Methods of treating diffuse large b-cell lymphoma using anti-CD79b immunoconjugates

Abstract

The present application provides a method of using an immunoconjugate comprising an anti-CD79b antibody in combination with an anti-CD20 antibody, chemotherapy, and a corticosteroid to treat a B cell proliferative disorder, such as diffuse large B cell lymphoma 'DLBCL'.

Description

[0001] This application is a divisional application of the invention application with the application date of August 5, 2022, Chinese application number 202280065851.7, and invention name “Method for treating diffuse large B-cell lymphoma using anti-CD79B immunoconjugate”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 282,002, filed on November 22, 2021, U.S. Provisional Application No. 63 / 230,735, filed on August 7, 2021, and U.S. Provisional Application No. 63 / 230,725, filed on August 7, 2021, each of which is incorporated herein by reference in its entirety.

[0004] References to electronic sequence listings

[0005] The contents of the electronic sequence listing (146392054640SEQLIST.xml; size: 75,734 bytes; and creation date: August 4, 2022) are incorporated herein by reference in their entirety. Technical Field

[0006] 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 Art

[0007] Non-Hodgkin lymphoma (NHL) is the most common hematological malignancy worldwide and ranks 13th among the most common cancers 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 rapidly enlarging masses, often accompanied by local and systemic symptoms of fever, recurrent night sweats and / or weight loss. Approximately 45% to 60% of patients have advanced disease (Ann Arbor stage III or IV). The incidence of DLBCL increases with age, with a median age of 64 years at onset (Armitage and Weisenburger, J Clin Oncol (1998) 6:2780-95). If untreated, patients with DLBCL have a median survival of approximately 6 months.

[0008] More than 20 years ago, rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) was determined to be the standard of care (SoC) therapy for DLBCL. The method for improving the current SoC therapy for DLBCL has been largely unsuccessful. These methods include attempting 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), and experimental treatments, such as those tested in large studies of DLBCL, including BO21005 / GOYA (Vitolo et al., Blood (2016) 128: 470), DA-EPOCH-R (Wilson et al., Blood (2016) 128: 469) and REMAC (Thieblemont et al., Blood (2016) 128: 471). Overall, since R-CHOP was established as a SoC therapy for DLBLC, 11 randomized phase III studies have failed to show any benefit compared with R-CHOP in first-line DLBCL.

[0009] For patients who are not cured by the therapy for previously untreated DLBCL, high-dose chemotherapy and subsequent autologous stem cell transplantation provide a second chance of cure. However, about 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 considerable number of patients do not meet the conditions of this radical therapy due to age or comorbidities. Patients who relapse after stem cell transplantation or do not meet the conditions of stem cell transplantation due to refractory disease or weakness have poor results. In most cases, the response rate to subsequent therapy is within the range of 10% to 35% (Seyfarth et al., Br J Haematol (2006) 133 (1): 3-18), with only occasional persistent responses. The fact that most patients who are not cured by standard first-line R-CHOP or comparable chemoimmunotherapy will die of lymphoma highlights the need for new methods for first-line therapy of this aggressive disease.

[0010] Therefore, there is a need in the art for new treatment methods for patients with DLBCL, such as previously untreated DLBCL.

[0011] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety. Summary of the Invention

[0012] In some aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) an immunoconjugate comprising the formula:

[0013]

[0014] Wherein Ab is an anti-CD79b antibody, the anti-CD79b antibody comprises: (i) a hypervariable region-H1 (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: NO:26 amino acid sequence, and wherein 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 an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, wherein the reference PFS is the PFS of a plurality of human patients who have received a control treatment, the control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone or methylprednisolone, but without the presence of an immunoconjugate. In some embodiments, PFS is measured or referenced to PFS: (a) from the start of the corresponding treatment to the time of the first occurrence of disease progression, relapse or death; or (b) from the start of up to 7 days before the start of the corresponding treatment to the time of the first occurrence of disease progression, relapse or death; or (c) from the time of randomization to the time of the first occurrence of disease progression, relapse or death. In some embodiments, PFS or reference PFS is the median PFS of a plurality of 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, wherein the hazard ratio does not exceed 0.75 (95% confidence interval: 0.57, 0.97). In some embodiments, the improvement in PFS is statistically significant, wherein the hazard ratio does not exceed 0.78 (95% confidence interval: 0.60, 1.00). In some embodiments, the improvement in PFS is statistically significant, wherein the hazard ratio does not exceed 0.79 (95% confidence interval: 0.61, 1.02).

[0015] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, wherein the reference PFS is the PFS of a plurality of human patients who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0016] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 60 years of age, wherein administration of such treatment to a plurality of human patients older than 60 years of age results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, and wherein the reference PFS is the PFS of a plurality of human patients older than 60 years of age who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0017] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 65 years of age, wherein administration of such treatment to a plurality of human patients older than 65 years of age results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, and wherein the reference PFS is the PFS of a plurality of human patients older than 65 years of age who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0018] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (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, wherein administration of such treatment to a plurality of human patients with an IPI score between 3 and 5 results in improved progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, and wherein the reference PFS is the PFS of a plurality of human patients with an IPI score between 3 and 5 who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0019] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 60 years of age and has an International Prognostic Index (IPI) score between 3 and 5, wherein administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 60 years of age and has an International Prognostic Index (IPI) score between 3 and 5 administration of such treatment 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 compared to a reference PFS, and wherein the reference PFS is the PFS of a plurality of human patients older than 60 years and having an IPI score between 3 and 5 who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0020] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 65 years of age and has an International Prognostic Index (IPI) score between 3 and 5, wherein administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 65 years of age and has an International Prognostic Index (IPI) score between 3 and 5 administration of such treatment 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 compared to a reference PFS, and wherein the reference PFS is the PFS of a plurality of human patients older than 65 years and having an IPI score between 3 and 5 who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0021] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient has activated B-cell (ABC) DLBCL, wherein administration of such treatment to a plurality of human patients with ABC DLBCL results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, and wherein the reference PFS is the PFS of a plurality of human patients with ABC DLBCL who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0022] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient has double-expressing lymphoma (DEL)-type DLBCL, wherein administration of such treatment to a plurality of human patients with DEL-type DLBCL results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, and wherein the reference PFS is the PFS of a plurality of human patients with DEL-type DLBCL who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0023] In some embodiments that may be combined with any of the preceding aspects or embodiments, PFS is measured or referenced to PFS: (a) from the start of the corresponding treatment to the time of first disease progression, relapse, or death; or (b) from up to 7 days before the start of the corresponding treatment to the time of first disease progression, relapse, or death; or (c) from the time of randomization to the time of first disease progression, relapse, or death. In some embodiments that may be combined with any of the preceding aspects or embodiments, PFS or referenced to PFS is the median PFS of a plurality of human patients receiving the corresponding treatment. In some embodiments that may be combined with any of the preceding aspects or embodiments, the improvement in PFS is statistically significant.

[0024] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in at least a 25% reduction in the risk of disease progression, relapse, or death in 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 vepotuzumab.

[0025] In other aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in a reduction in the risk of disease progression, relapse, or death in the plurality of human patients of at least 20%, 21%, 22%, 23%, or 24%, compared to a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0026] In some embodiments, the disease progression, relapse, or death is measured: (a) from the start of the corresponding treatment to the time of the first occurrence of disease progression, relapse, or death; or (b) from the start of the corresponding treatment up to 7 days before the start of the corresponding treatment to the time of the first occurrence of disease progression, relapse, or death; or (c) from the time of randomization to the time of the first occurrence of disease progression, relapse, or death. In some embodiments, the reduction in risk of disease progression, relapse, or death is calculated over 12 months, 24 months, or longer, and is measured from: (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 time of the first occurrence of disease progression, relapse, or death.

[0027] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in a stratified hazard ratio for progression-free survival (PFS) of no more than 0.75 for 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 vepotuzumab.

[0028] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in a stratified hazard ratio for progression-free survival (PFS) of no more than 0.78 for 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 vepotuzumab.

[0029] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in an unstratified hazard ratio for progression-free survival (PFS) of no more than 0.79 for 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 vepotuzumab.

[0030] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein: (i) the human patient is older than 60 years of age, and wherein administration of such treatment to a plurality of human patients older than 60 years of age results in a decrease in the number of human patients' disease progression compared to a control treatment. The invention provides a method for treating a plurality of human patients who are older than 65 years of age or older, wherein the stratified hazard ratio for progression-free survival (PFS) of the plurality of human patients does not exceed 0.72, or (ii) the human patients are older than 65 years of age, and wherein administration of such treatment to a plurality of human patients who are older than 65 years of age results in a stratified hazard ratio for PFS of the plurality of human patients does not exceed 0.79 as compared to a control treatment; wherein the control treatment comprises: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0031] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (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 administration of such treatment to a plurality of human patients having an IPI score between 3 and 5 results in a stratified hazard ratio for progression-free survival (PFS) of no more than 0.68 for 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 vepotuzumab.

[0032] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein: (i) the human patient has activated B-cell (ABC) DLBCL, and wherein administration of such treatment to a plurality of human patients having ABC DLBCL results in a decrease in the number of human patients compared to a control treatment; The invention provides a method for treating a plurality of human patients with DLBCL of the present invention wherein the stratified hazard ratio for progression-free survival (PFS) does not exceed 0.31, or (ii) the human patients have double-expressing lymphoma (DEL)-type DLBCL, and wherein administration of such treatment to a plurality of human patients with DEL-type DLBCL results in a stratified hazard ratio for PFS of the plurality of human patients of no more than 0.62, compared to a control treatment; wherein the control treatment comprises: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0033] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein: (i) the human patient is older than 60 years of age, and wherein administration of such treatment to a plurality of human patients older than 60 years of age results in an improvement in the number of human patients compared to a control treatment. The invention provides a method for treating a plurality of human patients aged 65 years and wherein the treatment results in an unstratified hazard ratio for progression-free survival (PFS) of no more than 0.72 for the human patients, or (ii) the human patients are older than 65 years of age, and wherein administration of such treatment to a plurality of human patients older than 65 years of age results in an unstratified hazard ratio for PFS of no more than 0.77 for the human patients, compared to a control treatment; wherein the control treatment comprises: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0034] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein: (i) the human patient is older than 60 years of age, and wherein administration of such treatment to a plurality of human patients older than 60 years of age results in an improvement in the number of human patients compared to a control treatment. The invention provides a method for treating a plurality of human patients aged 65 years and wherein the treatment results in an unstratified hazard ratio for progression-free survival (PFS) of no more than 0.76 for the human patient, or (ii) the human patient is older than 65 years of age, and wherein administration of such treatment to a plurality of human patients older than 65 years of age results in an unstratified hazard ratio for PFS of no more than 0.78 for the plurality of human patients compared to a control treatment; wherein the control treatment comprises: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0035] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (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 administration of such treatment to a plurality of human patients with an IPI score between 3 and 5 results in an unstratified hazard ratio for progression-free survival (PFS) of no more than 0.71 for 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 vepotuzumab.

[0036] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (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 administration of such treatment to a plurality of human patients with an IPI score between 3 and 5 results in an unstratified hazard ratio for progression-free survival (PFS) of no more than 0.75 for 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 vepotuzumab.

[0037] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein: (i) the human patient has activated B-cell (ABC) DLBCL, and wherein administration of such treatment to a plurality of human patients having ABC DLBCL results in a decrease in the number of human patients compared to a control treatment; The invention provides a method for treating a plurality of human patients with DLBCL of the present invention wherein the human patient has an unstratified hazard ratio for progression-free survival (PFS) of no more than 0.36, or (ii) the human patient has double-expressing lymphoma (DEL)-type DLBCL, and wherein administration of such treatment to a plurality of human patients with DEL-type DLBCL results in an unstratified hazard ratio for PFS of no more than 0.67 for the plurality of human patients compared to a control treatment; wherein the control treatment comprises: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone or methylprednisolone, in the absence of vepotuzumab.

[0038] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein: (i) the human patient has activated B-cell (ABC) DLBCL, and wherein administration of such treatment to a plurality of human patients having ABC DLBCL results in a decrease in the number of human patients compared to a control treatment; The invention provides a method for treating a plurality of human patients with DLBCL of the present invention wherein the human patient has an unstratified hazard ratio for progression-free survival (PFS) of no more than 0.39, or (ii) the human patient has double-expressing lymphoma (DEL)-type DLBCL, and wherein administration of such treatment to a plurality of human patients with DEL-type DLBCL results in an unstratified hazard ratio for PFS of no more than 0.65 for the plurality of human patients compared to a control treatment; wherein the control treatment comprises: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone or methylprednisolone, in the absence of vepotuzumab.

[0039] In some embodiments that may be combined with any of the preceding aspects or embodiments, PFS is measured: (a) from the start of corresponding treatment to the time to the first occurrence of disease progression, relapse, or death; or (b) from the start of corresponding treatment up to 7 days before the start of the treatment to the time to the first occurrence of disease progression, relapse, or death; or (c) from the time of randomization to the time to the first occurrence of disease progression, relapse, or death. In some embodiments that may be combined with any of the preceding aspects or embodiments, the stratified hazard ratios are stratified by: (a) 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 except (i)-(ii); (b) an International Prognostic Index (IPI) score of 2 and 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 treatment results in a statistically significant improvement in PFS compared to the control treatment, wherein the stratified hazard ratio does not exceed 0.75 (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 treatment results in a statistically significant improvement in PFS compared to the control treatment, wherein the stratified hazard ratio does not exceed 0.78 (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 treatment results in a statistically significant improvement in PFS compared to the control treatment, wherein the unstratified hazard ratio does not exceed 0.79 (95% confidence interval: 0.61, 1.02). In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) administration of such treatment to a plurality of human patients older than 60 years results in an improvement in PFS compared to the control treatment, wherein the stratified hazard ratio does not exceed 0.72 (95% confidence interval: 0.52, 0.99); or (b) administration of such treatment to a plurality of human patients older than 65 years results in an improvement in PFS compared to the control treatment, wherein the stratified hazard ratio does not exceed 0.79 (95% confidence interval: 0.54, 1.14). In some embodiments that may be combined with any of the preceding aspects or embodiments, administration of such 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, wherein the stratified hazard ratio does not exceed 0.68 (95% confidence interval: 0.50, 0.94).In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) administration of such treatment to a plurality of human patients with ABC-type DLBCL results in an improvement in PFS compared to the control treatment, wherein the stratified hazard ratio does not exceed 0.31 (95% confidence interval: 0.17, 0.56); or (b) administration of such treatment to a plurality of human patients with DEL-type DLBCL results in an improvement in PFS compared to the control treatment, wherein the stratified hazard ratio does not exceed 0.62 (95% confidence interval: 0.40, 0.97). In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) administration of such treatment to a plurality of human patients aged 60 years and older results in an improvement in PFS compared to the control treatment, wherein the unstratified hazard ratio does not exceed 0.72 (95% confidence interval: 0.53, 0.99); or (b) administration of such treatment to a plurality of human patients aged 65 years and older results in an improvement in PFS compared to the control treatment, wherein the unstratified hazard ratio does not exceed 0.77 (95% confidence interval: 0.54, 1.10). In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) administration of such treatment to a plurality of human patients older than 60 years results in an improvement in PFS compared to the control treatment, wherein the unstratified hazard ratio does not exceed 0.76 (95% confidence interval: 0.56, 1.02); or (b) administration of such treatment to a plurality of human patients older than 65 years results in an improvement in PFS compared to the control treatment, wherein the unstratified hazard ratio does not exceed 0.78 (95% confidence interval: 0.56, 1.10). In some embodiments that may be combined with any of the preceding aspects or embodiments, administration of such 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, wherein the unstratified hazard ratio does not exceed 0.71 (95% confidence interval: 0.51, 0.97). In some embodiments that may be combined with any of the preceding aspects or embodiments, administration of such treatment to a plurality of human patients having an IPI score between 3 and 5 results in an improvement in PFS compared to the control treatment, wherein the unstratified hazard ratio does not exceed 0.75 (95% confidence interval: 0.55, 1.01). In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) administration of such treatment to a plurality of human patients having ABC-type DLBCL results in an improvement in PFS compared to the control treatment, wherein the unstratified hazard ratio does not exceed 0.36 (95% confidence interval: 0.21, 0.62); or (b) administration of such treatment to a plurality of human patients having DEL-type DLBCL results in an improvement in PFS compared to the control treatment, wherein the unstratified hazard ratio does not exceed 0.67 (95% confidence interval: 0.44, 1.02).In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) administration of such treatment to a plurality of human patients with ABC-type DLBCL results in an improvement in PFS compared to the control treatment, wherein the unstratified hazard ratio does not exceed 0.39 (95% confidence interval: 0.23, 0.65); or (b) administration of such treatment to a plurality of human patients with DEL-type DLBCL results in an improvement in PFS compared to the control treatment, wherein the unstratified hazard ratio does not exceed 0.65 (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 ratios are calculated over 12 months, 24 months, or longer, measured from: (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 time of first occurrence of disease progression, relapse, or death.

[0040] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of 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 starting from: (a) the start of treatment; or (b) up to 7 days before the start of treatment; or (c) the time of randomization, to the time of first occurrence of disease progression, relapse, or death.

[0041] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in an improvement in the 24-month progression-free survival rate (PFS24) of the plurality of human patients compared to a reference PFS24, wherein the reference PFS24 is the 24-month progression-free survival rate of a plurality of human patients who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0042] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in an improvement in the 24-month progression-free survival rate (PFS24) of the plurality of human patients by at least about 6% compared to a reference PFS24, wherein the reference PFS24 is the 24-month progression-free survival rate of a plurality of human patients who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0043] In some embodiments that may be combined with any of the preceding aspects or embodiments, PFS24 or reference PFS24 is calculated at 24 months, measured starting from: (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 time of first occurrence of disease progression, relapse or death. In some embodiments that may be combined with any of the preceding aspects or embodiments, PFS24 or reference PFS24 is the progression-free survival (PFS) rate calculated using the Kaplan-Meier method.

[0044] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of 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, 12-month PFS is calculated at 12 months, measured starting from: (a) the start of treatment; or (b) up to 7 days prior to the start of treatment; or (c) the time of randomization, to the time of first occurrence of disease progression, relapse, or death.

[0045] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in an improvement in the 12-month progression-free survival (PFS) rate of the plurality of human patients compared to a reference 12-month PFS rate, wherein the reference 12-month PFS rate is the 12-month PFS rate of a plurality of human patients who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0046] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in an improvement in the 12-month progression-free survival (PFS) rate of the plurality of human patients by at least about 3% compared to a reference 12-month PFS rate, wherein the reference 12-month PFS rate is the 12-month PFS rate of a plurality of human patients who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0047] 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 starting from: (a) the start of the corresponding treatment; or (b) up to 7 days before the start of the corresponding treatment; or (c) starting from the time of randomization to the time of first occurrence of disease progression, relapse, 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.

[0048] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in an event-free survival (EFS) of the plurality of human patients. eff ) and reference EFS eff Improved compared to the reference EFS eff EFS of multiple human patients who have received control treatment eff , the control treatment comprises: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab. In some embodiments, EFS is measured eff Or refer to EFS eff :(a) Starting from the start of corresponding treatment to the first occurrence of EFS eff Time of event; or (b) starting up to 7 days before the start of corresponding treatment to the first occurrence of EFS eff Time to event; or (c) from the time of randomization to the first occurrence of EFS eff In some embodiments, EFS eff In some embodiments, EFS eff Improvement in EFS was calculated at 12 months, 24 months, or longer, with measurements starting from: (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 EFS. eff The time of the event.

