Methods for treating previously untreated follicular lymphoma using mosumotuzumab and lenalidomide

Abstract

The present invention relates to the treatment of subjects suffering from previously untreated follicular lymphoma (FL). More specifically, the present invention relates to the treatment of subjects suffering from previously untreated FL by administering a combination of mosumotuzumab and lenalidomide.

Description

[0001] Sequence Listing

[0002] This application contains a sequence listing, which has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy was created on June 2, 2023, named 50474-298WO2_Sequence_Listing_6_2_23, and is 34,004 bytes in size. Technical Field

[0003] The present invention relates to treating a subject with previously untreated follicular lymphoma (FL). More specifically, the present invention relates to the combined treatment of a subject with previously untreated FL by administering mosulatuzumab and lenalidomide. Background Art

[0004] Cancer is characterized by the uncontrolled growth of a subpopulation of cells. Cancer is the leading cause of death in developed countries and the second leading cause of death in developing countries, with more than 14 million new cancer cases diagnosed and more than eight million cancer deaths each year. Indolent cancers can also severely affect quality of life. Cancer care therefore represents a significant and growing societal burden.

[0005] B-cell proliferative disorders are the leading cause of cancer-related deaths. For example, non-Hodgkin's lymphoma (NHL) progresses rapidly and is fatal if left untreated. In the context of non-Hodgkin's lymphoma (NHL), lymphomas of B-cell origin constitute a group of different tumors. Follicular lymphoma (FL) is the most common indolent NHL subtype (Al-Hamandi et al. 2015). There is no standard treatment for the initial management of FL, and questions about the best anti-CD20 monoclonal antibody, the best chemotherapy-based regimen, and additional maintenance therapy remain unclear. Despite the encouraging response to currently available immunotherapy-based first-line therapies, most patients will eventually relapse. Relapse is characterized by increased refractoryness, and several important needs remain unmet, therapies are not yet curative, and most patients will experience progression of the disease. Therefore, novel therapies are needed to increase anti-tumor activity and prolong the remission time of patients with previously untreated FL. Summary of the invention

[0006] The present invention relates to methods of treating subjects with previously untreated follicular lymphoma (FL) by administering mosulatuzumab and lenalidomide as a combination therapy. Specifically, the present invention relates to methods of treating subjects with previously untreated FL by subcutaneous administration of mosulatuzumab and oral administration of lenalidomide.

[0007] In one aspect, the invention features a method of treating a subject having previously untreated follicular lymphoma (FL), the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and a second 28-day (±1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 (±1 day), and day 15 (±1 day) of the first dosing cycle, respectively, wherein C1D1 is about 5 mg (e.g., 5 The amount of C1D2 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), and the amount of C1D2 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg). 3 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg) g, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, e.g., 45 mg), and (c) the second dosing cycle further comprises oral administration of about 5 mg to about 20 mg (e.g., about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, or about 5 mg to about 15 mg, e.g., about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg) of lenalidomide daily on days 1 to 21 of the second dosing cycle. In some embodiments, the first dosing cycle is a three-dose dosing cycle (i.e., comprising three doses of mosulimab).

[0008] In some embodiments, the dosing regimen includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) additional dosing cycles. In some embodiments, the dosing regimen includes one to ten (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) additional dosing cycles. In some aspects, the dosing regimen includes ten additional dosing cycles. In some embodiments, each of the one or more additional dosing cycles is about 28 days (± 1 day) in length.

[0009] In some embodiments, each of the one or more additional dosing cycles includes an additional single dose of mosulatuzumab. In some embodiments, the method includes administering each additional single dose of mosulatuzumab subcutaneously to the subject on day 1 of each of the one or more additional dosing cycles. In some embodiments, the additional single dose of mosulatuzumab is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg, or ± 9 mg, e.g., 45 mg). In some embodiments, each additional single dose of mosulatuzumab is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg, or ± 9 mg, e.g., 45 mg).

[0010] In some embodiments, lenalidomide is not administered during the first dosing cycle. In some embodiments, lenalidomide is orally administered during any one of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) additional dosing cycles. In some embodiments, lenalidomide is orally administered during each of ten additional dosing cycles. In some embodiments, lenalidomide is orally administered on the 1st to 21st day of each of the additional dosing cycles including the administration of lenalidomide. In some embodiments, lenalidomide is not administered in the last 7 days (± 1 day) of any dosing cycle including the administration of lenalidomide. In some embodiments, lenalidomide is administered at a dosage of about 10 mg (e.g., 10 mg ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg or ± 2 mg, such as 10 mg). In some embodiments, lenalidomide is administered at a dose of about 20 mg (e.g., 20 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg or ± 4 mg, e.g., 20 mg).

[0011] In one aspect, the invention features a method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and a second 28-day (±1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 (±1 day), and day 15 (±1 day) of the first dosing cycle, respectively, wherein C1D1 is about 5 mg (e.g., 5 mg±0 .01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg or ±1 mg, for example, 5 mg), C1D2 is about 45 mg (for example, 45 mg ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, for example, 45 mg), and C1D 3 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, e.g., 45 mg), and (c) the second dosing cycle further comprises oral administration of about 10 mg (e.g., 10 mg ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ±1 mg or ±2 mg, e.g., 10 mg) of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0012] In one aspect, the invention features a method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and a second 28-day (±1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 (±1 day), and day 15 (±1 day) of the first dosing cycle, respectively, wherein C1D1 is about 5 mg (e.g., 5 mg±0 .01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg or ±1 mg, for example, 5 mg), C1D2 is about 45 mg (for example, 45 mg ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, for example, 45 mg), and C1D 3 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, e.g., 45 mg), and (c) the second dosing cycle further comprises oral administration of about 20 mg (e.g., 20 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg or ±4 mg, e.g., 20 mg) of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0013] In one aspect, the invention features a method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and eleven subsequent 28-day (±1 day) dosing cycles, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 (±1 day), and day 15 (±1 day) of the first dosing cycle, respectively, wherein C1D1 is about 5 mg (e.g., 5 mg±0.01 The invention relates to a pharmaceutical composition comprising: ... , 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab administered subcutaneously on day 1 of each dosing cycle, wherein C2D1 to C12D1 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg , ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, for example, 45 mg), and (c) the second to twelfth dosing cycles further comprise oral administration of about 10 mg (e.g., 10 mg ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ±1 mg or ±2 mg, for example 10 mg) of lenalidomide per day on days 1 to 21 of each dosing cycle.

