.85 mg / m 2 , 0.9 mg / m 2 , 0.95 mg / m 2 , 1.0 mg / m 2 , 1.05 mg / m 2 , 1.1 mg / m 2 , 1.15 mg / m 2 , 1.2 mg / m 2 , 1.25 mg / m 2 , 1.3 mg / m 2 , 1.35 mg / m 2 , or 1.4 mg / m 2 In some embodiments of any of the methods provided herein, 2 mg per dose is the maximum dose of vincristine.

[0270] In some embodiments of any of the methods for treating DLBCL provided herein, each dose of an anti-CD20 antibody (e.g., obinutuzumab or rituximab) may be administered to an individual over multiple days (e.g., over two days), for example, if the individual experiences infusion-related symptoms, infusion-related reactions, or adverse events. In some embodiments, when the dose of an anti-CD20 antibody (e.g., obinutuzumab or rituximab) is split over two days, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) and one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) are administered on the second day after completion of administration of the dose of the anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0271] In some embodiments of any of the methods for treating DLBCL provided herein, an anti-CD20 antibody (e.g., obinutuzumab or rituximab) and one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) are administered on day 1 of each 21-day cycle, and an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered on day 2 of each 21-day cycle (e.g., after administration of a corticosteroid, e.g., prednisone, prednisolone, or methylprednisolone).

[0272] In some embodiments of any of the methods for treating DLBCL provided herein, the treatment regimen is modified, adjusted, interrupted, or delayed as described in Example 1 herein (e.g., Table 3, Table 6, Table 8, and Table 9). In some embodiments of any of the methods for treating DLBCL provided herein, the method includes managing an infusion-related reaction and / or anaphylaxis as described in Example 1 herein (e.g., Table 6 and Table 7).

[0273] (vii) Exemplary Biomarkers In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises assessing minimal residual disease (MRD) in the individual before, during, and / or after treatment (e.g., by sequencing, such as next-generation sequencing, or by any other suitable method known in the art). In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises assessing circulating tumor DNA (ctDNA), e.g., before, during, and / or after treatment, e.g., by sequencing (e.g., next-generation sequencing, etc.) or by any other suitable method known in the art. In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises assessing leukocyte subsets before, during, and / or after treatment (e.g., by fluorescence-activated cell sorting (FACS) or any other suitable method known in the art). In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises assessing the cell-of-origin of the DLBCL (e.g., by RNA-based gene expression profiling or by any other suitable method known in the art) before, during, and / or after treatment. In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises assessing the presence or absence of one or more mutations in the DLBCL, e.g., one or more mutations in MYD88 or CD79B (e.g., by sequencing, such as next-generation sequencing, or by any other suitable method known in the art), before, during, and / or after treatment. In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises performing proteomic and / or immunohistochemical analysis of BCL2 and / or MYC in the DLBCL before, during, and / or after treatment.In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises obtaining a MYC, BCL2, and / or BCL6 translocation profile before, during, and / or after treatment, e.g., using sequencing, such as next-generation sequencing, fluorescence in situ hybridization (FISH), or any other suitable method known in the art. In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises evaluating an index clone of DLBCL, e.g., to determine minimal residual disease (MRD), e.g., by sequencing, such as next-generation sequencing, or using any other suitable method known in the art.

[0274] In some embodiments, an individual, e.g., a human patient, treated according to any of the methods provided herein has an International Prognostic Index (IPI) score of 2. In some embodiments, an individual, e.g., a human patient, treated according to any of the methods provided herein has an International Prognostic Index (IPI) score of between 3 and 5. In some embodiments, an individual, e.g., a human patient, treated according to any of the methods provided herein has bulky disease, with one lesion 7.5 cm or larger. In some embodiments, an individual, e.g., a human patient, treated according to any of the methods provided herein does not have bulky disease. In some embodiments, an individual, e.g., a human patient, treated according to any of the methods provided herein does not have a lesion 7.5 cm or larger.

[0275] In some embodiments of any of the methods provided herein, one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) and / or corticosteroids (e.g., prednisone, prednisolone, or methylprednisolone) may be replaced with suitable equivalents. In some embodiments of any of the methods provided herein, cyclophosphamide, doxorubicin, and / or prednisone, prednisolone, or methylprednisolone may be replaced with suitable equivalents.

[0276] C. Treatment Response and Assessment In some embodiments, the therapeutic response in an individual, e.g., a human patient, treated according to any of the methods for treating diffuse large B-cell lymphoma (DLBCL) provided herein is assessed according to the Lugano response criteria for malignant lymphoma ((Cheson et al., J Clin Oncol (2014) 32:1-9). In some embodiments, the therapeutic response is assessed as described in Example 1 or Example 2 herein (see, e.g., Table 2).

[0277] In some embodiments, progression-free survival (PFS) or absence of disease progression is assessed as the time from up to 7 days (e.g., any of 7, 6, 5, 4, 3, 2, 1, or 0 days) prior to the start of treatment according to the methods provided herein (e.g., at the date of randomization to the treatment regimen described in Example 1) to the first occurrence of disease progression or recurrence, or death from any cause. In some embodiments, PFS or absence of disease progression is assessed from the date of randomization to the treatment regimen described in Example 1 to the time of the first occurrence of disease progression or recurrence, or death from any cause. In some embodiments, disease progression or recurrence is assessed by the investigator using the 2014 Lugano Classification for Malignant Lymphoma (Cheson et al., 2014). In some embodiments, for individuals who have not progressed, relapsed, or died as of the clinical analysis cutoff date, PFS is censored at the date of the last disease assessment at which the individual was found to be progression-free. In some embodiments, if there are no post-baseline tumor assessments or all post-baseline tumor assessments result in an overall response of "unevaluable," PFS is censored up to 7 days (e.g., any of 7, 6, 5, 4, 3, 2, 1, or 0 days) prior to the start of treatment according to the methods provided herein (e.g., at the date of randomization with the treatment regimen described in Example 1). In some embodiments, PFS is the median PFS of multiple human patients treated according to the methods of the present disclosure. In some embodiments, the PFS of multiple human patients treated according to the methods of the present disclosure is compared to the baseline PFS of multiple human patients treated with a control treatment (e.g., R-CHOP). In some embodiments, the PFS and baseline PFS are compared based on hazard ratios. In some embodiments, the hazard ratio is calculated using any suitable method known in the art, such as stratified Cox proportional hazards analysis.In some embodiments, a stratified hazard ratio is calculated using one or more, or all, of the following stratification factors: (a) geographic region (e.g., selected from (i) Asia, (ii) Western Europe, the United States, Canada, and / or Australia, and (iii) the rest of the world excluding (i) and / or (ii)); (b) International Prognostic Index (IPI) score (e.g., an IPI score of 2 or between 3 and 5); and / or (c) the presence or absence of bulky disease (e.g., a single lesion ≥ 7.5 cm). In some embodiments, the PFS and the reference PFS are compared based on a stratified hazard ratio, e.g., as described above. In some embodiments, the PFS and the reference PFS are compared based on a non-stratified hazard ratio. In some embodiments, the 95% confidence interval for the hazard ratio is calculated.