[0049] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in an event-free survival (EFS) improvement in the plurality of human patients compared to a control treatment. eff ) with a stratified hazard ratio of no more than 0.77 for the comparator treatment group consisting of: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0050] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in an event-free survival (EFS) improvement in the plurality of human patients compared to a control treatment. eff ) with a stratified hazard ratio of no more than 0.81 for the comparator treatment group consisting of: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0051] In some embodiments, EFS is measured eff :(a) Starting from the start of corresponding treatment to the first occurrence of EFS eff Time of event; or (b) starting up to 7 days before the start of corresponding treatment to the first occurrence of EFS eff Time to event; or (c) from the time of randomization to the first occurrence of EFS eff In some embodiments, administration of such treatment results in an EFS compared to a control treatment. eff A statistically significant improvement is achieved, with a stratified hazard ratio of no more than 0.77 (95% confidence interval: 0.59, 1.00). In some embodiments, administration of such treatment results in an EFS of 1.5% or less compared to a control treatment. eff A statistically significant improvement was achieved, with a stratified hazard ratio of no more than 0.81 (95% confidence interval: 0.63, 1.04). In some embodiments, the hazard ratio is calculated at 12 months, 24 months, or longer, with measurements starting from: (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 EFS eff The time of the event.

[0052] In some embodiments that may be combined with any of the preceding aspects or embodiments, the EFS effThe event is: (a) disease progression; (b) disease relapse; (c) death; (d) leading to initiation of non-protocol-specified anti-lymphoma therapy (NALT) that is not a primary efficacy reason for disease progression or relapse; or (e) a positive biopsy for residual disease. In some embodiments that may be combined with any of the preceding aspects or embodiments, the stratified hazard ratios are stratified by: (a) geographic region selected from the group consisting of: (i) Asia, (ii) Western Europe, United States, Canada, or Australia, and (iii) rest of the world except (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.

[0053] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in a complete remission (CR) rate of at least about 77% in the plurality of human patients at the end of treatment (EOT), 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 a blinded independent central review committee (BICR). In some embodiments, administration of such treatment to a plurality of human patients results in an improvement in CR rate in the plurality of human patients by at least about 3% compared to a plurality of human patients who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0054] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in an objective response rate (ORR) of at least about 85% in the plurality of human patients at end of treatment (EOT), wherein the ORR is assessed by positron emission tomography-computed tomography (PET-CT).

[0055] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in an objective response rate (ORR) of at least about 84% in the plurality of human patients at end of treatment (EOT), wherein the ORR is assessed by positron emission tomography-computed tomography (PET-CT).

[0056] In some embodiments, the ORR is assessed by an investigator or by a blinded independent central review committee (BICR). In some embodiments, administration of such treatment to a plurality of human patients results in an improvement in the ORR of the plurality of human patients by at least about 2% compared to a plurality of human patients who have received a control treatment comprising: (a) rituximab; (b) cyclophosphamide; (c) doxorubicin; (d) vincristine; and (e) prednisone, prednisolone, or methylprednisolone, in the absence of vepotuzumab.

[0057] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 60 years old.

[0058] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 65 years of age.

[0059] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (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.

[0060] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 60 years old and has an International Prognostic Index (IPI) score between 3 and 5.

[0061] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 65 years of age and has an International Prognostic Index (IPI) score between 3 and 5.

[0062] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient has activated B-cell (ABC) DLBCL.

[0063] In certain aspects, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab; (b) rituximab; (c) cyclophosphamide; (d) doxorubicin; and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient has a dual-expressing lymphoma (DEL) type DLBCL.

[0064] In some embodiments that may be combined with any of the preceding aspects or embodiments, vepotuzumab 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 2 In 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 2In 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.

[0065] In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) vepotuzumab 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 human patients at a dose of about 750 mg / m 2 (d) doxorubicin is administered to human patients at a dose of about 50 mg / m 2 and (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.

[0066] In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) vepotuzumab 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 human patients 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 and (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.

[0067] In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) vepotuzumab 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 / kg 2 (c) cyclophosphamide was administered to human patients at a dose of about 375 mg / m 2 Up to about 750 mg / m 2 (d) doxorubicin is administered to human patients at a dose of about 25 mg / m 2 Up to 50 mg / m 2and (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.

[0068] In some embodiments that may be combined with any of the preceding aspects or embodiments, (a) vepotuzumab 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 / kg 2 (c) cyclophosphamide was administered intravenously to human patients at a dose of about 375 mg / m 2 Up to 750 mg / m 2 (d) doxorubicin is administered intravenously to human patients at a dose of about 25 mg / m 2 Up to 50 mg / m 2 and (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.

[0069] In some embodiments that may be combined with any of the preceding aspects or embodiments, vepotuzumab, rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone are administered to a human patient in a 21-day cycle. In some embodiments, vepotuzumab, rituximab, cyclophosphamide, and doxorubicin are administered on Day 1 of each 21-day cycle; and prednisone, prednisolone, or methylprednisolone is administered on Days 1 to 5 of each 21-day cycle. In some embodiments, (a) vepotuzumab 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 about 375 mg / m on Day 1 of each 21-day cycle. 2 (c) cyclophosphamide is administered intravenously to human patients at a dose of approximately 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 and (e) prednisone is administered orally to a human patient at a dose of about 100 mg / day on each of days 1 to 5 of each 21 day cycle; 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 methylprednisolone is administered intravenously to a human patient at a dose of about 80 mg / day on each of days 1 to 5 of each 21 day cycle.

[0070] In some embodiments that may be combined with any of the preceding aspects or embodiments, vepotuzumab, 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, vepotuzumab, 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, vepotuzumab, rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone are administered for six 21-day cycles.

[0071] In some embodiments that may be combined with any of the preceding aspects or embodiments, the control treatment of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone, or methylprednisolone is administered in a 21-day cycle. 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 to 5 of each 21-day cycle. In some embodiments, (a) rituximab is administered on Day 1 of each 21-day cycle at a dose of about 375 mg / m 2 (b) cyclophosphamide was 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 (e) prednisone is orally administered at a dose of about 100 mg / day on each of days 1 to 5 of each 21-day cycle; prednisolone is orally administered at a dose of about 100 mg / day on each of days 1 to 5 of each 21-day cycle; or methylprednisolone is orally administered at a dose of about 80 mg / day on each of days 1 to 5 of each 21-day cycle. In some embodiments that may be combined with any of the foregoing 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 foregoing 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.

[0072] In some embodiments that may be combined with any of the preceding aspects or embodiments, vepotuzumab, 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, vepotuzumab, 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, vepotuzumab, rituximab, cyclophosphamide, doxorubicin, and prednisolone are administered to a human patient.

[0073] In some embodiments that may be combined with any of the preceding aspects or embodiments, vepotuzumab, 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; rituximab is administered before vepotuzumab; and vepotuzumab is administered before cyclophosphamide and doxorubicin; or (b) rituximab, vepotuzumab, cyclophosphamide, and doxorubicin are administered in any order after administration of prednisone, prednisolone, or methylprednisolone.

[0074] 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 the seventh and eighth 21-day cycles following the sixth 21-day cycle; or (b) administering rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone to the human patient during the seventh and eighth 21-day cycles following the sixth 21-day cycle. In some embodiments, the method comprises administering rituximab monotherapy to the human patient on day 1 of each of the seventh and eighth 21-day cycles at a dose of about 375 mg / m 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 on day 1 of each of the seventh and eighth 21-day cycles at a dose of about 375 mg / m 2 (b) cyclophosphamide is administered intravenously at a dose of approximately 750 mg / m on day 1 of each of the seventh and eighth 21-day cycles. 2 (c) doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each of the seventh and eighth 21-day cycles. 2 (d) prednisone is administered orally at a dose of about 100 mg / day on each of days 1 to 5 of each of the seventh and eighth 21-day cycles; prednisolone is administered orally at a dose of about 100 mg / day on each of days 1 to 5 of each of the seventh and eighth 21-day cycles; or methylprednisolone is administered intravenously at a dose of about 80 mg / day on each of days 1 to 5 of each of the seventh and eighth 21-day cycles.

[0075] In some embodiments that may be combined with any of the preceding aspects or embodiments, the control treatment of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone, or methylprednisolone is administered sequentially on day 1 of each 21-day cycle. In some embodiments, (a) prednisone, prednisolone, or methylprednisolone is administered before rituximab; and rituximab 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 the seventh and eighth 21-day cycles after the sixth 21-day cycle; or (b) rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone, or methylprednisolone during the seventh and eighth 21-day cycles after the sixth 21-day cycle. In some embodiments, the control treatment further comprises rituximab monotherapy on day 1 of each of the seventh and eighth 21-day cycles at about 375 mg / m 2 In some embodiments, the control treatment further comprises rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone, or methylprednisolone during the seventh and eighth 21-day cycles following the sixth 21-day cycle, wherein: (a) rituximab is administered at about 375 mg / m2 on Day 1 of each of the seventh and eighth 21-day cycles; 2 (b) cyclophosphamide is administered intravenously at a dose of approximately 750 mg / m on day 1 of each of the seventh and eighth 21-day cycles. 2 (c) doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of each of the seventh and eighth 21-day cycles. 2 (d) vincristine is administered intravenously at a dose of approximately 1.4 mg / m on day 1 of each of the seventh and eighth 21-day cycles. 2 and (e) prednisone is administered orally at a dose of about 100 mg / day on each of days 1 to 5 of each of the seventh and eighth 21-day cycles; prednisolone is administered orally at a dose of about 100 mg / day on each of days 1 to 5 of each of the seventh and eighth 21-day cycles; or methylprednisolone is administered intravenously at a dose of about 80 mg / day on each of days 1 to 5 of each of the seventh and eighth 21-day cycles.

[0076] In some embodiments that can be combined with any one of the foregoing aspects or embodiments, the method further comprises administering an antihistamine, an analgesic and / or an antipyretic to the human patient. In some embodiments that can be combined with any one of the foregoing 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, G-CSF is filgrastim, or lenograstim, or pegfilgrastim.

[0077] 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 In some embodiments, the method further comprises administering to the human patient a prophylactic therapy for tumor lysis syndrome. In some embodiments, the prophylactic therapy for tumor lysis syndrome comprises administering to the human patient allopurinol or rasburicase. In some embodiments, the prophylactic therapy for tumor lysis syndrome comprises administering to the human patient a hydration regimen. In some embodiments, the hydration regimen comprises administering to the human patient about 3 liters / day of liquid between 1 day and 2 days before the start of treatment for DLBCL.

[0078] In some embodiments that may be combined with any of the preceding aspects or embodiments, the human patient has previously untreated DLBCL.

[0079] 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 DLBCL, not otherwise specified (NOS). In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is germinal center B cell DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is activated B cell (ABC) DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is dual expression (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 (double hit lymphoma or triple hit lymphoma) containing MYC, BCL2 and / or BCL6 rearrangements; or (h) high-grade B cell lymphoma, NOS.

[0080] 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 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 between 3 and 5.

[0081] 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 greater than 1.5 cm in its longest dimension as measured by computed tomography (CT) or magnetic resonance imaging (MRI).

[0082] 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 prior to the start 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 demyelinating form of Charcot-Marie-Tooth disease prior to the start 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 indolent lymphoma prior to the start 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, prior to the initiation of treatment for DLBCL: (a) grade 3B follicular lymphoma; (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's lymphoma; (f) primary or secondary involvement of the central nervous system (CNS) lymphoma; (g) primary effusion DLBCL; or (h) primary cutaneous DLBCL.

[0083] 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.

[0084] 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.

[0085] In certain aspects, provided herein is a kit comprising vepotuzumab for use in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone to treat a human patient in need thereof having diffuse large B-cell lymphoma (DLBCL) according to any of the methods provided herein. In some embodiments, the DLBCL is previously untreated DLBCL.

[0086] In certain aspects, provided herein is vepotuzumab for use in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, prednisolone, or methylprednisolone to treat a human patient in need thereof having diffuse large B-cell lymphoma (DLBCL) according to any of the methods provided herein. In some embodiments, the DLBCL is previously untreated DLBCL.

[0087] It should be understood that one, part, 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 become apparent to those skilled in the art. These and other embodiments of the present invention are further described by the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figure 1 Schematic diagram of the study design described in Example 1. DLBCL = diffuse large B-cell lymphoma; ECOGPS = 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.

[0089] Figure 2 Schematic representation of the treatment regimen used in the studies described in the Examples.

[0090] Figure 3 Figure 5 is a Kaplan-Meier plot of investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) patient population as described in the Examples.

[0091] Figure 4A and 4B as well as Figure 5A and 5B A time-to-event summary of investigator-assessed PFS in the ITT patient population as described in the Examples is provided.

[0092] Figure 6 A forest plot showing stratified hazard ratios for PFS by biomarker subgroup as assessed by investigator in the ITT patient population as described in the Examples is provided.

[0093] Figure 7 and Figure 8 A forest plot showing stratified hazard ratios for PFS by subgroup of baseline characteristics as assessed by investigator in the ITT patient population as described in the Examples is provided.

[0094] Figure 9A and 9B A summary of the overall AE characteristics of the safety-evaluable patient population as described in the Examples is provided.

[0095] Figure 10A and 10B A forest plot showing unstratified hazard ratios for PFS by subgroup of baseline characteristics as assessed by investigator in the ITT patient population as described in the Examples is provided.

[0096] Figure 11A forest plot showing unstratified hazard ratios for PFS by biomarker subgroup as assessed by investigator in the ITT patient population as described in the Examples is provided.

[0097] Figures 12A to 12E A summary of the demographic and baseline characteristics of the patients in the ITT patient population as described in the Examples is provided. Figure 12A The age, sex, and race of patients in the ITT population are provided. Figure 12B The ethnicity, baseline weight, baseline height, baseline Eastern Cooperative Oncology Group (ECOG) status, and Ann Arbor stage of patients in the ITT population were provided. Figure 12C Stratified International Prognostic Index (IPI) scores, screening-period IPI scores, stratified bulky disease status, baseline bulky disease status, and stratified geographic regions are provided for patients in the ITT population. Figure 12D Baseline lactate dehydrogenase (LDH) status, bone marrow involvement status at diagnosis, number of extranodal sites, time from diagnosis to study treatment administration, and non-Hodgkin lymphoma (NHL) histologic diagnosis were provided for patients in the ITT population. Figure 12E Cell of origin (COO), double-expressing lymphoma status (determined by immunohistochemistry [IHC]), and double / triple hit (DH / TH) lymphoma status of patients in the ITT cohort are provided.

[0098] Figure 13 A summary of the best overall response (BOR) as assessed by the investigator (INV) in the ITT patient population as described in the Examples is provided. Stratification factors included the International Prognostic Index (IPI) score, bulky disease status, and geographic region. 95% confidence intervals (CIs) for the ratios were constructed using the Clopper-Pearson method. 95% CIs for the differences in response rates were constructed using the Wilson method.

[0099] Figures 14A to 14C A time-to-event summary of disease-free survival (DFS; assessed by INV) of best overall response (BOR) complete responders in the ITT patient population as described in the Examples is provided. Figure 14A The percentages of patients who did and did not experience a DFS event, the time to event (in months), and stratified and unstratified hazard ratios are presented. Figures 14B to 14C Provided at 6, 12, 18 and 24 month duration points ( Figure 14B ) and at the 30-month and 36-month duration points ( Figure 14C ), the number of patients remaining at risk, the event-free rate and 95% confidence interval (CI), and the difference in event-free rate and 95% CI. Figures 14A to 14CDFS (median, percentiles) assessed by INV are summarized as Kaplan-Meier estimates. The 95% CI for the median was calculated using the method of Brookmeyer and Crowley. Hazard ratios were estimated by Cox regression. Stratification factors included geographic region, International Prognostic Index (IPI) score, and bulky disease (defined as a lesion ≥7.5 cm). Asterisks (*) indicate censored observations.

[0100] Figures 15A to 15C A time-to-event summary of duration of response (DOR; assessed by INV) for best overall response (BOR) complete responders in the ITT patient population as described in the Examples is provided. Figure 15A The percentages of patients who did and did not experience a DOR event, the time to event (in months), and stratified and unstratified hazard ratios are presented. Figures 15B to 15C Provided at 6, 12, 18 and 24 month duration points ( Figure 15B ) and at the 30-month and 36-month duration points ( Figure 15C ), the number of patients still at risk, the event-free rate and 95% CI, and the difference in event-free rate and 95% CI. Figures 15A to 15C The DOR (median, percentiles) assessed by INV are summarized as Kaplan-Meier estimates. The 95% CI for the median was calculated using the method of Brookmeyer and Crowley. Hazard ratios were estimated by Cox regression. Stratification factors included geographic region, International Prognostic Index (IPI) score, and bulky disease (defined as a lesion ≥7.5 cm). Asterisks (*) indicate censored observations.

[0101] Figures 16A to 16C A time-to-event summary of overall survival (OS) in the ITT patient population as described in the Examples is provided. Figure 16A The percentages of patients with and without OS events, time to event (in months), and stratified and unstratified p values ​​and hazard ratios are presented. Figures 16B to 16C Provided at 6, 12, 18 and 24 month duration points ( Figure 16B ) and at the 30-month and 36-month duration points ( Figure 16C ), the number of patients still at risk, the event-free rate and 95% CI, and the difference in event-free rate and 95% CI. Figures 16A to 16COS (median, percentiles) are summarized as Kaplan-Meier estimates. The 95% CI for the median was calculated using the method of Brookmeyer and Crowley. Hazard ratios were estimated by Cox regression. Stratification factors included geographic region, International Prognostic Index (IPI) score, and bulky disease (defined as a lesion ≥7.5 cm). Asterisks (*) indicate censored observations.

[0102] Figure 17 A forest plot of unstratified hazard ratios for PFS by biomarker subgroup as assessed by the investigator in the intention-to-treat (ITT) patient population as described in the Examples is provided.

[0103] Figure 18A and Figure 18B A forest plot showing unstratified hazard ratios for PFS by subgroup of baseline characteristics as assessed by investigator in the intention-to-treat (ITT) patient population as described in the Examples is provided.

[0104] Figure 19 The event-free survival (EFS) was assessed by the investigator in the intention-to-treat (ITT) patient population as described in the Examples. eff ) Kaplan-Meier plot.

[0105] Figure 20 Figure 2 is a Kaplan-Meier plot of overall survival (OS) in the intention-to-treat (ITT) patient population as described in the Examples.

[0106] Figure 21 Figure 5 is a Kaplan-Meier plot of investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) patient population as described in the Examples.

[0107] Figure 22A and Figure 22B Provides investigator-assessed event-free survival (EFS) in the intent-to-treat (ITT) patient population as described in the Examples. eff ) of the event time.

[0108] Figure 23A and Figure 23B A time-to-event summary of overall survival (OS) in the intention-to-treat (ITT) patient population as described in the Examples is provided.

[0109] Figure 24A and Figure 24B A time-to-event summary of investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) patient population as described in the Examples is provided.

[0110] Figure 25A summary of best overall response (BOR) as assessed by the investigator (INV) in the intention-to-treat (ITT) patient population as described in the Examples is provided.

[0111] Figure 26A and Figure 26B A time-to-event summary of disease-free survival (DFS) as assessed by the investigator for BOR complete responders in the intention-to-treat (ITT) patient population as described in the Examples is provided.

[0112] Figure 27A and Figure 27B A time-to-event summary of duration of response (DOR) as assessed by the investigator for BOR responders in the intention-to-treat (ITT) patient population as described in the Examples is provided.

[0113] Figure 28 A summary of novel anti-lymphoma therapies (NALTs) administered to the intent-to-treat (ITT) patient population as described in the Examples is provided.

[0114] Figure 29 A summary of the overall adverse event (AE) profile of the safety-evaluable patient population as described in the Examples is provided.

[0115] Figure 30 An overview of peripheral neuropathy, an AE of particular interest (AEPI), in the safety-evaluable patient population as described in the Examples is provided. DETAILED DESCRIPTION

[0116] As used herein, the term "polatuzumab vedotin" refers to an anti-CD79b immunoconjugate with IUPHAR / BPS number 8404, KEGG number D10761, or CAS registration number 1313206-42-6. Polatuzumab may also be referred to interchangeably as "polatuzumab-piiq," "huMA79bv28-MC-vc-PAB-MMAE," "DCDS4501A," or "RG7596." The term "polatuzumab" also refers to all corresponding anti-CD79b immunoconjugates that meet the requirements for obtaining marketing authorization for the same product or biosimilar product in a market selected from the United States, Europe, and Japan.

