Combination therapy of grofitamab and chemotherapy

Abstract

The present invention relates to a method for treating B-cell proliferative disorders, such as primary, refractory, or relapsed diffuse large B-cell lymphoma (DLBCL), by administering grofitamab in combination with gemcitabine and oxaliplatin. Furthermore, the present invention relates to an optimized corticosteroid prophylaxis for grofitamab that reduces the incidence of cytokine release syndrome (CRS).

Description

[Technical Field]

[0001] The present invention relates to a method for treating B-cell proliferative disorders, such as refractory or relapsed diffuse large B-cell lymphoma (DLBCL), by administering grofitamab in combination with gemcitabine and oxaliplatin (GemOx). [Background technology]

[0002] Non-Hodgkin lymphoma (NHL) is the most common hematological malignancy in the world and the 13th most common cancer overall (Bray et al. CA Cancer J Clin. 68(6):394-424, 2018). In 2018, an estimated 509,590 new cases of NHL were diagnosed worldwide (2.8% of all new cancer cases), and 248,724 people died from the disease (2.6% of all cancer-related deaths). The age-standardized risk of newly diagnosed NHL in Northern, Southern, Eastern, and Western Europe was 280.1 to 363.5 per 100,000 people per year for men and 216.5 to 292.1 per 100,000 people per year for women. In the same European region, the age-standardized risk of mortality from NHL was 118.4–171.0 person-years and 76.2–92.0 person-years per 100,000 people, respectively. In the United States, 74,680 people were diagnosed with NHL in 2018 (incidence rate, 19.4 per 100,000 people), and an estimated 19,910 patients died from the disease (National Cancer Institute [NCI] 2018).

[0003] NHL includes a heterogeneous group of lymphoproliferative disorders, but most commonly manifests as B lymphocyte defects. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of B-cell origin NHL (30%–40% of all NHL cases) (Al-Hamadani et al. Am J Hematol. 90(9):790-795, 2015).

[0004] DLBCL, which originates from mature B cells, is a progressive NHL with a median survival of <1 year in untreated patients (Rovira et al. Ann Hematol. 94(5):803-812, 2015). Despite the progressive course of the disease, approximately 50%–70% of patients can be cured with the current standard treatment consisting of rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy (Flowers et al. CA Cancer J Clin. 60(6):393-408, 2010). Nevertheless, R-CHOP has been found to be insufficient in 30%–50% of patients due to lack of response to initial treatment or relapse after achieving complete response (CR). Elderly patients remain a particularly difficult subset to treat, especially if they have reduced resistance to cytotoxic chemotherapy. There is a need for improved treatments for DLBCL that have a profile of improved efficacy and / or safety. [Overview of the Initiative]

[0005] The present invention features a method for treating patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). These patients may have relapsed after one line of prior treatment, or may not have been cured after one line of prior treatment, and may not be candidates for transplantation; or these patients may have relapsed after two or more lines of prior treatment, or may have been refractory to two or more lines of prior treatment. Patients with relapsed or refractory DLBCL may exhibit an improved response rate or a more sustained response after the method claimed by the present invention, for example, a combination of grofitamab, gemcitabine, and oxaliplatin (GemOx), compared to a control treatment, for example, rituximab, gemcitabine, and oxaliplatin (R-GemOx). Patients treated by the method claimed by the present invention may also exhibit an improved response and / or acceptance of autologous stem cell transplantation (ASCT) or chimeric antigen receptor T-cell therapy compared to a control treatment, for example, R-GemOx.

[0006] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in human patients requiring treatment for relapsed or refractory DLBCL, the method comprising: an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0007] In one embodiment, PFS or reference PFS is measured starting from the time of randomization and continuing until the first occurrence of disease progression or death from any cause.

[0008] In one embodiment, PFS or reference PFS is the median PFS of multiple human patients receiving the corresponding treatment.

[0009] In one embodiment, the improvement in PFS is statistically significant.

[0010] In one embodiment, improvement in the median PFS is defined as an increase of 1 to 18 months in PFS compared to a reference PFS.

[0011] In one embodiment, an improvement in the median PFS is an increase of approximately 9 months in PFS compared to the reference PFS. In another embodiment, an improvement in the median PFS is an increase of approximately 10 months in PFS compared to the reference PFS.

[0012] In one embodiment, applying such treatment to multiple human patients resulted in a statistically significant improvement in PFS compared to a control treatment, with a hazard ratio of approximately 0.42. In another embodiment, applying such treatment to multiple human patients resulted in a statistically significant improvement in PFS compared to a control treatment, with a hazard ratio of approximately 0.40.

[0013] In one embodiment, applying such treatment to multiple human patients resulted in a statistically significant improvement in PFS compared to a control treatment, with a hazard ratio of approximately 0.42 (95% confidence interval: 0.29, 0.61). In another embodiment, applying such treatment to multiple human patients resulted in a statistically significant improvement in PFS compared to a control treatment, with a hazard ratio of approximately 0.57 (95% confidence interval: 0.29, 0.61). In yet another embodiment, applying such treatment to multiple human patients resulted in a statistically significant improvement in PFS compared to a control treatment, with a hazard ratio of approximately 0.41 (95% confidence interval: 0.29, 0.58).

[0014] In one embodiment, the hazard ratio is a stratified hazard ratio.

[0015] In one embodiment, applying such treatment to multiple human patients increases the PFS rate by 5% to 45% compared to the reference PFS rate at 6 months.

[0016] In one embodiment, applying such treatment to multiple human patients increases the PFS rate by approximately 25% compared to the reference PFS rate at 6 months.

[0017] In one embodiment, applying such treatment to multiple human patients increases the PFS rate by 5 to 45% compared to a reference PFS at 12 months.

[0018] In one embodiment, applying such treatment to multiple human patients increases the PFS rate by approximately 25% compared to a reference PFS at 12 months.

[0019] In one embodiment, applying such treatment to multiple human patients improves the complete response rate (CR rate), objective response rate (ORR), duration of objective response, and / or duration of CR (DOCR) compared to a control treatment.

[0020] In one embodiment, the complete response (CR) rate is the percentage of patients whose best overall response is complete response (CR) in PET / computed tomography (CT).

[0021] In one embodiment, the improvement in the CR rate is an increase of 15% to 50%.

[0022] In one embodiment, the improvement in the CR rate is an increase of approximately 30%.

[0023] In one embodiment, ORR is the percentage of patients whose best overall response is a partial response (PR) or complete response (CR).

[0024] In one embodiment, the duration of objective response is measured as the time from the first recorded objective response (CR or PR) to disease progression or death from any cause, whichever comes first.

[0025] In one embodiment, DOCR is measured as the time from the first confirmed CR to disease progression or death from any cause, whichever comes first.

[0026] In one embodiment, a method is provided for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0027] In one embodiment, OS or reference OS is measured starting from the time of randomization until death from any cause.

[0028] In one embodiment, the OS or reference OS is the median OS of multiple human patients receiving the corresponding treatment.

[0029] In one embodiment, the improvement in the OS is statistically significant.

[0030] In one embodiment, an improvement in the median OS is an increase of 1 to 30 months in the OS compared to a reference OS.

[0031] In one embodiment, the improvement in the median OS is an increase of approximately 13 months compared to the reference OS.

[0032] In one embodiment, applying such treatment to multiple human patients resulted in a statistically significant improvement in overall survival (OS) compared to a control treatment, with a hazard ratio of approximately 0.62.

[0033] In one embodiment, applying such treatment to multiple human patients resulted in a statistically significant improvement in overall survival (OS) compared to a control treatment, with a hazard ratio of approximately 0.62 (95% confidence interval: 0.43, 0.88). In several embodiments, applying such treatment to multiple human patients resulted in a statistically significant improvement in OS compared to a control treatment, with a hazard ratio of approximately 0.60 (95% confidence interval: 0.42, 0.85).

[0034] In one embodiment, the hazard ratio is a stratified hazard ratio.

[0035] In one embodiment, applying such treatment to multiple human patients increases the OS rate by 5% to 30% compared to a reference OS at 12 months.

[0036] In one embodiment, applying such treatment to multiple human patients increases the OS rate by approximately 10% compared to a reference OS over 12 months.

[0037] In one embodiment, applying such treatment to multiple human patients increases the OS rate by 5% to 35% compared to a reference OS at 18 months.

[0038] In one embodiment, applying such treatment to multiple human patients increases the OS rate by approximately 20% compared to a reference OS at 18 months.

[0039] In one embodiment, applying such treatment to multiple human patients increases the OS rate by 5% to 40% compared to a reference OS at 24 months.

[0040] In one embodiment, applying such treatment to multiple human patients increases the OS rate by approximately 20% compared to a reference OS at 24 months.

[0041] In one embodiment, the stratified hazard ratio is stratified by: (a) the number of prior lines of systemic therapy for DLBCL (1 vs. ≥2); and / or (b) the outcome of the last systemic therapy (relapsed vs. refractory).

[0042] In one embodiment, the present invention features a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising administering an effective dose to a human patient: (a) grofitamab, (b) gemcitabine, and (c) oxaliplatin, and by applying such treatment to multiple human patients, a median duration of complete remission of at least 27 months can be obtained in multiple human patients.

[0043] In one embodiment, the present invention features a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising administering to a human patient an effective dose of: (a) grofitamab, (b) gemcitabine, and (c) oxaliplatin, wherein the application of such treatment to the patient results in complete remission, and multiple human patients who receive such treatment and achieve complete remission after the completion of treatment exhibit an overall survival rate of approximately 89% at 12 months.

[0044] In one embodiment, the present invention features a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising administering an effective dose to a human patient: (a) grofitamab, (b) gemcitabine, and (c) oxaliplatin, wherein the application of such treatment to the patient results in complete remission, and multiple human patients who achieve complete remission at the end of treatment after receiving such treatment exhibit a progression-free survival rate of approximately 82% at 12 months.

[0045] In one embodiment, the method comprises first and second administration cycles: The first administration cycle consists of a first dose of approximately 2.5 mg of grofitamab (C1D1) and a second dose of approximately 10 mg of grofitamab (C1D2). The second treatment cycle includes a single dose of approximately 30 mg of grofitamab (C2D1).

[0046] In one embodiment, grofitamab C1D1 and C1D2 are administered to the patient on day 8 and day 15 of the first dosing cycle, respectively.

[0047] In one embodiment, grofitamab C2D1 is administered to the patient on day 1 of the second dosing cycle.

[0048] In one embodiment, the first administration cycle includes a dose of approximately 1000 mg of obinutuzumab. In one embodiment, obinutuzumab is administered as a single dose of 1000 mg.

[0049] In one embodiment, obinutuzumab is administered approximately 7 days before the first grofitamab dose.

[0050] In one embodiment, obinutuzumab is administered on day 1 of the first administration cycle.

[0051] In one embodiment, the first and second administration cycles each consist of approximately 1000 mg / m² of gemcitabine. 2 The dosage and oxaliplatin approximately 100 mg / m² 2 This includes the dosage.

[0052] In one embodiment, gemcitabine and oxaliplatin are administered on day 2 of the first administration cycle.

[0053] In one embodiment, gemcitabine and oxaliplatin are administered on day 1 or day 2 of the second administration cycle.

[0054] In one embodiment, gemcitabine is administered on the same day before oxaliplatin.

[0055] In one embodiment, the first and second administration cycles are each 21-day administration cycles.

[0056] In one embodiment, the method includes 12 administration cycles.

[0057] In one embodiment, each administration cycle is 21 days long.

[0058] In one embodiment, the method includes the following: The patient is administered an effective dose of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin in one treatment cycle. The patient is administered effective doses of grofitamab, gemcitabine, and oxaliplatin for 2 to 8 cycles of administration; and The patient receives an effective dose of grofitamab for 9 to 12 cycles of administration.

[0059] In one embodiment, obinutuzumab is administered at a dose of approximately 1000 mg on day 1 of treatment cycle 1; grofitamab is administered at a dose of approximately 0.5 mg on day 8 and approximately 10 mg on day 15 of treatment cycle 1; and approximately 30 mg on day 1 of treatment cycles 2 through 12; and gemcitabine is administered at approximately 1000 mg / m². 2 At this dose, and oxaliplatin is approximately 100 mg / m². 2 It is administered at this dose on the second day of treatment cycle 1 and on the first or second day of treatment cycles 2 through 8.

[0060] In one embodiment, gemcitabine is administered on the same day before oxaliplatin.

[0061] In one embodiment, grofitamab is provided for use in a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment of DLBCL, wherein an effective dose of grofitamab is administered to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0062] In one embodiment, the present invention relates to grofitamab for use in a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein the method involves administering an effective dose to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0063] In one embodiment, the present invention relates to grofitamab for use in the manufacture of a pharmaceutical product for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for the disease, wherein the treatment is administered to a human patient in an effective dose: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0064] In one embodiment, the present invention relates to grofitamab for use in the manufacture of a pharmaceutical product for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for the disease, wherein the treatment is administered to a human patient in an effective dose: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0065] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, The patient has relapsed after one prior treatment line, or is refractory to one prior treatment line, and is not a candidate for HSCT, and the patient: (a) Having a left ventricular ejection fraction of ≤40%, (b) Having a creatinine clearance or glomerular filtration rate of ≤ 45 mL / min, (c) Having an East Coast Cancer Clinical Trials Group (ECOG) performance status of ≥ 2, (d) being 70 years of age or older, (e) has refused high-dose chemotherapy and / or transplantation, and / or (f) The patient's response to pre-transplant chemotherapy is insufficient, making it impossible to proceed with transplantation.

[0066] In one embodiment, the human patient has unspecified relapsed or refractory DLBCL (DLBCL NOS). In one embodiment, the human patient is not a candidate for hematopoietic stem cell transplantation (HSCT) (e.g., not eligible for HSCT). In one embodiment, the human patient has relapsed or refractory DLBCL NOS and is not a candidate for HSCT (e.g., not eligible for HSCT).

[0067] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. DLBCL is DLBCL NOS (unspecified DLBCL), and the patient is not a candidate for hematopoietic stem cell transplantation (HSCT).

[0068] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. DLBCL is DLBCL NOS (unspecified DLBCL), and the patient is not a candidate for hematopoietic stem cell transplantation (HSCT).

[0069] In one embodiment, the patient receives corticosteroid prophylaxis before and after administration of grofitamab.

[0070] In one embodiment, corticosteroid prophylaxis includes prednisolone, methylprednisolone, and / or dexamethasone.

[0071] In one embodiment, corticosteroid prophylaxis includes dexamethasone. In one embodiment, corticosteroid prophylaxis includes 20 mg of dexamethasone. In one embodiment, corticosteroid prophylaxis is administered one day before the administration of grofitamab.

[0072] In one embodiment, corticosteroid prophylaxis is administered approximately 24 hours before grofitamab administration. In one embodiment, corticosteroid prophylaxis is administered on the same day as grofitamab administration. In one embodiment, corticosteroid prophylaxis is administered approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration.

[0073] In one embodiment, corticosteroid prophylaxis is performed one day after administration of grofitamab.

[0074] In one embodiment, corticosteroid prophylaxis is performed approximately 24 hours after administration of grofitamab.

[0075] In one embodiment, corticosteroid prophylaxis is performed before the first dose (C1D1) of grofitamab.

[0076] In one embodiment, corticosteroid prophylaxis is administered before the second dose (C1D2) of grofitamab.

[0077] In one embodiment, corticosteroid prophylaxis is performed one day before grofitamab administration, before grofitamab administration on the same day, and one day after grofitamab administration.

[0078] In one embodiment, corticosteroid prophylaxis is administered approximately 24 hours before grofitamab administration, approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and approximately 24 hours after grofitamab administration.

[0079] In one embodiment, corticosteroid prophylaxis is dexamethasone.

[0080] In one embodiment, dexamethasone is administered at a dose of 20 mg.

[0081] In one embodiment, 20 mg of dexamethasone is administered orally one day before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally one day after grofitamab administration.

[0082] In one embodiment, 20 mg of dexamethasone is administered orally approximately 24 hours before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally approximately 24 hours after grofitamab administration.

[0083] In one embodiment, corticosteroid prophylaxis is administered before the third dose (C2D1) of grofitamab.

[0084] In one embodiment, corticosteroid prophylaxis is administered prior to any subsequent dose of grofitamab if the patient has experienced CRS with any previous 30 mg dose of grofitamab.

[0085] In one embodiment, corticosteroid prophylaxis includes 20 mg of dexamethasone.

[0086] In one embodiment, the incidence of CRS in multiple patients is reduced with corticosteroid prophylaxis compared to treatment consisting of grofitamab administration and one dose of corticosteroid on the same day.

[0087] In one embodiment, the patient does not have a Grade 3 CRS event.

[0088] In one embodiment, the patient does not need to be hospitalized after treatment with grofitamab.

[0089] In one embodiment, the present invention features a method for reducing the incidence of CRS events in a patient population treated with grofitamab, the method comprising administering grofitamab and dexamethasone to patients in the patient population in a dosing regimen comprising at least a first and a second dosing cycle: (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1), with dexamethasone administered one day before grofitamab administration, on the day of grofitamab administration, and one day after grofitamab administration.

[0090] In one embodiment, the present invention features a method for reducing the likelihood of CRS events in patients with CD20-positive B-cell proliferative disorders treated with grofitamab, the method comprising administering grofitamab and dexamethasone to the patient in a dosing regimen comprising at least a first and a second dosing cycle: (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1), with dexamethasone administered one day before grofitamab administration, on the day of grofitamab administration, and one day after grofitamab administration.

[0091] In one embodiment, dexamethasone is administered in a dose of 20 mg. In one embodiment, dexamethasone is administered approximately 24 hours before administration of grofitamab, approximately 30 to 90 minutes or approximately 60 minutes before administration of grofitamab, and approximately 24 hours after administration of grofitamab. In one embodiment, dexamethasone is administered in conjunction with the first dose (C1D1) and the second dose (C1D2) of grofitamab.

[0092] In one embodiment, 20 mg of dexamethasone is administered orally one day before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally one day after grofitamab administration.

[0093] In one embodiment, 20 mg of dexamethasone is administered orally approximately 24 hours before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally approximately 24 hours after grofitamab administration.

[0094] In one embodiment, dexamethasone is administered in addition to a third dose (C2D1) of grofitamab if the patient has experienced CRS with the first and / or second doses of grofitamab.

[0095] In one embodiment, dexamethasone is administered prior to any subsequent dose of grofitamab if the patient has experienced CRS with any previous 30 mg dose of grofitamab.

[0096] In one embodiment, dexamethasone is administered with the first and second doses (C2D1) of grofitamab, but not with any subsequent doses.

[0097] In one embodiment, the treatment does not cause grade 3 or higher CRS. In one embodiment, the incidence of cytokine release syndrome of any grade (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 40%. In one embodiment, the incidence of cytokine release syndrome of grade 3 or higher (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 1%. In one embodiment, the patient does not need to be hospitalized for the first two cycles of treatment with grofitamab.

[0098] In one embodiment, the method further comprises administering gemcitabine and oxaliplatin.

[0099] In one embodiment, grofitamab is provided for use in a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein the treatment method involves administering an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Patients receive corticosteroid prophylaxis before and after administration of grofitamab.

[0100] In one embodiment, the present invention relates to grofitamab for use in a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein the treatment method involves administering an effective dose to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Patients who do not receive grofitamab will receive corticosteroid prophylaxis before and after administration of grofitamab.

[0101] In one embodiment, the present invention relates to dexamethasone for use in a method for reducing the incidence of CRS events in a patient population treated with grofitamab, wherein patients in the patient population are administered grofitamab and dexamethasone in a dosing regimen comprising at least a first and a second dosing cycle: (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1), with dexamethasone administered one day before, on the day of, and one day after the administration of grofitamab.

[0102] In one embodiment, the present invention relates to dexamethasone for use in a method for reducing the likelihood of CRS events in patients with CD20-positive B-cell proliferative disorders treated with grofitamab, wherein the patient is administered grofitamab and dexamethasone in a dosing regimen comprising at least a first and a second dosing cycle: (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1), with dexamethasone administered one day before grofitamab administration, on the day of grofitamab administration, and one day after grofitamab administration.

[0103] Any embodiment can be combined, as long as it does not contradict the context. Any embodiment can be applied to any aspect of the present invention, as long as it does not contradict the context.