[0278] In some embodiments, event-free survival (EFS) eff ) is defined as EFS, including up to 7 days (e.g., any of days 7, 6, 5, 4, 3, 2, 1, or 0) prior to the initiation of treatment according to the methods provided herein (e.g., as of the date of randomization with the treatment regimen described in Example 1), including any of the following: disease progression or recurrence; death from any cause; a major investigator-determined reason for efficacy other than disease progression or recurrence that leads to the initiation of a different anti-lymphoma treatment (NALT); or a biopsy obtained after completion of treatment that is positive for residual disease, regardless of whether NALT is initiated. eff In some embodiments, primary efficacy outcomes include positron emission tomography-computed tomography (PET-CT) scan, bone marrow examination, CT / MRI, or physical examination findings suggestive of residual disease, or biopsy-confirmed residual disease. In some embodiments, event-free survival (EFS) is assessed as time to earliest occurrence of an event. eff ) is the EFS as described above from the date of randomization to the treatment regimen described in Example 1. eff In some embodiments, the EFS is assessed to the time of the earliest occurrence of an event. effEvent timing is the time of the test or biopsy leading to NALT, not the date of NALT initiation. eff If no event has been experienced, EFS is the time to relapse as of the date of the last tumor assessment in which the individual is known to be free of disease progression. eff In some embodiments, EFS is censored as an overall response with no post-baseline tumor assessments or with all post-baseline tumor assessments as "unevaluable." eff EFS for individuals without events eff is censored up to 7 days (e.g., any of 7, 6, 5, 4, 3, 2, 1, or 0 days) prior to the start of treatment according to the methods provided herein (e.g., at the date of randomization according to the treatment regimen described in Example 1). In some embodiments, the EFS of multiple human patients treated according to the methods of the present disclosure is eff However, the baseline EFS of multiple human patients treated with a control treatment (e.g., R-CHOP) eff In some embodiments, EFS eff and standard EFS eff are compared based on hazard ratios. In some embodiments, hazard ratios are calculated using any suitable method known in the art, such as using stratified Cox proportional hazards analysis. In some embodiments, stratified hazard ratios are calculated using one or more, or all, of the following stratification factors: (a) geographic region (e.g., selected from (i) Asia, (ii) Western Europe, the United States, Canada, and / or Australia, and (iii) the rest of the world excluding (i) and / or (ii)); (b) International Prognostic Index (IPI) score (e.g., an IPI score of 2 or between 3 and 5); and / or (c) the presence or absence of bulky disease (e.g., a single lesion 7.5 cm or larger). In some embodiments, EFS is calculated using one or more of the following stratification factors: (a) geographic region (e.g., selected from (i) Asia, (ii) Western Europe, the United States, Canada, and / or Australia, and (iii) the rest of the world excluding (i) and / or (ii)); (b) International Prognostic Index (IPI) score (e.g., an IPI score of 2 or between 3 and 5); and / or (c) the presence or absence of bulky disease (e.g., a single lesion 7.5 cm or larger). eff and standard EFS eff are compared based on stratified hazard ratios, e.g., as described above. eff and standard EFS effare compared based on unstratified hazard ratios. In some embodiments, the 95% confidence intervals of the hazard ratios are calculated. In some embodiments, the 12, 24, or 36 month EFS rates (95% CI) are used to compare EFS. eff is calculated for

[0279] In some embodiments, survival is assessed from up to 7 days (e.g., any of days 7, 6, 5, 4, 3, 2, 1, or 0) prior to initiation of treatment (e.g., date of randomization to the treatment regimen described in Example 1) according to the methods provided herein until death from any cause. In some embodiments, overall survival is assessed from up to 7 days (e.g., any of days 7, 6, 5, 4, 3, 2, 1, or 0) prior to initiation of treatment (e.g., date of randomization to the treatment regimen described in Example 1) until death from any cause according to the methods provided herein (e.g., date of randomization to the treatment regimen described in Example 1). In some embodiments, survival is assessed from the date of randomization to the treatment regimen described in Example 1 until death from any cause. In some embodiments, for individuals who have not died by the clinical analysis cutoff date, overall survival is censored at the last date the individual is known to be alive, e.g., as documented by the investigator. In some embodiments, the overall survival (OS) of a plurality of human patients treated according to the methods of the present disclosure is compared to a reference OS of a plurality of human patients treated with a control treatment (e.g., R-CHOP). In some embodiments, the OS and the reference OS are compared based on a hazard ratio. In some embodiments, the hazard ratio is calculated using any suitable method known in the art, such as using stratified Cox proportional hazards analysis. In some embodiments, a stratified hazard ratio is calculated using one or more, or all, of the following stratification factors: (a) geographic region (e.g., selected from (i) Asia, (ii) Western Europe, the United States, Canada, and / or Australia, and (iii) the rest of the world excluding (i) and / or (ii)); (b) International Prognostic Index (IPI) score (e.g., an IPI score of 2 or between 3 and 5); and / or (c) the presence or absence of bulky disease (e.g., a single lesion 7.5 cm or larger). In some embodiments, the OS and the reference OS are compared based on a stratified hazard ratio, for example, as described above. In some embodiments, the OS and the reference OS are compared based on unstratified hazard ratios, hi some embodiments, the 95% confidence intervals of the hazard ratios are calculated.

[0280] In some embodiments, the complete response rate at the end of treatment is assessed as the proportion of individuals (e.g., among individuals treated according to any of the methods provided herein) who exhibit a complete response at the end of treatment with any of the methods provided herein. In some embodiments, complete response is assessed by PET-CT by an investigator or by blinded independent central review (BICR), e.g., as described in Example 1 herein.

[0281] In some embodiments, the 1-year or 12-month progression-free survival rate is assessed as the proportion of individuals (e.g., among a plurality of individuals treated according to any of the methods provided herein) who exhibit a progression-free survival (PFS) at 1 year (i.e., 12 months), as assessed from up to 7 days (e.g., any of 7, 6, 5, 4, 3, 2, 1, or 0 days) prior to the start of treatment according to the methods provided herein (e.g., at the date of randomization according to the treatment regimen described in Example 1). In some embodiments, the 1-year (i.e., 12-month) progression-free survival rate is assessed as the proportion of individuals (e.g., among a plurality of individuals treated according to any of the methods provided herein) who exhibit a progression-free survival (PFS) at 1 year (i.e., 12 months), as assessed from the start of the date of randomization according to the treatment regimen described in Example 1.

[0282] In some embodiments, the 2-year or 24-month progression-free survival (PFS24) rate is assessed as the proportion of individuals (e.g., among a plurality of individuals treated according to any of the methods provided herein) who exhibit progression-free survival (PFS) at 2 years (i.e., 24 months), as assessed from up to 7 days (e.g., any of 7, 6, 5, 4, 3, 2, 1, or 0 days) prior to the start of treatment according to the methods provided herein (e.g., at the date of randomization according to the treatment regimen described in Example 1). In some embodiments, the 2-year progression-free survival (PFS24) rate is assessed as the proportion of individuals (e.g., among a plurality of individuals treated according to any of the methods provided herein) who exhibit progression-free survival (PFS) at 2 years (i.e., 24 months), as assessed from the start of the date of randomization according to the treatment regimen described in Example 1.

[0283] In some embodiments, the 3-year or 36-month progression-free survival (PFS36) rate is assessed as the proportion of individuals (e.g., among a plurality of individuals treated according to any of the methods provided herein) who exhibit progression-free survival (PFS) at 3 years (i.e., 36 months), as assessed from up to 7 days (e.g., any of 7, 6, 5, 4, 3, 2, 1, or 0 days) prior to the start of treatment according to the methods provided herein (e.g., at the date of randomization according to the treatment regimen described in Example 1). In some embodiments, the 3-year progression-free survival (PFS36) rate is assessed as the proportion of individuals (e.g., among a plurality of individuals treated according to any of the methods provided herein) who exhibit progression-free survival (PFS) at 3 years (i.e., 36 months), as assessed from the date of randomization according to the treatment regimen described in Example 1.

[0284] In some embodiments, the 42-month progression-free survival (PFS42) rate is assessed as the proportion of individuals (e.g., among a plurality of individuals treated according to any of the methods provided herein) who exhibit a progression-free survival (PFS) at 42 months, as assessed from up to 7 days (e.g., any of 7, 6, 5, 4, 3, 2, 1, or 0 days) prior to the start of treatment according to the methods provided herein (e.g., at the date of randomization according to the treatment regimen described in Example 1). In some embodiments, the PFS42 rate is assessed as the proportion of individuals (e.g., among a plurality of individuals treated according to any of the methods provided herein) who exhibit a PFS at 42 months, as assessed from the date of randomization according to the treatment regimen described in Example 1.