[0117] Provided herein are methods for treating or delaying progression of lymphoma (such as diffuse large B-cell lymphoma (DLBCL)) in an individual (e.g., a human patient), comprising administering to the individual an effective amount of an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE, also known as vepotuzumab), 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 treating an individual with diffuse large B-cell lymphoma (DLBCL) by administering to the individual: (a) an immunoconjugate comprising the formula:

[0118]

[0119] 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 wherein 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 about 1.0 mg / kg to 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 / kg. 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 include cyclophosphamide and doxorubicin. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m 2 and about 750 mg / m 2 Doses between (e.g., 375 mg / m 2, 563mg / m 2 or 750 mg / m 2 In some embodiments, cyclophosphamide is administered at about 750 mg / m 2 In some embodiments, doxorubicin is administered at a dose of about 25 mg / m 2 and about 50 mg / m 2 Doses between (e.g., 25 mg / m 2 , 37.5mg / m 2 or 50 mg / m 2 In some embodiments, doxorubicin is administered at about 50 mg / m 2 In 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.

[0120] I. General Technology

[0121] Unless otherwise noted, the implementation of the present invention will adopt the conventional techniques of molecular biology (including recombinant technology), microbiology, cell biology, biochemistry and immunology, which are within the technical scope of this area. Such techniques are fully explained in the following documents, such as "Molecular Cloning: A Laboratory Manual", Second Edition (Sambrook et al., 1989); "Oligonucleotide Synthesis" (MJ Gait compiles, 1984); "Animal Cell Culture" (RI Freshney compiles, 1987); "Methods in Enzymology" (Academic Press, Inc.); "Current Protocols in Molecular Biology" (FM Ausubel et al. compiles, 1987, and regularly updated); "PCR: The Polymerase Chain Reaction" (Mullis et al. compiles, 1994); "A Practical Guide to Molecular Cloning" (Perbal Bernard V., 1988); "Phage Display: A Laboratory Manual" (Barbas et al., 2001).

[0122] II. Definitions

[0123] Before describing the present invention in detail, it should be understood that the present invention is not limited to specific compositions or biological systems, which can certainly vary. Additionally, it should be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0124] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a molecule" optionally includes a combination of two or more such molecules, and so forth.

[0125] As used herein, the term "about" refers to the common error range of the corresponding value that is readily known to those skilled in the art. References to "about" values ​​or parameters herein include (and describe) embodiments involving the value or parameter itself.

[0126] It should be understood that aspects and embodiments of the invention described herein include aspects and embodiments referred to as "comprising," "consisting of," and "consisting essentially of."

[0127] Unless otherwise indicated, as used herein, the term "CD79b" refers to any natural 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 comprising a signal sequence is shown in SEQ ID NO: 1. An exemplary CD79b sequence without a signal sequence is shown in SEQ ID NO: 2. The term "CD79b" encompasses "full-length" unprocessed CD79b, as well as any form of CD79b produced by processing in cells. The term also encompasses naturally occurring variants of CD79b, e.g., splice variants, allelic variants, and isoforms. The CD79b polypeptides described herein can be isolated from a variety of sources, such as from human tissue types or other sources, or prepared by recombinant or synthetic methods. "Native sequence CD79b polypeptides" include polypeptides having the same amino acid sequence as the corresponding CD79b polypeptides derived from nature. Such native sequence CD79b polypeptides can be isolated from nature or produced by recombinant or synthetic means. The term "native sequence CD79b polypeptide" specifically encompasses naturally occurring truncated or secreted forms (e.g., extracellular domain sequences), naturally occurring variant forms (e.g., alternatively spliced ​​forms), and naturally occurring allelic variants of a particular CD79b polypeptide.

[0128] 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; the sequence is characterized by SwissProt database entry P11836), which is a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B and mature B lymphocytes. (Valentine, MA et al., J. Biol. Chem. 264 (19) (1989 11282-11287; Tedder, TF et al., Proc. Natl. Acad. Sci. USA 85 (1988) 208-12; Stamenkovic, I. et al., J. Exp. Med. 167 (1988) 1975-80; Einfeld, DA et 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 family of new proteins are characterized by common structural features and similar intron / exon splicing boundaries and exhibit distinct expression patterns in 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 located in a cluster of family members at 11q12. Alternative splicing of this gene produces two transcript variants encoding the same protein.

[0129] The terms "CD20" and "CD20 antigen" are used interchangeably herein and include any variants, isoforms, and species homologs of human CD20 that are naturally expressed by cells or expressed on cells transfected with the CD20 gene. Binding of the antibodies of the present invention to the CD20 antigen mediates killing of cells expressing CD20 (e.g., tumor cells) by inactivating CD20. Killing of cells expressing CD20 can occur through one or more of the following mechanisms: cell death / apoptosis induction, ADCC, and CDC. As recognized in the art, aliases for CD20 include B lymphocyte antigen CD20, B lymphocyte surface antigen B1, Leu-16, Bp35, BM5, and LF5.

[0130] The term "expression of the CD20 antigen" is intended to mean the expression of a significant level of the CD20 antigen in a cell (e.g., a T cell or a B cell). In one embodiment, a patient to be treated according to the methods of the present invention expresses significant levels of CD20 on a B cell tumor or cancer. Patients with "CD20-expressing cancers" can be determined by standard assays known in the art. For example, CD20 antigen expression is measured using immunohistochemistry (IHC) assays, FACS, or detection of the corresponding mRNA via PCR-based assays.

[0131] "Affinity" refers to the strength of the sum of the 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 intrinsic binding affinity, which 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 a dissociation constant (Kd). Affinity can be measured by conventional methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0132] An "affinity matured" antibody is one with one or more alterations in one or more hypervariable regions (HVRs) which result in an improvement in the affinity of the antibody for antigen, compared to a parent antibody which does not possess such alteration(s).

[0133] The term "antibody" herein is used in the broadest sense and encompasses various 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.

[0134] "Antibody fragments" refer to molecules other than intact antibodies that comprise a portion of an intact antibody and bind to 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')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0135] An "antibody that binds to the same epitope as a reference antibody" is an antibody that blocks the binding of the reference antibody to its antigen by 50% or more in a competition assay, whereas the reference antibody blocks the binding of the antibody to its antigen by 50% or more in a competition assay. An exemplary competition assay is provided herein.

[0136] The term "epitope" refers to a specific site on an antigen molecule to which an antibody binds.

[0137] 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.

[0138] The "class" of an antibody refers to the type of constant domain or region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these antibodies can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0139] The terms "anti-CD79b antibody" and "antibody that binds to CD79b" refer to an antibody that is capable of binding to CD79b with sufficient affinity so that the antibody can be used as a diagnostic and / or therapeutic agent targeting CD79b. Preferably, the degree of binding of the anti-CD79b antibody to unrelated, non-CD79b proteins is less than about 10% of the degree of binding of the antibody to CD79b, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the antibody that binds to CD79b has a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM. In certain embodiments, the anti-CD79b antibody binds to an epitope of CD79b that is conserved among CD79b from different species.

[0140] The term "anti-CD20 antibody" according to the present invention refers to an antibody that binds to CD20 with sufficient affinity so that the antibody can be used as a diagnostic and / or therapeutic agent targeting CD20. Preferably, the extent of binding of the anti-CD20 antibody to unrelated, non-CD20 proteins is less than about 10% of the extent of binding of the antibody to CD20, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the antibody binds to CD20 with a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM. In certain embodiments, the anti-CD20 antibody binds to an epitope of CD20 that is conserved among CD20 from different species.

[0141] "Isolated" antibodies are antibodies that have been separated from the components of their natural environment. In some embodiments, the antibody is purified to a purity greater than 95% or 99% as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reversed-phase HPLC). For a review of methods for assessing antibody purity, see, for example, 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 an antibody. The variable domain of the heavy chain may be referred to as "VH." The variable domain of the light chain may be referred to as "VL." These domains are typically the most variable parts of an antibody and contain the antigen binding site.

[0142] "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 molecules in a single vector or separate vectors, and such nucleic acid molecules present in one or more locations in a host cell.

[0143] As used herein, the term "monoclonal antibody" refers to the antibody obtained from a substantially homogeneous antibody population, that is, except possible variant antibodies (for example, containing naturally occurring mutations or producing during the production of monoclonal antibody preparations, such variants are generally present in a small amount), the individual antibodies comprising the population are identical and / or in conjunction with identical epi-positions. Contrary to the polyclonal antibody preparations typically comprising different antibodies for different determinants (epi-positions), each monoclonal antibody in the monoclonal antibody preparation is directed to a single determinant on the antigen. Therefore, the modifier "monoclonal" represents that the feature of an antibody is obtained from a substantially homogeneous antibody population, and should not be construed as needing to produce an antibody by any ad hoc method. For example, the monoclonal antibody to be used according to the present invention can be prepared by various techniques, including but not limited to hybridoma method, recombinant DNA method, phage display method and the method utilizing a transgenic animal containing all or part of a human immunoglobulin locus, and such methods and other exemplary methods for the preparation of monoclonal antibodies are described herein.

[0144] A "naked antibody" is an antibody that is not conjugated to a heterologous moiety (eg, a cytotoxic moiety) or a radiolabel. Naked antibodies can be present in pharmaceutical formulations.

[0145] "Natural antibodies" refer to naturally occurring immunoglobulin molecules with different structures. For example, natural IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, consisting of two identical light chains and two identical heavy chains bound by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also referred to as a variable heavy chain domain or a 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 referred to as a variable light chain domain or a light chain variable domain, followed by a constant light chain (CL) domain. The light chain of an antibody can be classified into one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0146] The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain, which comprises at least a portion of a constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, the 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) in the Fc region may be present or absent. Unless otherwise indicated herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also referred to as the EU index, as described by Kabat et al. (Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991).

[0147] "Framework" or "FR" refers to the variable domain residues excluding the hypervariable region (HVR) residues. The FR of a variable domain is typically composed of the following four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences typically appear in the following sequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0148] For the purposes of this paper, an "acceptor human framework" is a framework comprising an 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 an amino acid sequence identical to that of the human immunoglobulin framework or the human consensus framework, or it may comprise 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.

[0149] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody that has a structure substantially similar to a native antibody structure or has heavy chains that contain an Fc region as defined herein.

[0150] 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," which include the primary transformed cell and progeny derived from the primary transformed cell, regardless of the number of passages. Progeny may not be identical to the nucleic acid content of the parent cell but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected in the original transformed cell are included herein.

[0151] A "human antibody" is an antibody that possesses an amino acid sequence that corresponds to the amino acid sequence of an antibody produced by a human or human cell, or derived from a non-human source utilizing a repertoire of human antibodies or other human antibody coding sequences. This definition of a human antibody specifically excludes humanized antibodies comprising non-human antigen-binding residues.

[0152] 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. Typically, the selection of human immunoglobulin VL or VH sequences is from a subset of variable domain sequences. Typically, the subset of sequences is a subset as described in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), Volumes 1-3. In one embodiment, for VL, the subset is subgroup κI as described in Kabat et al., supra. In one embodiment, for VH, the subset is subgroup III as described in Kabat et al., supra.

[0153] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one, typically two, variable domains, wherein all or substantially all of the HVRs (e.g., CDRs) correspond to the HVRs of a non-human antibody, and all or substantially all of the FRs correspond to the FRs of a human antibody. A humanized antibody optionally may 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 been humanized.

[0154] As used herein, the term "hypervariable region" or "HVR" refers to each region in the antibody variable domain region that is highly variable in sequence and / or forms structurally defined loops ("hypervariable loops"). Typically, a natural four-chain antibody comprises six HVRs: three in VH (H1, H2, H3) and three in VL (L1, L2, L3). HVRs typically comprise amino acid residues from hypervariable loops and / or from "complementarity determining regions" (CDRs), which have the highest sequence variability and / or are involved in antigen recognition. Exemplary hypervariable loops occur at amino acid residues 26 to 32 (L1), 50 to 52 (L2), 91 to 96 (L3), 26 to 32 (H1), 53 to 55 (H2), and 96 to 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 to 34 of L1, 50 to 56 of L2, 89 to 97 of L3, 31 to 35B of H1, 50 to 65 of H2, and 95 to 102 of H3 (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)). Except for CDR1 in VH, CDRs generally comprise amino acid residues that form hypervariable loops. CDRs also comprise "specificity determining residues" or "SDRs," which are residues that make contact with the antigen. SDRs are contained within CDR regions known as shortened CDRs or α-CDRs. Exemplary α-CDRs (α-CDR-L1, α-CDR-L2, α-CDR-L3, α-CDR-H1, α-CDR-H2, and α-CDR-H3) appear at amino acid residues 31 to 34 of L1, amino acid residues 50 to 55 of L2, amino acid residues 89 to 96 of L3, amino acid residues 31 to 35B of H1, amino acid residues 50 to 58 of H2, and amino acid residues 95 to 102 of H3. See Almagro and Fransson, Front. Biosci. 13: 1619-1633 (2008). Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al. (supra).

[0155] The term "variable region" or "variable domain" refers to the domain of an antibody heavy chain or light chain that participates in binding of an antibody to an antigen. The variable domains of the heavy and light chains of natural antibodies (VH and VL, respectively) generally have similar structures, wherein each domain comprises four conserved framework regions (FR) and three hypervariable regions (HVR) (see, e.g., Kindt et al. Kuby Immunology, 6th edition, WH Freeman and Co., p. 91 (2007)). A single VH or VL domain may be sufficient to confer antigen binding specificity. In addition, antibodies that bind to a specific antigen can be isolated using the VH or VL domains from antibodies that bind to the antigen, respectively, to screen for libraries of complementary VL or VH domains. See, e.g., Portolano et al., J. Immunol. 150: 880-887 (1993); Clarkson et al., Nature 352: 624-628 (1991).

[0156] "Effector functions" refer to those biological activities attributable to the Fc region of an antibody, which vary with 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; downregulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[0157] "Percentage (%) of amino acid sequence identity relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence after aligning the candidate sequence with the reference polypeptide sequence and introducing gaps (if necessary) to achieve maximum sequence identity, and without considering any conservative substitutions as components of sequence identity. Alignment for determining percentages of amino acid sequence identity can be achieved in various 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 algorithm required for achieving maximum alignment over the full length of the compared sequences. However, for the purposes of this article, the sequence comparison computer program ALIGN-2 is used to generate values ​​for % amino acid sequence identity. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and the source code has been submitted to the US Copyright Office, Washington DC, 20559, along with user documentation, where it is registered with 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 the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not change.

[0158] In the case of amino acid sequence comparison using ALIGN-2, the % amino acid sequence identity between a given amino acid sequence A and a given amino acid sequence B (which can alternatively be expressed as the % that a given amino acid sequence A has or contains a certain amino acid sequence identity with a given amino acid sequence B) is calculated as follows:

[0159] Multiply 100 by the fraction X / Y

[0160] where 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 where Y is the total number of amino acid residues in B. It will be understood that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values ​​used herein are obtained using the ALIGN-2 computer program as described in the preceding paragraph.

[0161] As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it is linked. The term includes vectors that are self-replicating nucleic acid structures, as well as vectors that are incorporated into the genome of a host cell into which they have been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors."

[0162] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including but not limited to a cytotoxic agent.

[0163] In the context of the formulae provided herein, "p" refers to the average number of drug moieties per antibody, which can range, 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 a composition comprising a mixture of antibody-drug compounds of Formula I, wherein the average drug loading per antibody is from about 2 to about 5, or from about 3 to about 4 (e.g., about 3.4 or about 3.5).

[0164] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cell function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At 211 , I 131 , I 125 、Y 90 、Re 186 、Re 188 、Sm 153 、Bi 212 、P 32 , Pb 212 and radioisotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, doxorubicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitors; enzymes and fragments thereof such as nucleolytic enzymes; 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 drugs disclosed below.

[0165] 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 lymphomas (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 lymphocytic NHL; high-grade small non-cleaved cell NHL; bulky lesion NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphocytic leukemia (ALL); hairy cell leukemia; chronic myeloid leukemia; and post-transplant lymphoproliferative disorder (PTLD); as well as abnormal vascular proliferation associated with nevus hamartomatosis, edema (such as that associated with brain tumors), and Meigs' syndrome. More specific examples include, but are not limited to, relapsed or refractory NHL, first-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 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 lymphoma), follicular), follicular lymphoma (e.g., relapsed / refractory follicular lymphoma), intermediate-grade diffuse NHL, diffuse large B-cell lymphoma (DLBCL, e.g., relapsed / refractory DLBCL), aggressive NHL (including aggressive frontline NHL and aggressive relapsed NHL), NHL relapsed or refractory after autologous stem cell transplant, primary mediastinal large B-cell lymphoma, primary lymphoma, high-grade immunoblastic NHL, high-grade lymphocytic NHL, high-grade non-cleaved small cell NHL, bulky NHL, Burkitt lymphoma, precursor (peripheral) large granular lymphocytic leukemia, mycosis fungoides and / or Sézary syndrome, cutaneous (affecting the skin) lymphoma, anaplastic large cell lymphoma, angiocentric lymphoma.

[0166] An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans (such as human patients with DLBCL) and non-human primates (such as monkeys)), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human.

[0167] An "effective amount" of an agent (eg, pharmaceutical formulation) refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.

[0168] The term "pharmaceutical formulation" refers to a preparation that is in a form that permits the biological activity of the active ingredient contained therein to be effective, and that contains no additional components that are unacceptably toxic to a subject to which the formulation would be administered.

[0169] "Pharmaceutically acceptable carriers" refer to ingredients in a pharmaceutical formulation other than the active ingredient that are non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0170] As used herein, "treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to clinical intervention that attempts to alter the natural course of the individual being treated, and can be performed for prevention or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, reducing free light chains, preventing the occurrence or recurrence of the disease, alleviating symptoms, diminishing any direct or indirect pathological consequences of the disease, reducing the rate of disease progression, ameliorating or alleviating the disease state, and alleviating or improving prognosis. In some embodiments, the methods described herein are used to delay the development of the disease or slow the progression of the disease.

[0171] The term "CD79b positive cells" refers to cancers comprising cells expressing CD79b on their surface. In some embodiments, the expression of CD79b on the cell surface is determined using antibodies against CD79b, for example, using methods such as immunohistochemistry, FACS, etc. Alternatively, CD79b mRNA expression is considered to be correlated with CD79b expression on the cell surface and can be determined by a method selected from in situ hybridization and RT-PCR (including quantitative RT-PCR).

[0172] As used herein, "in conjunction with" means administering a therapeutic modality in addition to another therapeutic modality. Thus, "in conjunction with" means administering another therapeutic modality before, during, or after administering one therapeutic modality to a subject.

[0173] A "chemotherapeutic agent" is a chemical compound used to treat cancer.

[0174] The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products.

[0175] "Alkyl" is a C1-C2-alkyl group containing normal, secondary, tertiary or cyclic carbon atoms. 18 Hydrocarbons. 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 (-CH2CH2CH2CH2CH2CH3), 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.

[0176] 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; while branched C1-C8 alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl; unsaturated C1-C8 alkyl groups include, but are not limited to, -vinyl, - Allyl, -1-butenyl, -2-butenyl, -isobutenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, 1-hexyl, 2-hexyl, 3-alkenyl, -ethynyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl. The C1-C8 alkyl group may 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', -S03R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2, and -CN; wherein each R' is independently selected from H, -C1-C8 alkyl, and aryl.

[0177] As used herein, the term "C1-C 12 "Alkyl" refers to a straight or branched, saturated or unsaturated hydrocarbon having 1 to 12 carbon atoms. 12 The alkyl group may 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', -S03R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2, and -CN; wherein each R' is independently selected from H, -C1-C8 alkyl, and aryl.

[0178] As used herein, the term "C1-C6 alkyl" refers to a straight 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; while branched C1-C6 alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, isobutyl, -tert-butyl, isopentyl, and 2-methylbutyl; unsaturated C1-C6 alkyl groups include, but are not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, and -isobutenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, 1-hexyl, 2-hexyl, and 3-hexyl. C1-C6 alkyl groups may be unsubstituted or substituted with one or more groups, as described above for C1-C8 alkyl groups.