[0014] In one aspect, the invention features a method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and eleven subsequent 28-day (±1 day) dosing cycles, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 (±1 day), and day 15 (±1 day) of the first dosing cycle, respectively, wherein C1D1 is about 5 mg (e.g., 5 mg±0.01 m g, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg or ±1 mg, e.g., 5 mg), C1D2 is about 45 mg (e.g., 45 mg ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, e.g., 45 mg), and C1D3 is about 45 mg (e.g., 45 (a) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), The invention relates to a method for orally administering lenalidomide of at least 20 mg, for example, 45 mg, ±0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, for example, 45 mg), and (c) the second to twelfth dosing cycles further comprise oral administration of about 20 mg (e.g., 20 mg ±0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg or ±4 mg, for example, 20 mg) of lenalidomide per day on days 1 to 21 of each dosing cycle.

[0015] In some embodiments, the FL is histologically documented as grade 1, 2, or 3a, but not grade 3b, according to the World Health Organization classification of lymphoid neoplasms (as cited in Swerdlow SH et al. Blood 2016; 127: 2375-90).

[0016] In some embodiments, the subject has been previously determined to require systemic therapy for treatment of the previously untreated FL based on the Follicular Lymphoma Group (GELF) criteria (Brice et al. J Clin Oncol. 15(3): 1110-1117, 1997).

[0017] In certain embodiments, the first dosing cycle further includes the use of corticosteroids.In certain embodiments, the second dosing cycle further includes the use of corticosteroids.In certain embodiments, any one of one or more additional dosing cycles includes the use of corticosteroids.In certain embodiments, a single dose of corticosteroids is applied to the subject before the use of any dose of mosunetuzumab.In certain embodiments, corticosteroids include dexamethasone or methylprednisolone.In certain embodiments, corticosteroids are administered intravenously or orally.In certain embodiments, corticosteroids include dexamethasone and are administered at a dosage of about 20mg (e.g., 20mg ± 0.05mg, ± 0.1mg, ± 0.2mg, ± 0.3mg, ± 0.4mg, ± 0.5mg, ± 0.75mg, ± 1mg, ± 1.5mg, ± 2mg, ± 3mg or ± 4mg, e.g., 20mg). In some embodiments, the corticosteroid comprises methylprednisolone and is administered at a dose of about 80 mg (e.g., 80 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg, ± 10 mg, ± 12 mg, ± 14 mg, or ± 16 mg, e.g., 80 mg).

[0018] In some embodiments, the first dosing cycle further includes the use of antihistamines. In some embodiments, the second dosing cycle further includes the use of antihistamines. In some embodiments, any one of one or more additional dosing cycles includes the use of antihistamines. In some embodiments, before the use of any dose of mosunetuzumab (e.g., 30, 35, 40, 45, 50, 60, 70, 80, 90, 120, 150, 180 minutes or longer), a single dose of antihistamines is administered to the subject. In some embodiments, before the use of any dose of mosunetuzumab (e.g., 30, 35, 40, 45, 50, 60, 70, 80, 90, 120, 150, 180 minutes or longer), antihistamines are administered to the subject. In some embodiments, antihistamines are administered orally or intravenously. In some embodiments, the antihistamine comprises diphenhydramine hydrochloride and is administered at a dose of about 50 to 100 mg (e.g., 50 to 90 mg, 50 to 80 mg, 50 to 70 mg, 50 to 60 mg, 60 to 100 mg, 70 to 100 mg, 80 to 100 mg, 90 to 100 mg, 70 to 80 mg, 60 to 90 mg, 60 to 80 mg, 70 to 90 mg, or 65 to 85 mg, such as about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg).

[0019] In some embodiments, the first dosing cycle further includes the use of an antipyretic. In some embodiments, the second dosing cycle further includes the use of an antipyretic. In some embodiments, any one of one or more additional dosing cycles includes the use of an antipyretic. In some embodiments, a single dose of an antipyretic is administered to a subject before the administration of any dose of mosunetuzumab. In some embodiments, an antipyretic is administered to a subject at least 30 minutes (e.g., 30, 35, 40, 45, 50, 60, 70, 80, 90, 120, 150, 180 minutes or longer) before the administration of any dose of mosunetuzumab. In some embodiments, an antipyretic is administered orally. In some embodiments, the antipyretic comprises acetaminophen and is administered at a dose of about 500 to 1000 mg (e.g., 500 to 900 mg, 500 to 800 mg, 500 to 700 mg, 500 to 600 mg, 600 to 1000 mg, 700 to 1000 mg, 800 to 1000 mg, 900 to 1000 mg, 700 to 800 mg, 600 to 900 mg, 600 to 800 mg, 700 to 900 mg, or 650 to 850 mg, e.g., about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg).