[0285] In some embodiments, disease-free survival (DFS) is assessed as the time from the first occurrence of a complete response in an individual treated according to any of the methods provided herein to disease recurrence or death from any cause for individuals with a best overall response (BOR) of a complete response. In some embodiments, for individuals who achieve a complete response but have not relapsed or died at the time of analysis, DFS is censored at the date of the last tumor assessment at which the individual is known to be disease-free. In some embodiments, the DFS of multiple human patients treated according to the methods of the present disclosure is compared to the baseline DFS of multiple human patients treated with a control treatment (e.g., R-CHOP). In some embodiments, the DFS and the baseline DFS are compared based on hazard ratios. In some embodiments, the hazard ratio is calculated using any suitable method known in the art, such as using stratified Cox proportional hazards analysis. In some embodiments, stratified hazard ratios are calculated using one or more, or all, of the following stratification factors: (a) geographic region (e.g., selected from (i) Asia, (ii) Western Europe, the United States, Canada, and / or Australia, and (iii) the rest of the world excluding (i) and / or (ii)); (b) International Prognostic Index (IPI) score (e.g., an IPI score of 2 or between 3 and 5); and / or (c) the presence or absence of bulky disease (e.g., a single lesion ≥ 7.5 cm). In some embodiments, DFS and baseline DFS are compared based on stratified hazard ratios, e.g., as described above. In some embodiments, DFS and baseline DFS are compared based on unstratified hazard ratios. In some embodiments, 95% confidence intervals for hazard ratios are calculated.

[0286] In some embodiments, duration of response (DOR) is assessed from the time of first occurrence of a response (e.g., complete response or partial response) in an individual treated according to any of the methods provided herein to the time of progression, recurrence, or death from any cause for individuals with a best overall response of complete or partial response. In some embodiments, for individuals who achieve a response but do not progress, recur, or die at the time of analysis, the DOR is censored at the date of the last tumor assessment for which the patient is known to be progression-free. In some embodiments, the DOR of multiple human patients treated according to the methods of the present disclosure is compared to a baseline DOR of multiple human patients treated with a control treatment (e.g., R-CHOP). In some embodiments, the DOR and the baseline DOR are compared based on a hazard ratio. In some embodiments, the hazard ratio is calculated using any suitable method known in the art, such as using stratified Cox proportional hazards analysis. In some embodiments, a stratified hazard ratio is calculated using one or more, or all, of the following stratification factors: (a) geographic region (e.g., selected from (i) Asia, (ii) Western Europe, the United States, Canada, and / or Australia, and (iii) the rest of the world excluding (i) and / or (ii)); (b) International Prognostic Index (IPI) score (e.g., an IPI score of 2 or between 3 and 5); and / or (c) the presence or absence of bulky disease (e.g., a single lesion ≥ 7.5 cm). In some embodiments, the DOR and the reference DOR are compared based on a stratified hazard ratio, e.g., as described above. In some embodiments, the DOR and the reference DOR are compared based on a non-stratified hazard ratio. In some embodiments, a 95% confidence interval for the hazard ratio is calculated.

[0287] In some embodiments, best overall response (BOR) is assessed as the best response in an individual treated according to any of the methods provided herein. In some embodiments, response is assessed based on the Lugano response criteria for lymphoma (Cheson et al., J Clin Oncol (2014) 32:1-9). In some embodiments, response is assessed by the investigator. In some embodiments, an individual treated according to any of the methods provided herein who does not demonstrate a response according to the Lugano response criteria for lymphoma (Cheson et al., 2014) is considered a non-responder. In some embodiments, best overall response (BOR) is assessed from up to 7 days (e.g., 7, 6, 5, 4, 3, 2, 1, or 0 days) prior to initiating treatment according to the methods provided herein. In some embodiments, best overall response (BOR) is assessed from the date of randomization according to the treatment regimen described in Example 1. In some embodiments, best overall response (BOR) is assessed according to the methods and criteria for assessing objective response rate (ORR), for example, as described herein.

[0288] In some embodiments, EFS-all cause (EFS all ) is assessed from up to 7 days (e.g., any of 7, 6, 5, 4, 3, 2, 1, or 0 days) prior to the initiation of treatment with the methods provided herein until disease progression or recurrence, e.g., investigator assessment, death from any cause, or initiation of any new anti-lymphoma therapy (NALT). In some embodiments, EFS - all causes (EFS all ) is assessed from the date of randomization according to the treatment regimen described in Example 1 until disease progression or recurrence, e.g., investigator assessment, death from any cause, or initiation of any new anti-lymphoma therapy (NALT). In some embodiments, if disease progression or recurrence, death, or initiation of NALT does not occur, EFS is assessed. all is censored at the date of the last tumor assessment. In some embodiments, EFS is calculated for individuals who do not have a post-baseline tumor assessment, disease progression or recurrence, death, or initiation of NALT.all are censored up to 7 days (e.g., any of 7, 6, 5, 4, 3, 2, 1, or 0 days) prior to the start of treatment according to the methods provided herein (e.g., at the date of randomization according to the treatment regimen described in Example 1).

[0289] In some embodiments, the objective response rate (ORR) at the end of treatment is assessed as the proportion of individuals (e.g., among individuals treated according to any of the methods provided herein) who experience a complete or partial response at the end of treatment with any of the methods provided herein. In some embodiments, complete or partial response is assessed by PET-CT by an investigator or by blinded independent central review (BICR), e.g., as described in Example 1 herein.

[0290] In some embodiments of any of the methods described herein, the PET-CT refers to fluorodeoxyglucose positron emission tomography (FDG-PET), for example, as described in Example 1 herein.

[0291] In some embodiments of any of the methods described herein, the therapeutic or clinical response is assessed by an investigator or by blinded independent central review (BICR). In some embodiments, an investigator refers to a physician, oncologist, radiologist, nuclear medicine specialist, or any other medical professional qualified to assess therapeutic or clinical response in DLBCL. In some embodiments, BICR refers to the assessment of therapeutic or clinical response in a standardized manner by blinded radiologists, nuclear medicine specialists, and oncologists.

[0292] In some embodiments of any of the methods provided herein, the therapeutic response in an individual, e.g., a human patient, is evaluated according to the RECIL 2017 criteria (see Younes et al., International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Ann Oncol (2017) 28(7):1436-1447).

[0293] Further details regarding clinical staging and response criteria for lymphomas such as DLBCL can be found in, for example, Van Heertum et al. (2017) Drug Des. Devel. Ther. 11:1719-1728; Cheson et al. (2016) Blood. 128:2489-2496; Cheson et al. (2014) J. Clin. Oncol. 32(27):3059-3067; Barrington et al. (2017) J. Clin. Oncol. 32(27):3048-3058; Gallamini et al. (2014) Haematologica. 99(6):1107-1113; Barrinton et al. al. (2010) Eur. J. Nucl. Med. Mol. Imaging. 37(10):1824-33; Moskwitz (2012) Hematology Am Soc. Hematol. Educ. Program 2012:397-401; and Follows et al. (2014) Br. J. Haematology 166:34-49. The progress of any one of the treatment methods provided herein can be monitored by techniques known in the art.