[0179] As used herein, the term "C1-C4 alkyl" refers to a straight or branched, saturated or unsaturated hydrocarbon having 1 to 4 carbon atoms. Representative "C1-C4 alkyl" groups include, but are not limited to, -methyl, -ethyl, -n-propyl, and -n-butyl; while branched C1-C4 alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, and -tert-butyl; and unsaturated C1-C4 alkyl groups include, but are not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, and -isobutenyl. C1-C4 alkyl groups can be unsubstituted or substituted with one or more groups, as described above for C1-C8 alkyl groups.

[0180] "Alkoxy" is an alkyl group singly bonded to oxygen. Exemplary alkoxy groups include, but are not limited to, methoxy (-OCH3) and ethoxy (-OCH2CH3). "C1-C5 alkoxy" is an alkoxy group having 1 to 5 carbon atoms. Alkoxy groups can be unsubstituted or substituted with one or more groups, as described above for alkyl groups.

[0181] An "alkenyl" group is a group containing normal, secondary, tertiary or cyclic carbon atoms and having at least one site of unsaturation (ie, a carbon-carbon sp 2 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" is a C2-C8 alkenyl group containing 2 to 8 normal, secondary, tertiary, or cyclic carbon atoms and having at least one site of unsaturation (i.e., carbon-carbon sp 2 double bonds) hydrocarbons.

[0182] "Alkynyl" is a C2-C18 hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms and having at least one site of unsaturation (i.e., a carbon-carbon sp triple bond). Examples include, but are not limited to, acetylenic (-C≡CH) and propargyl (-CH2C≡CH). "C2-C8 alkynyl" is a hydrocarbon containing 2 to 8 normal, secondary, tertiary, or cyclic carbon atoms and having at least one site of unsaturation (i.e., a carbon-carbon sp triple bond).

[0183] "Alkylene" refers to a saturated, branched, straight-chain, or cyclic hydrocarbon radical having 1 to 18 carbon atoms, which has two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene groups include, but are not limited to, methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.

[0184] “C1-C 10 "Alkylene" is a group having the formula -(CH2) 1-10 -straight chain saturated hydrocarbon group. 10 Examples of the alkylene group include a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group, a hexylene group, a heptylene group, an octylene group, a nonylene group, and a decylene group.

[0185] "Alkenylene" refers to an unsaturated, branched, straight-chain, or cyclic hydrocarbon radical having 2 to 18 carbon atoms, which has two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent olefin. Typical alkenylene groups include, but are not limited to, 1,2-ethylene (-CH=CH-).

[0186] "Alkynylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon group having 2 to 18 carbon atoms, which has two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. Typical alkynylene groups include, but are not limited to, acetylene (-C≡C-), propargyl (-CH2C≡C-) and 4-pentynyl (-CH2CH2CH2C≡C-).

[0187] "Aryl" refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. A carbocyclic aromatic group or heterocyclic aromatic group may 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; wherein each R' is independently selected from H, -C1-C8 alkyl, and aryl.

[0188] “C5-C 20 "Aryl" is an aromatic group having 5 to 20 carbon atoms in the carbocyclic aromatic ring. 20 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. 20 Aryl groups may be substituted or unsubstituted as described above for aryl groups. 14 "Aryl" is an aromatic group having 5 to 14 carbon atoms in the carbocyclic aromatic ring. 14 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. 14 An aryl group may be substituted or unsubstituted as described above for an aryl group.

[0189] An "arylene" group is an aryl group having two covalent bonds and which can be in an ortho, meta, or para configuration, as shown in the following structure:

[0190]

[0191] wherein the phenyl group may be unsubstituted or 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; wherein each R' is independently selected from H, -C1-C8 alkyl, and aryl.

[0192] "Arylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms (usually a terminal or sp 3Carbon atoms) are replaced by aryl groups. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethane-1-yl, and the like. The arylalkyl group contains 6 to 20 carbon atoms, for example, the alkyl portion of the arylalkyl group (including alkyl, alkenyl, or alkynyl groups) has 1 to 6 carbon atoms, and the aryl portion has 5 to 14 carbon atoms.

[0193] "Heteroarylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms (usually a terminal or sp 3 carbon atoms) is replaced by a heteroaryl group. Typical heteroarylalkyl groups include, but are not limited to, 2-benzimidazolylmethyl, 2-furylethyl, and the like. The heteroarylalkyl group contains 6 to 20 carbon atoms, for example, the alkyl portion of the heteroarylalkyl group (including alkyl, alkenyl, or alkynyl groups) has 1 to 6 carbon atoms, and the heteroaryl portion has 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 monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms) or a bicyclic ring having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), for example: a bicyclic [4,5], [5,5], [5,6], or [6,6] system.

[0194] "Substituted alkyl", "substituted aryl" and "substituted arylalkyl" refer to alkyl, aryl and arylalkyl, respectively, in which one or more hydrogen atoms are independently replaced by a substituent. Typical 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)NR2, -C(=S)NR2, -C(=NR)NR2, wherein each X is independently halogen: F, Cl, Br or I; and each R is independently -H, C2-C 18Alkyl, C6-C 20 Aryl, C3-C 14 Heterocycles, protecting groups or prodrug moieties.Alkylene, alkenylene and alkynylene groups as described above may also be similarly substituted.

[0195] "Heteroaryl" and "heterocycle" refer to ring systems in which one or more of the ring atoms is a heteroatom (e.g., nitrogen, oxygen, and sulfur). A heterocyclic group contains 3 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. A heterocycle can be a monocyclic ring with 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), for example: a bicyclic [4,5], [5,5], [5,6], or [6,6] system.

[0196] Exemplary heterocycles are described, for example, in Paquette, Leo A, "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, Aseries 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.

[0197] Examples of heterocycles include, by way of example and not limitation, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidinyl), thiazolyl, tetrahydrothiophenyl, thiooxytetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, 1,2,5-thiadiazinyl, 2H-1,2,5-thiadiazole, 1,4-dihydro-1,4-dinitro-1,4-dinitro-2,4-dinitro-3,4-dinitro-4-dinitro-5-dinitro-6-dinitro-7-dinitro-8-dinitro-9-dinitro-10-dinitro-11-dinitro-12-dinitro-13-dinitro-14-dinitro-15-dinitro-26-dinitro-16-dinitro-17-dinitro-27-dinitro-18-dinitro-28-dinitro-29-dinitro-30-dinitro-31-dinitro-32-dinitro-33-dinitro-34-dinitro-35-dinitro-36-dinitro-37-dinitro-38-dinitro-39-dinitro-40-dinitro-31-dinitro-32-dinitro-33-dinitro-34-dinitro-36-dinitro-37-dinitro-41-dinitro-38-dinitro-39-dinitro-42-dinitro-38-dinitro-39-dinitro-43-dinitro-31-dinitro-3 ,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenothiazinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolyl, isoindolyl, quinoline, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.

[0198] By way of example, and not limitation, the carbon-bonded heterocycle is bonded at the 2, 3, 4, 5, or 6 position of a pyridine, the 3, 4, 5, or 6 position of a pyridazine, the 2, 4, 5, or 6 position of a pyrimidine, the 2, 3, 5, or 6 position of a pyrazine, the 2, 3, 4, or 5 position of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole ring, the 2, 4, or 5 position of an oxazole, imidazole, or thiazole, the 3, 4, or 5 position of an isoxazole, pyrazole, or isothiazole, the 2 or 3 position of an aziridine, the 2, 3, or 4 position of an azetidine, the 2, 3, 4, 5, 6, 7, or 8 position of a quinoline, or the 1, 3, 4, 5, 6, 7, or 8 position of an isoquinoline. More typically, the carbon-bonded 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.

[0199] By way of example and not limitation, nitrogen-bound heterocycles are bonded at the following positions: position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, dihydroindole, 1H-indazole; position 2 of isoindole or isodihydroindole; position 4 of morpholine; and position 9 of carbazole or β-carboline. More typically, nitrogen-bound heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0200] "C3-C8 heterocycle" refers to an aromatic or non-aromatic C3-C8 carbocycle in which one to four of the ring carbon atoms are independently replaced with heteroatoms selected from O, S and N. Representative examples of C3-C8 heterocycle include, but are not limited to, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, coumarinyl, isoquinolinyl, pyrrolyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridyl, pyridonyl, pyrazinyl, pyridazinyl, isothiazolyl, isoxazolyl and tetrazolyl. The C3-C8 heterocycle may 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; wherein each R' is independently selected from H, -C1-C8 alkyl, and aryl.

[0201] "C3-C8 heterocycle" refers to a C3-C8 heterocycle group as defined above, wherein one of the hydrogen atoms of the heterocycle group is replaced by a bond. The C3-C8 heterocycle may be unsubstituted or substituted with up to six 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; wherein each R' is independently selected from H, -C1-C8 alkyl, and aryl.

[0202] “C3-C 20"Heterocycle" refers to an aromatic or non-aromatic C3-C8 carbocyclic ring in which one to four of the ring carbon atoms are independently replaced by heteroatoms selected from O, S and N. 20 The heterocycle may 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; wherein each R' is independently selected from H, -C1-C8 alkyl, and aryl.

[0203] “C3-C 20 "Heterocycle" refers to a C3-C 20 A heterocyclic group wherein one of the hydrogen atoms of the heterocyclic group is replaced by a bond.

[0204] "Carbocycle" means a saturated or unsaturated ring, which is a monocycle with 3 to 7 carbon atoms or a bicycle with 7 to 12 carbon atoms. Monocyclic carbocycles have 3 to 6 ring atoms, more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, for example, arranged as a bicyclic [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclic [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.

[0205] "C3-C8 carbocycle" is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or unsaturated non-aromatic carbocycle. 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. The C3-C8 carbocyclic group may 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; wherein each R' is independently selected from H, -C1-C8 alkyl, and aryl.

[0206] "C3-C8 carbocycle" refers to a C3-C8 carbocyclic group as defined above wherein one of the hydrogen atoms of the carbocyclic group is replaced by a bond.

[0207] "Linker" refers to a chemical moiety comprising a covalent bond or chain of atoms that covalently links the antibody to the drug moiety. In various embodiments, the linker comprises a divalent group such as an alkyldiyl, aryldiyl, heteroaryldiyl, a moiety such as: -(CR2) n O(CR2) n -, alkoxy (e.g., polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, Jeffamine™) repeating units; and diacids and amides, including succinate, succinamide, diglycolate, malonate, and hexanamide. In various embodiments, the linker may comprise one or more amino acid residues, such as valine, phenylalanine, lysine, and homolysine.

[0208] The term "chiral" refers to molecules that have the property of being non-superimposable on their mirror image partner, while the term "achiral" refers to molecules that are superimposable on their mirror image partner.

[0209] 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.

[0210] "Diastereoisomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated under high-resolution analytical procedures, such as electrophoresis and chromatography.

[0211] "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0212] The stereochemical definitions and conventions used herein generally follow: SP 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 indicate the absolute configuration of the molecule around its chiral center. The prefixes d and 1 or (+) and (-) are used to indicate the sign of the rotation of the compound with respect to plane-polarized light, where (-) or 1 indicates that the compound is left-handed. Compounds with the (+) or d prefix are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in the absence of stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species that are not optically active.

[0213] A "leaving group" refers to a functional group that can be replaced 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), methylsulfonyl (mesyl), p-toluenesulfonyl (tosyl), trifluoromethylsulfonyl (triflate), and triflate.

[0214] The term "blocking group" refers to a substituent that is typically used to block or protect a specific functional group 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 functional group in the compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). For general information about blocking groups and their uses, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 or later.

[0215] III. Methods

[0216] Provided herein are methods for treating a B-cell proliferative disorder (such as 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 to 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, such as an anti-CD20 antibody. In some embodiments, the method comprises administering to the individual an effective amount of: (a) an immunoconjugate comprising 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.

[0217] In some embodiments, provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL) in an individual (human patient) in need thereof, the methods comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising the formula:

[0218]

[0219] 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 wherein p is between 1 and 8; (b) an anti-CD20 antibody; (c) one or more chemotherapeutic agents; and (d) a corticosteroid.

[0220] In some embodiments, the 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, the 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, the 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, the 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 vepotuzumab (or huMA79bv28-MC-vc-PAB-MMAE, or CAS Registry No. 1313206-42-6, e.g., as described in U.S. Pat. No. 8,545,850, which is incorporated herein by reference in its entirety).

[0221] 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.

[0222] In some embodiments, the one or more chemotherapeutic agents include cyclophosphamide and / or doxorubicin. In some embodiments, the one or more chemotherapeutic agents include cyclophosphamide and doxorubicin.

[0223] In some embodiments, the corticosteroid is prednisone, prednisolone, or methylprednisolone. In some embodiments, the corticosteroid is not hydrocortisone.

[0224] In some embodiments, the treatment or clinical response of a human patient or multiple human patients treated according to the methods of the present disclosure is compared with a control treatment. In some embodiments, the control treatment includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). In some embodiments, prednisone can be replaced by prednisolone or methylprednisolone. Therefore, 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 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.

[0225] In some embodiments, administration of an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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 plurality of human patients results in one or more of the following: (a) an improvement in progression-free survival (PFS) in the plurality of human patients compared to a reference PFS, wherein the reference PFS is the PFS of the plurality of human patients who have received a control treatment; (b) an improvement in progression-free survival (PFS) in the plurality of human patients compared to the control treatment; (c) a hazard ratio for PFS in multiple human patients compared to a control treatment of no more than 0.75 (e.g., 0.74, 0.73, 0.72, 0.71, 0.70); (d) a hazard ratio for PFS in multiple human patients compared to a control treatment of no more than 0.78 (e.g., 0.77, 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, 0.70); (e) a hazard ratio for PFS in multiple human patients compared to a control treatment of no more than 0.79 (e.g., For example, 0.78, 0.77, 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, 0.70); (f) a 24-month progression-free survival rate (PFS24) in a plurality of human patients is at least 75% (e.g., 76%, 77%, 78%, 79%, 80%); (g) a 24-month progression-free survival rate (PFS24) in a plurality of human patients is improved compared to a reference PFS24, wherein the reference PFS24 is the 24-month progression-free survival rate in a plurality of human patients who have received a control treatment; (h) a PFS24 in a plurality of human patients is improved by at least about 6% compared to a reference PFS24 (e.g., 7%, 8%, 9% or 10%), wherein the reference PFS24 is the 24-month progression-free survival rate of multiple human patients who have received a control treatment; (i) the PFS36 of multiple human patients is improved by at least about 6% (e.g., 7%, 8%, 9% or 10%) compared to the reference PFS36, wherein the reference PFS36 is the 36-month progression-free survival rate of multiple human patients who have received a control treatment; (j) the overall survival (OS) of multiple human patients is improved compared to the reference OS, wherein the reference OS is the OS of multiple human patients who have received a control treatment; (k) the event-free survival (EFS) of multiple human patients is improved compared to the reference OS eff ) and reference EFS eff Improved compared to the reference EFS eff EFS of multiple human patients who have received control treatment eff(l) an improvement in the 24-month event-free survival (EFS24) of 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 the EFS24 of a plurality of human patients compared to a control treatment eff hazard ratio of no more than 0.77 (e.g., 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, 0.70); (n) EFS in multiple human patients compared with control treatment eff(o) an improvement in 24-month event-free survival (EFS24) in a plurality of human patients compared to a reference PFS24, wherein the reference EFS24 is the 24-month event-free survival rate in a plurality of human patients who have received a control treatment, wherein the improvement is at least about 5% (e.g., 6%, 7%, 8%, 9%, or 10%); (p) a 24-month event-free survival rate of at least about 75% (e.g., 76%, 77%, 78%, 79%, or 80%) in a plurality of human patients; (q) a complete remission (CR) rate of about 77% (e.g., 78%, 79%, or 80%) in a plurality of human patients at the end of treatment (EOT), wherein the CR rate is assessed by positron emission tomography-computed tomography (PET-CT); (r) an objective response rate (ORR) of at least about 85% (e.g., 86%, 87%, 88%, 89%, or 90%) in a plurality of human patients at the end of treatment (EOT); 87%, 88%, 89% or 90%), wherein the ORR is assessed by PET-CT; (s) the 36-month event-free survival rate (EFS36) of a plurality of human patients is improved compared to a reference EFS36, wherein the reference EFS36 is the 36-month event-free survival rate of a plurality of human patients who have received a control treatment, wherein the improvement is at least about 6% (e.g., 6.5%, 7%, 8%, 9% or 10%); (t) the 36-month event-free survival rate of a plurality of human patients is at least about 70% (e.g., 71%). , 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79% or 80%); (u) an improvement in 42-month event-free survival (EFS42) in a plurality of human patients compared to a reference EFS42, wherein the reference EFS42 is the 42-month event-free survival of a plurality of human patients who have received a control treatment, wherein the improvement is at least about 5% (e.g., 6%, 7%, 8%, 9% or 10%); (t) a 42-month event-free survival in a plurality of human patients of at least about 68% (e.g., 68.(w) an improvement in 42-month progression-free survival (PFS42) in a plurality of human patients of at least about 6% (e.g., 7%, 8%, 9% or 10%) compared to a reference PFS42, wherein the reference PFS42 is the 42-month progression-free survival rate in a plurality of human patients who have received a control treatment; (x) a reduction in the risk of disease progression, relapse, or death in a plurality of human patients of at least 20% (e.g., 21%, 22%, 23% or 24%) compared to a control treatment; or (y) an objective response rate (ORR) at EOT in a plurality of human patients of at least about 84% (e.g., 85%, 86%, 87%, 88%, 89% or 90%), wherein the ORR is assessed by PET-CT. In some embodiments, the control treatment includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone, or methylprednisolone, in the absence of velpotuzumab (R-CHOP).

[0226] In some embodiments, administration of an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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 human patients prolongs the duration of progression-free survival (PFS) or overall survival (OS) in such patients.

[0227] Additional details regarding the dosing and administration of the immunoconjugate, anti-CD20 antibody, one or more chemotherapeutic agents, and corticosteroids, treatment regimens, and the response of DLBCL to treatment (e.g., progression-free survival, event-free survival, overall survival, complete remission, overall remission, and other therapeutic responses) are provided below.

[0228] A. Dosing and Administration

[0229] The anti-CD79b immunoconjugates and additional therapeutic agents (e.g., anti-CD20 antibodies, one or more chemotherapeutic agents, and corticosteroids) provided herein for any of the methods of treatment described herein will be formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the delivery site of the agent, the method of administration, the timing of administration, and other factors known to practitioners. The immunoconjugates are not necessarily, but optionally, co-formulated with one or more formulations currently used to prevent or treat the disorder in question. The amount of the anti-CD79b immunoconjugates and additional therapeutic agents (e.g., anti-CD20 antibodies, one or more chemotherapeutic agents, and corticosteroids) and the time 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 disorder being treated. The anti-CD79b immunoconjugate and the additional therapeutic agent (e.g., an anti-CD20 antibody, one or more chemotherapeutic agents, and a corticosteroid) are suitably co-administered to the patient at one time or over a series of treatments, e.g., according to any of the treatment regimens described below.