[0020] In some embodiments, the first dosing cycle further includes the administration of a pre-dose of a preventive agent for tumor lysis syndrome (TLS). In some embodiments, the second dosing cycle further includes the administration of a pre-dose of a preventive agent for TLS. In some embodiments, any one of one or more additional dosing cycles includes the administration of a pre-dose of a preventive agent for TLS. In some embodiments, a pre-dose of a preventive agent for TLS is administered to a subject before the administration of any dose of mosunetuzumab. In some embodiments, the preventive agent for TLS includes allopurinol. In some embodiments, a pre-dose of allopurinol is administered about 72 hours (e.g., 72 ± 0.5 hours, ± 1 hours, ± 2 hours, ± 3 hours, ± 4 hours, ± 8 hours, ± 12 hours or ± 16 hours, e.g., 72 hours) before the administration of any dose of mosunetuzumab. In some embodiments, an additional single dose of allopurinol is administered every day after the administration of the pre-dose for 6 to 10 days (± 1 day). In some embodiments, the initial dose of allopurinol is about 300 mg (e.g., 300 mg ± 5 mg, ± 10 mg, ± 15 mg, ± 20 mg, ± 25 mg, ± 30 mg, ± 45 mg, or ± 60 mg, e.g., 300 mg). In some embodiments, each additional single dose of allopurinol is about 300 mg (e.g., 300 mg ± 5 mg, ± 10 mg, ± 15 mg, ± 20 mg, ± 25 mg, ± 30 mg, ± 45 mg, or ± 60 mg, e.g., 300 mg). In some embodiments, allopurinol is administered orally. In some embodiments, the preventive agent for TLS includes rasburicase. In some embodiments, the initial dose of rasburicase is administered about 30 minutes (e.g., 30 ± 0.5 minutes, 1 minute, ± 2 minutes, ± 3 minutes, ± 4 minutes, ± 5 minutes, or ± 6 minutes, e.g., 30 minutes) prior to the administration of any dose of mosunetuzumab. In some embodiments, an additional single dose of rasburicase is administered daily for 1 to 5 days (±1 day) after administration of the initial dose. In some embodiments, the initial dose of rasburicase is about 0.2 mg / kg (e.g., 0.2±0.005 mg / kg, ±0.01 mg / kg, ±0.02 mg / kg, ±0.03 mg / kg, or ±0.04 mg / kg, e.g., 0.2 mg / kg). In some embodiments, each additional single dose of rasburicase is about 0.2 mg / kg (e.g., 0.2±0.005 mg / kg, ±0.01 mg / kg, ±0.02 mg / kg, ±0.03 mg / kg, or ±0.04 mg / kg, e.g., 0.2 mg / kg). In some embodiments, rasburicase is administered intravenously. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1is a schematic diagram of the study design for the dosing regimen for the combination therapy of mosulatuzumab and lenalidomide described in Example 1. Mosulatuzumab is administered subcutaneously via injection, and lenalidomide is administered orally. Len = lenalidomide; Cycle = dosing cycle. DETAILED DESCRIPTION

[0022] The present invention relates to a method for treating a subject with previously untreated follicular lymphoma (FL) by administering mosunetuzumab and lenalidomide as a combination therapy. The method described herein includes subcutaneously administering mosunetuzumab to a subject and orally administering lenalidomide according to a dosing regimen, the dosing regimen including at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle includes a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab, (b) the second dosing cycle includes a first dose (C2D1) of mosunetuzumab and a daily dose of lenalidomide. Specifically, the first dosing cycle is a 21-day (±1 day) dosing cycle, and C1D1, C1D2 and C1D3 doses are administered at or about the 1st day, the 8th day (±1 day) and the 15th day (±1 day), respectively, and the second dosing cycle is a 28-day (±1 day) dosing cycle, and C2D1 is administered on the 1st day. In addition, lenalidomide is administered on days 1 to 21 of the second dosing cycle. The methods of the present invention also additionally include administration of additional therapeutic agents, such as premedication (e.g., with corticosteroids, antihistamines, antipyretics, or prophylactic agents for tumor lysis syndrome (TLS)).

[0023] I. General Technology

[0024] Those skilled in the art generally readily understand and routinely use routine methods using the techniques and procedures described or referenced herein, such as, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd Edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (FM Ausubel et al., eds., (2003)); Methods in Enzymology series (Academic Press, Inc.): PCR 2: A Practical Approach (MJ MacPherson, BD Hames and GR Taylor, eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (RI Freshney, ed. (1987)); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Manual, ed. (2003 ... Molecular Biology, Humana Press; Cell Biology: A Laboratory Manual, ed. (2003); Methods in Enzymology series (Academic Press, Inc.): PCR 2: A Practical Approach (MJ MacPherson, BD Hames and GR Taylor, eds. (1995)), Notebook (JE Cellis, ed., 1998) Academic Press; Animal Cell Culture (RI Freshney, ed., 1987); Introduction to Cell and Tissue Culture (JPMather and PE Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, JB Griffiths, and DG Newell, ed., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (DM Weir and CC Blackwell, ed.); Gene Transfer Vectors for Mammalian Cells (JMMiller and MPCalos, ed., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., ed., 1994); Current Protocols in Immunology (J. E. Coligan et al., ed., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty, ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, ed., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 2001); The widely used methods described in The Antibodies (M. Zanetti and JD Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (VT DeVita et al., eds., JB Lippincott Company, 1993).

[0025] II. Definitions

[0026] It should be understood that aspects and embodiments of the invention described herein include aspects and embodiments referred to as "comprising," "consisting of," and "consisting essentially of."

[0027] As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated.

[0028] As used herein, the term "about" refers to the common error range of the corresponding value that is readily known to those skilled in the art. References to "about" values ​​or parameters herein include (and describe) embodiments involving the value or parameter itself. In some embodiments, the term "about" value or parameter refers to the value or parameter ± 10%.

[0029] A "disorder" is any condition that would benefit from treatment, including, but not limited to, chronic and acute disorders or diseases, including those pathological conditions which predispose a mammal to the disorder.

[0030] The terms "cell proliferative disorder" and "proliferative disorder" refer to a disorder associated with some degree of abnormal cell proliferation. In one embodiment, the cell proliferative disorder is cancer. In another embodiment, the cell proliferative disorder is a tumor.