[0104] Specific embodiments of the present invention will become apparent from the following more detailed description of certain preferred embodiments and the claims. [Brief explanation of the drawing]

[0105] [Figure 1] The experimental treatment group shows the regimen of grofitamab in combination with gemcitabine and oxaliplatin (Glofit-GemOx group). [Figure 2] The control group shows the rituximab regimen in combination with gemcitabine and oxaliplatin (R-GemOx group). [Figure 3] This Kaplan-Meier chart shows the overall survival (OS) rates of intent-to-treat (ITT) patients treated with rituximab, gemcitabine, and oxaliplatin (R-GemOx; solid line) or grofitamab, gemcitabine, and oxaliplatin (Glofit-GemOx; dashed line). Patients treated with Glofit-GemOx showed higher OS (hazard ratio = 0.59; P-value = 0.0107). [Figure 4] This Kaplan-Meier chart shows progression-free survival rates in intent-to-treat (ITT) patients treated with rituximab, gemcitabine, and oxaliplatin (R-GemOx; solid line) or grofitamab, gemcitabine, and oxaliplatin (Glofit-GemOx; dashed line). Patients treated with Glofit-GemOx showed higher PFS (hazard ratio = 0.34; P < 0.00001). [Figure 5]Kaplan–Meier plot showing overall survival (OS) rates of R / R DLBCL patients administered rituximab, gemcitabine, and oxaliplatin (R-GemOx; solid line) or glofitamab, gemcitabine, and oxaliplatin (Glofit-GemOx; dashed line) in a follow-up analysis with a cutoff date of February 16, 2024. Patients administered Glofit-GemOx exhibited higher OS (hazard ratio = 0.62; 95% CI: 0.43–0.88). [Figure 6] Shows the design of an in vivo test to evaluate the effect of dexamethasone scheduling on CRS and the efficacy of glofitamab. [Figure 7] Shows inhibition of tumor growth in mice treated with glofitamab and dexamethasone. [Figure 8A] Shows cytokine measurements in mice after 4 hours of Treatments A–G and after the first and second glofitamab infusions. A: Vehicle, B: Glofitamab; C: Glofitamab + dexamethasone (1 hour before); D: Glofitamab + dexamethasone (24 hours and 1 hour before + 24 hours after) 4 mg / kg; E: Glofitamab + dexamethasone (24 hours and 1 hour before) 2 mg / kg; F: Glofitamab + dexamethasone (24 hours and 1 hour before + 24 hours after) 2 / 4 mg / kg; G: Glofitamab + dexamethasone (24 hours and 1 hour before) 6 / 2 mg / kg. [Figure 8B] Shows cytokine measurements in mice 28 hours after Treatments A–G and after injection of the first and second glofitamab. A: Vehicle, B: Glofitamab; C: Glofitamab + dexamethasone (1 hour before); D: Glofitamab + dexamethasone (24 hours and 1 hour before + 24 hours after) 4 mg / kg; E: Glofitamab + dexamethasone (24 hours and 1 hour before) 2 mg / kg; F: Glofitamab + dexamethasone (24 hours and 1 hour before + 24 hours after) 2 / 4 mg / kg; G: Glofitamab + dexamethasone (24 hours and 1 hour before) 6 / 2 mg / kg. [Figure 9]Shows the design of an in vivo test to evaluate the effect of dexamethasone scheduling on the efficacy of glofitamab in combination with CRS, gemcitabine, and oxaliplatin. [Figure 10A] Shows the tumor growth rate in a preclinical trial evaluating the effect of dexamethasone scheduling on the efficacy of glofitamab in combination with CRS, gemcitabine, and oxaliplatin, presented as the median tumor volume. CD20-TCB = glofitamab, statistics: one-way ANOVA. *: p<0.05; **: p<0.01; ***: p<0.001; ****: p<0.0001. [Figure 10B] Shows the individual tumor growth trajectories for each mouse within various treatment groups in a preclinical trial evaluating the effect of dexamethasone scheduling on the efficacy of glofitamab in combination with CRS, gemcitabine, and oxaliplatin. CD20-TCB = glofitamab, statistics: one-way ANOVA. *: p<0.05; **: p<0.01; ***: p<0.001; ****: p<0.0001. [Figure 10C] Shows the tumor volumes of groups D - H at the end of the trial for statistical analysis in a preclinical trial evaluating the effect of dexamethasone scheduling on the efficacy of glofitamab in combination with CRS, gemcitabine, and oxaliplatin. CD20-TCB = glofitamab, statistics: one-way ANOVA. *: p<0.05; **: p<0.01; ***: p<0.001; ****: p<0.0001. [Figure 11A] Shows the measurement of cytokines (IL6 and IL2) in serum 6 hours after the last dexamethasone administration (day 10) in the first cycle of a preclinical trial evaluating the effect of dexamethasone scheduling on the efficacy of glofitamab in combination with CRS, gemcitabine, and oxaliplatin. CD20-TCB = glofitamab, statistics: one-way ANOVA. *: p<0.05; **: p<0.01; ***: p<0.001; ****: p<0.0001. [Figure 11B]This shows serum cytokine (MCP-1 and IFN-γ) measurements 6 hours after the last dexamethasone dose (day 10) in the first cycle of a preclinical trial evaluating the effect of dexamethasone scheduling on the efficacy of grofitamab in combination with CRS and gemcitabine and oxaliplatin. CD20-TCB = grofitamab, statistics: one-way ANOVA. *: p<0.05; **: p<0.01; ***: p<0.001; ****: p<0.0001. [Figure 11C] This shows serum cytokine (IL-8 and IL-10) measurements 6 hours after the last dexamethasone dose (day 10) in the first cycle of a preclinical trial evaluating the effect of dexamethasone scheduling on the efficacy of grofitamab in combination with CRS and gemcitabine and oxaliplatin. CD20-TCB = grofitamab, statistics: one-way ANOVA. *: p<0.05; **: p<0.01; ***: p<0.001; ****: p<0.0001. [Figure 12] The study schema for trial GO45434 is shown. Dexamethasone was administered orally on days 7, 9, 14, and 16. *Dexamethasone was administered intravenously for 60 minutes prior to grofitamab administration; **Dexamethasone was administered optionally based on the investigator's assessment of participants who tolerated at least one 30 mg dose of grofitamab without experiencing CRS. Note: In cycles 1-8, gemcitabine must be administered prior to oxaliplatin. In cycles 2-8, grofitamab must be administered prior to gemcitabine and oxaliplatin. [Figure 13] This Kaplan-Meier chart shows the overall survival (OS) rates in patients treated with rituximab, gemcitabine, and oxaliplatin (R-GemOx; solid line) or grofitamab, gemcitabine, and oxaliplatin (Glofit-GemOx; dashed line) in the latest analysis of the STARGLO clinical trial. Patients treated with Glofit-GemOx had a higher OS (hazard ratio = 0.62). [Figure 14]This Kaplan-Meier chart shows the progression-free survival (PFS) rates in patients treated with rituximab, gemcitabine, and oxaliplatin (R-GemOx; solid line) or grofitamab, gemcitabine, and oxaliplatin (Glofit-GemOx; dashed line) in the latest analysis of the STARGLO clinical trial. Patients treated with Glofit-GemOx showed a higher PFS (hazard ratio = 0.40). [Modes for carrying out the invention]

[0106] The present invention provides a method for treating patients having CD20-positive cell proliferative disorders (e.g., B-cell proliferative disorders (e.g., non-Hodgkin lymphoma (NHL) (e.g., relapsed and / or refractory NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed and / or refractory DLBCL), follicular lymphoma (FL) (e.g., relapsed and / or refractory FL or transformed FL), or mantle cell lymphoma (MCL) (e.g., relapsed or refractory MCL)), or central nervous system lymphoma (CNSL))), the method comprising administering grofitamab (Glofit-GemOx) in combination with gemcitabine and oxaliplatin to the patient.

[0107] (i) General techniques Unless otherwise specified, the implementation of this invention shall be carried out using general techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the scope of the art. Such techniques are described in detail in publications such as “Molecular Cloning: A Laboratory Manual,” second edition (Sambrook et al., 1989); “Oligonucleotide Synthesis” (MJ Gait, ed., 1984); “Animal Cell Culture” (RI Freshney, ed., 1987); “Methods in Enzymology” (Academic Press, Inc.); “Current Protocols in Molecular Biology” (FMAusubel et al., eds., 1987, and periodic updates); “PCR: The Polymerase Chain Reaction” (Mullis et al., ed., 1994); “A Practical Guide to Molecular Cloning” (Perbal Bernard V., 1988); and “Phage Display: A Laboratory Manual” (Barbas et al., 2001).

[0108] (ii) Definition The terms used herein shall be used as commonly used in the art unless otherwise defined below.

[0109] The aspects and embodiments of the present invention described herein should be understood to include "including," "consisting of," and / or "essentially consisting of."

[0110] As used herein, the singular forms "a," "an," and "the" include references to the plural form unless otherwise indicated.

[0111] As used herein, the term “about” refers to the normal range of error for each value that is readily known to those skilled in the art. Where “about” is mentioned before a value or parameter herein, embodiments that apply to that value or parameter itself are included (described). In some embodiments, “about” before a value or parameter refers to ±10% of the value or parameter.

[0112] As used herein, the terms “differentiation cluster 20” or “CD20” refer to any natural CD20 derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. CD20 (also known as B-lymphocyte antigen CD20, B-lymphocyte surface antigen B1, Leu-16, Bp35, BM5, and LF5; the human protein is characterized in UniProt database entry P11836) is a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD expressed on pre-B lymphocytes and mature B lymphocytes (Valentine, MA et al., J. Biol. Chem. 264 (1989) 11282-11287; Tedder, TF, et al., Proc. Natl. Acad. Sci. USA 85 (1988) 208-212; Stamenkovic, I., et al., J. Exp. Med. 167 (1988) 1975-1980; Einfeld, DA, et al., EMBO J.7(1988)711-717; Tedder, TF, et al., J.Immunol.142(1989)2560-2568). The corresponding human gene is a 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 nascent protein family are characterized by common structural features and similar intron / exon splice boundaries, and exhibit unique 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 localized to 11q12 within the cluster of family members. The term encompasses "full-length," untreated CD20 and any form of CD20 resulting from intracellular processing. The term also encompasses naturally occurring CD20 variants, such as splice variants or allele variants. This alternative splicing of the gene results in two transcriptional variants encoding the same protein. In one embodiment, CD20 is human CD20.

[0113] The terms "anti-CD20 antibody" and "antibody that binds to CD20" refer to an antibody that can bind to CD20 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent when targeting CD20. In one embodiment, the degree of binding of an anti-CD20 antibody to an irrelevant, non-CD20 protein is, for example, less than about 10% of the binding of the antibody to CD20, measured by, for example, radioimmunoassay (RIA). In some embodiments, the antibody that binds to CD20 has a dissociation constant (K -8 ) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or less, e.g., from 10 -13 M to 10 -9 M, e.g., from 10 -13 M). In some embodiments, the anti-CD20 antibody binds to an epitope of CD20 that is conserved among CD20s from different species.

[0114] "Type II anti-CD20 antibody" means an anti-CD20 antibody having the binding characteristics and biological activities of the type II anti-CD20 antibodies described in Cragg et al., Blood 103 (2004) 2738-2743; Cragg et al., Blood 101 (2003) 1045-1052, Klein et al., mAbs 5 (2013), 22-33, and summarized in Table 1 below.

[0115] TIFF2026522176000001.tif58170

[0116] Examples of type II anti-CD20 antibodies include, for example, obinutuzumab (GA101), tositumomab (B1), humanized B-Ly1 antibody IgG1 (a chimeric humanized IgG1 antibody disclosed in International Publication No. 2005 / 044859), 11B8 IgG1 (disclosed in International Publication No. 2004 / 035607), and AT80 IgG1.

[0117] ​​Examples of type I anti-CD20 antibodies include, for example, rituximab, ofatumumab, belimumab, ocrelizumab, obinutuzumab, PRO131921, ublituximab, HI47 IgG3 (ECACC, hybridoma), 2C6 IgG1 (disclosed in WO 2005 / 103081), 2F2 IgG1 (disclosed in WO 2004 / 035607 and WO 2005 / 103081) and 2H7 IgG1 (disclosed in WO 2004 / 056312).

[0118] Unless otherwise indicated, "CD3" refers to any native CD3 derived from any vertebrate source, including mammals such as primates (e.g., humans), non-human primates (e.g., cynomolgus monkeys), and rodents (e.g., mice and rats). The term encompasses "full-length", unprocessed CD3 and any form of CD3 resulting from intracellular processing. The term also encompasses naturally occurring variants of CD3, such as splice variants or allelic variants. In one embodiment, CD3 is human CD3, particularly the epsilon subunit of human CD3 (CD3ε). The amino acid sequence of human CD3ε is shown in UniProt (uniprot.org) accession number P07766 (version 144), or NCBI (ncbi.nlm.nih.gov) RefSeq NP_000724.1. The amino acid sequence of CD3ε of cynomolgus monkey [Macaca fascicularis] is shown in NCBI GENBANK® no. BAB71849.1.

[0119] Glofitamab is an anti-CD20 / anti-CD3 bispecific antibody (WHO Drug Information (International Generic Names of Drugs), Recommended INN:List 83, 2020, vol.34, no.1, p.39; Proposed INN:List 121 WHO Drug Information, Vol.33, No.2, 2019, page 276, also known as CD20-TCB, RO7082859, or RG6026; CAS #:2229047-91(8). Glofitamab is a novel T cell-involved bispecific (TCB) full-length antibody with a 2:1 molecular configuration for bivalent binding to CD20 on B cells and monovalent binding to CD3, particularly the CD3 epsilon chain (CD3ε), on T cells. Its CD3 binding domain is fused head-to-tail to one of the CD20 binding domains via a mobile linker. This structure gives grofitamab superior in inclusion compared to other CD20-CD3 bispecific antibodies with a 1:1 configuration. It confers in vitro efficacy and leads to deep antitumor efficacy in preclinical DLBCL models. The bivalent nature of CD20 retains this efficacy in the presence of competing anti-CD20 antibodies, providing opportunities for prior or combination therapy with these drugs. Glofitamab contains a modified heterodimer Fc region in which binding to FcgR and C1q is completely lost. By co-binding to CD3ε of the T cell receptor (TCR) complex on human CD20-expressing tumor cells and T cells, it induces T cell activation, proliferation, and cytokine release, as well as tumor cell lysis. The lysis of B cells mediated by grofitamab is CD20-specific and does not occur in the absence of CD20 expression or in the absence of co-binding (cross-linking) of T cells to CD20-expressing cells. In addition to killing, T cells undergo activation due to CD3 cross-linking, which can be detected by increased T cell activation markers (CD25 and CD69), cytokine release (IFNγ, TNFα, IL-2, IL-6, and IL-10), cytotoxic granule release (granzyme B), and T cell proliferation. The sequence of grofitamab is summarized in Table 2.

[0120] TIFF2026522176000002.tif98170

[0121] As used herein, the term “cytokine release” or “cytokine release” is synonymous with “cytokine storm” or “cytokine release syndrome” (abbreviated as “CRS”) and refers to an increase in the levels of cytokines in the blood of patients experiencing adverse symptoms during or immediately after administration of a therapeutic agent (e.g., within 1 day of administration), particularly tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-2 (IL-2), and / or interleukin-8 (IL-8). Cytokine release is defined as a paraphysiological response to the application of any immunotherapy resulting in the activation or involvement of endogenous or injected T cells and / or other immune effector cells. Symptoms may be progressive and may include fever at onset, hypotension, capillary leakage (hypoxia), and peripheral organ dysfunction (Lee et al. 2019). In some cases, CRS may occur, for example, after CAR-T cell administration, as CAR-T cells expand several days after administration. The incidence and severity generally decrease with subsequent infusions. Symptoms range from symptomatic discomfort to fatal events and may include fever, chills, dizziness, hypertension, hypotension, dyspnea, restlessness, sweating, flushing, rash, tachycardia, tachypnea, headache, tumor pain, nausea, vomiting, and / or organ failure.

[0122] As used herein, the term “amino acid mutation” is intended to encompass amino acid substitutions, deletions, insertions, and modifications. Any combination of substitutions, deletions, insertions, and modifications can be performed to arrive at the final construct if the final construct has a desired property, such as reduced binding to the Fc receptor. Deletions and insertions of amino acid sequences include deletions and insertions of amino acids at the amino-terminus and / or carboxy-terminus. A specific amino acid mutation is an amino acid substitution. For example, non-conservative amino acid substitutions, i.e., replacing one amino acid with another amino acid having different structural and / or chemical properties, are particularly preferred for the purpose of altering the binding properties of the Fc region. Amino acid substitutions include substitutions with amino acids that do not exist naturally, or substitutions with naturally occurring amino acid derivatives of 20 standard amino acids (e.g., 4-hydroxyproline, 3-methylhistidine, ornithine, homoserine, 5-hydroxylysine). Amino acid mutations can be generated using genetic or chemical methods well known in the art. Genetic methods may include site-directed mutagenesis, PCR, and gene synthesis. Methods other than genetic modification to alter the side chain groups of amino acids, such as chemical modification, are also considered potentially useful. In this specification, various notations may be used to indicate the same amino acid mutation. For example, the substitution of proline to glycine at position 329 of the Fc region can be expressed as 329G, G329, or G 329 It can be indicated as P329G or Pro329Gly.

[0123] "Affinity" refers to the sum of the non-covalent interactions between a single binding site of a molecule (e.g., a receptor) and its binding partner (e.g., a ligand). As used herein, unless otherwise indicated, "binding affinity" refers to the intrinsic binding affinity that reflects the 1:1 interaction between members of a binding pair (e.g., receptor and ligand). The affinity of molecule X for its partner Y is usually expressed by the dissociation rate constant and the binding rate constant (k, respectively). off and k on The dissociation constant (K) is the ratio of ). DIt can be expressed by ). Therefore, as long as the ratio of rate constants is the same, equivalent affinity may include different rate constants. Affinity can be measured by established methods known in the art. A specific method for measuring affinity is surface plasmon resonance (SPR).

[0124] "Affinity-matured" antibodies are those that, compared to a parent antibody without alterations in its hypervariable region (HVR), have one or more alterations in one or more hypervariable regions, and such alterations result in improved affinity of the antibody to the antigen.

[0125] As used herein, the term “antigen-binding moiety” refers to a polypeptide molecule that specifically binds to an antigenic determinant. In one embodiment, an antigen-binding moiety can direct the entity to which it binds (e.g., a cytokine or a second antigen-binding moiety) to a target site, for example, a specific type of tumor cell or tumor stroma containing an antigenic determinant. The antigen-binding moiety includes an antibody and fragments thereof, as further defined herein. Preferred antigen-binding moieties include the antigen-binding domain of an antibody, which includes an antibody heavy chain variable region and an antibody light chain variable region. In some embodiments, the antigen-binding moiety may include an antibody constant region, as further defined herein and known in the art. Useful heavy chain constant regions include any of five isotypes: α, δ, ε, γ, or μ. Useful light chain constant regions include any of two isotypes: κ and λ.

[0126] "Binding," "specifically binding," or "specific to" means that the binding is antigen-selective and can be distinguished from undesirable or nonspecific interactions. The ability of an antigen-binding moiety to bind to a specific antigenic determinant can be measured by enzyme-linked immunosorbent assay (ELISA) or other techniques well known to those skilled in the art, such as surface plasmon resonance (analyzed with a BIAcore instrument) (Liljeblad et al., Glyco J 17, 323329 (2000)) and classical binding assay (Heeley, Endocr Res 28, 217229 (2002)). In one embodiment, the degree of binding of an antigen-binding moiety to an unrelated protein is less than about 10% of the binding of the antigen-binding moiety to the antigen, as measured, for example, by SPR. In some embodiments, the antigen-binding portion that binds to the antigen, or the antigen-binding molecule containing the antigen-binding portion, has a minimum size of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (for example, 10 -8 M or less, for example, 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 The dissociation constant (K) of M D ) has.

[0127] "Reduced binding," for example, reduced binding to the Fc receptor, refers to a decrease in affinity for each interaction, as measured, for example, by SPR. To clarify, this term also includes a reduction in affinity to zero (or below the detection limit of the analytical method), i.e., complete disappearance of the interaction. Conversely, "increased binding" refers to an increase in binding affinity for each interaction.

[0128] As used herein, the term "antigen-binding molecule" in its broadest sense refers to a molecule that specifically binds to an antigenic determinant. Examples of antigen-binding molecules include immunoglobulins and their derivatives, such as fragments.

[0129] As used herein, the term “antigenic determinant” is synonymous with “antigen” and “epitope” and refers to a site on a polypeptide macromolecule (e.g., a conformational structure formed from a continuous sequence of amino acids or discontinuous regions of different amino acids) to which an antigen-binding moiety binds to form an antigen-antigen complex. Useful antigenic determinants can be found, for example, on the surface of tumor cells, on the surface of virus-infected cells, on the surface of other diseased cells, released in serum, and / or in the extracellular matrix (ECM). Unless otherwise indicated, a protein referred to herein as an antigen (e.g., CD3) can be any native form of a protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). In certain embodiments, the antigen is a human protein. Where a particular protein is referred to herein, the term encompasses not only the “full-length,” unprocessed protein but also any type of protein resulting from intracellular processing. The term also encompasses naturally occurring variants of a protein, such as splice variants or allele variants. Examples of human proteins useful as antigens include CD3, particularly the epsilon subunit of CD3 (see UniProt no. P07766 (version 130), NCBI RefSeq no. NP_000724.1 for the human sequence; see UniProt no. Q95LI5 (version 49), NCBI GenBank® no. BAB71849.1 for the cynomolgus monkey [Macaca fascicularis] sequence). In some embodiments, the T cell-activating bispecific antigen-binding molecules described herein bind to CD3 or target cell antigen epitopes that are conserved among CD3 or target cell antigens from different species.

[0130] As used herein, the term "polypeptide" refers to a molecule composed of monomers (amino acids) linearly linked by amino bonds (also known as peptide bonds). The term "polypeptide" refers to any chain of two or more amino acids, and not to a product of a specific length. Therefore, the definition of "polypeptide" includes peptide, dipeptide, tripeptide, oligopeptide, "protein," "amino acid chain," or any other term used to refer to a chain of two or more amino acids, and the term "polypeptide" may be used in place of or interchangeably with any of these terms. The term "polypeptide" is also intended to refer to the results of post-expression modifications of a polypeptide, including, but not limited to, glycosylation, acetylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, or modification with amino acids not naturally occurring. Polypeptides may be obtained from natural biological sources or produced by recombinant techniques, but are not necessarily translated from specified nucleic acid sequences. Polypeptides may be produced by any method, including chemical synthesis. The polypeptide of the present invention may consist of amino acids of approximately 3 or more, 5 or more, 10 or more, 20 or more, 25 or more, 50 or more, 75 or more, 100 or more, 200 or more, 500 or more, 1000 or more, or 2000 or more in size. The polypeptide may have a defined three-dimensional structure, but does not necessarily have such a structure. A polypeptide having a defined three-dimensional structure is said to be folded, while a polypeptide that does not have a defined three-dimensional structure and can take many different forms is said to be unfolded.

[0131] An "isolated" polypeptide or variant, or derivative thereof, is a polypeptide of interest that does not exist in its natural environment. No particular level of purification is required. For example, an isolated polypeptide can be removed from its natural or natural environment. It is considered that recombinant polypeptides and proteins expressed in host cells may be isolated for the purposes of this invention by any suitable technique, either by separation, fractionation, or partial or substantially purified natural or recombinant polypeptides.

[0132] "Percent (%) amino acid sequence identity" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues of the reference polypeptide, after the sequences have been aligned to obtain the maximum possible sequence identity percentage and gaps have been introduced as necessary, with no conservative substitutions considered part of the sequence identity. Alignment performed for the purpose of determining percent amino acid sequence identity can be achieved in various ways within the skill of a person skilled in the art using commercially available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. A person skilled in the art can determine appropriate parameters for aligning the sequences, including any algorithm necessary to achieve the maximum alignment over the entire length of the sequences being compared. However, for the purposes of this specification, the % amino acid sequence identity value is generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and its source code, along with user documentation, has been filed with the U.S. Copyright Office, Washington, DC, 20559, and is registered under U.S. Copyright Registration No. TXU510087. ALIGN-2 is publicly available from Genentech (South San Francisco, California) or can be compiled from its source code. The ALIGN-2 program should be compiled for use on UNIX® operating systems, including Digital UNIX® V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not change. In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to or with a given amino acid sequence B (or alternatively, a given amino acid sequence A having or containing a certain % amino acid sequence identity to or with a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y. Here, X is the number of amino acid residues for which A and B matched as identical in the alignment of the sequence alignment program ALIGN-2, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is different from the length of amino acid sequence B, the % amino acid sequence identity of A to B will be different from the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values ​​used herein are obtained using the ALIGN-2 computer program as described in the preceding paragraph.

[0133] The term "antibody" as used herein is used in its broadest sense and encompasses, without limitation, various antibody structures, but includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments insofar as they exhibit desired antigen-binding activity.

[0134] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used interchangeably herein and refer to antibodies having a structure substantially similar to that of a natural antibody, or having a heavy chain containing an Fc region as defined herein.

[0135] An "antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds to an 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. As used herein, the term "antibody fragment" also includes single-domain antibodies.

[0136] The term "immunoglobulin molecule" refers to a protein that has the structure of a naturally occurring antibody. For example, IgG class immunoglobulins are heterotetrameric glycoproteins with approximately 150,000 daltons, composed of two disulfide-bonded light chains and two heavy chains. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy chain domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3), also called heavy chain constant domains. Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light chain domain or light chain variable domain, followed by a constant light chain (CL) domain, also called a light chain constant domain. The heavy chain of an immunoglobulin is assigned to one of five classes called α(IgA), δ(IgD), ε(IgE), γ(IgG), or μ(IgM), some of which can be further divided into subclasses, such as γ1(IgG1), γ2(IgG2), γ3(IgG3), γ4(IgG4), α1(IgA1), and α2(IgA2). The light chain of an immunoglobulin can be assigned to one of two types called kappa (κ) or lambda (λ), based on the amino acid sequence of its constant domain. An immunoglobulin essentially consists of two Fab molecules and an Fc domain linked via the hinge region of the immunoglobulin.