[0230] In some embodiments, the dosage of the anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is between 1.0 mg / kg and 1.8 mg / kg. In some embodiments of any method, the dosage of the anti-CD79b immunoconjugate is about 1.0 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg 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 one of the methods, the anti-CD79b immunoconjugate is administered in a q3w (i.e., once every 3 weeks) manner. In some embodiments of any one of the methods, the anti-CD79b immunoconjugate is administered in a 21-day manner. In some embodiments, the anti-CD79b immunoconjugate is administered by intravenous infusion. In some embodiments, the dose administered via infusion is in the range of about 1 mg to about 1,500 mg per dose. Alternatively, the dose range is about 1 mg to about 1,500 mg, about 1 mg to about 1,000 mg, about 400 mg to about 1200 mg, about 600 mg to about 1000 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 dose administered via infusion is about 1 μg / m 2 to about 10,000 μg / m 2 Alternatively, the dosage range is about 1 μg / m 2 to about 1000 μg / m2, about 1 μg / m 2 to about 800 μg / m 2 , about 1 μg / m 2 to about 600 μg / m2, about 1 μg / m 2 to about 400 μg / m 2 , about 10 μg / m 2 to about 500 μg / m 2 , about 10 μg / m 2 to about 300 μg / m 2 , about 10 μg / m 2 to about 200 μg / m 2 and about 1 μg / m 2 to about 200 μg / m 2. The dose can be administered once a day, once a week, multiple times a week but less than once a day, multiple times a month but less than once a day, multiple times a month but less than once a week, once a month, once every 21 days, or intermittently to relieve or alleviate the symptoms of the disease. In some embodiments, the dose of the immunoconjugate is 1.8 mg / kg, administered in a 21-day cycle. In some embodiments, the dose of the immunoconjugate is 1.8 mg / kg, administered on day 1 of each 21-day cycle. Administration can be continued at any interval disclosed herein until the symptoms of the tumor or the treated B-cell proliferative disorder are alleviated. After symptom relief or alleviation is achieved, administration can be continued if such relief or alleviation can be prolonged by continued administration.

[0231] In some embodiments, the immunoconjugate is vepotuzumab. In some embodiments, vepotuzumab is administered at a dose of about 1.0 mg / kg to 1.8 mg / kg (e.g., 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg). In some embodiments, vepotuzumab is administered at a dose of about 1.0 mg / kg. In some embodiments, vepotuzumab is administered at a dose of about 1.4 mg / kg. In some embodiments, vepotuzumab is administered at a dose of about 1.8 mg / kg. In some embodiments, vepotuzumab is administered intravenously. In some embodiments, vepotuzumab is administered in 21-day cycles. In some embodiments, vepotuzumab is administered on the 1st day of each 21-day cycle. In some embodiments, vepotuzumab is administered between one and six 21-day cycles, for example, any one of 1, 2, 3, 4, 5, or 6 21-day cycles. In some embodiments, vepotuzumab is administered for at least six 21-day cycles. In some embodiments, vepotuzumab is administered for six 21-day cycles. In some embodiments, vepotuzumab is administered at a dose of about 1.0 mg / kg 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 six cycles. In some embodiments, vepotuzumab is administered at a dose of about 1.0 mg / kg 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 six cycles.

[0232] In some embodiments, the dose of the anti-CD20 agent (e.g., an anti-CD20 antibody such as rituximab or obinutuzumab) is about 300 mg / m 2 Up to 1600 mg / m 2 and / or between 300 mg and 2000 mg. In some embodiments, the dose of the anti-CD20 antibody is about 300 mg / m 2 , 375mg / m2 , 600mg / m 2 , 1000mg / m 2 or 1250 mg / m 2 and / or any of 300 mg, 1000 mg, or 2000 mg. In some embodiments, the anti-CD20 antibody is rituximab, and the dose administered is 375 mg / m 2 In some embodiments, the anti-CD20 antibody is obinutuzumab and the dose administered 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 dose of the afucosylated anti-CD20 antibody (preferably afucosylated humanized B-Ly1 antibody) can be 800 mg to 1600 mg (in one embodiment, 800 mg to 1200 mg, such as 1000 mg). In some embodiments, the dose is a fixed 1000 mg dose. In some embodiments, the dose of rituximab is 375 mg / m 2 , administered on day 1 of each 21-day cycle. In some embodiments, the anti-CD20 antibody is administered via intravenous infusion.

[0233] In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, rituximab is administered at about 375 mg / m 2 In 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 between one and eight 21-day cycles, for example, any one of 1, 2, 3, 4, 5, 6, 7, or 8 21-day cycles. In some embodiments, rituximab is administered between six and eight 21-day cycles, for example, any one of 6, 7, or 8 21-day cycles. In some embodiments, rituximab is administered for at least six 21-day cycles. In some embodiments, rituximab is administered for six 21-day cycles. In some embodiments, rituximab is administered for seven 21-day cycles. In some embodiments, rituximab is administered for eight 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 / m2 on Day 1 of each 21-day cycle. 2 In some embodiments, rituximab is administered at a dose of about 375 mg / m2 on day 1 of each 21-day cycle. 2 The dose was administered for six, seven or eight cycles.

[0234] In some embodiments, the one or more chemotherapeutic agents include cyclophosphamide. In some embodiments, the dose of cyclophosphamide is about 375 mg / m 2 and about 750 mg / m 2 Between about 375mg / m 2 and about 563mg / m 2 between, or about 563 mg / m 2 and about 750 mg / m 2 In some embodiments, the dose of cyclophosphamide is 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 2 In some embodiments, cyclophosphamide is administered q3w (i.e., once 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 via intravenous infusion. In some embodiments, cyclophosphamide is administered for between one and eight 21-day cycles, for example, any one of 1, 2, 3, 4, 5, 6, 7, or 8 21-day cycles. In some embodiments, cyclophosphamide is administered for between six and eight 21-day cycles, for example, any one of 6, 7, or 8 21-day cycles. In some embodiments, cyclophosphamide is administered for at least six 21-day cycles. In some embodiments, cyclophosphamide is administered for six 21-day cycles. In some embodiments, cyclophosphamide is administered for seven 21-day cycles. In some embodiments, cyclophosphamide is administered for eight 21-day cycles. In some embodiments, cyclophosphamide is administered for up to eight 21-day cycles. In some embodiments, cyclophosphamide is administered at a dose of approximately 375 mg / m2 on Day 1 of each 21-day cycle. 2 and about 750 mg / m 2 Doses between (e.g., 375 mg / m 2 , 562.5mg / m 2 or 750 mg / m 2 ) for at least six cycles. In some embodiments, cyclophosphamide is administered on day 1 of each 21-day cycle at a dose of about 375 mg / m 2 and about 750 mg / m 2 Doses between (e.g., 375 mg / m 2 , 562.5mg / m 2 or 750 mg / m 2 ) for six, seven, or eight cycles.

[0235] In some embodiments, the one or more chemotherapeutic agents include doxorubicin. In some embodiments, the dose of doxorubicin is about 25 mg / m 2 and about 50 mg / m 2 Between about 25mg / m 2 and about 38 mg / m 2 Between, or about 38 mg / m 2 and about 50 mg / m 2 In some embodiments, the dose of doxorubicin is about 25 mg / m 2 In some embodiments, the dose of doxorubicin is about 38 mg / m 2 In some embodiments, the dose of doxorubicin is about 50 mg / m 2 In some embodiments, doxorubicin is administered in a q3w (i.e., once every 3 weeks) manner. In some embodiments, doxorubicin is administered in a 21-day manner. In some embodiments, doxorubicin is administered on the 1st day of each 21-day cycle. In some embodiments, doxorubicin is administered via intravenous infusion. In some embodiments, doxorubicin is administered between one and eight 21-day cycles, for example, any one of 1, 2, 3, 4, 5, 6, 7, or 8 21-day cycles. In some embodiments, doxorubicin is administered between six to eight 21-day cycles, for example, any one of 6, 7, or 8 21-day cycles. In some embodiments, doxorubicin is administered for at least six 21-day cycles. In some embodiments, doxorubicin is administered for six 21-day cycles. In some embodiments, doxorubicin is administered for seven 21-day cycles. In some embodiments, doxorubicin is administered for eight 21-day cycles. In some embodiments, doxorubicin is administered for up to eight 21-day cycles. In some embodiments, doxorubicin is administered at about 25 mg / m2 on the 1st day of each 21-day cycle. 2 and about 50 mg / m 2 Doses between (e.g., 25 mg / m 2 , 37.5mg / m 2 or 50 mg / m 2 ) for at least six cycles. In some embodiments, doxorubicin is administered at about 25 mg / m on Day 1 of each 21-day cycle. 2 and about 50 mg / m 2 Doses between (e.g., 25 mg / m 2 , 37.5mg / m 2 or 50 mg / m 2 ) for six, seven, or eight cycles.

[0236] In some embodiments, the dosage of the corticosteroid is between about 50mg and about 100mg, between about 50mg and about 80mg, or between about 80mg and about 100mg. In some embodiments, the dosage of the corticosteroid is about 50mg. In some embodiments, the dosage of the corticosteroid is about 80mg. In some embodiments, the dosage of the corticosteroid is about 100mg. In some embodiments, the corticosteroid is administered in a 21-day cycle. In some embodiments, the corticosteroid is administered on the 1st, 2nd, 3rd, 4th, and 5th day of each 21-day cycle. In some embodiments, the corticosteroid is administered via intravenous infusion or oral administration. In some embodiments, the corticosteroid is prednisone. In some embodiments, the dosage of prednisone is about 100mg. In some embodiments, prednisone is administered on the 1st, 2nd, 3rd, 4th, and 5th day of each 21-day cycle at a dosage of about 100mg / day. 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 dosage of about 100 mg / day on the 1st, 2nd, 3rd, 4th, and 5th day 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 dosage of about 80 mg / day on the 1st, 2nd, 3rd, 4th, and 5th day of each 21-day cycle. In some embodiments, methylprednisolone is administered intravenously. In some embodiments, a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) is administered between one and eight 21-day cycles, for example, any one of 1, 2, 3, 4, 5, 6, 7, or 8 21-day cycles. In certain embodiments, corticosteroid (for example, prednisone, prednisolone or methylprednisolone) is through being administered between six and eight 21 day cycles, for example any one in 6,7 or 8 21 day cycles.In certain embodiments, corticosteroid (for example, prednisone, prednisolone or methylprednisolone) is through being administered for at least six 21 day cycles.In certain embodiments, corticosteroid (for example, prednisone, prednisolone or methylprednisolone) is through being administered for six 21 day cycles.In certain embodiments, corticosteroid (for example, prednisone, prednisolone or methylprednisolone) is through being administered for seven 21 day cycles.In certain embodiments, corticosteroid (for example, prednisone, prednisolone or methylprednisolone) is through being administered for eight 21 day cycles.In certain embodiments, prednisone is administered at the dosage of about 100mg / days on the 1st day, 2nd day, 3rd day, 4th day and 5th day of each 21 day cycle, for at least six cycles.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 for six, seven, or eight cycles. 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 for at least six cycles. 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 for six, seven, or eight 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 21-day cycle for at least six 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 21-day cycle for six, seven, or eight cycles.

[0237] Exemplary dosing regimens for combination therapy of an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) and one or more additional therapeutic agents include: an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) administered at a dose of about 1.0 mg / kg 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 vepotuzumab) administered at about 375 mg / kg; 2 Rituximab administered once every 21 days (e.g., on day 1 of each 21-day cycle); at a dose of about 375 mg / m 2 and about 750 mg / m 2 Doses between (e.g., 375 mg / m 2 , 562.5mg / m 2 or 750 mg / m 2 ) cyclophosphamide administered once every 21 days (e.g., on day 1 of each 21-day cycle); 2 and about 50 mg / m 2 Doses between (e.g., 25 mg / m 2 , 37.5mg / m 2 or 50 mg / m 2) doxorubicin administered once every 21 days (e.g., on day 1 of each 21-day cycle); and a corticosteroid administered on day 1 to day 5 of each 21-day cycle (e.g., prednisone administered at a dose of about 100 mg, prednisolone administered at a dose of about 100 mg, or methylprednisolone administered at a dose of about 80 mg). 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 / kg. 2 In some embodiments, doxorubicin is administered at a dose of about 50 mg / m 2 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.

[0238] Another exemplary dosing regimen for combination therapy of an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) and one or more additional therapeutic agents includes: an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) administered at a dose of about 1.0 mg / kg 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 vepotuzumab) administered at about 375 mg / kg; 2 Rituximab administered once every 21 days (e.g., on day 1 of each 21-day cycle); cyclophosphamide administered once every 21 days (e.g., on day 1 of each 21-day cycle); doxorubicin administered once every 21 days (e.g., on day 1 of each 21-day cycle); and corticosteroids (e.g., prednisone, prednisolone, or methylprednisolone) administered on days 1 to 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.

[0239] Exemplary dosing regimens for combination therapy of an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) and one or more additional therapeutic agents include: an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) administered at a dose of about 1.0 mg / kg 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 administered at a dose of about 1000 mg once every 21 days (e.g., on Day 1 of each 21-day cycle); and vepotuzumab administered at a dose of about 375 mg / kg. 2 and about 750 mg / m 2 Doses between (e.g., 375 mg / m 2 , 562.5mg / m 2 or 750 mg / m 2 ) cyclophosphamide administered once every 21 days (e.g., on day 1 of each 21-day cycle); 2 and about 50 mg / m 2 Doses between (e.g., 25 mg / m 2 , 37.5mg / m 2 or 50 mg / m 2 ) doxorubicin administered once every 21 days (e.g., on day 1 of each 21-day cycle); and a corticosteroid administered on day 1 to day 5 of each 21-day cycle (e.g., prednisone administered at a dose of about 100 mg, prednisolone administered at a dose of about 100 mg, or methylprednisolone administered at a dose of about 80 mg). 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 / kg. 2 In some embodiments, doxorubicin is administered at a dose of about 50 mg / m 2 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.

[0240] Another exemplary dosing regimen for combination therapy of an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) and one or more additional therapeutic agents includes administering an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) once every 21 days (e.g., on day 1 of each 21-day cycle) at a dose of about 1.0 mg / kg to 1.8 mg / kg (e.g., 1.0 mg / kg, 1.4 mg / kg, or 1.8 mg / kg). bv28-MC-vc-PAB-MMAE or vepotuzumab); obinutuzumab administered once every 21 days (e.g., on day 1 of each 21-day cycle) at a dose of about 1000 mg; cyclophosphamide administered once every 21 days (e.g., on day 1 of each 21-day cycle); doxorubicin administered once every 21 days (e.g., on day 1 of each 21-day cycle); and corticosteroids (e.g., prednisone, prednisolone, or methylprednisolone) administered on days 1 to 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.

[0241] The terms "co-administration," "co-administering," "combination," or "incombination" 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 two or more therapeutic agents as two (or more) separate formulations, or as a single formulation comprising two or more therapeutic agents. Where separate formulations are used, co-administration can be performed simultaneously (i.e., at the same time) or sequentially in any order, wherein preferably there is a time period during which all active agents simultaneously exert their biological activities. In some embodiments, two or more therapeutic agents are co-administered simultaneously or sequentially. In some embodiments, when all therapeutic agents are co-administered sequentially, the dose of each agent is administered on the same day in two or more separate administrations, or one of the agents is administered on day 1 and the other agents are co-administered on subsequent days, e.g., according to any of the treatment regimens described herein.

[0242] The immunoconjugates provided herein for use in any of the methods of treatment described herein (and any additional therapeutic agents, such as anti-CD20 antibodies, one or more chemotherapeutic agents, and corticosteroids) can be administered by any suitable means, including parenteral, intrapulmonary, and intranasal, and if desired for local treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Administration can be performed by any suitable route, for example, by injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is short-lived or long-term. Various dosing schedules are contemplated herein, including but not limited to single or multiple administrations, bolus administration, and pulse infusions at various time points. The anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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) can be administered by the same route of administration or by 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, intraventricularly, or intranasally. In some embodiments, the anti-CD20 antibody (such as obinutuzumab or rituximab) is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, 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, implanted, inhaled, intrathecally, intraventricularly, or intranasally. In some embodiments, corticosteroids (e.g., prednisone, prednisolone, or methylprednisolone) are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some embodiments, anti-CD79b immunoconjugates, anti-CD20 antibodies (such as obinutuzumab or rituximab), and one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) are each administered via intravenous infusion, and corticosteroids (e.g., prednisone or prednisolone) are administered orally. In some embodiments, the anti-CD79b immunoconjugate, anti-CD20 antibody (such as obinutuzumab or rituximab), one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin), and corticosteroid (e.g., methylprednisolone) are administered via intravenous infusion.Effective amounts of an anti-CD79b immunoconjugate, 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) can be administered to prevent or treat a disease (e.g., DLBCL).

[0243] B. Exemplary Treatment Regimens

[0244] In some embodiments, a method for treating diffuse large B-cell lymphoma (DLBCL) in an individual (e.g., a human patient) in need thereof comprises administering to the individual an anti-CD79b immunoconjugate comprising the formula:

[0245]

[0246] 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) 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, wherein p is between 1 and 8; 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, 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 vepotuzumab. In some embodiments, the anti-CD79b immunoconjugate, 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) are administered to an individual (e.g., a human patient) in a 21-day cycle. 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.

[0247] In some embodiments of any of the methods provided herein, the treatment for DLBCL according to any of the methods of the present disclosure is first-line treatment for DLBCL, ie, treatment of a human patient with previously untreated DLBCL.

[0248] (i) Treatment regimens including rituximab

[0249] In some embodiments of any of the methods provided herein, the anti-CD20 antibody is rituximab.

[0250] In some embodiments, the corticosteroid is prednisone.

[0251] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of between about 1.0 mg / kg and about 1.8 mg / kg; the anti-CD20 antibody is rituximab, which is administered at a dose of about 375 mg / kg. 2 The dose is administered intravenously on day 1 of each 21-day cycle; one or more chemotherapeutic agents include at about 375 mg / m 2 and about 750 mg / m 2 Cyclophosphamide administered intravenously on day 1 of each 21-day cycle and at a dose between 25 mg / m 2 and about 50 mg / m 2 In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) 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 vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.4 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m2 on day 1 of each 21-day cycle. 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 563 mg / m on day 1 of each 21-day cycle. 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 The dose was administered intravenously.

[0252] In some embodiments of any of the methods provided herein for treating diffuse large B-cell lymphoma (DLBCL), the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of between about 1.0 mg / kg and about 1.8 mg / kg; the anti-CD20 antibody is rituximab, which is administered intravenously at a dose of about 375 mg / kg and about 1.8 mg / kg on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 The dose is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles; one or more chemotherapeutic agents include at about 375 mg / m 2 and about 750 mg / m 2 Cyclophosphamide administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, and cyclophosphamide at 25 mg / m 2 and about 50 mg / m 2 In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.4 mg / kg. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 375 mg / m 2In some embodiments, cyclophosphamide is administered intravenously at a dose of about 563 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 750 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 The dose was administered intravenously.

[0253] In some embodiments, the corticosteroid is prednisolone.

[0254] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of between about 1.0 mg / kg and about 1.8 mg / kg; the anti-CD20 antibody is rituximab, which is administered at a dose of about 375 mg / kg. 2 The dose is administered intravenously on day 1 of each 21-day cycle; one or more chemotherapeutic agents include at about 375 mg / m 2 and about 750 mg / m 2 Cyclophosphamide administered intravenously on day 1 of each 21-day cycle and at a dose between 25 mg / m 2 and about 50 mg / m 2In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) 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 vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.4 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m2 on day 1 of each 21-day cycle. 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 563 mg / m on day 1 of each 21-day cycle. 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 The dose was administered intravenously.

[0255] In some embodiments of any of the methods provided herein for treating diffuse large B-cell lymphoma (DLBCL), the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of between about 1.0 mg / kg and about 1.8 mg / kg; the anti-CD20 antibody is rituximab, which is administered intravenously at a dose of about 375 mg / kg and about 1.8 mg / kg on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 The dose is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles; one or more chemotherapeutic agents include at about 375 mg / m 2 and about 750 mg / m 2Cyclophosphamide administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, and cyclophosphamide at 25 mg / m 2 and about 50 mg / m 2 In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.4 mg / kg. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 375 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 563 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 750 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 The dose was administered intravenously.

[0256] In some embodiments, the corticosteroid is methylprednisolone.

[0257] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of between about 1.0 mg / kg and about 1.8 mg / kg; the anti-CD20 antibody is rituximab, which is administered at a dose of about 375 mg / kg. 2 The dose is administered intravenously on day 1 of each 21-day cycle; one or more chemotherapeutic agents include at about 375 mg / m 2 and about 750 mg / m 2 Cyclophosphamide administered intravenously on day 1 of each 21-day cycle and at a dose between 25 mg / m 2 and about 50 mg / m 2 In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) 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 vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.4 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m2 on day 1 of each 21-day cycle. 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 563 mg / m on day 1 of each 21-day cycle. 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. 2In 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 The dose was administered intravenously.