[0031] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, blood cancers, such as mature B-cell cancers, excluding Hodgkin's lymphoma, but including non-Hodgkin's lymphoma (NHL), such as diffuse large B-cell lymphoma (DLBCL), which may be Richter's transformation. Other specific examples of cancer also include germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL), activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), transformed FL, mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), transformed MZL, high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (P MLBCL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), transformed LL, Waldenstrom's macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), precursor B-cell lymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia (unclassifiable), splenic diffuse red pulp small B-cell lymphoma, variant hairy cell leukemia, heavy chain disease (alpha heavy chain disease, gamma heavy chain disease disease, μ heavy chain disease), plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), lymph node marginal zone lymphoma, pediatric lymph node marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, T cell / histiocyte-rich large B cell lymphoma, primary DLBCL of the CNS, primary cutaneous DLBCL (leg type), EBV-positive DLBCL in the elderly, and chronic DLBCL associated with inflammatory bowel disease, lymphomatoid granuloma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma caused by HHV8-associated multicentric Castleman disease, primary effusion lymphoma: B-cell lymphoma (unclassifiable, with features intermediate between DLBCL and Burkitt's lymphoma), and B-cell lymphoma (unclassifiable, with features intermediate between DLBCL and classical Hodgkin's lymphoma). Other examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies, including B-cell lymphoma.More particular examples of such cancers include, but are not limited to, multiple myeloma (MM); low-grade / follicular NHL; small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-lytic cell NHL; bulky NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myeloid leukemia; and post-transplant lymphoproliferative disorder (PTLD).

[0032] As used herein, the term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive herein.

[0033] The term "B cell proliferative disorder" or "B cell malignancy" refers to a disorder associated with some degree of abnormal B cell proliferation, and includes, for example, lymphoma, leukemia, myeloma, and myelodysplastic syndrome. In some cases, the B cell proliferative disorder is a lymphoma, such as non-Hodgkin's lymphoma (NHL), including, for example, follicular lymphoma (FL) (e.g., previously untreated FL). In a specific embodiment, the subject has been determined to have previously untreated FL based on the Follicular Lymphoma Study Group (GELF) criteria (Brice et al., J Clin Oncol. 15(3): 1110-1117, 1997) to require systemic therapy to treat the previously untreated FL.

[0034] The terms "Follicular Lymphoma Study Group Criteria" and "GELF Criteria" refer to criteria used to determine whether immediate therapy for follicular lymphoma is needed. Specifically, a subject or individual who meets one or more GELF criteria is determined to be in need of treatment. GELF criteria include (i) any nodal or extranodal tumor mass ≥7 cm in diameter; (ii) involvement of at least 3 lymph node sites, each >3 cm in diameter; (iii) presence of type B symptoms (e.g., fever, night sweats, and weight loss); (iv) splenomegaly (>16 cm on computed tomography (CT) scan); (v) risk of local compression symptoms that may lead to organ damage; (vi) pleural effusion or peritoneal ascites; (vii) leukemia stage (>5×10 9 / L circulating malignant cells); and (viii) cytopenia (granulocyte count <1×10 9 / L and / or platelets <100×10 9 / L). See Brice et al. J Clin Oncol. 15(3): 1110-1117, 1997. In some embodiments, a subject who meets one or more GELF criteria is considered to have a high tumor burden.

[0035] "Follicular Lymphoma International Prognostic Index" or "FLIPI" refers to a scoring system or index used to determine the prognostic risk of a patient (e.g., having cancer; e.g., NHL; e.g., follicular lymphoma (FL)). The FLIPI score ranges from 0 to 5, depending on how many of the following five conditions or risk factors the patient may have: (i) age ≥ 60 years; (ii) Ann Arbor stage III to IV; hemoglobin level ≤ 120 g / L; serum lactate dehydrogenase (LDH) level ≥ upper limit of normal (ULN) (e.g., > 280 units / L); and (v) number of nodal sites > 4. FLIPI risk groups are defined as follows: (a) 0 or 1 FLIPI risk factor = low risk group; (b) 2 FLIPI risk factors = intermediate risk group; (c) 3 to 5 FLIPI risk factors = high risk group. See, e.g., Solal-Céligny et al. Blood. 2004; 104(5): 1258-1265. Table 4.

[0036] As used herein, the term "Ann Arbor staging" or "Ann Arbor stage" refers to a system for classifying the staging of lymphomas (e.g., NHL; e.g., FL; e.g., previously untreated FL). Lymphomas (e.g., NHL) can be classified into one of four Ann Arbor stages. Stage I refers to lymphomas that show involvement of a single lymph node region or a single extralymphatic organ or site. Stage II refers to lymphomas that show involvement of 2 or more lymph node regions on the same side of the diaphragm. Stage III refers to lymphomas that show involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by local involvement of extralymphatic organs or sites or involvement of the spleen, or both. Stage IV refers to lymphomas that show diffuse or disseminated involvement of 1 or more extralymphatic organs or tissues, with or without lymphadenopathy. Liver involvement is always considered diffuse and is therefore always considered Ann Arbor stage IV. Lymphatic structures include lymph nodes, thymus, spleen, appendix, Waldeyer's tonsillar rings and Peyer's patches. See Carbone, PP et al., Cancer Res. 1971, 31(11): 1860-1861.

[0037] As used herein, "treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the subject to be treated, and may be performed for prevention or during the course of clinical pathology. Desired effects of treatment include, but are not limited to, preventing the occurrence or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, ameliorating or alleviating the disease state, and alleviating or improving prognosis. In some embodiments, the antibodies of the invention are used to delay the development of a disease or slow the progression of a disease.

[0038] As used herein, "delaying progression" of a disorder or disease means delaying, hindering, slowing, delaying, stabilizing and / or postponing the development of a disease or disorder (e.g., previously untreated FL). Such delays may be of varying lengths of time, depending on the medical history and / or the individual to be treated. It will be apparent to one skilled in the art that a sufficient or significant delay may actually encompass prevention, as the individual will not develop the disease. For example, the development of advanced cancers, such as metastases, may be delayed.