[0137] The term "antigen-binding domain" refers to a portion of an antibody that includes an area that specifically binds to some or all of an antigen and is complementary to some or all of the antigen. The antigen-binding domain may be provided, for example, by one or more antibody variable domains (also called antibody variable regions). Preferably, the antigen-binding domain includes an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH).

[0138] The term "variable region" or "variable domain" refers to a domain of the antibody heavy chain or antibody light chain involved in the binding of an antibody to an antigen. The variable domains of the heavy and light chains of natural antibodies (VH and VL, respectively) typically have similar structures, and each domain contains four conserved framework regions (FRs) and three hypervariable regions (HVRs). For example, Kindt et al., Kuby Immunology, 6. th See ed., WH Freeman and Co., page 91 (2007). A single VH domain or VL domain may be sufficient to confer antigen-binding specificity.

[0139] The N-terminal glutamine or glutamate residue of an antibody heavy or light chain can be spontaneously converted to pyroglutamic acid (see, for example, Liu et al., Journal of Pharmaceutical Sciences. 97, 2426-2447 (2008), Rehder et al., Journal of Chromatography A. 1102, 164-175 (2006), and Chelius et al., Anal Chem. 78, 2370-2376 (2006)). Therefore, variable domains disclosed herein that include a glutamine (Q) or glutamate (E) amino acid residue at the N-terminus of an antibody heavy or light chain may include an N-terminal pyroglutamic acid (pyroE) residue instead of the N-terminal Q or E residue. Similarly, antibody heavy chains or light chains disclosed herein that contain a glutamine (Q) or glutamate (E) amino acid residue at the N-terminus may contain an N-terminal pyroglutamic acid (pyroE) residue instead of the N-terminal Q or E residue. Therefore, for each antibody heavy chain, light chain, or variable domain sequence disclosed herein that contains an N-terminal Q or E residue, the corresponding sequence having an N-terminal pyroE residue is also included.

[0140] A "human antibody" is an antibody that is produced by a human or human cell, or obtained from a non-human source using the human antibody repertoire or other human antibody-coding sequences, and possesses an amino acid sequence corresponding to the antibody sequence. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0141] A “humanized” antibody refers to a chimeric antibody containing amino acid residues derived from non-human HVR and amino acid residues derived from human FR. In some embodiments, a humanized antibody contains substantially all of at least one, typically two, variable domains, where all or substantially all of the HVR (e.g., CDR) corresponds to those of the non-human antibody, and all or substantially all of the FR corresponds to those of the human antibody. A humanized antibody may optionally contain at least a portion of the antibody constant region obtained from a human antibody. A “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0142] As used herein, the terms “hypervariable region” or “HVR” refer to each of the regions of an antibody variable domain that form a hypervariable sequence (“complementarity-determining region” or “CDR”) and / or a structurally defined loop (“hypervariable loop”) and / or an antigen contact residue (“antigen contact”). Generally, antibodies contain six HVRs: three in VH (H1, H2, H3) and three in VL (L1, L2, L3). Exemplary HVRs as used herein include: (a) Hypervariable loops present at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) CDRs present at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) Antigens present in amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and (d) A combination of (a), (b), and / or (c) containing HVR amino acid residues 46-56(L2), 47-56(L2), 48-56(L2), 49-56(L2), 26-35(H1), 26-35b(H1), 49-65(H2), 93-102(H3), and 94-102(H3). It includes.

[0143] Unless otherwise specified, HVR residues and other residues within the variable domain (e.g., FR residues) are numbered herein according to Kabat et al. (cited above).

[0144] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The variable domain FR generally consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, the HVR and FR sequences generally appear in the following order in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0145] The "Human Consensus Framework" is a framework representing the most commonly present amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is made from subgroups of variable domain sequences. Generally, the sequence subgroups are those of Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup Kappa I of Kabat et al. (cited above). In one embodiment, for VH, the subgroup is subgroup III of Kabat et al. (cited above).

[0146] For the purposes of this specification, “acceptor human framework” is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework obtained from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework “obtained from” a human immunoglobulin framework or a human consensus framework may include the same amino acid sequence or may include variations in the amino acid sequence. In some embodiments, the number of amino acid variations 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 sequence-identical to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0147] The "class" of an antibody refers to the type of constant domain or constant region contained in its heavy chain. Antibodies have five major classes: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0148] As used herein, the terms “isotype” or “subclass” of IgG mean any of the subclasses of immunoglobulins defined by their constant-region chemical and antigenic properties.

[0149] In this specification, the term “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain, including at least a portion of the constant region. This term includes both the native sequence Fc region and the mutant Fc region. In one embodiment, the human IgG heavy chain Fc region extends from cysteine ​​226 (C226) according to Kabat EU numbering, or from proline 230 (P230) according to Kabat EU numbering, to the carboxyl terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Thus, antibodies produced by host cells by expression of a particular nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain or cleaved variants of the full-length heavy chain. This is especially true when the last two C-terminal amino acids of the heavy chain (e.g., a monovalent heavy chain) are glycine (G448, Kabat EU numbering) and lysine (K449, Kabat EU numbering). Therefore, the C-terminal lysine (K449) of the Fc region, or the C-terminal glycine (G448) and lysine (K449), may or may not be present. Alternatively, the last two C-terminal amino acids of the heavy chain (e.g., a divalent heavy chain) are glycine (G673, Kabat EU numbering) and lysine (K674, Kabat EU numbering). In this alternative example, the C-terminal lysine (K674) of the Fc region, or the C-terminal glycine (G673) and lysine (K674), may or may not be present. The amino acid sequences of heavy chains containing the Fc region are shown herein without the C-terminal glycine-lysine dipeptide unless otherwise indicated. However, corresponding sequences containing a C-terminal glycine residue or a C-terminal glycine-lysine dipeptide are also included. Accordingly, in one embodiment, a heavy chain containing the Fc region specified herein (e.g., a monovalent heavy chain) comprises an additional C-terminal glycine-lysine dipeptide (G448 and K449, Kabat EU numbering), e.g., SEQ ID NO: 59. In one embodiment, a heavy chain containing the Fc region specified herein comprises an additional C-terminal glycine residue (G448, Kabat EU numbering).In one embodiment, a heavy chain containing the Fc region specified herein (e.g., a divalent heavy chain) includes an additional C-terminal glycine-lysine dipeptide (G673 and K674, Kabat EU numbering), e.g., SEQ ID NO: 58. In one embodiment, a heavy chain containing the Fc region specified herein includes an additional C-terminal glycine residue (G673, Kabat EU numbering). Unless otherwise specified herein, the numbering of amino acid residues within the Fc region or the constant region of the heavy chain follows the EU numbering system, also known as the EU index, as described in Kabat 1991.

[0150] As used herein, the term "subunit" of an Fc domain refers to one of the two polypeptides that form a dimeric Fc domain, i.e., a polypeptide that includes the C-terminal constant region of an immunoglobulin heavy chain and possesses stable self-associating ability. For example, a subunit of an IgG Fc domain includes the IgG CH2 and IgG CH3 constant domains.

[0151] "Modifications that promote the association of the first and second subunits of the Fc domain" are manipulations of the peptide backbone or post-translational modifications of the Fc domain subunits that reduce or prevent homodimerization by association between a polypeptide containing an Fc domain subunit and a polypeptide identical to that subunit. As used herein, association-promoting modifications particularly include separate modifications performed on each of two Fc domain subunits that are desirable to associate (i.e., the first and second subunits of the Fc domain), such modifications are complementary to each other in order to promote the association of the two Fc domain subunits. For example, association-promoting modifications may alter the structure or charge of one or both of these Fc domain subunits so that their association is sterically or electrostatically desirable, respectively. Thus, (hetero)dimerization occurs between a polypeptide containing a first Fc domain subunit and a polypeptide containing a second Fc domain subunit, which may not be identical in the sense that the further components fused to each subunit (e.g., antigen-binding moieties) are not the same. In some embodiments, association-promoting modifications include amino acid mutations, specifically amino acid substitutions, within the Fc domain. In certain embodiments, the modification that facilitates association includes distinct amino acid mutations, specifically amino acid substitutions, in each of the two subunits of the Fc domain. "Activated Fc receptors" are Fc receptors that, following involvement by the Fc region of an antibody, trigger a signaling event that stimulates receptor-hosting cells to perform effector functions. Activated Fc receptors include FcγRIIIa (CD16a), FcγRI (CD64), FcγRIIa (CD32), and FcαRI (CD89).

[0152] The term "effector function," when used in reference to antibodies, refers to the biological activity resulting from the Fc region of an antibody, which varies depending on the antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cell-mediated cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); antibody-dependent cell-mediated phagocytosis (ADCP); cytokine secretion; immune complex-mediated antigen uptake by antigen-presenting cells; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

[0153] As used herein, the term "effector cell" refers to a population of lymphocytes that express effector partial receptors, such as cytokine receptors and / or Fc receptors, on their surface, thereby binding to the Fc region of effector parts, such as cytokines and / or antibodies, and contributing to the destruction of target cells, such as tumor cells. Effector cells mediate, for example, cytotoxic or phagocytic effects. Effector cells include, but are not limited to, effector T cells, such as CD8 + cytotoxic T cells, CD4 + This includes helper T cells, γδ T cells, NK cells, lymphokine-activated killer (LAK) cells, and macrophages / monocytes.

[0154] As used herein, terms such as “modify,” “modified,” and “alter” are considered to include any manipulation of the peptide backbone, or post-translational modification of naturally occurring polypeptides, recombinant polypeptides, or fragments thereof. Modifications include modifications of amino acid sequences, modifications of glycosylation patterns, or modifications of side chain groups of individual amino acids, and combinations thereof. In particular, “modification” with the prefix “glyco-” and the term “modification of glycosylation” include metabolic modifications of cellular glycosylation mechanisms, including genetic manipulation of oligosaccharide synthesis pathways to achieve alterations in the glycosylation of glycoproteins expressed in cells. Furthermore, modifications of glycosylation include mutations and influences of the cellular environment on glycosylation. In one embodiment, a modification of glycosylation is a change in glycosyltransferase activity. In certain embodiments, a modification results in a change in glucosaminyltransferase activity and / or fucosyltransferase activity. By modifying glycosylation, it is possible to obtain "host cells with increased GnTIII activity" (e.g., host cells engineered to express one or more polypeptides with elevated levels of β(1,4)-N-acetylglucosaminyltransferase III (GnTIII) activity), "host cells with increased ManII activity" (e.g., host cells engineered to express one or more polypeptides with elevated levels of α-mannosidase II (ManII) activity), or "host cells with decreased α(1,6) fucosyltransferase activity" (e.g., host cells engineered to express decreased levels of α(1,6) fucosyltransferase).

[0155] The terms “host cell,” “host cell line,” and “host cell culture” refer to cells that are interchangeably used and into which exogenous nucleic acids have been introduced, and include the offspring of such cells. Host cells include “transformers” and “transformed cells,” which include primary transformed cells and their offspring, regardless of the number of passages. Offspring do not have to be exactly identical in nucleic acid content to the parent cells and may contain mutations. This specification includes mutant offspring that have the same function or biological activity as those screened or selected in the original transformed cells. Host cells are any type of cell line that can be used to produce the proteins used in the present invention. In one embodiment, host cells are modified to enable the production of antibodies having modified oligosaccharides. In some embodiments, host cells are engineered to express one or more polypeptides having elevated levels of β(1,4)-N-acetylglucosaminyltransferase III (GnTIII) activity. In some embodiments, host cells are further engineered to express one or more polypeptides having elevated levels of α-mannosidase II (ManII) activity. Host cells include, to name a few, cultured mammalian cells such as CHO cells, BHK cells, NS0 cells, SP2 / 0 cells, YO myeloma cells, P3X63 mouse myeloma cells, PER cells, PER.C6 cells, or hybridoma cells, as well as yeast cells, insect cells, and plant cells, and furthermore, cells contained within the tissues of transgenic animals, transgenic plants, or cultured plants or animals.

[0156] As used herein, the term "GnTIII-active polypeptide" refers to a polypeptide capable of catalyzing the addition of an N-acetylglucosamine (GlcNAc) residue to the β-1,4 binding of a trimannosyl core of an N-linked oligosaccharide to a β-linked mannoside. This includes fusion polypeptides that exhibit enzymatic activity similar to, but not necessarily identical to, β(1,4)-N-acetylglucosaminyltransferase III, also known as β-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyl-transferase (EC 2.4.1.144), as defined by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB), which may or may not be dose-dependent when measured in specific biological assays. If dose-dependency exists, it does not need to be identical to that of GnTIII, but rather needs to be substantially similar in dose-dependency to GnTIII when compared to a given activity (i.e., the candidate polypeptide will exhibit greater activity or a decrease in activity of about 1 / 25th or less, preferably about 1 / 10th or less, and most preferably about 1 / 3th or less, of GnTIII). In some embodiments, the polypeptide having GnTIII activity is a fusion polypeptide comprising the catalytic domain of GnTIII and the Golgi localization domain of a heterologous Golgi-resident polypeptide. In particular, the Golgi localization domain is the localization domain of mannosidase II or GnTI, most specifically the mannosidase II localization domain. Alternatively, the Golgi localization domain is selected from the group consisting of the localization domain of mannosidase I, the localization domain of GnTII, and the localization domain of α1,6 core fucosyltransferase. Methods for generating such fusion polypeptides and using them to generate antibodies with enhanced effector function are disclosed in International Publication No. 2004 / 065540, U.S. Provisional Patent Application No. 60 / 495,142 and U.S. Patent Application Publication No. 2004 / 0241817, the entire contents of which are expressly incorporated herein by reference.

[0157] As used herein, the term "Golgi localization domain" refers to the amino acid sequence of a Golgi-resident polypeptide that plays a role in fixing the polypeptide to a specific position within the Golgi complex. Typically, the localization domain includes the amino terminus, or "tail," of the enzyme.

[0158] As used herein, the term "ManII-active polypeptide" refers to a polypeptide capable of catalyzing the hydrolysis of terminal 1,3- and 1,6-linked α-D-mannose residues in the branched GlcNAcMan5GlcNAc2 mannose intermediate of N-linked oligosaccharides. This includes polypeptides that exhibit enzymatic activity similar to, but not necessarily identical to, Golgi α-mannosidase II, also known as mannosyl oligosaccharide 1,3-1,6-α-mannosidase II (EC 3.2.1.114), according to the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB).

[0159] Antibody-dependent cell-mediated cytotoxicity (ADCC) is an immune mechanism that causes the lysis of antibody-coated target cells by immune effector cells. Target cells are cells to which antibodies containing an Fc region or fragments thereof specifically bind, usually via a protein portion that is the N-terminus of the Fc region. As used herein, “increased / decreased ADCC” is defined as either an increase / decrease in the number of target cells lysed within a given time by the ADCC mechanism as defined above at a given antibody concentration in the medium surrounding the target cells, and / or a decrease / increase in the antibody concentration in the medium surrounding the target cells required to lyse a given number of target cells within a given time by the ADCC mechanism. Increased / decreased ADCC is defined as ADCC mediated by the same antibody, produced by the same type of host cells, but unmodified, using the same standard methods of production, purification, formulation, and storage (known to those skilled in the art). For example, an increase in ADCC mediated by an antibody produced by a host cell modified in such a way as described herein to alter its glycosylation pattern (e.g., glycosyltransferase, GnTIII, or other glycosyltransferase) is relative to ADCC mediated by the same antibody produced by an unmodified host cell of the same type.

[0160] "Antibodies with increased / decreased antibody-dependent cell-mediated cytotoxicity (ADCC)" means antibodies with increased / decreased ADCC as determined by any suitable method known to those skilled in the art. One acceptable in vitro ADCC assay is as follows: 1) The assay uses target cells known to express the target antigen recognized by the antigen-binding region of the antibody; 2) The assay uses human peripheral blood mononuclear cells (PBMCs) isolated from the blood of randomly selected healthy donors as effector cells; 3) The assay follows the protocol below: i) Isolate PBMCs using a standard density centrifugation procedure and place them in RPMI cell medium in 5 × 10⁶ units. 6 Suspend cells / ml; ii) Target cells are grown using standard tissue culture methods, harvested from the exponential growth phase when the viability exceeds 90%, washed in RPMI cell medium, and heated to 100 microcuries. 51 Labeled with Cr, washed twice with cell culture medium, 10 5 Resuspend in cell medium at a density of cells / mL; iii) Transfer 100 microliters of the final target cell suspension described above to each well of a 96-well microtiter plate; iv) The antibody is sequentially diluted in cell culture medium from 4000 ng / mL to 0.04 ng / mL, and 50 microliters of the resulting antibody solution is added to target cells in a 96-well microtiter plate. The test is then performed three times at various antibody concentrations covering the entire concentration range described above; v) For maximum release (MR) control, add 50 microliters of a 2% (V / V) aqueous solution of nonionic detergent (Nonidet, Sigma, St. Louis) to three additional wells in the plate containing labeled target cells, instead of the antibody solution (iv above); vi) For spontaneous release (SR) control, place 50 microliters of RPMI cell medium in three additional wells in the plate containing the labeled target cells instead of the antibody solution (iv above); vii) Next, centrifuge the 96-well microtiter plate at 50 × g for 1 minute and incubate at 4°C for 1 hour; viii) Add 50 microliters of PBMC suspension (as described in i above) to each well to achieve an effector:target cell ratio of 25:1, and place the plate in an incubator at 37°C for 4 hours under a 5% CO2 atmosphere; ix) Collect cell-free supernatant from each well and quantify the experimentally emitted radioactivity (ER) using a gamma counter; x) The percentage of specific lysis is calculated for each antibody concentration according to the formula (ER-MR) / (MR-SR)x 100 (wherein ER is the quantified average radioactivity for that antibody concentration (see ix above), MR is the quantified average radioactivity for the MR control (see v above) (see ix above), and SR is the quantified average radioactivity for the SR control (see vi above) (see ix above)). It will be carried out according to; 4) “Increased / decreased ADCC” is defined as an increase / decrease in the maximum percentage of specific lysis observed within the antibody concentration range tested above, and / or a decrease / increase in the antibody concentration required to achieve half of the maximum percentage of specific lysis observed within the antibody concentration range tested above. Increased / decreased ADCC is relative to ADCC measured in the above assay, which is produced by the same type of host cells, but unmodified, and mediated by the same antibody, using the same standard production, purification, formulation, and storage methods (known to those skilled in the art).

[0161] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies constituting that population are identical and / or bind to the same epitope, except for possible variant antibodies that are generally present in small amounts, such as those containing naturally occurring mutations or that arise during the production of the monoclonal antibody preparation. In contrast to polyclonal antibody preparations, which generally contain different antibodies against different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is against a single determinant on an antigen. Therefore, the modifier “monoclonal” indicates a characteristic of an antibody obtained from a substantially homogeneous population of antibodies and is not construed as requiring the production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention may be produced by a variety of techniques, including but not limited to hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of a human immunoglobulin locus, and such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0162] A "naked antibody" refers to an antibody that is not conjugated with a different part (e.g., a cytotoxic part) or a radiolabeled molecule. Naked antibodies can be present in pharmaceutical formulations.

[0163] "Natural antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, a natural IgG antibody is a heterotetrameric glycoprotein with approximately 150,000 daltons, composed of two identical light chains and two identical heavy chains linked by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy chain domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light chain domain or light chain variable domain, followed by a constant light chain (CL) domain. Based on the amino acid sequence of its constant domain, the light chains of an antibody can be assigned to one of two types called kappa (κ) or lambda (λ).

[0164] In this specification, terms such as “first,” “second,” and “third” used with respect to antigen-binding moieties or domains are used for convenience to distinguish between multiple moieties or domains. Unless explicitly stated otherwise, the use of such terms is not intended to confer any particular order or orientation.

[0165] The terms "multispecificity" and "bispecificity" refer to the ability of an antigen-binding molecule to specifically bind to at least two distinct antigenic determinants. Typically, a bispecific antigen-binding molecule contains two antigen-binding sites, each specific to a different antigenic determinant. In some embodiments, a bispecific antigen-binding molecule can simultaneously bind to two antigenic determinants, particularly two antigenic determinants expressed on two distinct cells.

[0166] As used herein, the terms "valence" or "valent" refer to the presence of a specific number of antigen-binding sites within an antigen-binding molecule. Therefore, the expression "monovalent binding to an antigen" refers to the presence of one (but not more than one) antigen-specific antigen-binding site within the antigen-binding molecule.

[0167] The "antigen-binding site" refers to the portion of an antigen-binding molecule that provides interaction with an antigen, i.e., one or more amino acid residues. For example, the antigen-binding site of an antibody contains amino acid residues derived from the complementarity-determining region (CDR). Natural immunoglobulin molecules generally have two antigen-binding sites, while Fab molecules generally have a single antigen-binding site.

[0168] As used herein, “T cell activating antigen” refers to an antigenic determinant expressed by T lymphocytes, particularly cytotoxic T lymphocytes, that can induce or enhance T cell activation upon interaction with an antigen-binding molecule. Specifically, the interaction between an antigen-binding molecule and a T cell activating antigen can induce T cell activation by triggering a signaling cascade of the T cell receptor complex. An exemplary T cell activating antigen is CD3. In a particular embodiment, the T cell activating antigen is CD3, particularly the epsilon subunit of CD3 (see UniProt no. P07766 (version 130), NCBI RefSeq no. NP_000724.1 for the human sequence; see UniProt no. Q95LI5 (version 49), NCBI GENBANK® no. BAB71849.1 for the cynomolgus monkey [Macaca fascicularis] sequence).

[0169] As used herein, “T cell activation” refers to one or more cellular responses of T lymphocytes, particularly cytotoxic T lymphocytes, selected from proliferation, differentiation, cytokine secretion, cytotoxic effector molecule release, cytotoxic activity, and expression of activation markers. The T cell activating therapeutic agents used in the present invention can induce T cell activation. Appropriate assays for measuring T cell activation are known in the art described herein.

[0170] As used herein, “target cell antigen” refers to an antigenic determinant presented on the surface of target cells, such as cancer cells or cells within a tumor, such as tumor stroma cells. In certain embodiments, the target cell antigen is CD20, particularly human CD20 (see UniProt no. P11836).

[0171] As used herein, "B cell antigen" refers to the antigenic determinant present on the surface of B lymphocytes, particularly malignant B lymphocytes (in this case, the antigen is also called "malignant B cell antigen").

[0172] As used herein, "T cell antigen" refers to the antigenic determinants presented on the surface of T lymphocytes, particularly cytotoxic T lymphocytes.

[0173] A "Fab molecule" refers to a protein consisting of the VH and CH1 domains of the immunoglobulin heavy chain ("Fab heavy chain") and the VL and CL domains of the light chain ("Fab light chain").

[0174] "Fused" means that the components (e.g., the Fab molecule and the Fc domain subunit) are linked by peptide bonds, either directly or via one or more peptide linkers.

[0175] The "effective dose" of a drug refers to the amount necessary to cause a physiological change in the cells or tissues to which it is administered.

[0176] The "therapeutic effective dose" of a drug, such as a pharmaceutical composition, refers to the effective amount required to achieve a desired therapeutic or preventive outcome in the necessary dosage and duration. For example, the therapeutic effective dose of a drug eliminates, reduces, delays, minimizes, or prevents the adverse effects of a disease.