[0294] In some embodiments, an individual, e.g., a human patient, treated according to any of the methods described herein achieves an improved response compared to an individual treated with a treatment comprising a single agent, e.g., an immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) alone (e.g., obinutuzumab or rituximab), an anti-CD20 antibody alone (e.g., cyclophosphamide, doxorubicin, and / or vincristine), one or more chemotherapeutic agents alone (e.g., prednisone, prednisolone, or methylprednisolone), or a corticosteroid alone. In some embodiments, an individual, e.g., a human patient, treated according to any of the methods described herein achieves an improved response compared to an individual treated with a treatment comprising an anti-CD20 antibody (e.g., obinutuzumab or rituximab) and one or more chemotherapeutic agents (e.g., cyclophosphamide, doxorubicin, and / or vincristine). In some embodiments, an individual, e.g., a human patient, treated according to any of the methods described herein achieves an improved response compared to an individual treated with a treatment comprising an anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide, doxorubicin, and / or vincristine), and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). In some embodiments, an individual, e.g., a human patient, treated according to any of the methods described herein achieves an improved response compared to an individual treated with a treatment comprising rituximab, cyclophosphamide, doxorubicin, vincristine, and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). In some embodiments, an individual, e.g., a human patient, treated according to any of the methods described herein achieves an improved response compared to an individual treated with a control treatment comprising rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisone, or methylprednisolone (R-CHOP).In some embodiments, individuals (e.g., human patients) treated according to any of the methods described herein achieve an improved response compared to individuals treated with standard of care treatment for DLBCL (e.g., rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone, prednisolone, or methylprednisolone (R-CHOP)); or cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone, or methylprednisolone (CHOP); or CHOP-like chemotherapy.

[0295] In some embodiments, the therapeutic or clinical response in an individual, e.g., a human patient, or a plurality of individuals, e.g., a plurality of human patients, with DLBCL treated according to any of the methods described herein is compared to the therapeutic or clinical response in an individual (e.g., a human) with DLBCL or a plurality of individuals (e.g., a plurality of humans) with DLBCL treated with a control treatment, where the control treatment is R-CHOP. In some embodiments, the individual or plurality of individuals with DLBCL treated according to any of the methods described herein achieves an improved therapeutic or clinical response compared to the therapeutic or clinical response in the individual or plurality of individuals with DLBCL treated with R-CHOP. In some embodiments, the individual or plurality of individuals with DLBCL treated with R-CHOP is treated according to the treatment regimen described below and in Example 1 herein.

[0296] In some embodiments, the individual or individuals with DLBCL treated with R-CHOP each receive about 375 mg / m given on day 1 of each 21-day cycle for at least 6 cycles (e.g., cycles 1-6). 2 Intravenous (IV) dose of rituximab, approximately 750 mg / m 2 IV dose of cyclophosphamide, approximately 50 mg / m 2 IV dose of doxorubicin, and approximately 1.4 mg / m 2In some embodiments, the individual or individuals with DLBCL treated with R-CHOP are treated with vincristine at a dose of about 375 mg / m IV (maximum 2 mg / dose) and (a) prednisone at a dose of about 100 mg / day orally (PO) given on days 1-5 of each 21-day cycle for at least six cycles (e.g., cycles 1-6), (b) prednisolone at a dose of about 100 mg / day PO given on days 1-5 of each 21-day cycle for at least six cycles (e.g., cycles 1-6), or (c) methylprednisolone at a dose of about 80 mg / day IV given on days 1-5 of each 21-day cycle for at least six cycles (e.g., cycles 1-6). In some embodiments, the individual or individuals with DLBCL treated with R-CHOP are treated with vincristine at a dose of about 375 mg / m IV on cycles 7 and 8 of the 21-day cycle, e.g., on day 1 of each cycle, as monotherapy after cycles 1-6. 2 Additional IV doses of rituximab will be administered.

[0297] In some embodiments, the individual or individuals with DLBCL treated with R-CHOP each receive about 375 mg / m given on day 1 of each 21-day cycle for 6 cycles (e.g., cycles 1-6). 2 Intravenous (IV) dose of rituximab, approximately 750 mg / m 2 IV dose of cyclophosphamide, approximately 50 mg / m 2 IV dose of doxorubicin, and approximately 1.4 mg / m 2In some embodiments, the individual or individuals with DLBCL treated with R-CHOP are treated with vincristine at a dose of about 100 mg / day orally (PO) given on days 1-5 of each 21-day cycle for six cycles (e.g., cycles 1-6), (b) prednisolone at a dose of about 100 mg / day PO given on days 1-5 of each 21-day cycle for six cycles (e.g., cycles 1-6), or (c) methylprednisolone at a dose of about 80 mg / day IV given on days 1-5 of each 21-day cycle for six cycles (e.g., cycles 1-6). In some embodiments, the individual or individuals with DLBCL treated with R-CHOP are treated with rituximab at a dose of about 375 mg / m IV given in 21-day cycles for two additional 21-day cycles (e.g., cycles 7 and 8), e.g., on day 1 of each cycle, as monotherapy. 2 Further doses are given IV.

[0298] In some embodiments, the individual or individuals with DLBCL treated with R-CHOP each receive about 375 mg / m given on day 1 of each 21-day cycle for 8 cycles (e.g., cycles 1-8). 2 Intravenous (IV) dose of rituximab, approximately 750 mg / m 2 IV dose of cyclophosphamide, approximately 50 mg / m 2 IV dose of doxorubicin, and approximately 1.4 mg / m 2 Vincristine at a dose of IV (maximum 2 mg / dose) and (a) prednisone at a dose of about 100 mg / day orally (PO) given on days 1-5 of each 21-day cycle for eight cycles (e.g., cycles 1-8), (b) prednisolone at a dose of about 100 mg / day PO given on days 1-5 of each 21-day cycle for eight cycles (e.g., cycles 1-8), or (c) methylprednisolone at a dose of about 80 mg / day IV given on days 1-5 of each 21-day cycle for eight cycles (e.g., cycles 1-8).

[0299] In some embodiments, the individual or individuals with DLBCL treated with R-CHOP each receive about 375 mg / m2 given on day 1 of each 21-day cycle for between 6 and 8 cycles (e.g., cycles 1-6, cycles 1-7, or cycles 1-8). 2 Intravenous (IV) dose of rituximab, approximately 750 mg / m 2 IV dose of cyclophosphamide, approximately 50 mg / m 2 IV dose of doxorubicin, and approximately 1.4 mg / m 2 Vincristine at a dose of IV (maximum 2 mg / dose) and (a) prednisone at a dose of about 100 mg / day orally (PO) given on days 1-5 of each 21-day cycle for between six and eight cycles (e.g., cycles 1-6, cycles 1-7, or cycles 1-8), (b) prednisolone at a dose of about 100 mg / day PO given on days 1-5 of each 21-day cycle for between six and eight cycles (e.g., cycles 1-6, cycles 1-7, or cycles 1-8), or (c) methylprednisolone at a dose of about 80 mg / day IV given on days 1-5 of each 21-day cycle for between six and eight cycles (e.g., cycles 1-6, cycles 1-7, or cycles 1-8).