[0039] "Prolonging survival" refers to increasing the overall survival or progression-free survival of a treated patient relative to untreated patients (e.g., relative to patients not treated with the drug), or relative to patients not expressing the biomarker at a specified level and / or relative to patients treated with an approved anti-tumor agent. An objective response refers to a measurable response, including a complete response (CR) or a partial response (PR).

[0040] "Reduce or inhibit" means to cause an overall reduction of, for example, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more. For clarity, the term also includes reduction to zero (or below the detection limit of the analytical method), i.e., complete removal or elimination. In certain embodiments, reduction or inhibition may refer to treatment with mosunetuzumab using the step-up dosing regimen of the present invention, relative to the unchanged preset dosing of mosunetuzumab with a target dose, reducing or inhibiting undesirable events, such as cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes and / or central nervous system (CNS) toxicity. In other embodiments, reduction or inhibition may refer to the effector functions of antibodies mediated by the Fc region of antibodies, such effector functions specifically including complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). In other embodiments, reduction or inhibition may refer to the symptoms of previously untreated FL treated, the presence or size of metastases or the size of primary tumors. In yet other embodiments, reduction or inhibition of cancer recurrence means reduction or inhibition of tumor or cancer recurrence or tumor or cancer progression (e.g., reducing the risk of FL or preventing the progression and / or recurrence of FL).

[0041] As used herein, "administering" means a method of administering a dose of a compound (e.g., a bispecific antibody; e.g., an anti-CD20 / anti-CD3 bispecific antibody; e.g., mosunetuzumab; e.g., a corticosteroid, an antihistamine, an antipyretic, an interleukin 6 receptor (IL-6R) antagonist, or a preventive agent for tumor lysis syndrome (TLS)) or a composition (e.g., a pharmaceutical composition; e.g., a pharmaceutical composition comprising a bispecific antibody (e.g., mosunetuzumab) or other therapeutic agent) to a subject. The compounds and / or compositions used in the methods described herein can be administered subcutaneously (e.g., by injection), intravenously (e.g., by intravenous infusion), or orally.

[0042] A fixed dose or flat dose of a therapeutic agent (e.g., a bispecific antibody) herein refers to a dose that is administered to a patient regardless of the patient's weight or body surface area (BSA). Thus, a fixed dose or flat dose is not a mg / kg dose or mg / m 2 Doses are not provided, but rather are provided in absolute amounts (eg, mg) of therapeutic agent.

[0043] A "subject" or "individual" is a mammal. Mammals include, but are not limited to, primates (e.g., humans and non-human primates such as monkeys), domestic animals (e.g., cows, sheep, cats, dogs, and horses), rabbits, and rodents (e.g., mice and rats). In specific embodiments, the subject or individual is a human.

[0044] Any endpoint indicative of benefit to the subject may be used to assess an "individual response" or "response", including, but not limited to (1) inhibiting disease progression (e.g., progression of previously untreated FL) to some extent, including slowing and complete arrest; (2) reducing tumor size; (3) inhibiting (i.e., reducing, slowing or completely stopping) cancer cell infiltration into adjacent peripheral organs and / or tissues; (4) inhibiting (i.e., reducing, slowing or completely stopping) metastasis; (5) alleviating to some extent one or more symptoms associated with previously untreated FL; (6) increasing or extending the length of survival, including overall survival and progression-free survival; and / or (9) reducing mortality at a given time point after treatment. In some embodiments, the Lugano response criteria for malignant lymphoma (Cheson BD, et al. J Clin Oncol 2014; 32: 1-9) are used to assess the response to treatment of previously untreated FL.

[0045] As used herein, the "Lugano criteria" or "Lugano response criteria" for malignant lymphoma are a set of criteria used to assess response assessment (eg, PET / CT scan) to the treatment methods described herein. The Lugano criteria are described in Table 1 below.

[0046] Table 1. Lugano response criteria for response assessment in malignant lymphoma

[0047]

[0048]

[0049] PK13859A

[0050]

[0051] 5PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; IHC = immunohistochemistry; LDi = the longest transverse diameter of the lesion; MRI = magnetic resonance imaging; PET = positron emission tomography; PPD = the cross product of LDi and the perpendicular diameter; SDi = the shortest axis perpendicular to LDi; SPD = the sum of the products of the perpendicular diameters of multiple lesions.

[0052] aA score of 3 in many patients indicates a good prognosis with standard treatment, especially if scanned at interim time. However, in studies involving PET, in which de-escalation studies are performed, it is best to consider a score of 3 as an inadequate response (to avoid undertreatment). Measured dominant lesions: Select up to six of the largest dominant lymph nodes, lymph node masses, and extranodal lesions, clearly measured in two diameters. Lymph nodes should preferably be from different regions of the body and should include the mediastinum and retroperitoneum where applicable. Non-nodal lesions include those of solid organs (e.g., liver, spleen, kidney, lung), gastrointestinal involvement, skin lesions, or those found on palpation. Non-measured lesions: Any disease not selected for measurement; dominant disease and truly evaluable disease should be considered not measured. These sites include any lymph nodes, lymph node masses, and extranodal sites that were not selected as appreciable or measurable or that did not meet the measurable requirements but were still considered abnormal, as well as truly evaluable disease, that is, any suspected site of disease that is difficult to track by measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and tracked by imaging. In the Waldeyer tonsillar ring or extranodal sites (e.g., gastrointestinal tract, liver, bone marrow), FDG uptake may be greater than the mediastinum with a complete metabolic response, but should not be higher than normal physiological uptake in the surrounding area (e.g., bone marrow activation caused by chemotherapy or bone marrow growth factors).