[0177] "Therapeutic agent" refers to the active ingredient of a pharmaceutical composition, for example, that is administered to a patient in an attempt to alter the natural course of the patient's disease, and can be used for prevention or in the course of clinicopathology. "Immunotherapy agent" refers to a therapeutic agent administered to a patient in an attempt to restore or enhance the patient's immune response, for example, against a tumor.

[0178] The term "pharmaceutical composition" refers to a preparation in which the biological activity of the active ingredients contained herein is activated, and which does not contain any additional ingredients that are unacceptably toxic to the patient to whom the composition is administered.

[0179] A "pharmaceutically acceptable carrier" refers to a component in a pharmaceutical composition other than the active ingredient that is not toxic to the patient. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0180] The terms “package insert” or “instructions for use” are used to refer to instructions that are typically included in the product packaging of a therapeutic product and include information about the indications, dosage, administration, combination therapy, contraindications and / or precautions for use of such therapeutic product.

[0181] As used herein, the term “combination therapy” encompasses both combination administration (where two or more therapeutic agents are included in the same or separate formulations) and individual administration, where, in the case of individual administration, the administration of the antibodies reported herein may be carried out with, before, and / or after the administration of one or more additional therapeutic agents, preferably antibodies or antibodies.

[0182] A "crossover" Fab molecule (also called a "Crossfab") refers to a Fab molecule in which the variable or constant domains of the Fab heavy chain and light chain are exchanged (i.e., replaced by each other). In other words, a crossover Fab molecule includes a peptide chain composed of a light chain variable domain VL and a heavy chain constant domain 1 CH1 (VL-CH1, from the N-terminus to the C-terminus), and a peptide chain composed of a heavy chain variable domain VH and a light chain constant domain CL (VH-CL, from the N-terminus to the C-terminus). Briefly, in a crossover Fab molecule in which the variable domains of the Fab light chain and Fab heavy chain are exchanged, the peptide chain containing the heavy chain constant domain 1 CH1 is referred to herein as the "heavy chain" of the (crossover) Fab molecule. Conversely, in a crossover Fab molecule in which the constant domains of the Fab light chain and Fab heavy chain are exchanged, the peptide chain containing the heavy chain variable domain VH is referred to herein as the "heavy chain" of the (crossover) Fab molecule.

[0183] In contrast, a "typical" Fab molecule is a Fab molecule that includes its native form, namely a heavy chain composed of a heavy chain variable domain and a constant domain (VH-CH1, from the N-terminus to the C-terminus), and a light chain containing a light chain variable domain and a constant domain (VL-CL, from the N-terminus to the C-terminus).

[0184] The term "polynucleotide" refers to an isolated nucleic acid molecule or construct, such as messenger RNA (mRNA), viral RNA, or plasmid DNA (pDNA). Polynucleotides may contain common phosphodiester bonds or non-common bonds (such as amide bonds, as found in peptide nucleic acids (PNAs)). The term "nucleic acid molecule" refers to any one or more nucleic acid segments present in a polynucleotide, such as DNA or RNA fragments.

[0185] "Isolated" nucleic acid molecules or polynucleotides refer to nucleic acid molecules, DNA, or RNA extracted from their natural environment. For example, recombinant polynucleotides encoding polypeptides contained in a vector are considered isolated for the purposes of this invention. Further examples of isolated polynucleotides include recombinant polynucleotides maintained within heterologous host cells, or (partially or substantially) purified polynucleotides in solution. Isolated polynucleotides include polynucleotide molecules found in cells that normally contain polynucleotide molecules, but where the polynucleotide molecules are located outside the chromosome or at chromosomal locations different from their natural chromosomal locations. Isolated RNA molecules include in vivo or in vitro RNA transcripts of this invention, as well as positive-strand and negative-strand and double-stranded forms. Isolated polynucleotides or nucleic acids according to this invention further include such molecules produced by synthesis. In addition, polynucleotides or nucleic acids may or may not include regulatory elements such as promoters, ribosome-binding sites, or transcription terminators.

[0186] When we refer to a nucleic acid or polynucleotide having a nucleotide sequence that is at least, for example, 95% "identical" to the reference nucleotide sequence of the present invention, it is intended that the nucleotide sequence of the polynucleotide is identical to that of the reference sequence, except that the polynucleotide sequence may contain up to 5 point mutations for every 100 nucleotides of the reference nucleotide sequence. In other words, to obtain a polynucleotide having a nucleotide sequence that is at least 95% identical to the reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or replaced with other nucleotides, or up to 5% of all nucleotides in the reference sequence may be inserted into the reference sequence. Such modifications to the reference sequence may occur at the 5' or 3' end of the reference nucleotide sequence, or either between these end positions, individually scattered among the residues of the reference sequence, or in one or more consecutive groups within the reference sequence. In practice, whether any particular polynucleotide sequence is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the nucleotide sequence of the present invention can be determined using a known computer program, such as the one described above for polypeptides (e.g., ALIGN-2).

[0187] The term “expression cassette” refers to a polynucleotide generated by recombinant or synthetic means using a set of specific nucleic acid elements that enable the transcription of a particular nucleic acid within a target cell. Recombinant expression cassettes can be incorporated into plasmids, chromosomes, mitochondrial DNA, plastid DNA, viruses, or nucleic acid fragments. Typically, the recombinant expression cassette portion of an expression vector contains the nucleic acid sequence to be transcribed and a promoter, among other sequences. In some embodiments, the expression cassette of the present invention includes a polynucleotide sequence encoding the bispecific antigen-binding molecule or fragment thereof of the present invention.

[0188] The term “vector” or “expression vector” is synonymous with “expression construct” and refers to a DNA molecule used to introduce and direct the expression of a specific gene to which it operably binds within a target cell. This term includes vectors as self-replicating nucleic acid structures and vectors integrated into the genome of the introduced host cell. The expression vector of the present invention comprises an expression cassette. The expression vector enables the transcription of a large amount of stable mRNA. Once the expression vector enters the target cell, the ribonucleic acid molecule or protein encoded by the gene is produced by the cellular transcription and / or translation mechanism. In one embodiment, the expression vector of the present invention comprises an expression cassette containing a polynucleotide sequence encoding the bispecific antigen-binding molecule or fragment thereof of the present invention.

[0189] As used herein, the term “about” refers to the normal range of error for each value that is readily known to those skilled in the art. Where “about” is mentioned before a value or parameter herein, embodiments relating to that value or parameter itself are included (described).

[0190] "B-cell proliferative disorders" refer to diseases in which the number of B cells in a patient increases compared to the number of B cells in a healthy patient, and in particular, diseases in which the increase in B cell count is the cause or evidence of the disease. "CD20-positive B-cell proliferative disorders" are B-cell proliferative disorders in which B cells, especially malignant B cells (in addition to normal B cells), express CD20.

[0191] Exemplary B-cell proliferative disorders include non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL; e.g., relapsed or refractory DLBCL unspecified (NOS), high-grade B-cell lymphoma (HGBCL; e.g., HGBCL NOS, double-hit HGBCL, and triple-hit HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), and DLBCL arising from FL (transformed FL; trFL)); follicular lymphoma (FL) including grade 1–3b FL; mantle cell lymphoma (MCL); and marginal laminar lymphoma (MZL) including splenic marginal laminar MZL, nodular marginal laminar MZL, or extranodal marginal laminar MZL. In one embodiment, the CD20-positive B-cell proliferative disorder is Burkitt lymphoma (BL); Burkitt leukemia (BAL; mature B-cell leukemia FAB L3); DLBCL; or PMBCL. In one embodiment, the CD20-positive B-cell proliferative disorder is relapsed or refractory NHL (e.g., relapsed or refractory DLBCL, relapsed or refractory FL, or relapsed or refractory MCL). In one embodiment, BL, BAL, DLBCL, or PMBCL is relapsed and / or refractory. In one embodiment, BL, BAL, DLBCL, or PMBCL is relapsed after first-line standard chemoimmunotherapy or is refractory to said chemoimmunotherapy.

[0192] A "refractory disease" is defined as a condition in which complete remission cannot be achieved with first-line treatment, and this includes the following: • When the best response to first-line treatment is in a progressive disease (PD) • The best response after at least 4 cycles of first-line treatment (e.g., 4 cycles of R-CHOP) is stable disease (SD). • The best response after at least 6 cycles is a partial response (PR), and biopsy confirms residual lesions or subsequent disease progression.

[0193] "Relapsing disease" is defined as a relapse of the disease or a relapse after complete remission with first-line treatment. In one embodiment, disease relapse is demonstrated by biopsy. In one embodiment, the patient relapsed or did not respond to at least two preceding systemic treatment regimens (including at least one preceding regimen containing anthracyclines and at least one regimen containing anti-CD20 targeted therapy).

[0194] An “individual,” “patient,” or “subject” is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans, and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). Preferably, an individual, patient, or subject is human. In one example, all patients in a patient population are human. In one example, all patients in a patient reference population are human. In one embodiment, a patient is considered a pediatric patient if they are under 18 years of age (i.e., 17 years or younger). In one embodiment, the age of a pediatric patient is between 6 months and 17 years. In one embodiment, a patient is considered a young adult if they are between 18 and 30 years of age. In one embodiment, a patient is considered an adult patient if they are 18 years of age or older.

[0195] A patient “eligible for transplantation” or “eligible for autologous stem cell transplantation (SCT)” is a patient who meets the eligibility requirements for autologous SCT, for whom autologous SCT is recommended, or who is eligible to receive autologous SCT. In one embodiment, “eligible for transplantation” is defined as being medically eligible for intensive platinum-based salvage therapy followed by autologous stem cell transplantation (ASCT). In one embodiment, an eligible patient is able to achieve an objective response and further mobilize a target dose of at least 2,000,000 CD34+ hematopoietic stem cells per kg. In one embodiment, “eligible for transplantation” is defined as being medically eligible for 2 to 3 cycles of salvage therapy with R-ICE and grofitamab to achieve a complete response (CR), followed by allogeneic or autologous hematopoietic stem cell transplantation (HSCT).

[0196] A patient "eligible for CAR-T cell therapy" is a patient who meets the eligibility requirements for chimeric antigen receptor (CAR) T cell therapy, for whom chimeric antigen receptor (CAR) T cell therapy is recommended, or who is able to receive chimeric antigen receptor (CAR) T cell therapy.

[0197] As used herein, “treatment” (and its grammatical variations such as “to treat” or “to treat”) refers to a clinical intervention in an attempt to alter the natural course of a disease in the individual being treated, and may be carried out for preventive purposes or during the course of a clinicopathological condition. Desired effects of treatment include, but are not limited to, preventing the onset or recurrence of the disease, alleviating symptoms, reducing the direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the condition, and achieving remission or improving the prognosis. In some embodiments, the methods of the present invention are used to delay the onset of a disease or to slow the progression of a disease. In one embodiment, the disease being treated is a CD20-positive B-cell proliferative disorder, such as Burkitt lymphoma (BL); Burkitt leukemia (BAL; mature B-cell leukemia FAB L3); DLBCL; or PMBCL.

[0198] As used herein, “delaying the progression” of a disorder or disease means delaying, preventing, slowing, stabilizing, and / or postponing the onset of a disease or disorder (e.g., CD20-positive B-cell proliferative disorders, e.g., NHL, e.g., DLBCL, e.g., Burkitt lymphoma (BL); e.g., Burkitt leukemia (BAL; mature B-cell leukemia FAB L3), or e.g., PMBCL). Such delay may relate to varying lengths of time depending on the disease being treated and / or the individual’s medical history. As will be apparent to those skilled in the art, a sufficient or significant delay may, in practice, include preventing the individual from developing the disease. For example, in late-stage cancer, the onset of central nervous system (CNS) metastases can be delayed.

[0199] "Reduce" or "inhibit" means the ability to cause an overall reduction of, for example, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or greater percentage. For clarity, this term also includes reduction to zero (or a value below the detection limit of the analytical method), i.e., complete disappearance or elimination. In some embodiments, "reduce" or "inhibit" may refer to the reduction or inhibition of undesirable events, such as cytokine-induced toxicity (e.g., cytokine release syndrome (CRS)), infusion-related events (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe oncolytic syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and / or central nervous system (CNS) toxicity, after treatment with grofitamab using the stepwise dosing regimen of the present invention, compared to a constant, pre-set dosing at a target dose of a bispecific antibody. In other embodiments, “reduce” or “inhibit” may refer to the effector function of an antibody mediated by the antibody Fc region, such effector functions specifically include complement-dependent cytotoxicity (CDC), antibody-dependent cytotoxicity (ADCC), and antibody-dependent phagocytosis (ADCP). In other embodiments, “reduce” or “inhibit” may refer to the symptoms, presence or size of metastases, or size of the primary tumor of the CD20-positive B-cell proliferative disorder being treated (e.g., NHL (e.g., DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), MCL, high-grade B-cell lymphoma, or PMLBCL). In one embodiment, the CD20-positive B-cell proliferative disorder being treated is Burkitt lymphoma (BL); Burkitt leukemia (BAL; mature B-cell leukemia FAB L3); DLBCL, or PMBCL.

[0200] As used herein, “administration” means a method of giving a patient a dosage of a compound (e.g., grofitamab) or a composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition containing grofitamab). The compounds and / or compositions used in the methods described herein may be administered intravenously (e.g., by intravenous infusion).

[0201] In this specification, a “fixed” or “flat” dose of a therapeutic agent (e.g., grofitamab) refers to the dose administered to a patient regardless of the patient’s weight or body surface area (BSA). Therefore, a fixed or flat dose is a mg / kg dose or mg / m² dose. 2 It is provided not as a dosage, but as an absolute amount of the therapeutic agent (e.g., mg).

[0202] In this specification, “target dose” refers to the dose of grofitamab that achieves the therapeutic effect, i.e., the desired clinical efficacy. In the case of grofitamab, possible target doses have been found to be 16 mg or 30 mg.

[0203] "Constant or pre-set dosage at a target dose" and "treatment regimens without a step-by-step dosing regimen" refer to a dosing schedule that uses the same dosage in the first and second cycles, and optionally in any subsequent cycles, in contrast to step-by-step dosing, which uses relatively small doses in the first few treatment cycles and reaches the target dose only in the second or subsequent treatment cycles.

[0204] As used herein, the term “treatment cycle” or “cycle” (abbreviated as “C”) means one or more therapeutic units of grofitamab repeated in a regular schedule with optionally intervening rest periods (no treatment). In one embodiment of the present invention, a first treatment cycle comprises first and second doses of grofitamab, followed by a rest period. In such an embodiment, the first treatment cycle comprises a first dose of grofitamab on day 8 of the first cycle, a second dose of grofitamab on day 15 of the first cycle, followed by a six-day rest. In one embodiment, the second cycle and any subsequent cycles comprise one dose of grofitamab on day 8 of that cycle, followed by a thirteen-day rest. In one embodiment, one treatment cycle comprises 21 days. In another embodiment, one treatment cycle comprises 14 days. A treatment schedule according to the present invention may comprise two or more treatment cycles, in particular three treatment cycles. In some embodiments, a treatment cycle is referred to as a “dosage cycle.”

[0205] "Individual response" or "response" can be assessed using any of the following endpoints that demonstrate a benefit to the patient, including, but are not limited to: (1) some degree of inhibition of disease progression (e.g., progression of CD20-positive B-cell proliferative disorders, e.g., non-Hodgkin lymphoma (NHL)), including slowing and complete suppression; (2) reduction of tumor size; (3) inhibition of cancer cell invasion into adjacent peripheral organs and / or tissues (i.e., reduction, slowing or complete cessation); (4) inhibition of metastasis (i.e., reduction, slowing or complete cessation); (5) some degree of alleviation of one or more symptoms associated with CD20-positive B-cell proliferative disorders, e.g., B-cell proliferative disorders; (6) increased or prolonged length of survival, including overall survival and progression-free survival; and / or (7) a reduction in mortality at a given time point after treatment.

[0206] As used herein, “complete response,” “CR,” or “complete remission” refers to the disappearance of all target lesions. In one embodiment, standard NHL response criteria are evaluated to determine CR. (Lugano Classification, Cheson et al. J Clin Oncol. 2014 Sep 20;32(27):3059-3067). In one embodiment, the CR rate is defined as the percentage of patients whose overall response is CR on positron emission tomography / computed tomography (PET / CT), as determined by the principal investigator according to the Lugano criteria. In one embodiment, CR is defined as a complete metabolic response as determined by PET / CT of lymph nodes and external lymph node sites, with a score of 1, 2, or 3 indicating the presence or absence of residual mass in 5PS, where PET 5PS is as follows: 1 = no uptake above background; 2 = uptake > mediastinum; 3 = uptake > mediastinum, but ≤ liver; 4 = moderately high uptake > liver; 5 = significantly higher uptake than liver and / or new lesion; X = new area of ​​uptake unlikely to be related to lymphoma. In one embodiment, CR is defined as a complete radiological response as determined by CT of lymph nodes and external lymph node sites, where the target node / nodular mass must have eluted to an LDi (longest transverse diameter of the lesion) of ≤ 1.5 cm and no external lymph node site of the disease should remain.

[0207] As used herein, “partial response” or “PR” refers to a partial metabolic response and / or partial remission as determined by PET / CT of lymph nodes and external lymph node sites. In one embodiment, a partial metabolic response is defined by a score of 4 or 5 when one or more residual tumors of any size are determined by PET / CT of lymph nodes and external lymph node sites, with reduced uptake compared to baseline, and PET 5PS is as follows: 1 = no uptake above background; 2 = uptake > mediastinum; 3 = uptake > mediastinum, but ≤ liver; 4 = moderately high uptake > liver; 5 = significantly higher uptake than liver and / or new lesions; X = new areas of uptake unlikely to be related to lymphoma. In one embodiment, partial remission is defined as a reduction of at least 50% in the product of diameters (SPD) of up to six target measurable lymph nodes and external lymph node sites, relative to baseline SPD. For pediatric patients (<18 years), PR is assessed using the International Pediatric NHL Response Criteria (Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015).

[0208] The expressions “effective response” or “responsiveness” of a patient to treatment with medicines and similar products refer to the clinical or therapeutic benefit provided to a patient who is at risk of or suffering from a disease or disorder such as cancer. In one embodiment, such benefit includes one or more of the following: extended survival (including overall survival and progression-free survival), objective response (including complete response or partial response), or improvement of signs or symptoms of cancer.

[0209] The duration of complete response (DOCR) is defined as the time from the first recorded complete response to disease progression or death from any cause (whichever occurs first), as determined by the principal investigator according to the Lugano criteria (Cheson et al. J Clin Oncol. 2014 Sep 20;32(27):3059-3067). For pediatric patients <18 years of age, CR is assessed by the principal investigator using the International Pediatric NHL Response Criteria (Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma response criteria. J.Clin.Oncol. 33:2106-2111, 2015).

[0210] The "Duration of Objective Response" (DOR) is defined as the time from the first recorded objective response (CR or PR) to disease progression or death from any cause (whichever occurs first), as determined by the principal investigator according to the Lugano criteria (Cheson et al. J Clin Oncol. 2014 Sep 20;32(27):3059-3067). CR and / or PR are assessed by the principal investigator using the International Pediatric NHL Response Criteria for pediatric patients <18 years of age (Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma response criteria. J.Clin.Oncol. 33:2106-2111, 2015).

[0211] Progression-free survival (PFS) is defined as the time from the first treatment with grofitamab to the first occurrence of disease progression or death from any cause, whichever occurs first. In one embodiment, PFS is assessed based on the Lugano classification (Cheson et al. J Clin Oncol. 2014 Sep 20;32(27):3059-3067). For pediatric patients <18 years of age, PFS is assessed by the principal investigator using the International Pediatric NHL Response Criteria (Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015).

[0212] Overall survival (OS) is defined as the time from the first treatment with grofitamab to the date of death from any cause.

[0213] As used herein, “event-free survival” (EFS) is defined as the time from the first treatment with grofitamab to the first occurrence of disease progression, initiation of new anti-lymphoma therapy (excluding planned ASCTs), or death from any cause (whichever occurs first), as determined by the principal investigator in accordance with the Lugano criteria.

[0214] As used herein, “objective response rate” (ORR) is defined as the sum of the partial response (PR) rate and the complete response (CR) rate. In one embodiment, the ORR is assessed based on the Lugano classification (Cheson et al. J Clin Oncol. 2014 Sep 20;32(27):3059-3067). In one embodiment, the ORR is defined as the proportion of participants who achieve CR or PR within three cycles of the grofitamab + GemOx treatment regimen described herein.

[0215] As used herein, "stable disease" or "SD" refers to a state in which, based on the smallest SLD since the start of treatment, there is neither sufficient shrinkage of the target lesion to qualify for a partial response (PR) nor sufficient enlargement to qualify for a progressive disease (PD).

[0216] As used herein, “progressive disease” or “PD” means an increase of at least 20% in the SLD of the target lesion relative to the smallest SLD, or an increase of at least 50% in the SPD of the target lesion relative to the smallest SPD, or the presence of one or more new lesions, as recorded since the initiation of treatment.

[0217] As used herein, “infusion-related reaction,” “IRR,” or “infusion-related adverse event” refers to an adverse event that occurs in a patient or subject during or within 24 hours after administration of a drug (e.g., grofitamab; or an anti-CD20 antibody, e.g., obinutuzumab or rituximab). IRRs may be graded as grades 1 to 5, for example, by the NCI CTCAE v.4.

[0218] The "Mobilization-Adjusted Response Rate (MARR)" is defined as the percentage of patients who achieve objective response and the mobilization of the target dose of 2,000,000 CD34+ hematopoietic stem cells / kg, which is typically required as the minimum for ASCT.

[0219] As used herein, the term "GemOx" refers to gemcitabine + oxaliplatin.

[0220] As used herein, the term “corticosteroid prophylaxis” refers to an optimized and increased steroid regimen for treating patients with grofitamab, in which corticosteroids are administered before and after administration of grofitamab, with the aim of optimizing the CRS profile of this treatment (e.g., reducing the incidence of CRS events in the patient population treated with grofitamab, reducing the likelihood of CRS events in patients treated with grofitamab, or reducing the CRS events or the severity (e.g., grade) of CRS events). In one embodiment, corticosteroids are administered for the first two step doses of grofitamab in cycle 1 (2.5 mg and 10 mg doses). In one embodiment, corticosteroids are administered approximately 1 day before, on the same day, and 1 day after administration of grofitamab. In one embodiment, corticosteroid prophylaxis is administered approximately 30 hours, 29 hours, 28 hours, 27 hours, 26 hours, 25 hours, 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, and 18 hours before administration of grofitamab. In one embodiment, corticosteroid prophylaxis is administered approximately 30 to 90 minutes or 60 minutes before administration of grofitamab. In one embodiment, corticosteroid prophylaxis is administered approximately 25 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, or 100 minutes before administration of grofitamab. In one embodiment, corticosteroid prophylaxis is administered approximately 24 hours after administration of grofitamab. In one embodiment, corticosteroid prophylaxis is administered approximately 30 hours, 29 hours, 28 hours, 27 hours, 26 hours, 25 hours, 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, and 18 hours after administration of grofitamab.

[0221] (iii) Combination therapy with grofitamab and GemOx The present invention provides a method for treating patients having CD20-positive cell proliferative disorders (e.g., B-cell proliferative disorders (e.g., non-Hodgkin lymphoma (NHL) (e.g., relapsed and / or refractory NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed and / or refractory DLBCL), follicular lymphoma (FL) (e.g., relapsed and / or refractory FL or transformed FL), or mantle cell lymphoma (MCL) (e.g., relapsed or refractory MCL)), or central nervous system lymphoma (CNSL))), the method comprising administering to the patient a combination of grofitamab and GemOx.