[0300] In some embodiments, treatment of a plurality of human patients with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a baseline PFS, where the baseline PFS is the PFS of a plurality of human patients who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients aged over 60 years with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a baseline PFS, where the baseline PFS is the PFS of a plurality of human patients aged over 60 years who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients aged over 65 years with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a baseline PFS, where the baseline PFS is the PFS of a plurality of human patients aged over 65 years who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with an International Prognostic Index (IPI) score between 3 and 5 with the methods of the disclosure results in an improvement in progression-free survival (PFS) compared to a reference PFS, where the reference PFS is the PFS of a plurality of human patients with an IPI score between 3 and 5 who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with an International Prognostic Index (IPI) score between 3 and 5 over 60 years of age with the methods of the disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients over 60 years of age and an IPI score between 3 and 5 who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with an International Prognostic Index (IPI) score between 3 and 5 with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, where the reference PFS is the PFS of a plurality of human patients with an IPI score between 3 and 5 and over 65 years of age who have been treated with R-CHOP.In some embodiments, treatment of a plurality of human patients with ABC DLBCL with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a baseline PFS, where the baseline PFS is the PFS of the plurality of human patients with ABC DLBCL treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with DEL DLBCL with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a baseline PFS, where the baseline PFS is the PFS of the plurality of human patients with DEL DLBCL treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with the methods of the present disclosure results in a hazard ratio of 0.75 or less (e.g., 0.74, 0.73, 0.72, 0.71, 0.70) in progression-free survival (PFS) of the plurality of human patients compared to treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients with the methods of the disclosure results in a hazard ratio of 0.78 or less (e.g., 0.77, 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, 0.70) in progression-free survival (PFS) for the plurality of human patients compared to treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients with the methods of the disclosure results in a hazard ratio of 0.79 or less (e.g., 0.78, 0.77, 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, 0.70) in progression-free survival (PFS) for the plurality of human patients compared to treatment with R-CHOP. In some embodiments, PFS or baseline PFS is measured from a maximum of 7 days (e.g., any of days 7, 6, 5, 4, 3, 2, 1, or 0) prior to the initiation of treatment to the first occurrence of disease progression, recurrence, or death. In some embodiments, PFS or baseline PFS is measured from the start of treatment to the time of the first occurrence of disease progression, recurrence, or death. In some embodiments, PFS or baseline PFS is measured from the date of randomization to the treatment regimen described in Example 1 to the time of the first occurrence of disease progression, recurrence, or death. In some embodiments, PFS is the median PFS of multiple human patients undergoing treatment with the methods described herein.In some embodiments, the reference PFS is the median PFS of human patients receiving R-CHOP. In some embodiments, the improvement in PFS is statistically significant. In some embodiments, the improvement in PFS is statistically significant at a stratified hazard ratio of 0.75 or less (95% confidence interval: 0.57, 0.97). In some embodiments, the improvement in PFS is statistically significant at a stratified hazard ratio of 0.78 or less (95% confidence interval: 0.60, 1.00). In some embodiments, the improvement in PFS is statistically significant at an unstratified hazard ratio of 0.79 or less (95% confidence interval: 0.61, 1.02). In some embodiments, treatment of a plurality of human patients aged over 60 years with the methods of the disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, where the hazard ratio is 0.8 or less (e.g., any of 0.8, 0.78, 0.75, 0.76, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4 or less), where the reference PFS is the PFS of the plurality of human patients aged over 60 years who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients aged over 60 years with the methods of the disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, where the stratified hazard ratio is 0.72 or less (95% confidence interval: 0.52, 0.99), where the reference PFS is the PFS of the plurality of human patients aged over 60 years who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients aged over 60 years with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, wherein the unstratified hazard ratio is less than or equal to 0.72 (95% confidence interval: 0.53, 0.99), and the reference PFS is the PFS of a plurality of human patients aged over 60 years who have been treated with R-CHOP.In some embodiments, treatment of a plurality of human patients aged over 60 years with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, wherein the unstratified hazard ratio is less than or equal to 0.76 (95% confidence interval: 0.56, 1.02), and the reference PFS is the PFS of a plurality of human patients aged over 60 years who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients over 65 years of age with the methods of the disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, wherein the hazard ratio is 0.9 or less (e.g., any of 0.9, 0.85, 0.8, 0.78, 0.76, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4 or less), where the reference PFS is the PFS of a plurality of human patients over 65 years of age treated with R-CHOP. In some embodiments, treatment of a plurality of human patients aged over 65 years with the methods of the disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, wherein the stratified hazard ratio is 0.79 or less (95% confidence interval: 0.54, 1.14), where the reference PFS is the PFS of the plurality of human patients aged over 65 years who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients aged over 65 years with the methods of the disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, wherein the unstratified hazard ratio is 0.77 or less (95% confidence interval: 0.54, 1.10), where the reference PFS is the PFS of the plurality of human patients aged over 65 years who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients aged over 65 years with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, wherein the unstratified hazard ratio is less than or equal to 0.78 (95% confidence interval: 0.56, 1.10), and the reference PFS is the PFS of a plurality of human patients aged over 65 years who have been treated with R-CHOP.In some embodiments, treatment of a plurality of human patients having an International Prognostic Index (IPI) score between 3 and 5 with the methods of the disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, where the hazard ratio is 0.8 or less (e.g., any of 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4 or less), where the reference PFS is the PFS of a plurality of human patients having an IPI score between 3 and 5 treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with International Prognostic Index (IPI) scores between 3 and 5 with the methods of the disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, where the stratified hazard ratio is 0.68 or less (95% confidence interval: 0.50, 0.94), where the reference PFS is the PFS of the plurality of human patients with IPI scores between 3 and 5 treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with International Prognostic Index (IPI) scores between 3 and 5 with the methods of the disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, where the unstratified hazard ratio is 0.71 or less (95% confidence interval: 0.51, 0.97), where the reference PFS is the PFS of the plurality of human patients with IPI scores between 3 and 5 treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with an International Prognostic Index (IPI) score between 3 and 5 with the methods of the disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, where the reference PFS is the PFS of a plurality of human patients with an IPI score between 3 and 5 treated with R-CHOP, with an unstratified hazard ratio of less than or equal to 0.75 (95% confidence interval: 0.55, 1.01).In some embodiments, treatment of a plurality of human patients with ABC DLBCL with the methods of the disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, where the hazard ratio is 0.4 or less (e.g., any of 0.4, 0.39, 0.38, 0.37, 0.36, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, or less), where the reference PFS is the PFS of the plurality of human patients with ABC DLBCL treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with ABC DLBCL with the methods of the disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, where the stratified hazard ratio is 0.31 or less (95% confidence interval: 0.17, 0.56), where the reference PFS is the PFS of the plurality of human patients with ABC DLBCL treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with ABC DLBCL with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to the baseline PFS, with an unstratified hazard ratio of 0.36 or less (95% confidence interval: 0.21, 0.62) and is greater than or equal to the baseline PFS. The PFS is the PFS of a plurality of human patients with ABC DLBCL treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with ABC DLBCL with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, where the unstratified hazard ratio is 0.39 or less (95% confidence interval: 0.23, 0.65), where the reference PFS is the PFS of a plurality of human patients with ABC DLBCL treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with DEL DLBCL with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, where the hazard ratio is 0.7 or less (e.g., 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4 or less), where the reference PFS is the PFS of a plurality of human patients with DEL DLBCL treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with DEL DLBCL with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a baseline PFS, where the stratified hazard ratio is 0.62 or less (95% confidence interval: 0.40, 0.97), and the baseline PFS is the PFS of the plurality of human patients with DEL DLBCL treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with DEL DLBCL with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a baseline PFS, where the unstratified hazard ratio is 0.65 or less (95% confidence interval: 0.43, 0.98), and the baseline PFS is the PFS of the plurality of human patients with DEL DLBCL treated with R-CHOP. In some embodiments, treatment of human patients with DEL DLBCL with the methods of the present disclosure results in an improvement in progression-free survival (PFS) of the human patients compared to a reference PFS, where the unstratified hazard ratio is 0.67 or less (95% confidence interval: 0.44, 1.02), where the reference PFS is the PFS of human patients with DEL DLBCL treated with R-CHOP. In some embodiments, the hazard ratio has a 95% confidence interval.In some embodiments, hazard ratios are calculated at the following starting points: (a) initiation of the corresponding treatment (i.e., treatment with a method of the disclosure or R-CHOP); (b) up to 7 days prior to initiation of the corresponding treatment (i.e., treatment with a method of the disclosure or R-CHOP); or (c) 12 months, 24 months, or 36 months or more, as measured from the date of randomization to the treatment regimen described in Example 1. In some embodiments, such treatments result in a statistically significant improvement in PFS when compared to the control treatment, with a stratified hazard ratio of 0.75 or less (95% confidence interval: 0.57, 0.97). In some embodiments, such treatments result in a statistically significant improvement in PFS when compared to the control treatment, with a stratified hazard ratio of 0.78 or less (95% confidence interval: 0.60, 1.00). In some embodiments, such treatment results in a statistically significant improvement in PFS when compared to control treatment, with an unstratified hazard ratio of 0.79 or less (95% confidence interval: 0.61, 1.02).