[0258] In some embodiments of any of the methods provided herein for treating diffuse large B-cell lymphoma (DLBCL), the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of between about 1.0 mg / kg and about 1.8 mg / kg; the anti-CD20 antibody is rituximab, which is administered intravenously at a dose of about 375 mg / kg and about 1.8 mg / kg on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 The dose is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles; one or more chemotherapeutic agents include at about 375 mg / m 2 and about 750 mg / m 2 Cyclophosphamide administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, and cyclophosphamide at 25 mg / m 2 and about 50 mg / m 2In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.4 mg / kg. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 375 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 563 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 750 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 The dose was administered intravenously.

[0259] (ii) Treatment regimens including obinutuzumab

[0260] In some embodiments of any of the methods provided herein, the anti-CD20 antibody is obinutuzumab.

[0261] In some embodiments, the corticosteroid is prednisone.

[0262] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of between about 1.0 mg / kg and about 1.8 mg / kg; the anti-CD20 antibody is obinutuzumab, which is administered intravenously on day 1 of each 21-day cycle at a dose of about 1000 mg; and the one or more chemotherapeutic agents include vepotuzumab at about 375 mg / kg. 2 and about 750 mg / m 2 Cyclophosphamide administered intravenously on day 1 of each 21-day cycle and at a dose between 25 mg / m 2 and about 50 mg / m 2 In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) 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 vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.4 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m2 on day 1 of each 21-day cycle. 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 563 mg / m on day 1 of each 21-day cycle. 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 / m2 on day 1 of each 21-day cycle. 2 The dose was administered intravenously.

[0263] In some embodiments of any of the methods provided herein for treating diffuse large B-cell lymphoma (DLBCL), the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of between about 1.0 mg / kg and about 1.8 mg / kg; the anti-CD20 antibody is obinutuzumab, which is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1000 mg; and the one or more chemotherapeutic agents include vepotuzumab at about 375 mg / kg and about 1.8 mg / kg. 2 and about 750 mg / m 2 Cyclophosphamide administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, and cyclophosphamide at 25 mg / m 2 and about 50 mg / m 2In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.4 mg / kg. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 375 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 563 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 750 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 The dose was administered intravenously.

[0264] In some embodiments, the corticosteroid is prednisolone.

[0265] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of between about 1.0 mg / kg and about 1.8 mg / kg; the anti-CD20 antibody is obinutuzumab, which is administered intravenously on day 1 of each 21-day cycle at a dose of about 1000 mg; and the one or more chemotherapeutic agents include vepotuzumab at about 375 mg / kg. 2 and about 750 mg / m 2 Cyclophosphamide administered intravenously on day 1 of each 21-day cycle and at a dose between 25 mg / m 2 and about 50 mg / m 2 In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) 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 vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.4 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m2 on day 1 of each 21-day cycle. 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 563 mg / m on day 1 of each 21-day cycle. 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 The dose was administered intravenously.

[0266] In some embodiments of any of the methods provided herein for treating diffuse large B-cell lymphoma (DLBCL), the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of between about 1.0 mg / kg and about 1.8 mg / kg; the anti-CD20 antibody is obinutuzumab, which is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1000 mg; and the one or more chemotherapeutic agents include vepotuzumab at about 375 mg / kg and about 1.8 mg / kg. 2 and about 750 mg / m 2 Cyclophosphamide administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, and cyclophosphamide at 25 mg / m 2 and about 50 mg / m 2 In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.4 mg / kg. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 375 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 563 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2In some embodiments, cyclophosphamide is administered intravenously at a dose of about 750 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 The dose was administered intravenously.

[0267] In some embodiments, the corticosteroid is methylprednisolone.

[0268] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of between about 1.0 mg / kg and about 1.8 mg / kg; the anti-CD20 antibody is obinutuzumab, which is administered intravenously on day 1 of each 21-day cycle at a dose of about 1000 mg; and the one or more chemotherapeutic agents include vepotuzumab at about 375 mg / kg. 2 and about 750 mg / m 2 Cyclophosphamide administered intravenously on day 1 of each 21-day cycle and at a dose between 25 mg / m 2 and about 50 mg / m 2In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) 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 vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.4 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each 21-day cycle at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered at a dose of about 375 mg / m2 on day 1 of each 21-day cycle. 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 563 mg / m on day 1 of each 21-day cycle. 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 The dose was administered intravenously.

[0269] In some embodiments of any of the methods provided herein for treating diffuse large B-cell lymphoma (DLBCL), the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of between about 1.0 mg / kg and about 1.8 mg / kg; the anti-CD20 antibody is obinutuzumab, which is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1000 mg; and the one or more chemotherapeutic agents include vepotuzumab at about 375 mg / kg and about 1.8 mg / kg. 2 and about 750 mg / m 2Cyclophosphamide administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, and cyclophosphamide at 25 mg / m 2 and about 50 mg / m 2 In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.4 mg / kg. In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 1.8 mg / kg. In some embodiments, cyclophosphamide is administered intravenously on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles at a dose of about 375 mg / m 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 563 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, cyclophosphamide is administered intravenously at a dose of about 750 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 25 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 In some embodiments, doxorubicin is administered intravenously at a dose of about 37.5 mg / m on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2In some embodiments, doxorubicin is administered intravenously at a dose of about 50 mg / m on Day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 The dose was administered intravenously.

[0270] (iii) Length of treatment regimen

[0271] In some embodiments of any of the methods provided herein for treating diffuse large B-cell lymphoma (DLBCL), an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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) are administered to an individual (e.g., a human patient) in a 21-day cycle. In some embodiments, an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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) are administered for less than one 21-day cycle. In some embodiments, an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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) are administered to an individual (e.g., a human patient) for 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 (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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) are administered to an individual (e.g., a human patient) for between one and six 21-day cycles. In some embodiments, an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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) are administered to an individual (e.g., a human patient) for six 21-day cycles.

[0272] In some embodiments of any of the methods provided herein for treating diffuse large B-cell lymphoma (DLBCL), an anti-CD20 antibody (such as obinutuzumab or rituximab) is administered as monotherapy after the sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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 obinutuzumab or rituximab) as monotherapy for one or two additional 21-day cycles after the sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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 obinutuzumab or rituximab) as monotherapy in a seventh 21-day cycle following a sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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 obinutuzumab or rituximab) as monotherapy in the seventh and eighth 21-day cycles following the sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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 obinutuzumab or rituximab) on day 1 of each cycle after the sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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), e.g., during the seventh 21-day cycle and optionally the eighth 21-day cycle.In some embodiments, the method comprises administering an anti-CD20 antibody (such as obinutuzumab or rituximab) on day 1 of the seventh and eighth 21-day cycles after the sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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).

[0273] In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises administering to the patient approximately 375 mg / m 2 after the sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), rituximab, cyclophosphamide, doxorubicin, and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). 2 Rituximab monotherapy is continued at a dose of about 375 mg / m2 for one or two additional 21-day cycles. In some embodiments, the method comprises administering an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), rituximab, cyclophosphamide, doxorubicin, and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) for six 21-day cycles (i.e., cycles 1 to 6), followed by continuing rituximab monotherapy at about 375 mg / m2 after the sixth cycle. 2 Rituximab is administered at a dose of 1% for one or two additional 21-day cycles (ie, in cycle 7 and optionally in cycle 8). In some embodiments, rituximab is administered on day 1 of each 21-day cycle.

[0274] In some embodiments of any of the methods provided herein for treating diffuse large B-cell lymphoma (DLBCL), 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) are administered for one or two additional 21-day cycles after the sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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 obtuzumab 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 following a sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), an anti-CD20 antibody (such as obtuzumab 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 obtuzumab 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 and eighth 21-day cycle following the sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), an anti-CD20 antibody (such as obtuzumab 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 obinutuzumab or rituximab) and one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) on day 1 and administering a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) on days 1 to 5 of each cycle after the sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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 obinutuzumab or rituximab) and one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) on day 1 and refractory corticosteroids (e.g., prednisone, prednisolone, or methylprednisolone) on days 1 to 5 of the seventh and eighth 21-day cycles following the sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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).

[0275] In some embodiments of any of the methods provided herein for treating DLBCL, the method comprises administering rituximab at about 375 mg / m 2 after the sixth 21-day cycle of treatment with an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), rituximab, cyclophosphamide, doxorubicin, and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone). 2 Cyclophosphamide is given at a dose of approximately 375 mg / m 2 and about 750 mg / m 2 Dosages between 25 mg / m 2 and about 50 mg / m 2 In some embodiments, the method comprises administering an anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), rituximab, cyclophosphamide, doxorubicin, and a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) for six 21-day cycles (i.e., cycles 1 to 6), followed by administration of rituximab at about 375 mg / m 2 Cyclophosphamide is given at a dose of approximately 375 mg / m 2 and about 750 mg / m 2 Dosages between 25 mg / m 2 and about 50 mg / m 2In some embodiments, rituximab, cyclophosphamide, and doxorubicin are each administered on day 1 of each 21-day cycle, 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) is administered on days 1 to 5 of each 21-day cycle.

[0276] In some embodiments of any of the methods provided herein, rituximab is replaced with obinutuzumab, administered at a dose of 1000 mg.

[0277] (iv) Order and timing of administration

[0278] In some embodiments, an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), 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 sequentially, e.g., on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. In some embodiments, a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) is administered prior to an anti-CD20 antibody (e.g., obinutuzumab or rituximab); an anti-CD20 antibody (e.g., obinutuzumab or rituximab) is administered prior to an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab); an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) is administered prior to 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 21-day cycles. In some embodiments, the anti-CD20 antibody (e.g., obinutuzumab or rituximab), the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), and one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) are administered after the administration of a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) in any order. In some embodiments, the anti-CD20 antibody (e.g., obinutuzumab or rituximab), the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), and one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) are administered after the administration of a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone) in any order, for example, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles.

[0279] 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 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 vepotuzumab). In some embodiments, when an anti-CD20 antibody (e.g., obinutuzumab or rituximab) is administered as a monotherapy (e.g., on day 1 of the seventh and eighth 21-day cycles), a 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).

[0280] (v) Premedication and preventive treatment

[0281] In some embodiments of any method for treating DLBCL provided herein, the method further includes administering a premedication to the individual (e.g., a human patient) prior to initiating treatment. In some embodiments, the method includes administering an antihistamine (e.g., 50 mg to 100 mg of diphenhydramine), an analgesic, and / or an antipyretic (e.g., 650 mg to 1000 mg of acetaminophen / paracetamol) to the individual prior to initiating treatment, e.g., at least about 30 minutes prior to each administration of an anti-CD20 antibody (e.g., obinutuzumab or rituximab) and / or each administration of an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab). In some embodiments, the method comprises administering to the individual an antihistamine and an analgesic and / or antipyretic (e.g., 500 mg to 1000 mg oral acetaminophen or paracetamol and 50 mg to 100 mg diphenhydramine) 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 vepotuzumab). In some embodiments, the method comprises administering to the individual an antihistamine and an analgesic and / or antipyretic (e.g., 650 mg to 1000 mg oral acetaminophen or paracetamol and 50 mg to 100 mg diphenhydramine) 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 vepotuzumab).

[0282] 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., treatment with a corticosteroid (e.g., up to 100 mg oral prednisone per day or equivalent) for up to 7 days prior to initiation of treatment.

[0283] In some embodiments of any method for treating DLBCL provided herein, the method further includes administering to individual the preventive therapy for neutropenia.In certain embodiments, for the preventive therapy of neutropenia such as American Society of Clinical Oncology (ASCO) recommendation guide (see, for example, Smith et al., J Clin Oncol (2015) 33:3199-212) it is summarized in and administered.In certain embodiments, for the preventive therapy of neutropenia including administering granulocyte colony stimulating factor (G-CSF, such as filgrastim or legrastim or pegfilgrastim) to individual, for example, at each administration of one or more chemotherapeutic agents (for example, cyclophosphamide and / or doxorubicin) and / or immunoconjugates (for example, huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) about 1 day to about 3 days start.

[0284] In some embodiments of any of the methods provided herein for treating DLBCL, the method further comprises administering to the individual a central nervous system prophylaxis, such as intrathecal chemotherapy. In some embodiments, the central nervous system prophylaxis administered is not high-dose IV methotrexate (e.g., 1 g / m per cycle). 2 ).

[0285] In some embodiments of any of the methods for treating DLBCL provided herein, the method further comprises administering to the individual a prophylactic treatment for hemorrhagic cystitis, such as adequate hydration and / or mesna.

[0286] In some embodiments of any of the methods provided herein for treating DLBCL, the method further comprises administering to the individual an anti-infective prophylaxis (e.g., against viral, fungal, bacterial, or pneumocystis infection). In some embodiments, the anti-infective prophylaxis is administered, for example, as described in Flowers et al., J Clin Oncol (2013) 31:794-810; National Comprehensive Cancer NCCN clinical practice guidelines in oncology(NCCN ): Prevention and treatment of cancer-related infections, 2nd edition [resource from the Internet]. 2017 [reference date June 9, 2017]. Available from the following website: www[dot]nccn[dot]org / professionals / physician_gls / f_guidelines.asp; Reddy et al., Gastroenterology (2015) 148: 215–19. In some embodiments, antiviral prophylaxis is administered, for example, as described in the American College of Gastroenterology guidelines (see, for example, Reddy et al., Gastroenterology (2015) 148: 215–19).

[0287] In some embodiments of any of the methods provided herein for treating DLBCL, the method further comprises administering to the individual a prophylactic therapy for tumor lysis syndrome. In some embodiments, a prophylactic therapy for tumor lysis syndrome is administered to an individual at risk for developing tumor lysis syndrome. In some embodiments, a prophylactic therapy for tumor lysis syndrome is administered to an individual with a high tumor burden (e.g., lymphocyte count ≥ 25×10 9 In some embodiments, the prophylactic treatment for tumor lysis syndrome is administered to individuals with leukemia (eg, leukemia / L or massive lymphadenopathy). In some embodiments, the prophylactic treatment for tumor lysis syndrome comprises administering allopurinol (eg, ≥300 mg / day orally) or a suitable alternative treatment such as rasburicase prior to administering treatment according to the methods provided herein, e.g., beginning administration about 48 to 72 hours prior to administering treatment according to the methods provided herein. In some embodiments, the prophylactic treatment for tumor lysis syndrome comprises adequate hydration, e.g., beginning approximately 3 L / day of fluid intake 1 or 2 days prior to initiating treatment according to the methods provided herein.

[0288] (vi) Treatment adjustments and modifications

[0289] 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 vepotuzumab) after initiation of treatment, e.g., if the individual experiences infusion-related symptoms, infusion-related reactions, or adverse events, e.g., as described herein in Example 1. In some embodiments of any of the methods provided herein, the dose of the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) 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.

[0290] In some embodiments of any of the methods provided herein for treating DLBCL, the method comprises adjusting the dose of cyclophosphamide after initiation of treatment, e.g., if the individual experiences infusion-related symptoms, infusion-related reactions, or adverse events, e.g., as described herein in Example 1. In some embodiments of any of the methods provided herein, the dose of cyclophosphamide administered to the individual is increased from a starting dose (e.g., 750 mg / m 2 ) to about 75% of the starting dose, for example, to about 563 mg / m 2 In some embodiments of any of the methods provided herein, the dose of cyclophosphamide administered to the individual is increased from a starting dose (e.g., 750 mg / m 2 ) to about 50% of the starting dose, for example, to about 375 mg / m 2 .

[0291] In some embodiments of any of the methods provided herein for treating DLBCL, the method comprises adjusting the dose of doxorubicin after initiation of treatment, e.g., if the individual experiences infusion-related symptoms, infusion-related reactions, or adverse events, e.g., as described herein in Example 1. In some embodiments of any of the methods provided herein, the dose of doxorubicin administered to the individual is increased from a starting dose (e.g., 50 mg / m 2 ) to about 75% of the starting dose, for example, to 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 increased from a starting dose (e.g., 50 mg / m 2 ) to about 50% of the starting dose, for example, to about 25 mg / m 2 .

[0292] In some embodiments, treatment with R-CHOP can be adjusted as described above (eg, control treatment).

[0293] In some embodiments, the dose of cyclophosphamide during R-CHOP treatment can be adjusted, for example, if infusion-related symptoms, infusion-related reactions, or adverse events occur, for example, as described in Example 1 herein. In some embodiments, the dose of cyclophosphamide is increased from a starting dose (e.g., 750 mg / m 2 ) to about 75% of the starting dose, for example, to about 563 mg / m 2 In some embodiments, the dose of cyclophosphamide is increased from the starting dose (e.g., 750 mg / m 2 ) to about 50% of the starting dose, for example, to about 375 mg / m 2 .

[0294] In some embodiments, the dose of doxorubicin during R-CHOP treatment can be adjusted, for example, if infusion-related symptoms, infusion-related reactions, or adverse events occur, for example, as described herein in Example 1. In some embodiments, the dose of doxorubicin is increased from a starting dose (e.g., 50 mg / m 2 ) to about 75% of the starting dose, for example, to about 37.5 mg / m 2 In some embodiments, the dose of doxorubicin is increased from a starting dose (e.g., 50 mg / m 2 ) to about 50% of the starting dose, for example, to about 25 mg / m 2 .

[0295] In some embodiments, the dose of vincristine in R-CHOP treatment can be adjusted, for example, if infusion-related symptoms, infusion-related reactions, or adverse events occur, for example, as described in Example 1 herein. In some embodiments, the dose of vincristine (also known as ankylosing pine) is increased from a starting dose (e.g., 1.4 mg / m 2 ) to about 75% of the starting dose, for example, to about 1.05 mg / m 2 In some embodiments, the dose of vincristine is increased from a starting dose (e.g., 1.4 mg / m 2 ) to about 50% of the starting dose, for example, to about 0.7 mg / m 2 In some embodiments of any of the methods provided herein, the dose of vincristine is about 1.4 mg / m 2 and about 0.5 mg / m 2 between, or around 1.4 mg / m 2 and about 0.7 mg / m 2 In some embodiments of any of the methods provided herein, the dose of vincristine is about 0.5 mg / m2 , 0.55mg / m 2 , 0.6mg / m 2 , 0.65mg / m 2 , 0.7mg / m 2 , 0.75mg / m 2 , 0.8mg / m 2 , 0.85mg / m 2 , 0.9mg / m 2 , 0.95mg / m 2 , 1.0mg / m 2 , 1.05mg / m 2 , 1.1mg / m 2 , 1.15mg / m 2 , 1.2mg / m 2 , 1.25mg / m 2 , 1.3mg / m 2 , 1.35mg / m 2 or 1.4 mg / m 2 In some embodiments of any of the methods provided herein, the maximum dose of vincristine is 2 mg per dose.

[0296] In some embodiments of any of the methods provided herein for treating DLBCL, each dose of an anti-CD20 antibody (e.g., obinutuzumab or rituximab) can be administered to an individual over multiple days (e.g., over 2 days), e.g., if the individual experiences infusion-related symptoms, infusion-related reactions, or adverse events. In some embodiments, if the dose of the anti-CD20 antibody (e.g., obinutuzumab or rituximab) is split over two days, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab) and one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) are administered the day after the dose of the anti-CD20 antibody (e.g., obinutuzumab or rituximab) is completed.

[0297] In some embodiments of any of the methods provided herein for treating DLBCL, an anti-CD20 antibody (such as 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 vepotuzumab) is administered on day 2 of each 21-day cycle (e.g., after administration of a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone)).

[0298] In some embodiments of any of the methods for treating DLBCL provided herein, the treatment regimen is modified, adjusted, interrupted, or delayed, as described herein in Example 1, e.g., as shown in Tables 3, 6, 8, and 9. In some embodiments of any of the methods for treating DLBCL provided herein, the method comprises managing infusion-related reactions and / or allergic reactions, as described herein in Example 1, e.g., as shown in Tables 6 and 7.