[0222] In some cases, this method is used to treat patients with relapsed and / or refractory NHL (e.g., progressive NHL (e.g., relapsed and / or refractory DLBCL, relapsed and / or refractory FL, or relapsed and / or refractory MCL)). In some cases, patients had relapsed after one or more (e.g., one, two, three, four, five, or more) prior therapies (e.g., one or more prior systemic therapies, e.g., one or more prior systemic chemotherapy (e.g., one or more prior systemic therapies including anthracycline administration), one or more prior stem cell therapies, or one or more prior CAR-T cell therapies) following a recorded history of response (e.g., complete or partial response) for at least six months in duration from the completion of treatment. In some cases, the patient is refractory to any prior therapy (e.g., did not respond to prior therapy or progressed within 6 months of completing the last dose of treatment). Therefore, in some embodiments, this administration regimen is a second-line treatment. In some embodiments, this administration regimen is a third-line treatment. In some embodiments, the patient has transformed FL and / or is refractory to standard treatment for transformed FL. In some embodiments, the FL is graded FL (e.g., grade 1, 2, 3a, or 3b FL). In some embodiments, the DLBCL is DLBCL NOS.

[0223] In some embodiments, the patient is not eligible for stem cell transplantation (e.g., not qualified for stem cell transplantation). In some embodiments, the patient is not eligible for hematopoietic stem cell transplantation (HSCT) (e.g., not qualified for HSCT). In some embodiments, the patient is not eligible for autologous stem cell transplantation (ASCT) (e.g., not qualified for ASCT).

[0224] In some embodiments, the patient is either relapsed after one prior treatment line or refractory to one prior treatment line and is not eligible for HSCT, and this patient has: (a) a left ventricular ejection fraction of ≤40%, (b) a creatinine clearance or glomerular filtration rate of ≤45 mL / min, (c) an East Coast Clinical Oncology Group (ECOG) performance status of ≥2, (d) is 70 years of age or older, (e) has refused high-dose chemotherapy and / or transplantation, and / or (f) has an inadequate response to pre-transplant chemotherapy and is unable to proceed to transplantation.

[0225] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising an effective amount to a human patient: (a) Grofitamab (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0226] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising an effective amount to a human patient: (a) Grofitamab (b) gemcitabine, and (c) Oxaliplatin This includes administering, The patient has relapsed after one prior treatment line, or is refractory to one prior treatment line, and is not a candidate for HSCT, and the patient: (a) Having a left ventricular ejection fraction of ≤40%, (b) Having a creatinine clearance or glomerular filtration rate of ≤ 45 mL / min, (c) Having an East Coast Cancer Clinical Trials Group (ECOG) performance status of ≥ 2, (d) being 70 years of age or older, (e) has refused high-dose chemotherapy and / or transplantation, and / or (f) The patient's response to pre-transplant chemotherapy is insufficient, making it impossible to proceed with transplantation.

[0227] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. DLBCL is DLBCL NOS (unspecified DLBCL), and the patient is not a candidate for hematopoietic stem cell transplantation (HSCT).

[0228] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. DLBCL is DLBCL NOS (unspecified DLBCL), and the patient is not a candidate for hematopoietic stem cell transplantation (HSCT).

[0229] In one embodiment, the present invention features a method for treating unspecified relapsed or refractory diffuse large B-cell lymphoma (DLBCL NOS) in a human patient who is in need of treatment for the unspecified relapsed or refractory diffuse large B-cell lymphoma (DLBCL NOS), the patient being a candidate for hematopoietic stem cell transplantation (HSCT), and the method comprises administering an effective dose of grofitamab, gemcitabine, and oxaliplatin.

[0230] In one embodiment, the present invention features a method for treating unspecified relapsed or refractory diffuse large B-cell lymphoma (DLBCL NOS) in a human patient requiring treatment for the disease, the patient being 18 years of age or older, and the method comprising administering an effective dose of grofitamab, gemcitabine, and oxaliplatin.

[0231] In one embodiment, the present invention features a method for treating unspecified relapsed or refractory diffuse large B-cell lymphoma (DLBCL NOS) in adult human patients who require treatment for the disease, and who are not candidates for hematopoietic stem cell transplantation (HSCT), and the method comprises administering an effective dose of grofitamab, gemcitabine, and oxaliplatin. In one embodiment, the adult human patients are 18 years of age or older.

[0232] In one embodiment, PFS or reference PFS is measured starting from the time of randomization and continuing until the first occurrence of disease progression or death from any cause.

[0233] In one embodiment, PFS or reference PFS is the median PFS of multiple human patients receiving the corresponding treatment.

[0234] In one embodiment, the improvement in PFS is statistically significant.

[0235] In one embodiment, improvement in the median PFS is an increase of at least one month (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30 months, or longer) compared to the reference PFS.

[0236] In one embodiment, improvement in the median PFS is an increase of 1 to 18 months (e.g., 1 to 8 months, 8 to 18 months, 5 to 15 months, or 6 to 10 months; e.g., approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 months) in PFS compared to a reference PFS.

[0237] In one embodiment, an improvement in the median PFS is an increase of approximately 9 months in PFS compared to the reference PFS. In another embodiment, an improvement in the median PFS is an increase of approximately 10 months in PFS compared to the reference PFS.

[0238] In one embodiment, applying such treatment to multiple human patients results in a statistically significant improvement in PFS compared to a control treatment, with a hazard ratio of 0.2, 0.3, 0.4, 0.5, 0.6, or 0.7 or less.

[0239] In one embodiment, applying such treatment to multiple human patients results in a statistically significant improvement in PFS compared to a control treatment, with a hazard ratio of approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, or 0.7. In one embodiment, the hazard ratio is approximately 0.42. In one embodiment, the hazard ratio is approximately 0.42 (95% confidence interval: 0.29, 0.61). In one embodiment, the hazard ratio is approximately 0.40. In one embodiment, the hazard ratio is approximately 0.40 (95% confidence interval: 0.28, 0.57). In one embodiment, applying such treatment to multiple human patients results in a statistically significant improvement in PFS compared to a control treatment, with a hazard ratio of approximately 0.41 (95% confidence interval: 0.29, 0.58).

[0240] In one embodiment, the hazard ratio is a stratified hazard ratio.

[0241] In one embodiment, applying such treatment to multiple human patients increases the PFS rate by at least 5% (e.g., at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or more) compared to a reference PFS at 6 months.

[0242] In one embodiment, applying such treatment to multiple human patients increases the PFS rate by 5% to 45% (e.g., 5% to 25%, 25% to 45%, 10% to 40%, or, for example, 20% to 30%; for example, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45%) compared to a reference PFS at 6 months.

[0243] In one embodiment, applying such treatment to multiple human patients increases the PFS rate by approximately 25% compared to a reference PFS at 6 months.

[0244] In one embodiment, applying such treatment to multiple human patients increases the PFS rate by at least 5% (e.g., at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or more) compared to a reference PFS at 12 months.

[0245] In one embodiment, applying such treatment to multiple human patients increases the PFS rate by 5% to 45% (e.g., 5% to 25%, 25% to 45%, 10% to 40%, or, for example, 20% to 30%; for example, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45%) compared to a reference PFS at 12 months.

[0246] In one embodiment, applying such treatment to multiple human patients increases the PFS rate by approximately 25% compared to a reference PFS at 12 months.

[0247] In one embodiment, applying such treatment to multiple human patients improves the complete response rate (CR rate), objective response rate (ORR), duration of objective response, and / or duration of CR (DOCR) compared to a control treatment.

[0248] In one embodiment, the complete response (CR) rate is the percentage of patients whose best overall response is complete response (CR) in PET / computed tomography (CT).

[0249] In one embodiment, the improvement in the CR rate is an increase of at least 15% (e.g., at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or more).

[0250] In one embodiment, the improvement in the CR rate is an increase of 15% to 50% (for example, 20% to 30%, 30% to 45%, 25% to 40%, for example, 25% to 35%, or 20% to 45%; for example, about 20%, 25%, 30%, 35%, 40%, or 45%).

[0251] In one embodiment, the improvement in the CR rate is an increase of approximately 30%. In another embodiment, the improvement in the CR rate is an increase of approximately 33%.

[0252] In one embodiment, ORR is the percentage of patients whose overall response is a partial response (PR) or complete response (CR).

[0253] In one embodiment, DOCR is measured as the time from the first recorded objective response (CR or PR) to disease progression or death from any cause, whichever comes first.

[0254] In one embodiment, the improvement in DOCR is an increase of at least two months (e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30 months, or longer).

[0255] In one embodiment, the improvement in DOCR is an increase of 2 to 20 months (e.g., 2 to 8 months, 8 to 20 months, 5 to 15 months, or 6 to 10 months; e.g., about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 months).

[0256] In one embodiment, the increase in DOCR is approximately an 8-month increase.

[0257] In one embodiment, the duration of a complete response (CR) is measured as the time from the first recorded occurrence of CR to disease progression or death from any cause, whichever comes first.

[0258] In one embodiment, a method is provided for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0259] In one embodiment, OS or reference OS is measured starting from the time of randomization until death from any cause.

[0260] In one embodiment, the OS or reference OS is the median OS of multiple human patients receiving the corresponding treatment.

[0261] In one embodiment, the improvement in the OS is statistically significant.

[0262] In one embodiment, improvement in the median OS is an increase of at least one month (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50 months, or longer) compared to the reference OS.

[0263] In one embodiment, the improvement in the median OS is an increase of 1 to 30 months (e.g., 1 to 9 months, 9 to 30 months, 5 to 15 months, or 5 to 25 months; e.g., approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 months) compared to a reference OS.

[0264] In one embodiment, the improvement in the median OS is an increase of approximately 13 months compared to the reference OS.

[0265] In one embodiment, applying such treatment to multiple human patients results in a statistically significant improvement in overall survival (OS) compared to a control treatment, with a hazard ratio of 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8 or less.

[0266] In one embodiment, applying such treatment to multiple human patients results in a statistically significant improvement in overall survival (OS) compared to a control treatment, with a hazard ratio of approximately 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8. In one embodiment, the hazard ratio is approximately 0.62. In another embodiment, the hazard ratio is approximately 0.62 (95% confidence interval: 0.43-0.88). In several embodiments, applying such treatment to multiple human patients results in a statistically significant improvement in OS compared to a control treatment, with a hazard ratio of approximately 0.60 (95% confidence interval: 0.42, 0.85).

[0267] In one embodiment, the hazard ratio is a stratified hazard ratio.

[0268] In one embodiment, applying such treatment to multiple human patients increases the overall survival rate by at least 5% (e.g., at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or more) compared to a reference OS over 12 months.

[0269] In one embodiment, applying such treatment to multiple human patients increases the OS rate by 5% to 30% (e.g., 5% to 10%, 10% to 30%, 10% to 20%, or 5% to 15%; e.g., approximately 5%, 10%, 15%, 20%, 25%, or 30%) compared to a reference OS over 12 months.

[0270] In one embodiment, applying such treatment to multiple human patients increases the OS rate by approximately 10% compared to a reference OS over 12 months.

[0271] In one embodiment, applying such treatment to multiple human patients increases the overall survival rate by at least 5% (e.g., at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or more) compared to a reference OS at 18 months.

[0272] In one embodiment, applying such treatment to multiple human patients increases the OS rate by 5% to 35% (e.g., 5% to 20%, 20% to 35%, 10% to 30%, or 15% to 25%; e.g., approximately 5%, 10%, 15%, 20%, 25%, 30%, or 35%) compared to a reference OS at 18 months.

[0273] In one embodiment, applying such treatment to multiple human patients increases the OS rate by approximately 20% compared to a reference OS at 18 months.

[0274] In one embodiment, applying such treatment to multiple human patients increases the overall survival rate by at least 5% (e.g., at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or more) compared to a reference OS at 24 months.

[0275] In one embodiment, applying such treatment to multiple human patients increases the OS rate by 5% to 40% (e.g., 5% to 20%, 20% to 40%, 10% to 30%, or 15% to 25%; e.g., approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%) compared to the reference OS rate at 24 months.

[0276] In one embodiment, applying such treatment to multiple human patients increases the OS rate by approximately 20% compared to a reference OS at 24 months.

[0277] In one embodiment, the stratified hazard ratio is stratified by: (a) the number of prior lines of systemic therapy for DLBCL (1 vs ≥ 2); and / or (b) the outcome of the last systemic therapy (relapsed vs refractory).

[0278] In one embodiment, the present invention features a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising administering an effective dose to a human patient: (a) grofitamab, (b) gemcitabine, and (c) oxaliplatin, and by applying such treatment to multiple human patients, a median duration of complete remission of at least 27 months can be obtained in multiple human patients.

[0279] In one embodiment, the present invention features a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising administering to a human patient an effective dose of: (a) grofitamab, (b) gemcitabine, and (c) oxaliplatin, wherein the application of such treatment to the patient results in complete remission, and multiple human patients who receive such treatment and achieve complete remission at the end of treatment exhibit an overall survival rate of approximately 89% at 12 months.

[0280] In one embodiment, the present invention features a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, the method comprising administering an effective dose to a human patient: (a) grofitamab, (b) gemcitabine, and (c) oxaliplatin, wherein the application of such treatment to the patient results in complete remission, and multiple human patients who achieve complete remission at the end of treatment after receiving such treatment exhibit a progression-free survival rate of approximately 82% at 12 months.

[0281] In one embodiment, the method comprises first and second administration cycles:

[0282] The first administration cycle consists of a first dose of approximately 2.5 mg of grofitamab (C1D1) and a second dose of approximately 10 mg of grofitamab (C1D2).

[0283] The second treatment cycle includes a single dose of approximately 30 mg of grofitamab (C2D1).

[0284] In one embodiment, grofitamab C1D1 and C1D2 are administered to the patient on day 8 and day 15 of the first dosing cycle, respectively.

[0285] In one embodiment, grofitamab C2D1 is administered to the patient on day 1 of the second dosing cycle.

[0286] In one embodiment, the first administration cycle includes a dose of 1000 mg of obinutuzumab.

[0287] In one embodiment, obinutuzumab is administered approximately 7 days before the first grofitamab dose.

[0288] In one embodiment, obinutuzumab is administered on day 1 of the first administration cycle.

[0289] In one embodiment, the first and second administration cycles consist of gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 This includes the dosage.

[0290] In one embodiment, gemcitabine and oxaliplatin are administered on day 2 of the first administration cycle.

[0291] In one embodiment, gemcitabine and oxaliplatin are administered on day 1 or day 2 of the second administration cycle.

[0292] In one embodiment, gemcitabine is administered on the same day before oxaliplatin.

[0293] In one embodiment, the first and second administration cycles are each 21-day administration cycles.

[0294] In one embodiment, the method includes 12 administration cycles.

[0295] In one embodiment, each administration cycle is 21 days long.

[0296] In one embodiment, the method includes the following: The patient is administered an effective dose of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin in one treatment cycle. The patient is administered effective doses of grofitamab, gemcitabine, and oxaliplatin for 2 to 8 cycles of administration; and The patient receives an effective dose of grofitamab for 9 to 12 cycles of administration.

[0297] In one embodiment, obinutuzumab is administered at a dose of 1000 mg on day 1 of treatment cycle 1; grofitamab is administered at a dose of 0.5 mg on day 8 and 10 mg on day 15 of treatment cycle 1; 30 mg is administered on day 1 of treatment cycles 2 through 12; and gemcitabine is administered at a dose of 1000 mg / m². 2 The dose is 100 mg / m², and oxaliplatin is 100 mg / m². 2 It is administered at this dose on the second day of treatment cycle 1 and on the first or second day of treatment cycles 2 through 8.

[0298] In one embodiment, gemcitabine is administered on the same day before oxaliplatin.

[0299] In one embodiment, grofitamab is provided for use in a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein an effective dose of grofitamab is administered to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0300] In one embodiment, the present invention relates to grofitamab for use in a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for the disease, wherein the treatment method involves administering an effective dose to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0301] In one embodiment, the present invention relates to grofitamab for use in the manufacture of a pharmaceutical product for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for the disease, wherein the treatment is administered to a human patient in an effective dose: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0302] In one embodiment, the present invention relates to grofitamab for use in the manufacture of a pharmaceutical product for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for the disease, wherein the treatment is administered to a human patient in an effective dose: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0303] In one embodiment, the present invention is characterized by a method for treating a patient having a CD20-positive cell proliferative disorder, for example, a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL), DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), or CNSL), wherein the method involves administering an effective amount to the patient: (a) Grofitamab; (b) gemcitabine; and (c) Oxaliplatin This includes administering the drug in a dosing regimen that includes at least a first and a second dosing cycle.

[0304] In one embodiment, the human patient has unspecified relapsed or refractory DLBCL (DLBCL NOS). In one embodiment, the human patient is not a candidate for hematopoietic stem cell transplantation (HSCT) (e.g., not eligible for HSCT). In one embodiment, the human patient has relapsed or refractory DLBCL NOS and is not a candidate for HSCT (e.g., not eligible for HSCT).

[0305] In one embodiment, the first administration cycle comprises a first dose (C1D1) and a second dose (C1D2) of grofitamab, where C1D1 of grofitamab is approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of grofitamab is approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); the second administration cycle comprises grofitamab The single dose (C2D1) of grofitamab is approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg), approximately 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, or ± 1.6 mg), or approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg). In certain embodiments, grofitamab C1D1 is approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and grofitamab C1D2 is approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg). In certain embodiments, C2D1 is approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg). In certain embodiments, the C2D1 dose of grofitamab is approximately 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, or ± 1.6 mg). In certain embodiments, the C2D1 dose of grofitamab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0306] In one embodiment, the first administration cycle comprises a first dose (C1D1) and a second dose (C1D2) of grofitamab, where C1D1 of grofitamab is approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of grofitamab is approximately 10 mg (e.g., 10 mg) The dose is ±0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg, or ±1 mg); the second administration cycle consists of a single dose of grofitamab (C2D1), with grofitamab in C2D1 being approximately 30 mg (e.g., 30 mg ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg).

[0307] In one embodiment, a first dose of grofitamab (C1D1) and a second dose of grofitamab (C1D2) are administered to the patient on day 8 or approximately day 8 (±1 day) and day 15 or approximately day 15 (±1 day), respectively, of the first administration cycle.

[0308] In one embodiment, a first dose (C1D1) and a second dose (C1D2) of grofitamab are administered to the patient on day 8 and day 15 of the first dosing cycle, respectively. In some embodiments, grofitamab C2D1 is administered to the patient on day 8 or approximately day 8 (±1 day) of the second dosing cycle. In some embodiments, grofitamab C2D1 is administered to the patient on day 8 or approximately day 8 of the second dosing cycle.

[0309] In one embodiment, a single dose of obinutuzumab C1D1 is administered on day 1 of the first cycle. In one embodiment, the single dose is approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg).

[0310] In some embodiments, the method characterized by the present invention further comprises administering one or more additional therapeutic agents to the patient. In some embodiments, one or more additional therapeutic agents are tocilizumab. In one embodiment, the patient's weight is about 30 kg or more, and tocilizumab is administered at a dose of about 8 mg / kg (e.g., 8 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, or ± 0.8 mg / kg). In one embodiment, the patient's weight is less than 30 kg, and tocilizumab is administered at a dose of about 12 mg / kg (e.g., 12 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, ± 1 mg / kg, or ± 1.2 mg / kg). In some embodiments, the maximum dose of tocilizumab is approximately 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

[0311] In some embodiments, one or more additional therapeutic agents are corticosteroids. In some embodiments, the corticosteroid is prednisone, prednisolone, methylprednisolone, or dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or longer) before administration of any dose of grofitamab. In one embodiment, dexamethasone is administered intravenously at a dose of approximately 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg) at least approximately 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or longer) prior to the administration of any dose of obinutuzumab. In one embodiment, methylprednisolone is administered intravenously at a dose of approximately 80 mg (e.g., 80 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, or ± 8 mg) at least approximately 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or longer) prior to the administration of any dose of grofitamab. In one embodiment, methylprednisolone is administered intravenously at a dose of approximately 80 mg (e.g., 80 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, or ± 8 mg) at least approximately 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or longer) prior to the administration of any dose of obinutuzumab.In one embodiment, prednisone is administered orally at a dose of approximately 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) at least approximately 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or longer) before administration of any dose of grofitamab. In one embodiment, prednisolone is administered intravenously at a dose of approximately 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) at least approximately 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or longer) prior to the administration of any dose of grofitamab.

[0312] In some embodiments, one or more additional therapeutic agents are antihistamines. In some embodiments, the antihistamine is diphenhydramine. In one embodiment, diphenhydramine is administered orally or intravenously in a dose of about 50 mg (e.g., 50 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, or ± 5 mg) at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or longer) before administration of any dose of grofitamab.

[0313] In some embodiments, one or more additional therapeutic agents include allopurinol and rasburicase.

[0314] In some embodiments, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is administered orally at doses of about 500 mg to about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or longer) before administration of any dose of grofitamab. In one embodiment, acetaminophen or paracetamol is administered orally or intravenously in doses ranging from about 500 mg to about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or longer) before administration of any dose of obinutuzumab.

[0315] In some embodiments, one or more additional therapeutic agents include granulocyte colony-stimulating factor (G-CSF). In one embodiment, G-CSF is administered about 1 to 2 days (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours) after administration of any dose of rituximab, ifosfamide, carboplatin, and / or etoposide.

[0316] In some embodiments, one or more additional therapeutic agents are mesna. In one embodiment, mesna is present in an amount of about 5000 mg / m². 2 (For example, 5000 mg / m²) 2 ±50 mg / m² 2 ±100 mg / m² 2 ±200 mg / m² 2 ±300 mg / m² 2 ±400 mg / m² 2 , or ±500 mg / m² 2 ), approx. 4000mg / m2 (For example, 4000 mg / m²) 2 ±40 mg / m² 2 ±50 mg / m² 2 ±100 mg / m² 2 ±200 mg / m² 2 ±300 mg / m² 2 , or ±400 mg / m² 2 ), or approximately 1666 mg / m² 2 (For example, 1666 mg / m²) 2± 25 mg / m² 2 ±50 mg / m² 2 ±100 mg / m² 2 , or ±166.6 mg / m² 2 It is administered intravenously at the dose of ).

[0317] Glofitamab is an anti-CD20 / anti-CD3 bispecific antibody (WHO Drug Information (International Generic Name of Drugs), Recommended INN: List 83, 2020, vol.34, no.1, p.39 (the whole is incorporated herein by reference); Recommended INN: List 121 WHO Drug Information, Vol.33, No.2, 2019, page 276 (the whole is incorporated herein by reference), also known as CD20-TCB, RO7082859, or RG6026; CAS #:2229047-91(8).

[0318] In one embodiment, grofitamab comprises two Fab molecules that specifically bind to CD20, which contains the following six hypervariable regions (HVRs): (i) HVR-H1 containing the amino acid sequence of YSWIN (SEQ ID NO: 1) (ii) HVR-H2 containing the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO: 2); (iii) HVR-H3 containing the amino acid sequence NVFDGYWLVY (SEQ ID NO: 3); (iv) HVR-L1 containing the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO: 4); (v) HVR-L2 containing the amino acid sequence of QMSNLVS (SEQ ID NO: 5); and (vi) HVR-L3 containing the amino acid sequence of AQNLELPYT (SEQ ID NO: 6).