[0053] b PET 5PS: 1 = no uptake above background; 2 = uptake ≤ mediastinum; 3 = uptake > mediastinum but ≥ liver; 4 = moderate uptake > liver; 5 = uptake markedly above liver and / or new lesions; X = new areas of uptake unlikely to be related to lymphoma.

[0054] See Cheson BD et al. J Clin Oncol 2014;32:1-9.

[0055] For assessment, target lesions including up to six largest target lymph nodes, lymphadenopathy, or other lymphoma lesions that can be measured by two diameters and include mediastinal and retroperitoneal disease (if involved) should be identified from different body regions representing the patient's overall disease burden. At baseline, the longest diameter (LDi) of the measurable lymph node sites must be greater than 15 mm. Measurable extranodal disease may be included in the six representative measured lesions. At baseline, measurable extranodal lesions should be greater than 10 mm LDi. All other lesions (including lymph node, extranodal, and evaluable disease) should be included as non-target lesions (e.g., skin, gastrointestinal tract, bone, spleen, liver, kidney, pleural or pericardial effusion, ascites, bone, bone, bone marrow). Over time, lesions may split or fuse. In the case of split lesions, the individual products of the perpendicular diameters (PPD) of the lymph node sites should be added together to represent the PPD of the split lesion; this PPD is added to the sum of the PPDs of the remaining lesions to measure the response. If any or all of these discrete lymph nodes subsequently grow, the nadir of each individual lymph node is used to determine progression. In the case of confluent lesions, the PPD of the confluent mass should be compared to the sum of the PPDs of the individual lymph nodes, with an increase of more than 50% in the PPD of the confluent mass compared with the sum of the individual lymph nodes indicating progressive disease. LDi and minimal diameter (SDi) are no longer required to determine progression.

[0056] As used herein, "objective response rate" (ORR) refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0057] As used herein, "duration of objective response" (DOR) is defined as the time from the first documented objective response to disease progression, relapse, or death from any cause, whichever occurs first.

[0058] As used herein, "duration of complete response" (DOCR) is defined as the time from the first occurrence of a documented complete response to disease progression, relapse, or death from any cause, whichever occurs first.

[0059] As used herein, "tumor burden" refers to the total amount of a tumor (e.g., tumor cells or tumor mass) in a subject (e.g., a human subject) having cancer, e.g., NHL, e.g., FL. In some embodiments, tumor burden is defined as the sum of the diameters of target lesions or the sum of the products of target lesions. In specific embodiments, tumor burden is defined as the sum of the products of the diameters of (SPD) target lesions. In some embodiments, the diameter of the target lesions is quantified by computed tomography (CT).

[0060] A "sustained response" refers to a persistent effect on reducing tumor growth after treatment has ceased. For example, the tumor size can remain the same or smaller than the size at the beginning of the administration period. In some embodiments, the duration of the sustained response is at least the same as the duration of treatment, at least 1.5 times, 2.0 times, 2.5 times, or 3.0 times as long as the duration of treatment.

[0061] "Effective response" of a subject to a drug and treatment or "responsiveness" of a subject and similar expressions refer to a clinical or therapeutic benefit conferred on a subject at risk of or suffering from a disease or disorder such as cancer. In one embodiment, such benefit includes one or more of: prolonging survival (including overall survival and progression-free survival); resulting in an objective response (including complete response or partial response); or improving signs or symptoms of cancer.

[0062] A subject who "does not effectively respond" to treatment is one who does not have any of the following: prolong survival (including overall survival and progression-free survival); result in an objective response (including complete response or partial response); or improve signs or symptoms of cancer.

[0063] The term "survival" refers to whether the patient is still alive and includes overall survival as well as progression-free survival.

[0064] As used herein, "overall survival" (OS) refers to the percentage of subjects in a group who are alive after a specified duration, such as 1 year or 5 years from the time of diagnosis or treatment.

[0065] As used herein, "progression-free survival (PFS)" refers to the length of time during and after treatment during which the disease being treated (e.g., previously untreated FL) does not worsen. Progression-free survival may include the amount of time a patient experiences a complete response or partial response, and the amount of time a patient experiences stable disease.

[0066] The term "antibody" herein is used in the broadest sense and includes various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0067] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody and binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments.

[0068] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.

[0069] Unless otherwise indicated, the term "cluster of differentiation 3" or "CD3" as used herein refers to any native CD3 from any vertebrate source, including, for example, primates (e.g., humans) and rodents (e.g., mice and rats), including, for example, CD3ε, CD3γ, CD3α, and CD3β chains. The term encompasses "full-length" unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ), as well as any form of CD3 produced by processing in cells. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, a human CD3ε protein (NCBI RefSeq No. NP_000724) having a length of 207 amino acids and a human CD3γ protein (NCBI RefSeq No. NP_000064) having a length of 182 amino acids.

[0070] Unless otherwise indicated, the term "cluster of differentiation 20" or "CD20" as used herein refers to any native CD20 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term includes "full-length" unprocessed CD20, as well as any form of CD20 produced by processing in cells. The term also encompasses naturally occurring variants of CD20, including, for example, splice variants or allelic variants. CD20 includes, for example, human CD20 protein (see, for example, NCBI RefSeq Nos. NP_068769.2 and NP_690605.1), which is 297 amino acids in length and can be produced, for example, from variant mRNA transcripts lacking a portion of the 5'UTR (see, for example, NCBI RefSeq No. NM_021950.3) or longer variant mRNA transcripts (see, for example, NCBI RefSeq No. NM_152866.2).

[0071] The terms "anti-CD20 / anti-CD3 bispecific antibody," "bispecific anti-CD20 / anti-CD3 antibody," and "antibody that binds to CD20 and CD3," or variations thereof, refer to mosunituzumab.