[0301] In some embodiments, treatment of a plurality of human patients with the methods of the disclosure results in at least a 20% (e.g., 21%, 22%, 23%, or 24%) reduction in the risk of disease progression, recurrence, or death in the plurality of human patients compared to treatment with R-CHOP. In other embodiments, treatment of a plurality of human patients with the methods of the disclosure results in at least a 25% (e.g., 26%, 27%, 28%, 29%, or 30%) reduction in the risk of disease progression, recurrence, or death in the plurality of human patients compared to treatment with R-CHOP. In some embodiments, disease progression, recurrence, or death is measured from up to 7 days (e.g., any of days 7, 6, 5, 4, 3, 2, 1, or 0) prior to the initiation of treatment to the time of the first occurrence of disease progression, recurrence, or death. In some embodiments, disease progression, recurrence, or death is measured from the initiation of treatment to the time of the first occurrence of disease progression, recurrence, or death. In some embodiments, disease progression, recurrence, or death is measured from the date of randomization to the treatment regimen described in Example 1 to the time of the first occurrence of disease progression, recurrence, or death. In some embodiments, the risk reduction has a 95% confidence interval. In some embodiments, the reduced risk of disease progression, recurrence, or death is statistically significant. In some embodiments, the reduced risk of disease progression, recurrence, or death is calculated from the following starting points: (a) initiation of the corresponding treatment (i.e., treatment with a method of the present disclosure or R-CHOP); (b) up to 7 days prior to initiation of the corresponding treatment (i.e., treatment with a method of the present disclosure or R-CHOP); or (c) 12 months, 24 months, or 36 months or more, as measured from the date of randomization to the treatment regimen described in Example 1. In some embodiments, such treatment results in a statistically significant improvement in PFS compared to the control treatment, reducing the risk of disease progression, recurrence, or death by at least 20% (e.g., 21%, 22%, 23%, or 24%). In some embodiments, such treatment results in a statistically significant improvement in PFS compared to a control treatment, reducing the risk of disease progression, recurrence, or death by at least 25% (e.g., 26%, 27%, 28%, 29%, or 30%).

[0302] In some embodiments, treatment of a plurality of human patients with the methods of the disclosure results in a 12-month progression-free survival rate of at least about 83% (e.g., any of 83%, 84%, 85%, 86%, 87%, 88%, 90%, or more). In some embodiments, treatment of a plurality of human patients with the methods of the disclosure results in an improvement in the 12-month progression-free survival rate of the plurality of human patients compared to a reference 12-month progression-free survival rate, where the reference 12-month progression-free survival rate is the 12-month progression-free survival rate of the plurality of human patients treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with a method of the present disclosure results in an improvement in the 12-month progression-free survival rate of the plurality of human patients of at least about 3% (e.g., at least about any of 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more) compared to a reference 12-month progression-free survival rate, where the reference 12-month progression-free survival rate is the 12-month progression-free survival rate of the plurality of human patients treated with R-CHOP. In some embodiments, the 12-month progression-free survival rate or the reference 12-month progression-free survival rate is calculated at 12 months as measured from up to 7 days (e.g., any of 7, 6, 5, 4, 3, 2, 1, or 0 days) prior to the initiation of the corresponding treatment (i.e., treatment with a method of the present disclosure or R-CHOP). In some embodiments, the 12-month progression-free survival rate or the reference 12-month progression-free survival rate is calculated at 12 months as measured from the initiation of the corresponding treatment (i.e., treatment with a method of the present disclosure or R-CHOP). In some embodiments, the 12-month progression-free survival rate or baseline 12-month progression-free survival rate is calculated at 12 months, measured from the date of randomization according to the treatment regimen described in Example 1. In some embodiments, the 12-month progression-free survival rate or baseline 12-month progression-free survival rate is a progression-free survival (PFS) rate calculated using the Kaplan-Meier method. In some embodiments, the improvement in 12-month progression-free survival rate is statistically significant.

[0303] In some embodiments, treatment of a plurality of human patients with the methods of the present disclosure results in a 24-month progression-free survival (PFS24) of at least about 75% (e.g., 76%, 77%, 78%, 79%, 80%). In some embodiments, treatment of a plurality of human patients with the methods of the present disclosure results in an improvement in the 24-month progression-free survival (PFS24) of the plurality of human patients as compared to a reference PFS24, where the reference PFS24 is a 24-month progression-free survival rate of a plurality of human patients who have been treated with R-CHOP. In some embodiments, treating a plurality of human patients with the methods of the disclosure results in at least about a 5% (e.g., about any of 5%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6%, or more) improvement in 24-month progression-free survival (PFS24) of the plurality of human patients compared to a reference PFS24, where the reference PFS24 is the 24-month progression-free survival rate of the plurality of human patients treated with R-CHOP. In some embodiments, treating a plurality of human patients with the methods of the disclosure results in at least about a 6% (e.g., 6%, 7%, 8%, 9%, 10%) improvement in 24-month progression-free survival (PFS24) of the plurality of human patients compared to a reference PFS24, where the reference PFS24 is the 24-month progression-free survival rate of the plurality of human patients treated with R-CHOP. In some embodiments, PFS24 or baseline PFS24 is calculated at 24 months as measured from up to 7 days (e.g., any of 7, 6, 5, 4, 3, 2, 1, or 0 days) prior to the initiation of the corresponding treatment (i.e., treatment with a method of the disclosure or R-CHOP). In some embodiments, PFS24 or baseline PFS24 is calculated at 24 months as measured from the initiation of the corresponding treatment (i.e., treatment with a method of the disclosure or R-CHOP). In some embodiments, PFS24 or baseline PFS24 is calculated at 24 months as measured from the date of randomization according to the treatment regimen described in Example 1. In some embodiments, PFS24 or baseline PFS24 is the progression-free survival (PFS) rate calculated using the Kaplan-Meier method. In some embodiments, the improvement in PFS24 is statistically significant.

[0304] In some embodiments, treatment of a plurality of human patients with the methods of the disclosure results in a 36-month progression-free survival (PFS36) of at least about 70% (e.g., 71%, 72%, 73%, 74%, 75%, 76%, 7...

Claims

1. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, administering treatment with the medicament to a plurality of human patients results in an improvement in progression-free survival (PFS) for said plurality of human patients as compared to a reference PFS; the baseline PFS is in the absence of polatuzumab vedotin: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone The PFS of a plurality of human patients receiving a control treatment comprising:

2. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, the human patient is over 60 years of age; administering treatment with the medicament to a plurality of human patients having an age greater than 60 years results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS; the baseline PFS is in the absence of polatuzumab vedotin: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone PFS in multiple human patients over 60 years of age who received a control treatment comprising:

3. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, the human patient is over 65 years of age; administering treatment with the medicament to a plurality of human patients having an age greater than 65 years results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS; the baseline PFS is in the absence of polatuzumab vedotin: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone PFS in multiple human patients over 65 years of age who received a control treatment comprising:

4. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, the human patient has an International Prognostic Index (IPI) score between 3 and 5; administering treatment with the medicament to a plurality of human patients having an IPI score between 3 and 5 results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS; the baseline PFS is in the absence of polatuzumab vedotin: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone The PFS of a plurality of human patients with an IPI score between 3 and 5 who received a control treatment comprising the medication.

5. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, the human patient has an age greater than 60 years and an International Prognostic Index (IPI) score between 3 and 5; administering treatment with the medicament to a plurality of human patients over 60 years of age and having an IPI score between 3 and 5 results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS; the baseline PFS is in the absence of polatuzumab vedotin: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone PFS of multiple human patients with an age greater than 60 years and an IPI score between 3 and 5 who received a control treatment comprising

6. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, the human patient has an age greater than 65 years and an International Prognostic Index (IPI) score between 3 and 5; administering treatment with the medicament to a plurality of human patients over 65 years of age and having an IPI score between 3 and 5 results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS; the baseline PFS is in the absence of polatuzumab vedotin: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone PFS in multiple human patients with an age greater than 65 years and an IPI score between 3 and 5 who received a control treatment comprising

7. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, the human patient has activated B-cell (ABC) DLBCL; administering treatment with the medicament to a plurality of human patients having ABC DLBCL results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS; the baseline PFS is in the absence of polatuzumab vedotin: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone PFS of human patients with ABC DLBCL who received a control treatment comprising:

8. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, comprising an effective amount of polatuzumab vedotin for treatment in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, The human patient has double expressor lymphoma (DEL) type DLBCL; administering treatment with the medicament to a plurality of human patients having DEL DLBCL results in an improvement in progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS; the baseline PFS is in the absence of polatuzumab vedotin: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone The PFS of human patients with DEL-type DLBCL who received a control treatment comprising:

9. The PFS or the reference PFS is (a) From the start of the corresponding treatment to the first occurrence of disease progression, recurrence, or death; or (b) from a maximum of 7 days before the start of the corresponding treatment until the first occurrence of disease progression, relapse, or death; or (c) From the time of randomization to the first occurrence of disease progression, relapse, or death. The pharmaceutical composition according to any one of claims 1 to 8, wherein the medicament is measured.

10. The method of any one of claims 1 to 8, wherein the PFS or the reference PFS is the median PFS of the plurality of human patients receiving corresponding treatment.

11. The method of any one of claims 1 to 8, wherein the improvement in PFS is statistically significant.

12. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, administering treatment with the medicament to a plurality of human patients in the absence of polatuzumab vedotin; (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone or resulting in at least a 25% reduction in the risk of disease progression, recurrence, or death in said plurality of human patients compared to a control treatment comprising:

13. said disease progression, recurrence or death being (a) From the start of the corresponding treatment to the first occurrence of disease progression, recurrence, or death; or (b) from a maximum of 7 days before the start of the corresponding treatment until the first occurrence of disease progression, relapse, or death; or (c) From the time of randomization to the first occurrence of disease progression, relapse, or death. The pharmaceutical composition according to claim 12, wherein the amount of the steroid hormone is measured.

14. A reduction in the risk of disease progression, recurrence, or death begins at: (a) at the start of the corresponding treatment, or (b) up to 7 days before the start of the corresponding treatment, or (c) From the time of randomization to the first occurrence of disease progression, relapse, or death. The method of claim 12 or 13, wherein the time to presentation is calculated at 12 months, 24 months or more, measured from the time of presentation.

15. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, administering treatment with the medicament to a plurality of human patients in the absence of polatuzumab vedotin; (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone or a stratified hazard ratio for progression-free survival (PFS) of said plurality of human patients of equal to or less than 0.75, or a stratified hazard ratio for progression-free survival (PFS) of said plurality of human patients of equal to or less than 0.78, or a non-stratified hazard ratio for progression-free survival (PFS) of said plurality of human patients, when compared to a control treatment comprising

16. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, (i) the human patient is greater than 60 years of age, and administering treatment with the medicament to a plurality of human patients greater than 60 years of age results in a stratified hazard ratio of 0.72 or less in progression-free survival (PFS) for the plurality of human patients compared to a control treatment; or (ii) the human patient is greater than 65 years of age, and administering treatment with the medicament to a plurality of human patients greater than 65 years of age results in a stratified hazard ratio of 0.79 or less in PFS for said plurality of human patients compared to a control treatment; the control treatment is in the absence of polatuzumab vedotin; (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone Pharmaceuticals, including

17. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, the human patient has an International Prognostic Index (IPI) score between 3 and 5; administering treatment with the medicament to a plurality of human patients having an IPI score between 3 and 5, in the absence of polatuzumab vedotin; (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone 10. The method of claim 1, wherein the medicament results in a stratified hazard ratio of 0.68 or less for progression-free survival (PFS) in said plurality of human patients when compared to a control treatment comprising:

18. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, (i) the human patient has activated B-cell (ABC) DLBCL, and administering treatment with the medicament to a plurality of human patients with ABC DLBCL results in a stratified hazard ratio of 0.31 or less in progression-free survival (PFS) for the plurality of human patients compared to a control treatment; or (ii) the human patient has double expressing lymphoma (DEL) DLBCL, and administering treatment with the medicament to a plurality of human patients with DEL DLBCL results in a stratified hazard ratio of 0.62 or less in PFS for the plurality of human patients compared to a control treatment; the control treatment is in the absence of polatuzumab vedotin; (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone Pharmaceuticals, including

19. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, (i) the human patient is greater than 60 years of age, and administering treatment with the medicament to a plurality of human patients greater than 60 years of age results in an unstratified hazard ratio for progression-free survival (PFS) of the plurality of human patients compared to a control treatment of 0.72 or less, or an unstratified hazard ratio for progression-free survival (PFS) of the plurality of human patients compared to a control treatment of 0.76 or less; or (ii) the human patient is greater than 65 years of age, and administering treatment with the medicament to a plurality of human patients greater than 65 years of age results in an unstratified hazard ratio for PFS in the plurality of human patients compared to a control treatment of 0.77 or less, or an unstratified hazard ratio for PFS in the plurality of human patients compared to a control treatment of 0.78 or less; the control treatment is in the absence of polatuzumab vedotin; (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone Pharmaceuticals, including

20. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, the human patient has an International Prognostic Index (IPI) score between 3 and 5; administering treatment with the medicament to a plurality of human patients having an IPI score between 3 and 5, in the absence of polatuzumab vedotin; (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone or an unstratified hazard ratio for progression-free survival (PFS) of said plurality of human patients of 0.71 or less when compared to a control treatment comprising:

21. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, (i) the human patient has activated B-cell (ABC) DLBCL, and administering treatment with the medicament to a plurality of human patients with ABC DLBCL results in an unstratified hazard ratio for progression-free survival (PFS) of 0.36 or less for the plurality of human patients, or an unstratified hazard ratio for progression-free survival (PFS) of 0.39 or less for the plurality of human patients, as compared to a control treatment; or (ii) the human patient has double expressing lymphoma (DEL) DLBCL, and administering treatment with the medicament to a plurality of human patients with DEL DLBCL results in an unstratified hazard ratio for PFS of the plurality of human patients of 0.65 or less, or an unstratified hazard ratio for PFS of the plurality of human patients of 0.67 or less, compared to a control treatment; the control treatment is in the absence of polatuzumab vedotin; (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone Pharmaceuticals, including

22. The PFS is (a) from the start of the corresponding treatment to the first occurrence of disease progression, recurrence, or death; or (b) from a maximum of 7 days before the start of the corresponding treatment until the first occurrence of disease progression, relapse, or death; or (c) From the time of randomization to the first occurrence of disease progression, relapse, or death. The pharmaceutical composition according to any one of claims 16, 18, 19 and 21, wherein the

23. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, A medicament, wherein administering treatment with said medicament to a plurality of human patients results in a 24-month progression-free survival rate (PFS24) of at least 75%.

24. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, administering treatment with the medicament to a plurality of human patients results in an improvement in 24-month progression-free survival (PFS24) for said plurality of human patients as compared to a reference PFS24; The baseline PFS24 is in the absence of polatuzumab vedotin (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone 24-month progression-free survival rate of human patients receiving a control treatment comprising:

25. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, administering treatment with the medicament to a plurality of human patients results in at least about a 6% improvement in 24-month progression-free survival (PFS24) for said plurality of human patients as compared to a reference PFS24; The baseline PFS24 is in the absence of polatuzumab vedotin (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone 24-month progression-free survival rate of human patients receiving a control treatment comprising:

26. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, A medicament, wherein administering treatment with said medicament to a plurality of human patients results in a 12-month progression-free survival (PFS) rate of at least 83%.

27. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, administering treatment with the medicament to a plurality of human patients results in an improvement in 12-month progression-free survival (PFS) rate for the plurality of human patients as compared to a reference 12-month PFS rate; The baseline 12-month PFS rate in the absence of polatuzumab vedotin is: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone 12-month PFS rate for human patients receiving a control treatment comprising the medication.

28. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, administering treatment with the medicament to a plurality of human patients results in at least about a 3% improvement in 12-month progression-free survival (PFS) rate for said plurality of human patients as compared to a reference 12-month PFS rate; The baseline 12-month PFS rate in the absence of polatuzumab vedotin is: (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone The 12-month PFS of human patients receiving a control treatment comprising:

29. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, Administering treatment with the medicament to a plurality of human patients results in a baseline event-free survival (EFS) ｅｆｆ ) the EFS of the plurality of human patients as compared to ｅｆｆ leading to improvements in EFS of the above criteria ｅｆｆ However, in the absence of polatuzumab vedotin, (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone EFS of multiple human patients receiving control treatments including ｅｆｆ That is, medicine.

30. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, administering treatment with the medicament to a plurality of human patients in the absence of polatuzumab vedotin; (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone, or methylprednisolone event-free survival (EFS) in said plurality of human patients compared to a control treatment comprising ｅｆｆ a stratified hazard ratio of 0.77 or less for the EFS in said plurality of human patients ｅｆｆ A drug that results in a stratified hazard ratio of 0.81 or less.

31. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, 1. A medicament, wherein administering treatment with said medicament to a plurality of human patients results in a complete response (CR) rate at end of treatment (EOT) of at least about 77% in said plurality of human patients, said CR rate being assessed by positron emission tomography-computed tomography (PET-CT).

32. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, administering treatment with the medicament to a plurality of human patients results in an objective response rate (ORR) at end of treatment (EOT) of at least about 84% in said plurality of human patients, or an ORR at EOT of at least about 85% in said plurality of human patients; The ORR is assessed by positron emission tomography-computed tomography (PET-CT).

33. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, The human patient is over 60 years old.

34. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need of treatment, comprising an effective amount of polatuzumab vedotin in combination with (i) rituximab, (ii) cyclophosphamide, (iii) doxorubicin, and (iv) prednisone, prednisolone, or methylprednisolone, The human patient is over 65 years of age.

35. (a) the polatuzumab vedotin is administered to the human patient at a dose of about 1.8 mg / kg; (b) the rituximab is about 375 mg / m ２ administered to the human patient at a dose of (c) the cyclophosphamide is about 750 mg / m ２ administered to the human patient at a dose of (d) the doxorubicin is about 50 mg / m ２ is administered to said human patient at a dose of (e) The pharmaceutical composition of any one of claims 1 to 8, 12, 13, 15 to 21, and 23 to 34, wherein the prednisone is administered to the human patient at a dose of about 100 mg, the prednisolone is administered to the human patient at a dose of about 100 mg, or the methylprednisolone is administered to the human patient at a dose of about 80 mg.

36. (a) the polatuzumab vedotin is administered intravenously to the human patient at a dose of about 1.8 mg / kg; (b) the rituximab is about 375 mg / m ２ administered intravenously to said human patient at a dose of (c) the cyclophosphamide is about 750 mg / m ２ administered intravenously to said human patient at a dose of (d) the doxorubicin is about 50 mg / m ２ is administered intravenously to said human patient at a dose of (e) The pharmaceutical composition of any one of claims 1 to 8, 12, 13, 15 to 21, and 23 to 34, wherein the prednisone is administered orally to the human patient at a dose of about 100 mg, the prednisolone is administered orally to the human patient at a dose of about 100 mg, or the methylprednisolone is administered intravenously to the human patient at a dose of about 80 mg.

37. (a) the polatuzumab vedotin is administered to the human patient at a dose of about 1.0 mg / kg to about 1.8 mg / kg; (b) the rituximab is about 375 mg / m ２ administered to the human patient at a dose of (c) the cyclophosphamide is about 375 mg / m ２ ~Approx. 750mg / m ２ administered to the human patient at a dose of (d) the doxorubicin is about 25 mg / m ２ ~Approx. 50mg / m ２ is administered to said human patient at a dose of (e) The pharmaceutical composition of any one of claims 1 to 8, 12, 13, 15 to 21, and 23 to 34, wherein the prednisone is administered to the human patient at a dose of about 100 mg, the prednisolone is administered to the human patient at a dose of about 100 mg, or the methylprednisolone is administered to the human patient at a dose of about 80 mg.

38. (a) the polatuzumab vedotin is administered intravenously to the human patient at a dose of about 1.0 mg / kg to about 1.8 mg / kg; (b) the rituximab is about 375 mg / m ２ administered intravenously to said human patient at a dose of (c) the cyclophosphamide is about 375 mg / m ２ ~Approx. 750mg / m ２ administered intravenously to said human patient at a dose of (d) the doxorubicin is about 25 mg / m ２ ~Approx. 50mg / m ２ is administered intravenously to said human patient at a dose of (e) The pharmaceutical composition of any one of claims 1 to 8, 12, 13, 15 to 21, and 23 to 34, wherein the prednisone is administered orally to the human patient at a dose of about 100 mg, the prednisolone is administered orally to the human patient at a dose of about 100 mg, or the methylprednisolone is administered intravenously to the human patient at a dose of about 80 mg.

39. The control treatment of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone, or methylprednisolone is administered in 21-day cycles; (a) the rituximab is administered at a concentration of about 375 mg / m ２ administered intravenously on day 1 of each 21-day cycle at a dose of (b) the cyclophosphamide is about 750 mg / m ２ administered intravenously on day 1 of each 21-day cycle at a dose of (c) the doxorubicin is about 50 mg / m ２ administered intravenously on day 1 of each 21-day cycle at a dose of (d) the vincristine is about 1.4 mg / m ２ and up to 2 mg at each dose administered intravenously on day 1 of each 21-day cycle; and (e) The pharmaceutical composition of any one of claims 1 to 8, 12, 13, 15 to 21, 24, 25, and 27 to 30, wherein the prednisone is administered orally at a dose of about 100 mg / day on each of days 1 to 5 of each 21-day cycle, the prednisolone is administered orally at a dose of about 100 mg / day on each of days 1 to 5 of each 21-day cycle, or the methylprednisolone is administered intravenously at a dose of about 80 mg / day on each of days 1 to 5 of each 21-day cycle.

40. (a) the human patient has previously untreated DLBCL; (b) whether the DLBCL is CD20 positive; (c) the DLBCL is DLBCL of not specified type (NOS); (d) the DLBCL is germinal center B-cell DLBCL; (e) the DLBCL is activated B-cell (ABC) DLBCL; or (f) The DLBCL is double expression (DEL) DLBCL; The pharmaceutical composition according to any one of claims 1 to 8, 12, 13, 15 to 21, and 23 to 34.

41. The medicament of any one of claims 1 to 3, 7, 8, 12, 13, 15, 16, 18, 19, 21, 23 to 34, wherein the human patient has an International Prognostic Index (IPI) score between 2 and 5.

42. A kit comprising polatuzumab vedotin for use in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone to treat a human patient with diffuse large B-cell lymphoma (DLBCL) in need of treatment with the medicament of any one of claims 1 to 8, 12, 13, 15 to 21, and 23 to 34.

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