[0319] In one embodiment, grofitamab comprises (a) a heavy chain variable (VH) domain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 8; or (c) two Fab molecules that specifically bind to CD20, each containing the VH domain of (a) and the VL domain of (b).

[0320] In one embodiment, the Fab molecule that specifically binds to CD20 includes (a) a VH domain containing the amino acid sequence of SEQ ID NO: 7 and (b) a VL domain containing the amino acid sequence of SEQ ID NO: 8.

[0321] In one embodiment, grofitamab contains a single Fab molecule that specifically binds to CD3 containing the following six HVRs: (i) HVR-H1 containing the amino acid sequence of TYAMN (SEQ ID NO: 9) (ii) HVR-H2 containing the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO: 10); (iii) HVR-H3 containing the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO: 11); (iv) HVR-L1 containing the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO: 12); (v) HVR-L2 containing the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and (vi) HVR-L3 containing the amino acid sequence ALWYSNLWV (SEQ ID NO: 14).

[0322] In one embodiment, grofitamab comprises (a) a heavy chain variable (VH) domain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 15; (b) a light chain variable (VL) domain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 16; or (c) a single Fab molecule that specifically binds to CD3 and comprises the VH domain of (a) and the VL domain of (b).

[0323] In one embodiment, the Fab molecule that specifically binds to CD3 includes (a) a VH domain containing the amino acid sequence of SEQ ID NO: 15 and (b) a VL domain containing the amino acid sequence of SEQ ID NO: 16.

[0324] In certain embodiments, grofitamab comprises a polypeptide that is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 17, a polypeptide that is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 18, a polypeptide that is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 19, and a polypeptide that is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 20. In further certain embodiments, grofitamab comprises the polypeptide sequence of SEQ ID NO: 17, the polypeptide sequence of SEQ ID NO: 18, the polypeptide sequence of SEQ ID NO: 19, and the polypeptide sequence of SEQ ID NO: 20. In further certain embodiments, grofitamab comprises one polypeptide chain containing the amino acid sequence of SEQ ID NO: 17, one polypeptide chain containing the amino acid sequence of SEQ ID NO: 18, one polypeptide chain containing the amino acid sequence of SEQ ID NO: 19, and two polypeptide chains, each containing the amino acid sequence of SEQ ID NO: 20.

[0325] In certain embodiments, grofitamab comprises a polypeptide that is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 58, a polypeptide that is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 59, a polypeptide that is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 19, and a polypeptide that is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 20. In further certain embodiments, grofitamab comprises the polypeptide sequence of SEQ ID NO: 58, the polypeptide sequence of SEQ ID NO: 59, the polypeptide sequence of SEQ ID NO: 19, and the polypeptide sequence of SEQ ID NO: 20. In further certain embodiments, grofitamab comprises one polypeptide chain containing the amino acid sequence of SEQ ID NO: 58, one polypeptide chain containing the amino acid sequence of SEQ ID NO: 59, one polypeptide chain containing the amino acid sequence of SEQ ID NO: 19, and two polypeptide chains, each containing the amino acid sequence of SEQ ID NO: 20.

[0326] In some embodiments, the method characterized by the present invention further comprises administering one or more additional therapeutic agents to a patient. In some embodiments, one or more additional therapeutic agents are tocilizumab. In some embodiments, one or more additional therapeutic agents are corticosteroids. In some embodiments, the corticosteroid is prednisone, prednisolone, methylprednisolone, or dexamethasone. In some embodiments, one or more additional therapeutic agents are antihistamines. In some embodiments, the antihistamine is diphenhydramine. In some embodiments, one or more additional therapeutic agents include allopurinol and rasburicase. In some embodiments, one or more additional therapeutic agents are antipyretics. In some embodiments, one or more additional therapeutic agents include granulocyte colony-stimulating factor (G-CSF). In some embodiments, one or more additional therapeutic agents are mesna.

[0327] (iv) CRS risk mitigation strategies This invention relates to a novel combination therapy using grofitamab and GemOx.

[0328] The methods and uses described herein provide an acceptable safety profile for cytokine release syndrome in a population of patients with diffuse large B-cell lymphoma (DLBCL), such as DLBCL NOS, to be administered grofitamab, gemcitabine, and oxaliplatin (Glofit-GemOx). In some embodiments, patients in this population are not candidates for hematopoietic stem cell transplantation (HSCT) or autologous stem cell transplantation (ASCT) (e.g., not eligible for HSCT or ASCT).

[0329] In some embodiments, the patient population exhibits a cytokine release syndrome rate of approximately 50% or less (e.g., approximately 40% or less, approximately 30% or less, approximately 20% or less, approximately 10% or less, approximately 5%, or approximately 1% or less; for example, approximately 0% to approximately 50%, approximately 5% to approximately 40%, approximately 5% to approximately 20%, approximately 5% to approximately 10%, approximately 20% to approximately 50%, approximately 30% to approximately 40%, approximately 20% to approximately 40%, approximately 15% to approximately 35%, approximately 15% to approximately 25%, approximately 35% to approximately 50%, or approximately 25% to approximately 50%; for example, approximately 50%, approximately 45%, approximately 40%, approximately 35%, approximately 30%, approximately 25%, approximately 20%, approximately 15%, approximately 10%, approximately 5%, approximately 1%, or approximately 0%).

[0330] In some embodiments, the proportion of cytokine release syndrome with grade ≥ 3 in a group of 25 patients is approximately 50% or less (e.g., approximately 40% or less, approximately 30% or less, approximately 20% or less, approximately 10% or less, approximately 5%, or approximately 1% or less; for example, approximately 0% to approximately 50%, approximately 5% to approximately 40%, approximately 5% to approximately 20%, approximately 5% to approximately 10%, approximately 20% to approximately 50%, approximately 30% to approximately 40%, approximately 20% to approximately 40%, approximately 15% to approximately 35%, approximately 15% to approximately 25%, approximately 35% to approximately 50%, or approximately 25% to approximately 50%; for example, approximately 50%, approximately 45%, approximately 40%, approximately 35%, approximately 30%, approximately 25%, approximately 20%, approximately 15%, approximately 10%, approximately 5%, approximately 1%, or approximately 0%). In some embodiments, the proportion of cytokine release syndrome with grade ≥ 3 in the patient population is approximately 20% or less. In a specific embodiment, the proportion of cytokine release syndrome with grade ≥ 3 in a patient population of 35 is approximately 10% or less. In a specific embodiment, the proportion of cytokine release syndrome with grade ≥ 3 in the patient population is approximately 5% or less.

[0331] Glofitamab, which is involved in T cell activation, has been associated with cytokine release syndrome (CRS). CRS is a potentially life-threatening group of symptoms caused by the excessive release of cytokines by immune effector or target cells during an excessive and persistent immune response. CRS can be triggered by a variety of factors, including infection by toxic pathogens, or by the application of drugs that activate or enhance the immune response, and can result in a marked and persistent immune response.

[0332] Regardless of the inducing agent, severe or fatal CRS is a medical emergency. If not properly managed, severe or fatal CRS can lead to significant physical disability or death. Current clinical management focuses on treating the individual's signs and symptoms, providing supportive care, and attempting to suppress the inflammatory response with high-dose corticosteroids. However, this approach is not always successful, especially in late interventions. Furthermore, steroids can negatively impact T-cell function, potentially reducing the clinical benefits of immunomodulatory therapies in cancer treatment.

[0333] A. CRS symptoms and grading CRS is graded according to the Modified Cytokine Release Syndrome Grading System established by Lee et al., Blood, 124:188-195, 2014 or Lee et al., Biol Blood Marrow Transplant, 25(4):625-638, 2019, as described in Table 3. In addition to the diagnostic criteria, recommendations are provided for the management of CRS based on its severity, including early intervention with corticosteroids and / or anti-cytokine therapy (see Tables 3 and 4).

[0334] TIFF2026522176000003.tif185170Lee 2014 criteria:Lee et al.,Blood,124:188-195,2014. ASTCT overall grading: Lee et al., Biol Blood Marrow Transplant, 25(4):625-638, 2019. BiPAP = Bilevel Positive Airway Pressure; C-PAP = Continuous Positive Airway Pressure; CRS = Cytokine Release Syndrome; ASTCT = American Society for Transplantation and Cellular Therapy NCI CTCAE v5.0 = The National Cancer Institute's Common Terminology Criteria for Adverse Events, version 5.0. Note: Organ toxicity associated with CRS may be graded according to NCI CTCAE v5.0, but this does not affect CRS grading. a Low-dose vasopressors: Single vasopressors in the doses shown in Table 4 below. b High-dose vasopressors: Defined in Table 4 c Grade 5 CRS is defined as death due to CRS. *Fever is defined as a body temperature of ≥38°C that is not caused by any other factor. In patients with CRS receiving antipyretics such as tocilizumab or steroids, or anti-cytokine therapy, fever is not necessary for grading the subsequent severity of CRS. In this case, CRS grading is performed based on hypotension and / or hypoxia. † The grade of CRS is determined by more severe events: hypotension or hypoxia not attributable to any other cause. For example, a patient with a body temperature of 39.5°C, hypotension requiring one vasopressor, and hypoxia requiring a low-flow nasal cannula would be classified as Grade 3 CRS. ‡ Low-flow nasal cannulas are defined as oxygen delivery at ≤6 L / min. Low flow also includes blow-by oxygen delivery, which is sometimes used in pediatrics. High-flow nasal cannulas are defined as oxygen delivery at 6 L / min.

[0335] TIFF2026522176000004.tif50170min=minutes;VASST=Vasopressin and septic shock clinical trial. a VASST vasopressor equivalent formula: Norepinephrine equivalent = [Norepinephrine (μg / min)] + [Dopamine (μg / kg / min) ÷ 2] + [Epinephrine (μg / min)] + [Phenylephrine (μg / min) ÷ 10].

[0336] Mild to moderate symptoms of CRS and / or infusion-related events (IRRs), including fever, headache, and muscle pain, can be treated symptomatically with analgesics, antipyretics, and antihistamines as needed. Severe or life-threatening symptoms of CRS and / or IRRs, such as hypotension, tachycardia, dyspnea, or chest discomfort, should be treated contactively with symptomatic and resuscitation measures as needed, including the use of high-dose corticosteroids, IV fluids, admission to the intensive care unit, and other symptomatic measures. Severe CRS may be associated with other clinical sequelae such as disseminated intravascular coagulation, capillary vascular leak syndrome, or macrophage activation syndrome (MAS). There is no established standard treatment for severe or life-threatening CRS caused by immunotherapy; case reports and recommendations using anti-cytokine therapies such as tocilizumab have been published (Teachey et al., Blood, 121:5154-5157, 2013; Lee et al., Blood, 124:188-195, 2014; Maude et al., New Engl J Med, 371:1507-1517, 2014).

[0337] Optimized steroid regimens for patient treatment with B. grofitamab Glofitamab can induce cytokine release syndrome (CRS), a severe side effect requiring management. Preclinical in vivo trial results indicate that dexamethasone is a viable option for managing CRS in patients treated with grofitamab and enhancing the safety profile of the treatment without compromising its antitumor efficacy. Provided herein is an optimized steroid regimen for the treatment of patients with grofitamab, which optimizes the CRS profile of this treatment.

[0338] The present invention provides a method for treating patients having CD20-positive cell proliferative disorders (e.g., B-cell proliferative disorders (e.g., non-Hodgkin lymphoma (NHL) (e.g., relapsed and / or refractory NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed and / or refractory DLBCL), follicular lymphoma (FL) (e.g., relapsed and / or refractory FL or transformed FL), or mantle cell lymphoma (MCL) (e.g., relapsed or refractory MCL)), or central nervous system lymphoma (CNSL))), the method comprising administering to the patient a combination of grofitamab and GemOx as described herein, wherein the patient receives corticosteroid prophylaxis before and after administration of grofitamab.

[0339] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising: an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, The patient does not receive grofitamab, and receives prophylaxis before and after administration of grofitamab.

[0340] In one embodiment, a method is provided herein for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Patients who do not receive grofitamab will receive corticosteroid prophylaxis before and after administration of grofitamab.

[0341] In one embodiment, the corticosteroid prophylaxis comprises prednisolone, methylprednisolone, and / or dexamethasone. In one embodiment, the corticosteroid prophylaxis comprises dexamethasone. In one embodiment, the corticosteroid prophylaxis comprises 20 mg of dexamethasone.

[0342] In one embodiment, corticosteroid prophylaxis is administered one day before grofitamab administration. In another embodiment, corticosteroid prophylaxis is administered approximately 24 hours before grofitamab administration.

[0343] In one embodiment, corticosteroid prophylaxis is administered approximately 30 hours, 29 hours, 28 hours, 27 hours, 26 hours, 25 hours, 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, and 18 hours before grofitamab administration.

[0344] In one embodiment, corticosteroid prophylaxis is administered on the same day as grofitamab administration.

[0345] In one embodiment, corticosteroid prophylaxis is administered approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration. In another embodiment, corticosteroid prophylaxis is administered approximately 25 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, or 100 minutes before grofitamab administration.

[0346] In one embodiment, corticosteroid prophylaxis is performed one day after administration of grofitamab.

[0347] In one embodiment, corticosteroid prophylaxis is performed approximately 24 hours after administration of grofitamab.

[0348] In one embodiment, corticosteroid prophylaxis is administered approximately 30 hours, 29 hours, 28 hours, 27 hours, 26 hours, 25 hours, 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, and 18 hours after administration of grofitamab.

[0349] In one embodiment, corticosteroid prophylaxis is administered before the first dose (C1D1) of grofitamab. In one embodiment, corticosteroid prophylaxis is administered before the second dose (C1D2) of grofitamab. In one embodiment, corticosteroid prophylaxis is administered one day before grofitamab administration, before grofitamab administration on the same day, and one day after grofitamab administration.

[0350] In one embodiment, corticosteroid prophylaxis is administered approximately 24 hours before grofitamab administration, approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and approximately 24 hours after grofitamab administration.

[0351] In one embodiment, corticosteroid prophylaxis is dexamethasone. In one embodiment, dexamethasone is administered at a dose of 20 mg.

[0352] In one embodiment, 20 mg of dexamethasone is administered orally one day before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally one day after grofitamab administration.

[0353] In one embodiment, 20 mg of dexamethasone is administered orally approximately 24 hours before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally approximately 24 hours after grofitamab administration.

[0354] In one embodiment, corticosteroid prophylaxis is administered before the third dose (C2D1) of grofitamab.

[0355] In one embodiment, corticosteroid prophylaxis is performed before any subsequent dose of grofitamab if the patient has experienced CRS with any previous 30 mg dose of grofitamab.

[0356] In one embodiment, corticosteroid prophylaxis includes 20 mg of dexamethasone.

[0357] In one embodiment, the incidence of CRS in multiple patients is reduced with corticosteroid prophylaxis compared to treatment consisting of grofitamab administration and one dose of corticosteroid on the same day.

[0358] In one embodiment, the patient does not have a Grade 3 CRS event.

[0359] In one embodiment, the patient does not need to be hospitalized after treatment with grofitamab. In one embodiment, the proportion of cytokine release syndromes of grade 2 or higher (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than approximately 10%, 5%, or 2%.

[0360] In one embodiment, the cycle length is 21 days.

[0361] In one embodiment, premedication with corticosteroids resulted in superior antitumor activity compared to patients treated without corticosteroid premedication.

[0362] In one embodiment, if the infusion of grofitamab is delayed or prolonged in administration cycles 2-12 due to a delay in the start date or a reduction in the infusion rate caused by IRR or CRS, GemOx is administered on day 2 of each cycle.

[0363] In one embodiment, there is an observation period between the completion of grofitamab infusion and before GemOx infusion. In one embodiment, the length of the observation period is approximately 90 minutes. In one embodiment, the length of the observation period is 90 minutes ± 15 minutes. In cycle 3 and beyond, if the participant did not have CRS in the previous cycle and was tolerant to the previous grofitamab infusion without signs or symptoms of CRS, the observation window is less than approximately 90 minutes. In one embodiment, the length of the observation period is 60 minutes ± 20 minutes, 60 minutes ± 15 minutes, or 60 minutes ± 10 minutes.

[0364] In one embodiment, the first dose of 2.5 mg of grofitamab (C1D1) on day 8 of the first administration cycle is infused over 4 hours (±15 minutes), followed by 4 hours (±15 minutes) of monitoring before discharge. In one embodiment, the second dose of 10 mg of grofitamab (C1D2) on day 15 of the first administration cycle is infused over 4 hours (±15 minutes), followed by 4 hours (±15 minutes) of monitoring before discharge. In one embodiment, the dose of 30 mg of grofitamab on day 1 of the second administration cycle is infused over 4 hours (±15 minutes), followed by 90 minutes (±30 minutes) of monitoring before discharge. In one embodiment, the dose of 30 mg of grofitamab on day 1 of administration cycles 2-12 is infused over 4 hours (±15 minutes), followed by 90 minutes (±30 minutes) of monitoring before discharge.

[0365] In one embodiment, the 30 mg dose on day 1 of administration cycles 3-12 is infused over 2 hours (±15 minutes), with an observation window of less than 90 minutes.

[0366] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising: an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, patients receive dexamethasone one day before grofitamab administration, on the same day as grofitamab administration, and one day after grofitamab administration.

[0367] In one embodiment, a method is provided herein for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, patients receive dexamethasone one day before grofitamab administration, on the same day as grofitamab administration, and one day after grofitamab administration.

[0368] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising: an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1), in which the patient receives dexamethasone one day before, on the same day as, and one day after the administration of grofitamab.

[0369] In one embodiment, a method is provided herein for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Glofitamab is not included; grofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1), in which the patient receives dexamethasone one day before, on the same day as, and one day after the administration of grofitamab.

[0370] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising: an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), along with gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 Including the dosage, (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1) and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 Including the dosage, Patients receive dexamethasone one day before grofitamab administration, on the same day as grofitamab administration, and one day after grofitamab administration.

[0371] In one embodiment, a method is provided herein for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Glofitamab is not included; grofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), along with gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 Including the dosage, (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1) and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 Including the dosage, Patients receive dexamethasone one day before grofitamab administration, on the same day as grofitamab administration, and one day after grofitamab administration.

[0372] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising: an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0373] Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second administration cycle, and the patient is administered dexamethasone one day before, on the same day as, and one day after the administration of grofitamab.

[0374] In one embodiment, a method is provided herein for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Glofitamab is not included; grofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second administration cycle, and the patient is administered dexamethasone one day before, on the same day as, and one day after the administration of grofitamab.

[0375] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising: an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Does not contain grofitamab.

[0376] Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle.

[0377] In one embodiment, dexamethasone is administered in the second treatment cycle. In such an embodiment, dexamethasone is administered one day before the administration of the third dose (C2D1) of grofitamab, on the same day as the third dose (C2D1) of grofitamab, and one day after the third dose (C2D1) of grofitamab.

[0378] In one embodiment, if a patient has experienced CRS with any previous dose of 30 mg of grofitamab, dexamethasone is administered in cycles 1 through 12 one day before administration of grofitamab, on the same day as grofitamab, and one day after all subsequent doses of grofitamab.

[0379] In one embodiment, dexamethasone is administered in a dose of 20 mg. In one embodiment, dexamethasone is administered approximately 24 hours before administration of grofitamab, approximately 30 to 90 minutes or approximately 60 minutes before administration of grofitamab, and approximately 24 hours after administration of grofitamab. In one embodiment, dexamethasone is administered in conjunction with the first dose (C1D1) and the second dose (C1D2) of grofitamab.

[0380] In one embodiment, 20 mg of dexamethasone is administered orally one day before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally one day after grofitamab administration.

[0381] In one embodiment, 20 mg of dexamethasone is administered orally approximately 24 hours before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally approximately 24 hours after grofitamab administration.

[0382] In one embodiment, a method is provided herein for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Glofitamab is not included; grofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle.

[0383] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising: an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab, gemcitabine, oxaliplatin, and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle, and gemcitabine 1000 mg / m² is administered during the first and second treatment cycles. 2 The dosage and oxaliplatin 100 mg / m² 2 This includes the dosage.

[0384] In one embodiment, a method is provided herein for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Excluding grofitamab, grofitamab, gemcitabine, oxaliplatin, and dexamethasone are administered in a regimen comprising at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle, and gemcitabine 1000 mg / m² is administered during the first and second treatment cycles. 2 The dosage and oxaliplatin 100 mg / m² 2 This includes the dosage.

[0385] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising: an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab, gemcitabine, oxaliplatin, and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; gemcitabine 1000 mg / m² 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered on the second day of the first dosing cycle. (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle, along with gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered on day 1 of the second dosing cycle.

[0386] In one embodiment, gemcitabine 1000 mg / m² 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered on the first day of the subsequent administration cycle.

[0387] In one embodiment, a method is provided herein for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Excluding grofitamab, grofitamab, gemcitabine, oxaliplatin, and dexamethasone are administered in a regimen comprising at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; gemcitabine 1000 mg / m² 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered on the second day of the first dosing cycle. (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle, along with gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered on day 1 of the second dosing cycle.

[0388] In one embodiment, dexamethasone is administered in the second treatment cycle. In such an embodiment, dexamethasone is administered one day before the administration of the third dose (C2D1) of grofitamab, on the same day as the third dose (C2D1) of grofitamab, and one day after the third dose (C2D1) of grofitamab.

[0389] In one embodiment, if a patient has experienced CRS with any previous 30 mg dose of grofitamab, dexamethasone is administered in cycles 1 through 12 one day before administration of grofitamab, on the same day as grofitamab, and one day after administration of all subsequent doses of grofitamab.

[0390] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising: an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), along with effective doses of obinutuzumab, gemcitabine, and oxaliplatin; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in a dosing cycle 1; (2) The patient is administered a single dose of 30 mg of grofitamab, an effective dose of gemcitabine, and oxaliplatin for 2 to 8 cycles of administration; and (3) The patient is administered a single dose of 30 mg of grofitamab for 9 to 12 cycles of administration. Includes.

[0391] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising: an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient is administered a single dose of 30 mg of grofitamab, an effective dose of gemcitabine, and oxaliplatin for 2 to 8 cycles of administration; and (3) The patient is administered a single dose of 30 mg of grofitamab for 9 to 12 cycles of administration. Includes.

[0392] In one embodiment, a method is provided herein for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient is administered a single dose of 30 mg of grofitamab, an effective dose of gemcitabine, and oxaliplatin for 2 to 8 cycles of administration; and (3) The patient is administered a single dose of 30 mg of grofitamab for 9 to 12 cycles of administration. Includes.

[0393] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising: an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient receives a single dose of 30 mg of grofitamab and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered, for administration cycles 2 through 8; and (3) The patient is administered a single dose of 30 mg of grofitamab for 9 to 12 cycles of administration. Includes.

[0394] In one embodiment, a method is provided herein for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient receives a single dose of 30 mg of grofitamab and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered for 2 to 8 cycles of administration; and (3) The patient is administered a single dose of 30 mg of grofitamab for 9 to 12 cycles of administration. Includes.