[0072] As used herein, the term "mosulatuzumab" refers to an anti-CD20 / anti-CD3 bispecific antibody having International Nonproprietary Name (INN) List 117 (WHO Drug Information, Vol. 31, No. 2, 2017, pp. 304-305) or CAS Registry Number 1905409-39-3.

[0073] As used herein, the term "lenalidomide" refers to the compound having CAS Registry Number 191732-72-6 and IUPAC name (3RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. Lenalidomide is also known by trade names including Linamid and lenalid. The DrugBank accession number of lenalidomide is DB00480, PubChem CID 216326, and the chemical formula is C 13 H 13 N3O3.

[0074] As used herein, the terms "bind," "specifically bind," or "have specificity" refer to a measurable and reproducible interaction, such as binding between a target and an antibody, that determines the presence of the target in the presence of a heterogeneous population of molecules (including biomolecules). For example, an antibody that specifically binds to a target (which may be an epitope) is an antibody that binds to the target with greater affinity, avidity, more readily, and / or longer duration than it binds to other targets. In one embodiment, the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the antigen, for example, as measured by radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds to a target has a dissociation constant (K) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM. D ). In certain embodiments, an antibody specifically binds to an epitope on a protein that is conserved between proteins of different species. In another embodiment, specific binding may include but does not require exclusive binding. As used herein, the term may be illustrated, for example, by a molecule having a dissociation constant with a target, K D For 10 -4 M or lower, alternatively 10 -5 M or lower, alternatively 10 -6 M or lower, alternatively 10 -7 M or lower, alternatively 10 -8 M or lower, alternatively 10 -9 M or lower, alternatively 10 -10 M or lower, alternatively 10 -11 M or lower, alternatively 10 -12 M or lower; or KD Range is 10 -4 M to 10 -6 M or 10 -6 M to 10 -10 M or 10 -7 M to 10 -9 M. As will be appreciated by those skilled in the art, affinity is related to K D The high affinity for the antigen is due to the low K D In one embodiment, the term "specific binding" refers to the binding of a molecule to a specific polypeptide or epitope on a specific polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

[0075] The term "pharmaceutical formulation" refers to a preparation that is in a form that permits the biological activity of the active ingredient contained therein to be effective, and that contains no additional components that would be unacceptably toxic to a subject to which the preparation would be administered.

[0076] "Pharmaceutically acceptable carrier" refers to a component of a pharmaceutical preparation other than the active ingredient that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0077] As used herein, the term "chemotherapeutic agent" refers to a compound that can be used to treat cancer (such as previously untreated FL). Examples of chemotherapeutic agents include EGFR inhibitors (including small molecule inhibitors (e.g., erlotinib ( Genentech / OSI Pharm.); PD 183805 (CI 1033, 2-acrylamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); and dual EGFR / HER2 tyrosine kinase inhibitors, such as lapatinib (( GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2-methylsulfonyl]ethyl]amino]methyl]-2-furyl]-4-quinazolinamine)), tyrosine kinase inhibitors (e.g., EGFR inhibitors, small molecule HER2 tyrosine kinase inhibitors such as TAK165 (Takeda), CP-724, 714, oral selective inhibitors of ErbB2 receptor tyrosine kinase (Pfizer and OSI), dual HER inhibitors such as EKB- 569 (available from Wyeth), which preferentially binds to EGFR but inhibits both HER2 and EGFR overexpressing cells, PKI-166 (Novartis), pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as the antisense agent ISIS-5132 (ISIS Pharmaceuticals), which inhibits Raf-1 signaling; non-HER targeted tyrosine kinase inhibitors such as imatinib mesylate ( Glaxo SmithKline; multi-target tyrosine kinase inhibitors, such as sunitinib ( Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (Pharmacia); quinazolines such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP59326, CGP 60261 and CGP 62706; pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrosine phosphorylation inhibitors containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (e.g., antisense molecules that bind to HER encoding nucleic acids); quinoxalines (U.S. Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors, such as CI-1033 (Pfizer); Affinitac (ISIS 3521; ISIS / Lilly); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1C11 (Imclone); and rapamycin (sirolimus, ); proteasome inhibitors such as bortezomib ( Millennium Pharm.); disulfiram; epigallocatechin gallate; salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; lactate dehydrogenase A (LDH-A); fulvestrant ( AstraZeneca; letrozole ( Novartis; phenazone ( Novartis; Oxaliplatin ( Sanofi); 5-FU (5-fluorouracil); leucovorin; lonafilmide (SCH 66336); sorafenib ( Bayer Labs); AG1478, alkylating agents such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquinone, methopa and uredopa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trihydroxymethylmelamine; polyacetylamines (particularly bratacin and bratacinone); camptothecins (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adolesine, carzeresine and biszeresine synthetic analogs); candidin (particularly candidin 1 and candidin 8); adrenocortical steroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductases, including finasteride and dutasteride); voltamyl linostat, romidepsin, panobinostat, valproic acid, moxistat, dolastatin; aldesleukin, talc, duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); acanthopanacin; pancratistatin; coralin; spongin; nitrogen mustards, such as chlorambucil, chlorphenazine, clofosamide, estramustine, ifosfamide, mechlorethamine, oxazolidinone hydrochloride, melphalan, new mechlorethamine, phenamic acid, prednimustine, trofosamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin gamma 1 and calicheamicin omega 1); dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicins; and the neocarcinogens and related chromoprotein enediyne antibiotic chromophores), aclarubicin, actinomycin, authramycin, azaserine, actinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, actinomycin D, detomycin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitogen-activated protein kinase inhibitors, mycobacterium such as mitomycin C, mycophenolic acid, nogamycin, olive mycin, peplomycin, porfibrinocin, puromycin, quinamycin, antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as dimethylfolate, methotrexate, pteroxine, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as kalutestosterone, drostanolone propionate, cyclothiosteroid, melastane, testolactone; antiadrenergics such as aminoglutethimide, mitotane, trilostane;Folic acid supplements such as folinic acid; acepramide; aldehyde phosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; betribucil; bisantrene; edatrexate; difoamide; colchicine; diazocone; elfomithine; elitrimide acetate; epothilones; etogluconate; gallium nitrate; hydroxyurea; lentinan; lonidanine; maytansine alkaloids such as maytansine and ansamitocin; mitoguanidine; mitoxantrone; mopidanol; nitric acid; pentostatin; phenammet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; Polysaccharide complex (JHS natural product); razoxane; rhizoxin; sizofuran; spirogermanium; tenidronic acid; triazinon; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, baculosporin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulanol; pipobroman; cytosine; arabinoside ("Ara-C"); thiotepa; chlorambucil; (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; etoposide (VP-16); ifosfamide; mitoxantrone; novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine Ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; and pharmaceutically acceptable salts, acids, prodrugs and derivatives of any of the foregoing.