[0299] (vii) Exemplary biomarkers

[0300] In some embodiments of any method for treating DLBCL provided herein, the method further includes assessing individual minimal residual disease (MRD) before, during, and / or after treatment (e.g., by sequencing such as second-generation sequencing, or by any other suitable method known in the art). In some embodiments of any method for treating DLBCL provided herein, the method further includes assessing circulating tumor DNA (ctDNA) before, during, and / or after treatment (e.g., by sequencing such as second-generation sequencing, or by any other suitable method known in the art). In some embodiments of any method for treating DLBCL provided herein, the method further includes assessing lymphocyte 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 method for treating DLBCL provided herein, the method further includes assessing the cell of origin of DLBCL before, during, and / or after treatment (e.g., by gene expression profiling based on RNA, or by any other suitable method known in the art). In some embodiments of any method for treating DLBCL provided herein, the method further includes assessing the presence or absence of one or more mutations (such as, one or more mutations in MYD88 or CD79B) in DLBCL before, during, and / or after treatment (e.g., by sequencing such as second-generation sequencing, or by any other suitable method known in the art). In some embodiments of any method for treating DLBCL provided herein, the method further includes proteomic and / or immunohistochemical analysis of BCL2 and / or MYC in DLBCL before, during, and / or after treatment. In some embodiments of any method for treating DLBCL provided herein, the method further includes obtaining translocation features of MYC, BCL2, and / or BCL6 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 method for treating DLBCL provided herein, the method further includes assessing the index clone of DLBCL, for example, to determine minimal residual disease (MRD) (e.g., by sequencing such as second-generation sequencing, or using any other suitable method known in the art).

[0301] In some embodiments, the individual (e.g., human patient) treated according to any of the methods provided herein has an International Prognostic Index (IPI) score of 2. In some embodiments, the individual (e.g., 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, the individual (e.g., human patient) treated according to any of the methods provided herein has a bulky lesion (having a lesion of ≥7.5 cm). In some embodiments, the individual (e.g., human patient) treated according to any of the methods provided herein does not have a bulky lesion. In some embodiments, the individual (e.g., human patient) treated according to any of the methods provided herein does not have a lesion of ≥7.5 cm.

[0302] In some embodiments of any method provided herein, one or more chemotherapeutic agents (e.g., cyclophosphamide and / or doxorubicin) and / or corticosteroids (e.g., prednisone, prednisolone or methylprednisolone) can be substituted through suitable equivalent drugs. In some embodiments of any method provided herein, cyclophosphamide, doxorubicin, and / or prednisone, prednisolone or methylprednisolone can be substituted through suitable equivalent drugs.

[0303] C. Treatment Response and Assessment

[0304] In some embodiments, the treatment response of an individual (e.g., a human patient) treated according to any of the methods provided herein for treating diffuse large B-cell lymphoma (DLBCL) is assessed according to the Lugano Lymphoma Remission Criteria (Cheson et al., J Clin Oncol (2014) 32: 1-9). In some embodiments, the treatment response is assessed as described in Examples 1 or 2 herein, see, e.g., Table 2.

[0305] In some embodiments, progression-free survival (PFS) or the absence of disease progression is assessed as the time from the start of treatment according to the methods provided herein (e.g., any one of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) to the first occurrence of disease progression or relapse, or the time of death from any cause. In some embodiments, PFS or the absence of disease progression is assessed from the randomization date of the treatment regimen described in Example 1 to the first occurrence of disease progression or relapse, or the time of death from any cause. In some embodiments, disease progression or relapse is assessed by the investigator using the 2014 Lugano Classification of Malignant Lymphoma (Cheson et al., 2014). In some embodiments, for individuals who have not progressed, relapsed, or died by the clinical analysis cutoff date, PFS is censored on the last disease assessment date at which the individual is known to have no progression. In some embodiments, if no tumor assessment is performed after baseline or all post-baseline tumor assessment results have an overall response of "not evaluable", PFS is censored up to 7 days (e.g., any one of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) before starting treatment according to the methods provided herein (e.g., on the randomization date according to 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 with a reference PFS of multiple human patients treated with a control treatment (e.g., R-CHOP). In some embodiments, PFS is compared with a reference PFS based on a hazard ratio. 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, the 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 of America, Canada and / or Australia, and (iii) the rest of the world except (i) and / or (ii)); (b) International Prognostic Index (IPI) score (e.g., an IPI score of 2 versus between 3 and 5); and / or (c) the presence or absence of bulky disease (e.g., a lesion ≥ 7.5 cm). In some embodiments, PFS is compared to a reference PFS based on a stratified hazard ratio, e.g., as described above. In some embodiments, PFS is compared to a reference PFS based on an unstratified hazard ratio. In some embodiments, a 95% confidence interval for the hazard ratio is calculated.

[0306] In some embodiments, event-free survival (EFS) eff) is assessed as a maximum of 7 days (e.g., any of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) before the start of treatment according to the methods provided herein (e.g., on the randomization date according to the treatment regimen described in Example 1) to the first occurrence of EFS eff Time to an event, which includes any of the following: disease progression or relapse; death from any cause; a primary efficacy reason other than disease progression or relapse that led to initiation of a different anti-lymphoma therapy (NALT) as determined by the investigator; or if a biopsy result was obtained after completion of treatment or was positive for residual disease, regardless of whether NALT was initiated. In some embodiments, a primary efficacy reason includes one in which a positron emission tomography-computed tomography (PET-CT) scan, bone marrow examination, CT / MRI, or physical findings suggest residual disease; or one in which a biopsy confirms residual disease. In some embodiments, event-free survival (EFS) eff ) is the period from the date of randomization according to the treatment regimen described in Example 1 to the earliest occurrence of EFS as described above eff In some embodiments, the EFS eff The time to event is the time of the test or biopsy that led to the NALT, not the date the NALT was initiated. In some embodiments, if the individual does not experience EFS eff If an event occurs, then the EFS is calculated on the date of the last tumor assessment when the individual is known to be disease-free. eff In some embodiments, for those who do not have EFS eff Individuals with an event, no post-baseline tumor assessment results, or all post-baseline tumor assessment results with an overall response of "not evaluable" have a maximum of 7 days (e.g., any of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) prior to starting treatment according to the methods provided herein (e.g., on the date of randomization according to the treatment regimen described in Example 1) for EFS eff In some embodiments, the EFS of multiple human patients treated according to the methods of the present disclosure are eff Compared to the reference EFS of multiple human patients treated with a control treatment (e.g., R-CHOP) eff In some embodiments, EFS eff With reference to EFS effComparisons are made based on hazard ratios. In some embodiments, hazard ratios are calculated using any suitable method known in the art, such as using a 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 of America, Canada and / or Australia, and (iii) other parts of the world except (i) and / or (ii)); (b) International Prognostic Index (IPI) score (e.g., an IPI score of 2 versus between 3 and 5); and / or (c) the presence or absence of bulky lesions (e.g., a lesion ≥7.5 cm). In some embodiments, EFS is used as the stratification factor for the stratification of the patient's risk of death. eff With reference to EFS eff Comparisons are made based on stratified hazard ratios, such as those described above. eff With reference to EFS eff Comparisons are made based on unstratified hazard ratios. In some embodiments, 95% confidence intervals for hazard ratios are calculated. In some embodiments, EFS is calculated. eff 12-, 24-, or 36-month EFS rates (95% CI).

[0307] In some embodiments, survival is assessed from the time of starting treatment according to the methods provided herein (e.g., at the randomization date according to the treatment regimen described in Example 1) up to 7 days (e.g., any one of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) to death from any cause. In some embodiments, overall survival is assessed from the time of starting treatment according to the methods provided herein (e.g., at the randomization date according to the treatment regimen described in Example 1) up to 7 days (e.g., any one of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) to death from any cause. In some embodiments, survival is assessed from the randomization date according to the treatment regimen described in Example 1 to death from any cause. In some embodiments, overall survival is assessed from the randomization date according to the sub-treatment regimen described in Example 1 to death from any cause. In some embodiments, for individuals who have not died at the clinical analysis cutoff date, overall survival is censored at the last date on which the individual is known to be alive (e.g., as recorded by the investigator). In some embodiments, the overall survival (OS) of multiple human patients treated according to the methods of the present disclosure is compared with the reference OS of multiple human patients treated with a control treatment (e.g., R-CHOP). In some embodiments, OS is compared with a reference OS based on a hazard ratio. In some embodiments, any suitable method known in the art (such as using a stratified Cox proportional hazards analysis) is used to calculate the hazard ratio. In some embodiments, one or more or all of the following stratification factors are used to calculate the stratified hazard ratio: (a) geographic region (e.g., selected from (i) Asia, (ii) Western Europe, the United States of America, Canada and / or Australia, and (iii) other parts of the world except (i) and / or (ii))); (b) International Prognostic Index (IPI) score (e.g., an IPI score of 2 and between 3 and 5); and / or (c) the presence or absence of bulky lesions (e.g., a lesion ≥7.5 cm). In some embodiments, OS is compared with a reference OS based on a stratified hazard ratio, such as described above. In some embodiments, OS is compared with a reference OS based on an unstratified hazard ratio. In some embodiments, a 95% confidence interval for the hazard ratio is calculated.

[0308] In certain embodiments, the complete remission rate at the end of treatment is assessed as the ratio of individuality that shows complete remission at the end of treatment according to any method provided herein (e.g., the ratio in multiple individuals treated according to any method provided herein). In certain embodiments, complete remission is assessed by PET-CT by the researcher or by a blinded independent central review committee (BICR), as described in Example 1 herein.

[0309] In some embodiments, the 1-year or 12-month progression-free survival rate is assessed as the proportion of individuals (e.g., among multiple individuals treated according to any of the methods provided herein) who exhibit progression-free survival (PFS) at 1 year (i.e., 12 months), assessed from a maximum of 7 days (e.g., any of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) prior to the start of treatment according to the methods provided herein (e.g., on 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 multiple individuals treated according to any of the methods provided herein) who exhibit progression-free survival (PFS) at 1 year (i.e., 12 months), assessed from the date of randomization according to the treatment regimen described in Example 1.

[0310] In some embodiments, the 2-year or 24-month progression-free survival (PFS24) rate is assessed as the proportion of individuals (e.g., among individuals treated according to any of the methods provided herein) who exhibit progression-free survival (PFS) at 2 years (i.e., 24 months), assessed as of up to 7 days (e.g., any of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) prior to the start of treatment according to the methods provided herein (e.g., on 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 individuals treated according to any of the methods provided herein) who exhibit progression-free survival (PFS) at 2 years (i.e., 24 months), assessed as of the date of randomization according to the treatment regimen described in Example 1.

[0311] In some embodiments, the 3-year or 36-month progression-free survival (PFS36) rate is assessed as the proportion of individuals (e.g., among individuals treated according to any of the methods provided herein) who exhibit progression-free survival (PFS) at 3 years (i.e., 36 months), assessed as of up to 7 days (e.g., any of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) prior to the start of treatment according to the methods provided herein (e.g., on 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 individuals treated according to any of the methods provided herein) who exhibit progression-free survival (PFS) at 3 years (i.e., 36 months), assessed as of the date of randomization according to the treatment regimen described in Example 1.

[0312] In some embodiments, the 42-month progression-free survival (PFS42) rate is assessed as the proportion of individuals (e.g., among individuals treated according to any of the methods provided herein) who exhibit progression-free survival (PFS) at 42 months, assessed starting from a maximum of 7 days (e.g., any of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) prior to the start of treatment according to the methods provided herein (e.g., on 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 individuals treated according to any of the methods provided herein) who exhibit PFS at 42 months, assessed starting from the date of randomization according to the treatment regimen described in Example 1.

[0313] In some embodiments, disease-free survival (DFS) is assessed as the time from the first occurrence of complete remission in an individual treated according to any method provided herein to the time of individual disease recurrence or death from any cause in which the best overall remission (BOR) is complete remission. In some embodiments, for individuals who achieve complete remission but have not yet relapsed or died at the time of analysis, DFS is censored on the date of the last tumor assessment in which it is known that the individual has no disease. In some embodiments, the DFS of multiple human patients treated according to the methods disclosed herein is compared with the reference DFS of multiple human patients treated with a control treatment (e.g., R-CHOP). In some embodiments, DFS is compared with a reference DFS based on a hazard ratio. In some embodiments, the hazard ratio is calculated using any suitable method known in the art (such as using a stratified Cox proportional hazards analysis). In some embodiments, the 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 of America, Canada and / or Australia, and (iii) the rest of the world except (i) and / or (ii)); (b) International Prognostic Index (IPI) score (e.g., an IPI score of 2 versus between 3 and 5); and / or (c) the presence or absence of bulky lesions (e.g., a lesion ≥ 7.5 cm). In some embodiments, the DFS is compared to a reference DFS based on a stratified hazard ratio, e.g., as described above. In some embodiments, the DFS is compared to a reference DFS based on an unstratified hazard ratio. In some embodiments, a 95% confidence interval for the hazard ratio is calculated.

[0314] In certain embodiments, duration of remission (DOR) is the time from the individual first occurrence of remission (for example, complete remission or partial remission) according to any method treated herein to the time when the best overall remission with is the individual occurrence of progression, relapse or any cause of death in complete remission or partial remission and is assessed. In certain embodiments, for individuals who achieve remission but have not yet progressed, relapsed or died at the time of analysis, DOR is censored on the last tumor assessment date when the patient is known to have no progress. In certain embodiments, the DOR of multiple human patients treated according to the methods of the present disclosure is compared with the reference DOR of multiple human patients treated with a control treatment (for example, R-CHOP). In certain embodiments, DOR is compared with a reference DOR based on a hazard ratio. In certain embodiments, hazard ratios are calculated using any suitable method known in the art (such as using stratified Cox proportional hazards analysis). In some embodiments, the 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 of America, Canada and / or Australia, and (iii) rest of the world excluding (i) and / or (ii)); (b) International Prognostic Index (IPI) score (e.g., an IPI score of 2 versus between 3 and 5); and / or (c) the presence or absence of bulky lesions (e.g., a lesion ≥ 7.5 cm). In some embodiments, the DOR is compared to a reference DOR based on a stratified hazard ratio, e.g., as described above. In some embodiments, the DOR is compared to a reference DOR based on an unstratified hazard ratio. In some embodiments, a 95% confidence interval for the hazard ratio is calculated.

[0315] In certain embodiments, the best overall response (BOR) is assessed as the best response in an individual treated according to any method provided herein. In certain embodiments, response is assessed based on the Lugano lymphoma response criteria (Cheson et al., J Clin Oncol (2014) 32: 1-9). In certain embodiments, response is assessed by a researcher. In certain embodiments, response that does not meet the Lugano lymphoma response criteria (Cheson et al., 2014) is treated according to any method provided herein and is considered as a non-responder. In certain embodiments, the best overall response (BOR) is assessed from the start of treatment according to the method provided herein for up to 7 days (e.g., 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day or 0 day). In certain embodiments, the best overall response (BOR) is assessed from the randomization date of the treatment regimen described in Example 1. In certain embodiments, the best overall response (BOR) is assessed according to the method and criteria for assessing objective response rate (ORR), e.g., as described herein.

[0316] In some embodiments, EFS-all causes (EFS 全部 ) is assessed from a maximum of 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 to disease progression or relapse (e.g., as assessed by the investigator), death from any cause, or initiation of any new anti-lymphoma therapy (NALT). In some embodiments, EFS-all causes (EFS 全部 ) is assessed from the date of randomization according to the treatment regimen described in Example 1 to disease progression or relapse (e.g., as assessed by the investigator), death from any cause, or initiation of any new anti-lymphoma therapy (NALT). In some embodiments, if no disease progression or relapse, death, or initiation of NALT occurs, EFS is assessed at the date of the last tumor assessment. 全部 In some embodiments, for individuals who have not undergone post-baseline tumor assessment and have not experienced disease progression or recurrence, died, or initiated NALT, EFS is monitored up to 7 days (e.g., any one of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) prior to starting treatment according to the methods provided herein (e.g., on the date of randomization according to the treatment regimen described in Example 1). 全部 Perform censoring.

[0317] In certain embodiments, the objective response rate (ORR) at the end of treatment is assessed as the ratio of individuals who show complete remission or partial remission at the end of treatment according to any method provided herein (e.g., the ratio in multiple individuals treated according to any method provided herein). In certain embodiments, complete remission or partial remission is assessed by a researcher or by a blinded independent central review committee (BICR) by PET-CT, as described in Example 1 herein.

[0318] In some embodiments of any of the methods described herein, PET-CT refers to fluorodeoxyglucose positron emission tomography (FDG-PET), e.g., as described in Example 1 herein.

[0319] In some embodiments of any of the methods described herein, treatment or clinical response is assessed by an investigator or by a blinded independent central review committee (BICR). In some embodiments, an investigator refers to a physician, oncologist, radiologist, nuclear medicine specialist, or any other healthcare professional qualified to assess treatment or clinical response for DLBCL. In some embodiments, BICR refers to the assessment of treatment or clinical response in a standardized manner by a blinded radiologist, nuclear medicine specialist, and oncologist.

[0320] In some embodiments of any of the methods provided herein, the therapeutic response in an individual (e.g., a human patient) is assessed 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).

[0321] Further details on clinical staging and response criteria for lymphomas such as DLBCL are provided 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. (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 of the treatment methods provided herein can be monitored by techniques known in the art.

[0322] 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 method comprising a single agent, such as, for example, a treatment method using only an immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE or vepotuzumab), a treatment method using only an anti-CD20 antibody (e.g., obinutuzumab or rituximab), a treatment method using only one or more chemotherapeutic drugs (e.g., cyclophosphamide, doxorubicin and / or vincristine), or a treatment method using only 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 method comprising an anti-CD20 antibody (e.g., obinutuzumab or rituximab) and one or more chemotherapeutic drugs (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 method comprising an anti-CD20 antibody (e.g., obinutuzumab or rituximab), one or more chemotherapeutic drugs (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 method 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 method comprising rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, prednisolone 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 treatments 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 chemotherapy similar to CHOP).

[0323] In some embodiments, the treatment or clinical response of an individual (e.g., a human patient) or multiple individuals (e.g., multiple human patients) with DLBCL treated with any of the methods described herein is compared to the treatment or clinical response of an individual (e.g., a human) or multiple individuals (e.g., multiple humans) with DLBCL treated with a control treatment method, wherein the control treatment method is R-CHOP. In some embodiments, an individual or multiple individuals with DLBCL treated with any of the methods described herein achieves an improved treatment or clinical response compared to the treatment or clinical response of an individual or multiple individuals with DLBCL treated with R-CHOP. In some embodiments, an individual or multiple individuals with DLBCL treated with R-CHOP is treated according to the treatment regimen described below and in Example 1 herein.

[0324] In some embodiments, the individual or individuals with DLBCL treated with R-CHOP receive: 2 Rituximab administered intravenously (IV) at a dose of approximately 750 mg / m 2 Cyclophosphamide administered IV at a dose of approximately 50 mg / m 2 Doxorubicin administered IV at a dose of about 1.4 mg / m 2 In some embodiments, the individual or individuals with DLBCL who are being treated with R-CHOP are further administered IV at a dose of about 375 mg / m2. 2 Rituximab is administered as monotherapy in the 7th and 8th 21-day cycles following cycles 1 to 6, for example, on day 1 of each cycle.

[0325] In some embodiments, the individual or individuals with DLBCL treated with R-CHOP receive: 2Rituximab administered intravenously (IV) at a dose of approximately 750 mg / m 2 Cyclophosphamide administered IV at a dose of approximately 50 mg / m 2 Doxorubicin administered IV at a dose of about 1.4 mg / m 2 In some embodiments, the individual or individuals with DLBCL who are being treated with R-CHOP are further administered IV at a dose of about 375 mg / m2. 2 Rituximab is administered as monotherapy in 21-day cycles for two additional 21-day cycles (e.g., in cycles 7 and 8), e.g., on day 1 of each cycle.