[0395] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising: an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient receives a single dose of 30 mg of grofitamab and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The doses of the following are administered; gemcitabine and oxaliplatin are administered on day 1 of the second administration cycle and on day 1 of administration cycles 3 to 8, administration cycles 2 to 8; and (3) The patient is given a single dose of 30 mg of grofitamab on day 1, for 9 to 12 treatment cycles. Includes.

[0396] In one embodiment, a method is provided herein for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient receives a single dose of 30 mg of grofitamab and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered; gemcitabine and oxaliplatin are administered on day 1 of the second administration cycle and on day 1 of administration cycles 3 to 8, administration cycles 2 to 8; and (3) The patient is given a single dose of 30 mg of grofitamab on day 1, for 9 to 12 treatment cycles. Includes.

[0397] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method is For human patients, an effective dose: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Patients who do not receive grofitamab will receive corticosteroid prophylaxis before and after administration of grofitamab.

[0398] In one embodiment, a method is provided for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective dose of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Patients who do not receive grofitamab will receive corticosteroid prophylaxis before and after administration of grofitamab.

[0399] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, patients receive dexamethasone one day before grofitamab administration, on the same day as grofitamab administration, and one day after grofitamab administration.

[0400] In one embodiment, a method is provided for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective dose of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, patients receive dexamethasone one day before grofitamab administration, on the same day as grofitamab administration, and one day after grofitamab administration.

[0401] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1), in which the patient receives dexamethasone one day before, on the same day as, and one day after the administration of grofitamab.

[0402] In one embodiment, a method is provided for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective dose of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1), in which the patient receives dexamethasone one day before, on the same day as, and one day after the administration of grofitamab.

[0403] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) Gemcitabine, and (c) Oxaliplatin comprising, not comprising golphitamab, golphitamab and dexamethasone are administered in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, (1) The first dosing cycle comprises a first dose of 2.5 mg of golphitamab (C1D1) and a second dose of 10 mg of golphitamab (C1D2), and a dose of gemcitabine 1000 mg / m 2 and a dose of oxaliplatin 100 mg / m 2 and, (2) The second dosing cycle comprises a single dose of 30 mg of golphitamab (C2D1), and a dose of gemcitabine 1000 mg / m 2 and a dose of oxaliplatin 100 mg / m 2 and, The patient is administered dexamethasone one day before the administration of golphitamab, on the same day as golphitamab, and one day after the administration of golphitamab.

[0404] In one aspect, there is provided a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient who requires treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL), wherein the patient has relapsed after one prior treatment line or is refractory to one prior treatment line and is not eligible for hematopoietic stem cell transplantation, and the method comprises administering to the human patient an effective amount of: (a) Golphitamab, (b) Gemcitabine, and (c) Oxaliplatin comprising administering, By applying such treatment to a plurality of human patients, the overall survival (OS) of the plurality of human patients is improved as compared to the reference OS, and the reference OS is the OS of a plurality of human patients who received a control treatment, and the control treatment is: (a) Rituximab, (b) Gemcitabine, and (c) Oxaliplatin comprising excluding grofitamab, grofitamab and dexamethasone are administered in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, (1) The first dosing cycle comprises a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), and a dose of gemcitabine of 1000 mg / m 2 and a dose of oxaliplatin of 100 mg / m 2 ; (2) The second dosing cycle comprises a single dose of 30 mg of grofitamab (C2D1), and a dose of gemcitabine of 1000 mg / m 2 and a dose of oxaliplatin of 100 mg / m 2 ; The patient is administered dexamethasone 1 day before, on the same day as, and 1 day after the administration of grofitamab.

[0405] In one aspect, the present invention features a method of treating relapsed or refractory DLBCL in a human patient who needs treatment for relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior treatment line or is refractory to one prior treatment line and is not eligible for hematopoietic stem cell transplantation, and the method comprises administering to the human patient an effective amount of: (a) grofitamab, (b) gemcitabine, and (c) oxaliplatin ; By applying such treatment to a plurality of human patients, the progression-free survival (PFS) of the plurality of human patients is improved as compared to the reference PFS, where the reference PFS is the PFS of a plurality of human patients who received a control treatment, and the control treatment: (a) rituximab, (b) gemcitabine, and (c) oxaliplatin ; excluding grofitamab, Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second administration cycle, and the patient is administered dexamethasone one day before, on the same day as, and one day after the administration of grofitamab.

[0406] In one embodiment, a method is provided for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective dose of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second administration cycle, and the patient is administered dexamethasone one day before, on the same day as, and one day after the administration of grofitamab.

[0407] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle.

[0408] In one embodiment, a method is provided for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective dose of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle.

[0409] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab, gemcitabine, oxaliplatin, and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle, and gemcitabine 1000 mg / m² is administered during the first and second treatment cycles. 2 The dosage and oxaliplatin 100 mg / m² 2 This includes the dosage.

[0410] In one embodiment, a method is provided for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective dose of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab, gemcitabine, oxaliplatin, and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle, and gemcitabine 1000 mg / m² is administered during the first and second treatment cycles. 2 The dosage and oxaliplatin 100 mg / m² 2 This includes the dosage.

[0411] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Excluding grofitamab, grofitamab, gemcitabine, oxaliplatin, and dexamethasone are administered in a regimen comprising at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; gemcitabine 1000 mg / m² 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered on the second day of the first dosing cycle. (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle, along with gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered on day 1 of the second dosing cycle.

[0412] In one embodiment, a method is provided for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective dose of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab, gemcitabine, oxaliplatin, and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; gemcitabine 1000 mg / m² 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered on the second day of the first dosing cycle. (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle, along with gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered on day 1 of the second dosing cycle.

[0413] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), along with effective doses of obinutuzumab, gemcitabine, and oxaliplatin; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in a dosing cycle 1; (2) The patient is administered a single dose of 30 mg of grofitamab, an effective dose of gemcitabine, and oxaliplatin for 2 to 8 cycles of administration; and (3) The patient is administered a single dose of 30 mg of grofitamab for 9 to 12 cycles of administration. Includes.

[0414] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient is administered a single dose of 30 mg of grofitamab, an effective dose of gemcitabine, and oxaliplatin for 2 to 8 cycles of administration; and (3) The patient is administered a single dose of 30 mg of grofitamab for 9 to 12 cycles of administration. Includes.

[0415] In one embodiment, a method is provided for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective dose of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient is administered a single dose of 30 mg of grofitamab, an effective dose of gemcitabine, and oxaliplatin for 2 to 8 cycles of administration; and (3) The patient is administered a single dose of 30 mg of grofitamab for 9 to 12 cycles of administration. Includes.

[0416] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) Patients receive a single dose of grofitamab 30 mg and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered, for administration cycles 2 through 8; and (3) The patient is administered a single dose of 30 mg of grofitamab for 9 to 12 cycles of administration. Includes.

[0417] In one embodiment, a method is provided for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective dose of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient receives a single dose of 30 mg of grofitamab and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered, for administration cycles 2 through 8; and (3) The patient is administered a single dose of 30 mg of grofitamab for 9 to 12 cycles of administration. Includes.

[0418] In one embodiment, the treatment does not cause grade 3 or higher CRS. In one embodiment, the incidence of cytokine release syndrome of any grade (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 40%. In one embodiment, the incidence of cytokine release syndrome of grade 3 or higher (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 1%. In one embodiment, the patient does not need to be hospitalized for the first two cycles of treatment with grofitamab.

[0419] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient receives a single dose of 30 mg of grofitamab and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The doses of the following are administered; gemcitabine and oxaliplatin are administered on day 1 of the second administration cycle and on day 1 of administration cycles 3 to 8, administration cycles 2 to 8; and (3) The patient is given a single dose of 30 mg of grofitamab on day 1, for 9 to 12 treatment cycles. Includes.

[0420] In one embodiment, a method is provided for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective dose of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, the method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient receives a single dose of 30 mg of grofitamab and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The doses of the following are administered; gemcitabine and oxaliplatin are administered on day 1 of the second administration cycle and on day 1 of administration cycles 3 to 8, administration cycles 2 to 8; and (3) The patient is given a single dose of 30 mg of grofitamab on day 1, for 9 to 12 treatment cycles. Includes.

[0421] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method is For human patients, an effective dose: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin The patient receives prophylaxis before and after administration of grofitamab, which includes administering the drug.

[0422] In one embodiment, the corticosteroid prophylaxis comprises prednisolone, methylprednisolone, and / or dexamethasone. In one embodiment, the corticosteroid prophylaxis comprises dexamethasone. In one embodiment, the corticosteroid prophylaxis comprises 20 mg of dexamethasone.

[0423] In one embodiment, corticosteroid prophylaxis is administered one day before grofitamab administration. In another embodiment, corticosteroid prophylaxis is administered approximately 24 hours before grofitamab administration. In yet another embodiment, corticosteroid prophylaxis is administered on the same day as grofitamab administration.

[0424] In one embodiment, corticosteroid prophylaxis is administered approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration. In another embodiment, corticosteroid prophylaxis is administered one day after grofitamab administration.

[0425] In one embodiment, corticosteroid prophylaxis is administered approximately 24 hours after the administration of grofitamab. In one embodiment, corticosteroid prophylaxis is administered before the first dose (C1D1) of grofitamab. In one embodiment, corticosteroid prophylaxis is administered before the second dose (C1D2) of grofitamab. In one embodiment, corticosteroid prophylaxis is administered one day before the administration of grofitamab, before the administration of grofitamab on the same day, and one day after the administration of grofitamab.

[0426] In one embodiment, corticosteroid prophylaxis is administered approximately 24 hours before grofitamab administration, approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and approximately 24 hours after grofitamab administration.

[0427] In one embodiment, corticosteroid prophylaxis is dexamethasone. In one embodiment, dexamethasone is administered at a dose of 20 mg.

[0428] In one embodiment, 20 mg of dexamethasone is administered orally one day before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally one day after grofitamab administration.

[0429] In one embodiment, 20 mg of dexamethasone is administered orally approximately 24 hours before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally approximately 24 hours after grofitamab administration.

[0430] In one embodiment, corticosteroid prophylaxis is administered before the third dose (C2D1) of grofitamab.

[0431] In one embodiment, corticosteroid prophylaxis is administered prior to any subsequent dose of grofitamab if the patient has experienced CRS with any previous 30 mg dose of grofitamab.

[0432] In one embodiment, corticosteroid prophylaxis includes 20 mg of dexamethasone.

[0433] In one embodiment, the incidence of CRS in multiple patients is reduced with corticosteroid prophylaxis compared to treatment consisting of grofitamab administration and one dose of corticosteroid on the same day.

[0434] In one embodiment, the patient does not have a Grade 3 CRS event.

[0435] In one embodiment, the patient does not need to be hospitalized after treatment with grofitamab.

[0436] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin The patient receives dexamethasone one day before grofitamab administration, on the same day as grofitamab administration, and one day after grofitamab administration.

[0437] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1), in which the patient receives dexamethasone one day before, on the same day as, and one day after the administration of grofitamab.

[0438] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), along with gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 Including the dosage, (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1) and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 Including the dosage, Patients receive dexamethasone one day before grofitamab administration, on the same day as grofitamab administration, and one day after grofitamab administration.

[0439] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second administration cycle, and the patient is administered dexamethasone one day before, on the same day as, and one day after the administration of grofitamab.

[0440] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle.

[0441] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, Glofitamab, gemcitabine, oxaliplatin, and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle, and gemcitabine 1000 mg / m² is administered during the first and second treatment cycles. 2 The dosage and oxaliplatin 100 mg / m² 2 This includes the dosage.

[0442] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, Glofitamab, gemcitabine, oxaliplatin, and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; dexamethasone is administered one day before the administration of the first and second doses of grofitamab, on the same day as the administration of the first and second doses of grofitamab, and one day after the administration of the first and second doses of grofitamab; gemcitabine 1000 mg / m² 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered on the second day of the first dosing cycle. (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second treatment cycle, along with gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered on day 1 of the second dosing cycle.

[0443] In one embodiment, gemcitabine 1000 mg / m² 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered on the first day of the subsequent administration cycle.

[0444] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, The method is: (1) The patient is administered a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), along with effective doses of obinutuzumab, gemcitabine, and oxaliplatin; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in a dosing cycle 1; (2) The patient is administered a single dose of 30 mg of grofitamab, an effective dose of gemcitabine, and oxaliplatin for 2 to 8 cycles of administration; and (3) The patient is administered a single dose of 30 mg of grofitamab for 9 to 12 cycles of administration. Includes.

[0445] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, The method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient is administered a single dose of 30 mg of grofitamab, an effective dose of gemcitabine, and oxaliplatin for 2 to 8 cycles of administration; and (3) The patient is administered a single dose of 30 mg of grofitamab for 9 to 12 cycles of administration. Includes.

[0446] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, The method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient receives a single dose of 30 mg of grofitamab and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The dose is administered for 2 to 8 cycles of administration; and (3) The patient is administered a single dose of 30 mg of grofitamab for 9 to 12 cycles of administration. Includes.

[0447] In one embodiment, the present invention is characterized by a method for treating relapsed or refractory DLBCL in a human patient requiring the treatment of relapsed or refractory DLBCL as described herein, wherein the patient has relapsed after one prior line of treatment or is refractory to one prior line of treatment and is not eligible for hematopoietic stem cell transplantation, and the method provides to the human patient an effective amount of: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, The method is: (1) The patient is administered effective doses of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin, with the first dose of 2.5 mg of grofitamab (C1D1) administered on day 8 of the first administration cycle, and the second dose of 10 mg of grofitamab (C1D2) administered on day 15; dexamethasone is administered one day before the first and second doses of grofitamab, on the same day as the first and second doses of grofitamab, and one day after the first and second doses of grofitamab, in administration cycle 1; (2) The patient receives a single dose of 30 mg of grofitamab and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 The doses of the following are administered; gemcitabine and oxaliplatin are administered on day 1 of treatment cycles 2 to 8, treatment cycles 2 to 8, (3) The patient is given a single dose of 30 mg of grofitamab on day 1, for 9 to 12 treatment cycles. Includes.

[0448] In one embodiment, the present invention features grofitamab for use in a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising administering an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Patients who do not receive grofitamab will receive corticosteroid prophylaxis before and after administration of grofitamab.

[0449] In one embodiment, grofitamab for use in a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment of DLBCL is provided herein, the method comprising administering an effective dose to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Patients who do not receive grofitamab will receive corticosteroid prophylaxis before and after administration of grofitamab.

[0450] In one embodiment, the corticosteroid prophylaxis comprises prednisolone, methylprednisolone, and / or dexamethasone. In one embodiment, the corticosteroid prophylaxis comprises dexamethasone. In one embodiment, the corticosteroid prophylaxis comprises 20 mg of dexamethasone.

[0451] In one embodiment, corticosteroid prophylaxis is administered one day before grofitamab administration. In another embodiment, corticosteroid prophylaxis is administered approximately 24 hours before grofitamab administration. In yet another embodiment, corticosteroid prophylaxis is administered on the same day as grofitamab administration.

[0452] In one embodiment, corticosteroid prophylaxis is administered approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration. In another embodiment, corticosteroid prophylaxis is administered one day after grofitamab administration.

[0453] In one embodiment, corticosteroid prophylaxis is administered approximately 24 hours after the administration of grofitamab. In one embodiment, corticosteroid prophylaxis is administered before the first dose (C1D1) of grofitamab. In one embodiment, corticosteroid prophylaxis is administered before the second dose (C1D2) of grofitamab. In one embodiment, corticosteroid prophylaxis is administered one day before the administration of grofitamab, before the administration of grofitamab on the same day, and one day after the administration of grofitamab.

[0454] In one embodiment, corticosteroid prophylaxis is administered approximately 24 hours before grofitamab administration, approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and approximately 24 hours after grofitamab administration.

[0455] In one embodiment, corticosteroid prophylaxis is dexamethasone. In one embodiment, dexamethasone is administered at a dose of 20 mg.

[0456] In one embodiment, 20 mg of dexamethasone is administered orally one day before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally one day after grofitamab administration.

[0457] In one embodiment, 20 mg of dexamethasone is administered orally approximately 24 hours before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally approximately 24 hours after grofitamab administration.

[0458] In one embodiment, corticosteroid prophylaxis is administered before the third dose (C2D1) of grofitamab.

[0459] In one embodiment, corticosteroid prophylaxis is administered prior to any subsequent dose of grofitamab if the patient has experienced CRS with any previous 30 mg dose of grofitamab.

[0460] In one embodiment, corticosteroid prophylaxis includes 20 mg of dexamethasone.

[0461] In one embodiment, the incidence of CRS in multiple patients is reduced with corticosteroid prophylaxis compared to treatment consisting of grofitamab administration and one dose of corticosteroid on the same day.

[0462] In one embodiment, the patient does not have a Grade 3 CRS event.

[0463] In one embodiment, the patient does not need to be hospitalized after treatment with grofitamab.

[0464] In one embodiment, the present invention features grofitamab for use in a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising administering an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, patients receive dexamethasone one day before grofitamab administration, on the same day as grofitamab administration, and one day after grofitamab administration.

[0465] In one embodiment, dexamethasone is administered in a dose of 20 mg. In one embodiment, dexamethasone is administered approximately 24 hours before administration of grofitamab, approximately 30 to 90 minutes or approximately 60 minutes before administration of grofitamab, and approximately 24 hours after administration of grofitamab. In one embodiment, dexamethasone is administered in conjunction with the first dose (C1D1) and the second dose (C1D2) of grofitamab.

[0466] In one embodiment, 20 mg of dexamethasone is administered orally one day before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally one day after grofitamab administration.

[0467] In one embodiment, 20 mg of dexamethasone is administered orally approximately 24 hours before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally approximately 24 hours after grofitamab administration.

[0468] In one embodiment, the treatment does not cause grade 3 or higher CRS. In one embodiment, the incidence of cytokine release syndrome of any grade (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 40%. In one embodiment, the incidence of cytokine release syndrome of grade 3 or higher (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 1%. In one embodiment, the patient does not need to be hospitalized for the first two cycles of treatment with grofitamab.

[0469] In one embodiment, grofitamab for use in a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment of DLBCL is provided herein, the method comprising administering an effective dose to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Without grofitamab, patients receive dexamethasone one day before grofitamab administration, on the same day as grofitamab administration, and one day after grofitamab administration.

[0470] In one embodiment, dexamethasone is administered in a dose of 20 mg. In one embodiment, dexamethasone is administered approximately 24 hours before administration of grofitamab, approximately 30 to 90 minutes or approximately 60 minutes before administration of grofitamab, and approximately 24 hours after administration of grofitamab. In one embodiment, dexamethasone is administered in conjunction with the first dose (C1D1) and the second dose (C1D2) of grofitamab.

[0471] In one embodiment, 20 mg of dexamethasone is administered orally one day before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally one day after grofitamab administration.

[0472] In one embodiment, 20 mg of dexamethasone is administered orally approximately 24 hours before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally approximately 24 hours after grofitamab administration.

[0473] In one embodiment, the treatment does not cause grade 3 or higher CRS. In one embodiment, the incidence of cytokine release syndrome of any grade (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 40%. In one embodiment, the incidence of cytokine release syndrome of grade 3 or higher (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 1%. In one embodiment, the patient does not need to be hospitalized for the first two cycles of treatment with grofitamab.

[0474] In one embodiment, the present invention features grofitamab for use in a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising administering an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1), in which the patient receives dexamethasone one day before, on the same day as, and one day after the administration of grofitamab.

[0475] In one embodiment, dexamethasone is administered in a dose of 20 mg. In one embodiment, dexamethasone is administered approximately 24 hours before administration of grofitamab, approximately 30 to 90 minutes or approximately 60 minutes before administration of grofitamab, and approximately 24 hours after administration of grofitamab. In one embodiment, dexamethasone is administered in conjunction with the first dose (C1D1) and the second dose (C1D2) of grofitamab.

[0476] In one embodiment, 20 mg of dexamethasone is administered orally one day before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally one day after grofitamab administration.

[0477] In one embodiment, 20 mg of dexamethasone is administered orally approximately 24 hours before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally approximately 24 hours after grofitamab administration.

[0478] In one embodiment, the treatment does not cause grade 3 or higher CRS. In one embodiment, the incidence of cytokine release syndrome of any grade (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 40%. In one embodiment, the incidence of cytokine release syndrome of grade 3 or higher (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 1%. In one embodiment, the patient does not need to be hospitalized for the first two cycles of treatment with grofitamab.

[0479] In one embodiment, grofitamab for use in a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment of DLBCL is provided herein, the method comprising administering an effective dose to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Glofitamab is not included; grofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1), in which the patient receives dexamethasone one day before, on the same day as, and one day after the administration of grofitamab.

[0480] In one embodiment, dexamethasone is administered in a dose of 20 mg. In one embodiment, dexamethasone is administered approximately 24 hours before administration of grofitamab, approximately 30 to 90 minutes or approximately 60 minutes before administration of grofitamab, and approximately 24 hours after administration of grofitamab. In one embodiment, dexamethasone is administered in conjunction with the first dose (C1D1) and the second dose (C1D2) of grofitamab.

[0481] In one embodiment, 20 mg of dexamethasone is administered orally one day before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally one day after grofitamab administration.

[0482] In one embodiment, 20 mg of dexamethasone is administered orally approximately 24 hours before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally approximately 24 hours after grofitamab administration.

[0483] In one embodiment, the treatment does not cause grade 3 or higher CRS. In one embodiment, the incidence of cytokine release syndrome of any grade (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 40%. In one embodiment, the incidence of cytokine release syndrome of grade 3 or higher (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 1%. In one embodiment, the patient does not need to be hospitalized for the first two cycles of treatment with grofitamab.

[0484] In one embodiment, the present invention features grofitamab for use in a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising administering an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), along with gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2Including the dosage, (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1) and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 Including the dosage, Patients receive dexamethasone one day before grofitamab administration, on the same day as grofitamab administration, and one day after grofitamab administration.

[0485] In one embodiment, dexamethasone is administered in a dose of 20 mg. In one embodiment, dexamethasone is administered approximately 24 hours before administration of grofitamab, approximately 30 to 90 minutes or approximately 60 minutes before administration of grofitamab, and approximately 24 hours after administration of grofitamab. In one embodiment, dexamethasone is administered in conjunction with the first dose (C1D1) and the second dose (C1D2) of grofitamab.

[0486] In one embodiment, 20 mg of dexamethasone is administered orally one day before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally one day after grofitamab administration.

[0487] In one embodiment, 20 mg of dexamethasone is administered orally approximately 24 hours before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally approximately 24 hours after grofitamab administration.

[0488] In one embodiment, the treatment does not cause grade 3 or higher CRS. In one embodiment, the incidence of cytokine release syndrome of any grade (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 40%. In one embodiment, the incidence of cytokine release syndrome of grade 3 or higher (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 1%. In one embodiment, the patient does not need to be hospitalized for the first two cycles of treatment with grofitamab.

[0489] In one embodiment, a method is provided herein for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient requiring treatment of the DLBCL, the method comprising an effective dose to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, overall survival (OS) improved in multiple human patients compared to reference OS, where reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Glofitamab is not included; grofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first administration cycle consists of a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), along with gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2Including the dosage, (2) The second administration cycle consists of a single dose of 30 mg of grofitamab (C2D1) and gemcitabine 1000 mg / m². 2 The dosage and oxaliplatin 100 mg / m² 2 Including the dosage, Patients receive dexamethasone one day before grofitamab administration, on the same day as grofitamab administration, and one day after grofitamab administration.

[0490] In one embodiment, dexamethasone is administered in a dose of 20 mg. In one embodiment, dexamethasone is administered approximately 24 hours before administration of grofitamab, approximately 30 to 90 minutes or approximately 60 minutes before administration of grofitamab, and approximately 24 hours after administration of grofitamab. In one embodiment, dexamethasone is administered in conjunction with the first dose (C1D1) and the second dose (C1D2) of grofitamab.

[0491] In one embodiment, 20 mg of dexamethasone is administered orally one day before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally one day after grofitamab administration.

[0492] In one embodiment, 20 mg of dexamethasone is administered orally approximately 24 hours before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally approximately 24 hours after grofitamab administration.

[0493] In one embodiment, the treatment does not cause grade 3 or higher CRS. In one embodiment, the incidence of cytokine release syndrome of any grade (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 40%. In one embodiment, the incidence of cytokine release syndrome of grade 3 or higher (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 1%. In one embodiment, the patient does not need to be hospitalized for the first two cycles of treatment with grofitamab.

[0494] In one embodiment, the present invention features grofitamab for use in a method for treating relapsed or refractory DLBCL in human patients requiring treatment of relapsed or refractory DLBCL as described herein, the method comprising administering an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying this treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to reference PFS, where reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. Glofitamab and dexamethasone are administered in a regimen that includes at least a first and second administration cycle. (1) The first dose of 2.5 mg of grofitamab (C1D1) is administered on day 8 of the first treatment cycle, and the second dose of 10 mg of grofitamab (C1D2) is administered on day 15; (2) A single dose of 30 mg of grofitamab (C2D1) is administered on day 1 of the second administration cycle, and the patient is administered dexamethasone one day before, on the same day as, and one day after the administration of grofitamab.

[0495] In one embodiment, dexamethasone is administered in a dose of 20 mg. In one embodiment, dexamethasone is administered approximately 24 hours before administration of grofitamab, approximately 30 to 90 minutes or approximately 60 minutes before administration of grofitamab, and approximately 24 hours after administration of grofitamab. In one embodiment, dexamethasone is administered in conjunction with the first dose (C1D1) and the second dose (C1D2) of grofitamab.

[0496] In one embodiment, 20 mg of dexamethasone is administered orally one day before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally one day after grofitamab administration.

[0497] In one embodiment, 20 mg of dexamethasone is administered orally approximately 24 hours before grofitamab administration, 20 mg of dexamethasone is administered intravenously approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and 20 mg of dexamethasone is administered orally approximately 24 hours after grofitamab administration.

[0498] In one embodiment, the treatment does not cause grade 3 or higher CRS. In one embodiment, the incidence of cytokine release syndrome of any grade (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 40%. In one embodiment, ...

Claims

1. A method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein an effective amount is given to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying the aforementioned treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to the reference PFS, where the reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, A method that does not involve grofitamab.

2. The method according to claim 1, wherein the PFS or reference PFS is measured starting from the time of randomization and continuing until the first occurrence of disease progression or death from any cause.

3. The method according to claim 1 or 2, wherein the PFS or reference PFS is the median PFS of a plurality of human patients receiving the corresponding treatment.

4. The method according to any one of claims 1 to 3, wherein the improvement in PFS is statistically significant.

5. The method according to claim 3 or 4, wherein the improvement in the median PFS is an increase of 1 to 16 months in PFS compared to the reference PFS.

6. The method according to claim 5, wherein the improvement in the median PFS is an increase of approximately 9 months in PFS compared to the reference PFS.

7. The method according to claim 5, wherein the improvement in the median PFS is an increase of approximately 10 months in PFS compared to the reference PFS.

8. The method according to any one of claims 1 to 7, wherein, by applying the treatment to multiple human patients, PFS is statistically significantly improved compared to a control treatment, with a hazard ratio of approximately 0.42 (95% confidence interval: 0.29, 0.61).

9. The method according to any one of claims 1 to 7, wherein, by applying the treatment to multiple human patients, PFS is statistically significantly improved compared to a control treatment, with a hazard ratio of approximately 0.40 (95% confidence interval: 0.29, 0.61).

10. The method according to any one of claims 1 to 7, wherein, by applying the treatment to multiple human patients, PFS is statistically significantly improved compared to a control treatment, with a hazard ratio of approximately 0.41 (95% confidence interval: 0.29, 0.58).

11. The method according to claim 8 or 9, wherein the hazard ratio is a stratified hazard ratio.

12. The method according to any one of claims 1 to 11, wherein by applying the treatment to multiple human patients, the PFS rate increases by 5 to 45% compared to the reference PFS rate at 6 months.

13. The method according to claim 12, wherein by applying the treatment to multiple human patients, the PFS rate increases by approximately 25% compared to the reference PFS rate at 6 months.

14. The method according to any one of claims 1 to 13, wherein by applying the treatment to multiple human patients, the PFS rate increases by 5 to 45% compared to the reference PFS rate over 12 months.

15. The method according to claim 14, wherein by applying the treatment to multiple human patients, the PFS rate increases by approximately 25% compared to the reference PFS rate over 12 months.

16. The method according to any one of claims 1 to 15, wherein by applying the treatment to multiple human patients, the complete response rate (CR rate), objective response rate (ORR), duration of objective response, and / or duration of CR (DOCR) are improved compared to a control treatment.

17. The method according to claim 16, wherein the CR rate is the percentage of patients whose best overall response is CR in PET / computed tomography (CT).

18. The method according to claim 16 or 17, wherein the improvement in the CR rate is 15% to 50%.

19. The method according to claim 18, wherein the improvement in the CR rate is an increase of approximately 30%.

20. The method according to claim 18, wherein the improvement in the CR rate is an increase of approximately 33%.

21. The method according to claim 16, wherein ORR is the percentage of patients whose best overall response is a partial response (PR) or complete response (CR).

22. The method according to claim 16, wherein the duration of objective response is measured as the time from the first occurrence of a recorded objective response (CR or PR) to disease progression or death from any cause, whichever comes first.

23. The method according to claim 16, wherein DOCR is measured as the time from the first recorded occurrence of CR to disease progression or death from any cause, whichever comes first.

24. A method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein an effective amount is given to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying the aforementioned treatment to multiple human patients, the overall survival (OS) of multiple human patients improved compared to the reference OS, where the reference OS is the OS of multiple human patients who received the control treatment, and the control treatment is: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, A method that does not involve grofitamab.

25. The method according to claim 24, wherein OS or reference OS is measured starting from the time of randomization until death from any cause.

26. The method according to claim 24 or 25, wherein OS or reference OS is the median OS of a plurality of human patients receiving the corresponding treatment.

27. The method according to any one of claims 24 to 26, wherein the improvement in OS is statistically significant.

28. The method according to claim 26 or 27, wherein the improvement in median OS is an increase of 1 to 30 months in OS compared to a reference OS.

29. The method according to claim 28, wherein the improvement in the median OS is an increase of approximately 13 months in OS compared to the reference OS.

30. The method according to any one of claims 24 to 29, wherein, by applying the treatment to multiple human patients, overall survival (OS) is statistically significantly improved compared to a control treatment, with a hazard ratio of approximately 0.62 (95% confidence interval: 0.43, 0.88).

31. The method according to any one of claims 24 to 29, wherein, by applying the treatment to multiple human patients, overall survival (OS) is statistically significantly improved compared to a control treatment, with a hazard ratio of approximately 0.60 (95% confidence interval: 0.42, 0.85).

32. The method according to claim 30, wherein the hazard ratio is a stratified hazard ratio.

33. The method according to any one of claims 24 to 32, wherein by applying the treatment to multiple human patients, the OS rate increases by 5% to 30% compared to the reference OS rate over 12 months.

34. The method according to claim 33, wherein by applying the treatment to multiple human patients, the OS rate increases by approximately 10% compared to the reference OS rate over 12 months.

35. The method according to any one of claims 24 to 34, wherein by applying the treatment to multiple human patients, the OS rate increases by 5% to 35% compared to the reference OS rate at 18 months.

36. The method according to claim 35, wherein by applying the treatment to multiple human patients, the OS rate increases by approximately 20% compared to the reference OS rate at 18 months.

37. The method according to any one of claims 24 to 36, wherein by applying the treatment to multiple human patients, the OS rate increases by 5% to 40% compared to the reference OS rate at 24 months.

38. The method according to claim 37, wherein by applying the treatment to multiple human patients, the OS rate increases by approximately 20% compared to the reference OS rate at 24 months.

39. The method according to claim 11 or 32, wherein the stratified hazard ratio is stratified by: (a) the number of prior lines of systemic therapy for DLBCL (1 vs. ≥2); and / or (b) the outcome of the last systemic therapy (relapsed vs. refractory).

40. A method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein an effective amount is given to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, A method by which complete remission can be achieved in a patient by applying the aforementioned treatment.

41. A method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein an effective amount is given to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, A method for obtaining a median duration of complete remission of at least 27 months in multiple human patients by applying the aforementioned treatment to multiple human patients.

42. A method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein an effective amount is given to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, A method wherein, by applying the aforementioned treatment to a patient, the patient achieves complete remission, and multiple human patients who receive the aforementioned treatment and exhibit complete remission at the end of treatment show an overall survival rate of approximately 89% at 12 months.

43. A method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein an effective amount is given to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, A method wherein, by applying the aforementioned treatment to a patient, the patient achieves complete remission, and multiple human patients who receive the aforementioned treatment and exhibit complete remission at the end of treatment show a progression-free survival rate of approximately 82% at 12 months.

44. The treatment includes the first and second administration cycles, The first administration cycle consists of a first dose of approximately 2.5 mg of grofitamab (C1D1) and a second dose of approximately 10 mg of grofitamab (C1D2). The second administration cycle includes a single dose of approximately 30 mg of grofitamab (C2D1). The method according to any one of claims 1 to 43.

45. The method according to claim 44, wherein grofitamab C1D1 and C1D2 are administered to the patient on day 8 and day 15 of the first administration cycle, respectively.

46. The method according to claim 44 or 45, wherein grofitamab C2D1 is administered to the patient on day 1 of the second administration cycle.

47. The method according to any one of claims 44 to 46, wherein the first administration cycle comprises a dose of obinutuzumab 1000 mg.

48. The method according to claim 47, wherein obinutuzumab is administered about seven days before the first dose of grofitamab.

49. The method according to claim 47 or 48, wherein obinutuzumab is administered on day 1 of the first administration cycle.

50. The first and second administration cycles consist of gemcitabine 1000 mg / m². ２ The dosage and oxaliplatin 100 mg / m² ２ The method according to any one of claims 44 to 49, comprising the dose of the following:

51. The method according to claim 50, wherein gemcitabine and oxaliplatin are administered on the second day of the first administration cycle.

52. The method according to claim 50 or 51, wherein gemcitabine and oxaliplatin are administered on day 1 or day 2 of the second administration cycle.

53. The method according to any one of claims 50 to 52, wherein gemcitabine is administered on the same day before oxaliplatin.

54. The method according to any one of claims 44 to 53, wherein the first and second administration cycles are each 21-day administration cycles.

55. The method according to any one of claims 1 to 54, comprising 12 administration cycles.

56. The method according to claim 55, wherein each administration cycle is a 21-day administration cycle.

57. The patient is administered an effective dose of obinutuzumab, grofitamab, gemcitabine, and oxaliplatin in cycle 1. The patient is administered effective doses of grofitamab, gemcitabine, and oxaliplatin for 2 to 8 cycles of administration; and The patient receives an effective dose of grofitamab for 9 to 12 cycles of administration. The method according to claim 55 or 56, including the method described in claim 55 or 56.

58. Obinutuzumab was administered at a dose of 1000 mg on day 1 of the first treatment cycle; Glofitamab was administered at a dose of 2.5 mg on day 8 and 10 mg on day 15 of treatment cycle 1; and at a dose of 30 mg on day 1 of treatment cycles 2 through 12; Gemcitabine is administered at a dose of 1000 mg / m² on day 2 of treatment cycle 1 and on day 1 or 2 of treatment cycles 2 through 8. ２ It is administered at a dose of 100 mg / m² of oxaliplatin. ２ It is administered in the following dose: The method according to claim 57.

59. The method according to claim 57 or 58, wherein gemcitabine is administered on the same day before oxaliplatin.

60. The method according to any one of claims 1 to 59, wherein DLBCL is an unspecified DLBCL (DLBCL NOS).

61. The method according to any one of claims 1 to 59, wherein the patient is not a candidate for hematopoietic stem cell transplantation (HSCT).

62. The method according to any one of claims 1 to 61, wherein the patient has relapsed or refractory DLBCL NOS and is not a candidate for HSCT.

63. Glofitamab for use in a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein the method provides an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying the aforementioned treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to the reference PFS, where the reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Contains no grofitamab. Glofitamab.

64. Glofitamab for use in a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein the method provides an effective amount to a human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying the aforementioned treatment to multiple human patients, the overall survival (OS) of multiple human patients improved compared to the reference OS, where the reference OS is the OS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Contains no grofitamab. Glofitamab.

65. The use of grofitamab in the manufacture of a pharmaceutical product for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein the treatment is administered to a human patient in an effective dose: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying the aforementioned treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to the reference PFS, where the reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Contains no grofitamab. Use of grofitamab.

66. The use of grofitamab in the manufacture of a pharmaceutical product for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein the treatment is administered to a human patient in an effective dose: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying the aforementioned treatment to multiple human patients, the overall survival (OS) of multiple human patients improved compared to the reference OS, where the reference OS is the OS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, Contains no grofitamab. Use of grofitamab.

67. A method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein an effective amount is given to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, The patient has relapsed after one prior treatment line, or is refractory to one prior treatment line, and is not a candidate for HSCT, and the patient: (a) Having a left ventricular ejection fraction of ≤ 40%, (b) Having a creatinine clearance or glomerular filtration rate of ≤ 45 mL / min, (c) Having an East Coast Cancer Clinical Trials Group (ECOG) performance status of ≥ 2, (d) Being 70 years of age or older, (e) has refused high-dose chemotherapy and / or transplantation, and / or (f) Insufficient response to pre-transplant chemotherapy, making it impossible to proceed with transplantation. method.

68. A method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein an effective amount is given to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying the aforementioned treatment to multiple human patients, progression-free survival (PFS) was improved in multiple human patients compared to the reference PFS, where the reference PFS is the PFS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. DLBCL is unspecified DLBCL (DLBCL NOS), and the patient is not a candidate for hematopoietic stem cell transplantation (HSCT).

69. A method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in human patients requiring treatment for DLBCL, wherein an effective amount is given to the human patient: (a) Grofitamab, (b) gemcitabine, and (c) Oxaliplatin This includes administering, By applying the aforementioned treatment to multiple human patients, the overall survival (OS) of multiple human patients improved compared to the reference OS, where the reference OS is the OS of multiple human patients who received the control treatment, and the control treatment was: (a) Rituximab, (b) gemcitabine, and (c) Oxaliplatin Includes, It does not contain grofitamab. DLBCL is unspecified DLBCL (DLBCL NOS), and the patient is not a candidate for hematopoietic stem cell transplantation (HSCT).

70. The method according to claim 49, wherein obinutuzumab is administered as a single dose of 1000 mg.

71. The method according to any one of claims 1 to 62 and 67 to 70, wherein the patient receives corticosteroid prophylaxis before and after administration of grofitamab.

72. The method according to claim 71, wherein the corticosteroid prophylaxis comprises prednisolone, methylprednisolone, and / or dexamethasone.

73. The method according to claim 71 or 72, wherein the corticosteroid prophylaxis comprises dexamethasone.

74. The method according to claim 73, wherein the corticosteroid prophylaxis comprises 20 mg of dexamethasone.

75. The method according to any one of claims 71 to 74, wherein corticosteroid prophylaxis is performed one day before administration of grofitamab.

76. The method according to any one of claims 71 to 74, wherein corticosteroid prophylaxis is performed approximately 24 hours before administration of grofitamab.

77. The method according to any one of claims 71 to 76, wherein corticosteroid prophylaxis is performed on the same day as the administration of grofitamab.

78. The method according to claim 77, wherein corticosteroid prophylaxis is performed approximately 30 to 90 minutes or approximately 60 minutes before administration of grofitamab.

79. The method according to any one of claims 71 to 78, wherein corticosteroid prophylaxis is performed one day after administration of grofitamab.

80. The method according to any one of claims 71 to 79, wherein corticosteroid prophylaxis is performed approximately 24 hours after administration of grofitamab.

81. The method according to any one of claims 71 to 80, wherein corticosteroid prophylaxis is performed prior to the first dose (C1D1) of grofitamab.

82. The method according to any one of claims 71 to 81, wherein corticosteroid prophylaxis is performed prior to the second dose (C1D2) of grofitamab.

83. The method according to any one of claims 71 to 82, wherein corticosteroid prophylaxis is performed one day before administration of grofitamab, before administration of grofitamab on the same day, and one day after administration of grofitamab.

84. The method according to claim 83, wherein corticosteroid prophylaxis is performed approximately 24 hours before grofitamab administration, approximately 30 to 90 minutes or approximately 60 minutes before grofitamab administration, and approximately 24 hours after grofitamab administration.

85. The method according to claim 84, wherein the corticosteroid prophylaxis is dexamethasone.

86. The method according to claim 85, wherein dexamethasone is administered in a dose of 20 mg.

87. The method according to any one of claims 71 to 86, wherein 20 mg of dexamethasone is administered orally one day before administration of grofitamab, 20 mg of dexamethasone is administered intravenously about 30 to 90 minutes or about 60 minutes before administration of grofitamab, and 20 mg of dexamethasone is administered orally one day after administration of grofitamab.

88. The method according to claim 87, wherein 20 mg of dexamethasone is administered orally about 24 hours before administration of grofitamab, 20 mg of dexamethasone is administered intravenously about 30 to 90 minutes or about 60 minutes before administration of grofitamab, and 20 mg of dexamethasone is administered orally about 24 hours after administration of grofitamab.

89. The method according to any one of claims 71 to 88, wherein corticosteroid prophylaxis is performed prior to the third dose (C2D1) of grofitamab.

90. The method according to claim 89, wherein if the patient has experienced CRS with any previous 30 mg dose of grofitamab, corticosteroid prophylaxis is administered before any subsequent dose of grofitamab.

91. The method according to claim 89 or 90, wherein the corticosteroid prophylaxis comprises 20 mg of dexamethasone.

92. The method according to any one of claims 71 to 91, wherein the incidence of CRS in multiple patients is reduced by corticosteroid prophylaxis compared to treatment consisting of grofitamab administration and one dose of corticosteroid on the same day.

93. The method according to claim 92, wherein the patient does not have a Grade 3 CRS event.

94. The method according to any one of claims 71 to 91, wherein the patient does not need to be hospitalized after treatment with grofitamab.

95. A method for reducing the incidence of CRS events in a patient population treated with grofitamab, comprising administering grofitamab and dexamethasone to patients in the patient population in a dosing regimen comprising at least a first and a second dosing cycle: (1) The first administration cycle includes a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle includes a single dose of 30 mg of grofitamab (C2D1), and dexamethasone is administered one day before the administration of grofitamab, on the day of the administration of grofitamab, and one day after the administration of grofitamab. method.

96. A method for reducing the likelihood of CRS events in patients with CD20-positive B-cell proliferative disorders treated with grofitamab, comprising administering grofitamab and dexamethasone to the patient in a dosing regimen comprising at least a first and a second dosing cycle: (1) The first administration cycle includes a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle includes a single dose of 30 mg of grofitamab (C2D1), and dexamethasone is administered one day before the administration of grofitamab, on the day of the administration of grofitamab, and one day after the administration of grofitamab. method.

97. The method according to claim 95 or 96, wherein dexamethasone is administered in a dose of 20 mg.

98. The method according to any one of claims 95 to 97, wherein dexamethasone is administered about 24 hours before administration of grofitamab, about 30 to 90 minutes or about 60 minutes before administration of grofitamab, and about 24 hours after administration of grofitamab.

99. The method according to any one of claims 95 to 98, wherein dexamethasone is administered in addition to a first dose (C1D1) and a second dose (C1D2) of grofitamab.

100. The method according to any one of claims 95 to 99, wherein 20 mg of dexamethasone is administered orally one day before administration of grofitamab, 20 mg of dexamethasone is administered intravenously about 30 to 90 minutes or about 60 minutes before administration of grofitamab, and 20 mg of dexamethasone is administered orally one day after administration of grofitamab.

101. The method according to any one of claims 95 to 100, wherein 20 mg of dexamethasone is administered orally about 24 hours before administration of grofitamab, 20 mg of dexamethasone is administered intravenously about 30 to 90 minutes or about 60 minutes before administration of grofitamab, and 20 mg of dexamethasone is administered orally about 24 hours after administration of grofitamab.

102. The method according to any one of claims 95 to 101, wherein if the patient experiences CRS with a first and / or second dose of grofitamab, dexamethasone is administered in addition to a third dose (C2D1) of grofitamab.

103. The method according to claim 102, wherein if the patient has experienced CRS with any previous 30 mg dose of grofitamab, dexamethasone is administered before any subsequent dose of grofitamab.

104. The method according to any one of claims 95 to 103, wherein dexamethasone is administered with the first and second doses (C2D1) of grofitamab, but not with any subsequent doses.

105. The method according to any one of claims 95 to 104, wherein the treatment does not cause grade 3 or higher CRS.

106. The method according to any one of claims 95 to 105, wherein the incidence of cytokine release syndrome of any grade (as defined by the American Society for Translation and Cellular Therapy, 2019; ASTCT) is less than 40%.

107. The method according to any one of claims 95 to 106, wherein the incidence of cytokine release syndrome of grade 3 or higher (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than 1%.

108. The method according to any one of claims 95 to 107, wherein the patient does not need to be hospitalized for the first two cycles of treatment with grofitamab.

109. The method according to any one of claims 95 to 108, further comprising administering gemcitabine and oxaliplatin.

110. Glofitamab for use according to claim 63 or 64, wherein the patient receives corticosteroid prophylaxis before and after administration of grofitamab.

111. Dexamethasone for use in a method to reduce the incidence of CRS events in a patient population treated with grofitamab, wherein patients in the patient population are administered grofitamab and dexamethasone in a dosing regimen comprising at least a first and a second dosing cycle: (1) The first administration cycle includes a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle includes a single dose of 30 mg of grofitamab (C2D1), and dexamethasone is administered one day before the administration of grofitamab, on the day of the administration of grofitamab, and one day after the administration of grofitamab. Dexamethasone.

112. Dexamethasone for use in a method to reduce the likelihood of CRS events in patients with CD20-positive B-cell proliferative disorders treated with grofitamab, wherein the patient is administered grofitamab and dexamethasone in a dosing regimen comprising at least a first and a second dosing cycle: (1) The first administration cycle includes a first dose of 2.5 mg of grofitamab (C1D1) and a second dose of 10 mg of grofitamab (C1D2), (2) The second administration cycle includes a single dose of 30 mg of grofitamab (C2D1), and dexamethasone is administered one day before the administration of grofitamab, on the day of the administration of grofitamab, and one day after the administration of grofitamab. Dexamethasone.

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