[0326] In some embodiments, the individual or individuals with DLBCL treated with R-CHOP receive: 2 Rituximab administered intravenously (IV) at a dose of approximately 750 mg / m 2 Cyclophosphamide administered IV at a dose of approximately 50 mg / m 2 Doxorubicin administered IV at a dose of about 1.4 mg / m 2 The invention relates to a method of treating a patient with a 21-day cycle comprising: administering vincristine at a dose of about 100 mg / day (maximum 2 mg / dose) administered IV, each on Day 1 of a 21-day cycle for eight cycles (e.g., Cycles 1 to 8); and (a) prednisone administered orally (PO) at a dose of about 100 mg / day administered on Days 1 to 5 of a 21-day cycle for eight cycles (e.g., Cycles 1 to 8); (b) prednisolone administered PO at a dose of about 100 mg / day administered on Days 1 to 5 of a 21-day cycle for eight cycles (e.g., Cycles 1 to 8); or (c) methylprednisolone administered IV at a dose of about 80 mg / day administered on Days 1 to 5 of a 21-day cycle for eight cycles (e.g., Cycles 1 to 8).

[0327] In some embodiments, the individual or individuals with DLBCL treated with R-CHOP receive: 2 Rituximab administered intravenously (IV) at a dose of approximately 750 mg / m 2 Cyclophosphamide administered IV at a dose of approximately 50 mg / m 2 Doxorubicin administered IV at a dose of about 1.4 mg / m 2 (a) vincristine administered IV at a dose of about 100 mg / day (up to 2 mg / dose), each given on Day 1 of each 21-day cycle for between 6 and 8 cycles (e.g., Cycle 1 to Cycle 6, Cycle 1 to Cycle 7, or Cycle 1 to Cycle 8); and (b) prednisone administered orally (PO) at a dose of about 100 mg / day, given on Days 1 to 5 of each 21-day cycle for between 6 and 8 cycles (e.g., Cycle 1 to Cycle 6, Cycle 1 to Cycle 7, or Cycle 1 to Cycle 8); (b) prednisolone administered PO at a dose of about 100 mg / day on Days 1 to 5 of each 21-day cycle for between 6 and 8 cycles (e.g., Cycle 1 to Cycle 6, Cycle 1 to Cycle 7, or Cycle 1 to Cycle 8); or (c) methylprednisolone administered IV at a dose of about 80 mg / day on Days 1 to 5 of each 21-day cycle for between 6 and 8 cycles (e.g., Cycle 1 to Cycle 6, Cycle 1 to Cycle 7, or Cycle 1 to Cycle 8).

[0328] In some embodiments, treatment of a plurality of human patients according to 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, wherein the reference 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 older than 60 years of age according to 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, wherein the reference PFS is the PFS of a plurality of human patients older than 60 years of age who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients older than 65 years of age according to 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, wherein the reference PFS is the PFS of a plurality of human patients older than 65 years of age who have been treated with R-CHOP. In some embodiments, treatment according to the methods of the present disclosure of a plurality of human patients having an International Prognostic Index (IPI) score of between 3 and 5 results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, wherein the reference PFS is the PFS of a plurality of human patients who have received treatment with R-CHOP and have an IPI score of between 3 and 5. In some embodiments, treatment according to the methods of the present disclosure of a plurality of human patients who are older than 60 years and have an International Prognostic Index (IPI) score of between 3 and 5 results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, wherein the reference PFS is the PFS of a plurality of human patients who have received treatment with R-CHOP and have an IPI score of between 3 and 5. In some embodiments, treatment of a plurality of human patients aged 65 years or older and having an International Prognostic Index (IPI) score of 3 to 5 according to 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, wherein the reference PFS is the PFS of a plurality of human patients aged 65 years or older and having an IPI score of 3 to 5 who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with ABC-type DLBCL according to 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, wherein the reference PFS is the PFS of a plurality of human patients with ABC-type DLBCL who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with DEL-type DLBCL according to 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, wherein the reference PFS is the PFS of a plurality of human patients with DEL-type DLBCL who have been treated with R-CHOP.In some embodiments, treatment of a plurality of human patients according to the methods of the present disclosure results in a hazard ratio for progression-free survival (PFS) of no more than 0.75 (e.g., 0.74, 0.73, 0.72, 0.71, 0.70) for the plurality of human patients compared to treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients according to the methods of the present disclosure results in a hazard ratio for progression-free survival (PFS) of no more than 0.78 (e.g., 0.77, 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, 0.70) for the plurality of human patients compared to treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients according to the methods of the present disclosure results in a hazard ratio for progression-free survival (PFS) of no more than 0.79 (e.g., 0.78, 0.77, 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, 0.70) for the plurality of human patients compared to treatment with R-CHOP. In some embodiments, PFS or reference PFS is measured from a maximum of 7 days (e.g., any one of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) before the start of treatment to the time of first disease progression, relapse, or death. In some embodiments, PFS or reference PFS is measured from the start of treatment to the time of first disease progression, relapse, or death. In some embodiments, PFS or reference PFS is measured from the date of randomization according to the treatment regimen described in Example 1 to the time of first disease progression, relapse, or death. In some embodiments, PFS is the median PFS of multiple human patients receiving treatment according to the methods described herein. In some embodiments, the reference PFS is the median PFS of multiple 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, wherein the stratified hazard ratio does not exceed 0.75 (95% confidence interval: 0.57, 0.97). In some embodiments, the improvement in PFS is statistically significant, wherein the stratified hazard ratio does not exceed 0.78 (95% confidence interval: 0.60, 1.00). In some embodiments, the improvement in PFS is statistically significant, wherein the unstratified hazard ratio does not exceed 0.79 (95% confidence interval: 0.61, 1.02). In some embodiments, treatment of a plurality of human patients aged 60 years or older according to 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, wherein the hazard ratio does not exceed 0.8 (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), wherein the reference PFS is the PFS of a plurality of human patients aged 60 years or older who have received treatment with R-CHOP.In some embodiments, treatment of a plurality of human patients aged 60 years or older according to 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, wherein the stratified hazard ratio does not exceed 0.72 (95% confidence interval: 0.52, 0.99), wherein the reference PFS is the PFS of a plurality of human patients aged 60 years or older who have received treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients aged 60 years or older according to 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, wherein the unstratified hazard ratio does not exceed 0.72 (95% confidence interval: 0.53, 0.99), wherein the reference PFS is the PFS of a plurality of human patients aged 60 years or older who have received treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients aged 60 years or older according to 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, wherein the unstratified hazard ratio does not exceed 0.76 (95% confidence interval: 0.56, 1.02), wherein the reference PFS is the PFS of a plurality of human patients aged 60 years or older who have received treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients aged 65 years or older according to 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, wherein the hazard ratio does not exceed 0.9 (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), wherein the reference PFS is the PFS of a plurality of human patients aged 65 years or older who have received treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients aged 65 years or older according to 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, wherein the stratified hazard ratio does not exceed 0.79 (95% confidence interval: 0.54, 1.14), wherein the reference PFS is the PFS of a plurality of human patients aged 65 years or older who have received treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients aged 65 years or older according to 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, wherein the unstratified hazard ratio does not exceed 0.77 (95% confidence interval: 0.54, 1.10), wherein the reference PFS is the PFS of a plurality of human patients aged 65 years or older who have received treatment with R-CHOP.In some embodiments, treatment of a plurality of human patients aged 65 years or older according to 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, wherein the unstratified hazard ratio does not exceed 0.78 (95% confidence interval: 0.56, 1.10), wherein the reference PFS is the PFS of a plurality of human patients aged 65 years or older who have received treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients having an International Prognostic Index (IPI) score between 3 and 5 according to 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, wherein the hazard ratio does not exceed 0.8 (e.g., any of 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4 or less), wherein the reference PFS is the PFS of a plurality of human patients having an IPI score between 3 and 5 who have received treatment with R-CHOP. In some embodiments, treatment according to the methods of the present disclosure of a plurality of human patients having an International Prognostic Index (IPI) score between 3 and 5 results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, wherein the stratified hazard ratio does not exceed 0.68 (95% confidence interval: 0.50, 0.94), wherein the reference PFS is the PFS of a plurality of human patients having an IPI score between 3 and 5 who have received treatment with R-CHOP. In some embodiments, treatment according to the methods of the present disclosure of a plurality of human patients having an International Prognostic Index (IPI) score between 3 and 5 results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, wherein the unstratified hazard ratio does not exceed 0.71 (95% confidence interval: 0.51, 0.97), wherein the reference PFS is the PFS of a plurality of human patients having an IPI score between 3 and 5 who have received treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients with an International Prognostic Index (IPI) score between 3 and 5 according to 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, wherein the unstratified hazard ratio does not exceed 0.75 (95% confidence interval: 0.55, 1.01), wherein the reference PFS is the PFS of a plurality of human patients with an IPI score between 3 and 5 who have received treatment with R-CHOP.In some embodiments, treatment of a plurality of human patients with ABC-type DLBCL according to 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, wherein the hazard ratio is no more than 0.4 (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), wherein the reference PFS is the PFS of a plurality of human patients with ABC-type DLBCL who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with ABC-type DLBCL according to 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, wherein the stratified hazard ratio is no more than 0.31 (95% confidence interval: 0.17, 0.56), wherein the reference PFS is the PFS of a plurality of human patients with ABC-type DLBCL who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with ABC-type DLBCL according to 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, wherein the unstratified hazard ratio does not exceed 0.36 (95% confidence interval: 0.21, 0.62), wherein the reference PFS is the PFS of a plurality of human patients with ABC-type DLBCL who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with ABC-type DLBCL according to 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, wherein the unstratified hazard ratio does not exceed 0.39 (95% confidence interval: 0.23, 0.65), wherein the reference PFS is the PFS of a plurality of human patients with ABC-type DLBCL who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with DEL-type DLBCL according to 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, wherein the hazard ratio does not exceed 0.7 (e.g., any of 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4 or less), wherein the reference PFS is the PFS of a plurality of human patients with DEL-type DLBCL who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with DEL-type DLBCL according to 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, wherein the stratified hazard ratio does not exceed 0.62 (95% confidence interval: 0.40, 0.97), wherein the reference PFS is the PFS of a plurality of human patients with DEL-type DLBCL who have been treated with R-CHOP.In some embodiments, treatment of a plurality of human patients with DEL-type DLBCL according to 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, wherein the unstratified hazard ratio does not exceed 0.65 (95% confidence interval: 0.43, 0.98), wherein the reference PFS is the PFS of a plurality of human patients with DEL-type DLBCL who have been treated with R-CHOP. In some embodiments, treatment of a plurality of human patients with DEL-type DLBCL according to 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, wherein the unstratified hazard ratio does not exceed 0.67 (95% confidence interval: 0.44, 1.02), wherein the reference PFS is the PFS of a plurality of human patients with DEL-type DLBCL who have been treated with R-CHOP. In some embodiments, the hazard ratio has a 95% confidence interval. In some embodiments, the hazard ratio is calculated at 12 months or longer, 24 months or longer, or 36 months or longer, measured starting from: (a) the start of the corresponding treatment (i.e., treatment according to the methods of the present disclosure, or R-CHOP); (b) up to 7 days prior to the start of the corresponding treatment (i.e., treatment according to the methods of the present disclosure, or R-CHOP); or (c) the date of randomization according 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, wherein the stratified hazard ratio does not exceed 0.75 (95% confidence interval: 0.57, 0.97). In some embodiments, such treatment results in a statistically significant improvement in PFS compared to the control treatment, wherein the stratified hazard ratio does not exceed 0.78 (95% confidence interval: 0.60, 1.00). In some embodiments, such treatment results in a statistically significant improvement in PFS compared to the control treatment, wherein the unstratified hazard ratio does not exceed 0.79 (95% confidence interval: 0.61, 1.02).

[0329] In some embodiments, treatment of a plurality of human patients according to the methods of the present disclosure results in a reduction of at least 20% (e.g., 21%, 22%, 23%, or 24%) in the risk of disease progression, relapse, or death in the plurality of human patients compared to treatment with R-CHOP. In other embodiments, treatment of a plurality of human patients according to the methods of the present disclosure results in a reduction of at least 25% (e.g., 26%, 27%, 28%, 29%, or 30%) in the risk of disease progression, relapse, or death in the plurality of human patients compared to treatment with R-CHOP. In some embodiments, disease progression, relapse, or death is measured from the time of the first occurrence of disease progression, relapse, or death up to 7 days (e.g., any one of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) before the start of treatment. In some embodiments, disease progression, relapse, or death is measured from the time of the start of treatment to the time of the first occurrence of disease progression, relapse, or death. In some embodiments, disease progression, relapse, or death is measured from the date of randomization according to the treatment regimen described in Example 1 to the time of the first occurrence of disease progression, relapse, or death. In some embodiments, the reduction in risk has a 95% confidence interval. In some embodiments, the reduction in risk of disease progression, relapse or death is statistically significant. In some embodiments, the reduction in risk of disease progression, relapse or death is calculated at 12 months or longer, 24 months or longer, or 36 months or longer, measured starting from: (a) the start of the corresponding treatment (i.e., treatment according to the methods of the present disclosure, or R-CHOP); (b) up to 7 days before the start of the corresponding treatment (i.e., treatment according to the methods of the present disclosure, or R-CHOP); or (c) the randomization date of 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, wherein the reduction in risk of disease progression, relapse or death is 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 the control treatment, wherein the reduction in risk of disease progression, relapse or death is at least 25% (e.g., 26%, 27%, 28%, 29% or 30%).

[0330] In some embodiments, treatment of a plurality of human patients according to the methods of the present disclosure results in a 12-month progression-free survival rate of at least about 83% (e.g., any one of 83%, 84%, 85%, 86%, 87%, 88%, 90% or more). In some embodiments, treatment of a plurality of human patients according to the methods of the present 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, wherein the reference 12-month progression-free survival rate is the 12-month progression-free survival rate of a plurality of human patients who have received treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients according to the methods of the present 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 of at least about 3% (e.g., at least about any one of 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or more), wherein the reference 12-month progression-free survival rate is the 12-month progression-free survival rate of a plurality of human patients who have received treatment with R-CHOP. In some embodiments, the 12-month progression-free survival rate or reference 12-month progression-free survival rate is calculated at 12 months, and the measurement starts at most 7 days (e.g., any one of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) before the start of the corresponding treatment (i.e., treatment according to the methods of the present disclosure, or R-CHOP). In some embodiments, the 12-month progression-free survival rate or reference 12-month progression-free survival rate is calculated at 12 months, and the measurement starts at the start of the corresponding treatment (i.e., treatment according to the methods of the present disclosure, or R-CHOP). In some embodiments, the 12-month progression-free survival rate or reference 12-month progression-free survival rate is calculated at 12 months, and the measurement starts at the randomization date according to the treatment regimen described in Example 1. In some embodiments, the 12-month progression-free survival rate or reference 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.

[0331] In some embodiments, treatment of a plurality of human patients according to the methods of the present disclosure results in a 24-month progression-free survival rate (PFS24) of at least about 75% (e.g., 76%, 77%, 78%, 79%, 80%). In some embodiments, treatment of a plurality of human patients according to the methods of the present disclosure results in an improvement in the 24-month progression-free survival rate (PFS24) of the plurality of human patients compared to a reference PFS24, wherein the reference PFS24 is the 24-month progression-free survival rate of a plurality of human patients who have received treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients according to the methods of the present disclosure results in an improvement of at least about 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) in the 24-month progression-free survival rate (PFS24) of the plurality of human patients compared to a reference PFS24, wherein the reference PFS24 is the 24-month progression-free survival rate of a plurality of human patients who have received treatment with R-CHOP. In some embodiments, treatment of a plurality of human patients according to the methods of the present disclosure results in an improvement of at least about 6% (e.g., 6%, 7%, 8%, 9%, 10%) in the 24-month progression-free survival rate (PFS24) of the plurality of human patients compared to a reference PFS24, wherein the reference PFS24 is the 24-month progression-free survival rate of a plurality of human patients who have received treatment with R-CHOP. In some embodiments, PFS24 or reference PFS24 is calculated at 24 months, measured starting at most 7 days (e.g., any one of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days) before the start of the corresponding treatment (i.e., treatment according to the methods of the present disclosure, or R-CHOP). In some embodiments, PFS24 or reference PFS24 is calculated at 24 months, measured starting at the start of the corresponding treatment (i.e., treatment according to the methods of the present disclosure, or R-CHOP). In some embodiments, PFS24 or reference PFS24 is calculated at 24 months, measured starting at the randomization date according to the treatment regimen described in Example 1. In some embodiments, PFS24 or reference PFS24 is a progression-free survival (PFS) rate calculated using the Kaplan-Meier method. In some embodiments, the improvement in PFS24 is statistically significant. ...

Claims

1. A method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab, (b) Rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone; wherein administration of such treatment to a plurality of human patients results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, Wherein the reference PFS is the PFS of a plurality of human patients who have received a control treatment, wherein the control treatment comprises: (a) Rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone or methylprednisolone, Vempotuzumab was not present.

2. A method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab, (b) Rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 60 years old, wherein administration of such treatment to a plurality of human patients older than 60 years results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, and The reference PFS is the PFS of a plurality of human patients aged 60 years or older who have received a control treatment, wherein the control treatment comprises: (a) Rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone or methylprednisolone, Vempotuzumab was not present.

3. A method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab, (b) Rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 65 years old, wherein administration of such treatment to a plurality of human patients older than 65 years results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, and The reference PFS is the PFS of a plurality of human patients aged 65 years or older who have received a control treatment, wherein the control treatment comprises: (a) Rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone or methylprednisolone, Vempotuzumab was not present.

4. A method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab, (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, wherein administration of such treatment 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 compared to a reference PFS, and wherein the reference PFS is the PFS of a plurality of human patients with an IPI score between 3 and 5 who have received a control treatment, the control treatment comprising: (a) Rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone or methylprednisolone, Vempotuzumab was not present.

5. A method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab, (b) Rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 60 years old and has an International Prognostic Index (IPI) score between 3 and 5, wherein administration of such treatment to a plurality of human patients who are older than 60 years of age and have an IPI score between 3 and 5 results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, and wherein the reference PFS is the PFS of a plurality of human patients aged greater than 60 years and having an IPI score between 3 and 5 who have received a control treatment, the control treatment comprising: (a) Rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone or methylprednisolone, Vempotuzumab was not present.

6. A method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab, (b) Rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient is older than 65 years old and has an International Prognostic Index (IPI) score between 3 and 5, wherein administration of such treatment to a plurality of human patients who are older than 65 years of age and have an IPI score between 3 and 5 results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, and wherein the reference PFS is the PFS of a plurality of human patients aged greater than 65 years and having an IPI score between 3 and 5 who have received a control treatment, the control treatment comprising: (a) Rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone or methylprednisolone, Vempotuzumab was not present.

7. A method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab, (b) Rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient suffers from activated B-cell (ABC) DLBCL, wherein administering such treatment to a plurality of human patients having ABC-type DLBCL results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, and Wherein the reference PFS is the PFS of a plurality of human patients with ABC-type DLBCL who have received a control treatment, wherein the control treatment comprises: (a) Rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone or methylprednisolone, Vempotuzumab was not present.

8. A method for treating diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, the method comprising administering to the human patient an effective amount of: (a) vepotuzumab, (b) Rituximab, (c) cyclophosphamide, (d) doxorubicin, and (e) prednisone, prednisolone, or methylprednisolone; wherein the human patient suffers from double-expressing lymphoma (DEL) type DLBCL, wherein administering such treatment to a plurality of human patients having DEL-type DLBCL results in an improvement in progression-free survival (PFS) of the plurality of human patients compared to a reference PFS, and Wherein the reference PFS is the PFS of a plurality of human patients with DEL-type DLBCL who have received a control treatment, wherein the control treatment comprises: (a) Rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone, prednisolone or methylprednisolone, Vempotuzumab was not present.

9. The method according to any one of claims 1 to 8, wherein the PFS or the reference PFS is measured: (a) from the start of corresponding treatment to the first occurrence of disease progression, relapse or death; or (b) starting from up to 7 days before the start of corresponding treatment to the time of first disease progression, relapse or death; or (c) The time from randomization to the first occurrence of disease progression, relapse, or death.

10. The method according to any one of claims 1 to 9, wherein the PFS or the reference PFS is the median PFS of the plurality of human patients receiving the corresponding treatment.

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