[0078] Chemotherapeutic agents also include: (i) antihormonal agents that act to modulate or inhibit the effects of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including Tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and (toremifine citrate); (ii) aromatase inhibitors that inhibit aromatase, the enzyme that regulates estrogen production by the adrenal glands, such as, for example, 4(5)-imidazole, aminoglutethimide, (Megestrol acetate), (exemestane; Pfizer), formestanie, fadrozole, (vorozole), (letrozole; Novartis AG) and (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all trans-retinoic acid, fenretinide, and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways associated with abnormal cell proliferation, such as, for example, PKC-α, Ralf, and H-Ras; (vii) ribozymes, such as inhibitors of VEGF expression (e.g., ) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, e.g. and (ix) Growth inhibitors, including vinca (e.g., vincristine and vinblastine), (vinorelbine), taxanes (e.g., paclitaxel, albumin-bound paclitaxel and docetaxel), topoisomerase II inhibitors (e.g., doxorubicin, epirubicin, daunomycin, etoposide and bleomycin) and DNA alkylating agents (e.g., tamoxifen, dacarbazine, dichloromethane, cisplatin, methotrexate, 5-fluorouracil and ara-C); and (x) pharmaceutically acceptable salts, acids, prodrugs and derivatives of any of the foregoing.

[0079] The term "chemoimmunotherapy" refers to a combination therapy that includes both a chemotherapeutic drug and an immunotherapeutic agent. In some embodiments, chemoimmunotherapy is used to treat cancer, e.g., a CD20-positive cancer; e.g., NHL; e.g., FL. In some embodiments, the immunotherapeutic agent includes an antibody, e.g., an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody). In some embodiments, the anti-CD20 antibody or anti-CD20 monoclonal antibody is rituximab or obinutuzumab. In some embodiments, the chemoimmunotherapy includes R-CHOP.

[0080] As used herein, the term "cytotoxic agent" refers to any agent that is detrimental to cells (e.g., causes cell death, inhibits proliferation, or otherwise impedes cell function). Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., 211 At 131 I. 125 I. 90Y. 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P. 212 Pb and Lu radioisotopes); chemotherapeutic agents; enzymes and fragments thereof, such as nucleolytic enzymes; and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof. Exemplary cytotoxic agents may be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, LDH-A inhibitors, fatty acid biosynthesis inhibitors, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors and cancer metabolism inhibitors. In one case, the cytotoxic agent is a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin). In one case, the cytotoxic agent is an antagonist of EGFR, for example, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine (e.g., erlotinib). In one instance, the cytotoxic agent is a RAF inhibitor, e.g., a BRAF and / or CRAF inhibitor. In one instance, the RAF inhibitor is vemurafenib. In one instance, the cytotoxic agent is a PI3K inhibitor.

[0081] The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products.

[0082] III. Treatment Methods

[0083] Provided herein is a method for treating a subject with previously untreated follicular lymphoma (FL) by administering mosulatuzumab and lenalidomide as a combination therapy. Specifically, the present invention relates to a method for treating a subject with 1 / L FL by subcutaneous administration of mosulatuzumab and oral administration of lenalidomide. In some embodiments, FL is a graded FL (e.g., grade 1, grade 2, or grade 3a, but not grade 3b FL). In some embodiments, according to the World Health Organization Classification of Lymphoid Tumors (as cited in Swerdlow SH et al. Blood 2016; 127: 2375-90), each subject's FL is histologically recorded as grade 1, grade 2, or grade 3a, but not grade 3b.

[0084] In some cases, the subject has not been treated with any standard or investigational anti-cancer therapy, including, but not limited to: (i) exposure to lenalidomide within 12 months prior to administration of the first dose of mosulatuzumab (e.g., C1D1 dose) of the methods of the present invention; (ii) taking fludarabine or alemtuzumab within 12 months prior to administration of the first dose of mosulatuzumab (e.g., C1D1 dose) of the methods of the present invention; (iii) taking levofloxacin or tadalafil within 12 months prior to administration of the first dose of mosulatuzumab (e.g., C1D1 dose) of the methods of the present invention; ) within 12 weeks prior to administration of a radioimmunoconjugate in the methods of the invention; (iv) prior anti-lymphoma treatment with a monoclonal antibody or antibody-drug conjugate within 4 weeks prior to administration of the first dose of mosulatuzumab in the methods of the invention (e.g., a C1D1 dose); and (v) treatment with any other chemotherapeutic agent within 4 weeks or 5 drug half-lives (whichever is shorter) prior to administration of the first dose of mosulatuzumab in the methods of the invention (e.g., a C1D1 dose), or treatment with any other anti-cancer drug (investigational or other).

[0085] In some embodiments, the subject has been previously determined to require systemic therapy for treatment of the previously untreated FL based on the Follicular Lymphoma Group (GELF) criteria (Brice et al. J Clin Oncol. 15(3): 1110-1117, 1997).

[0086] A. Therapeutic Methods for Administering Mosulatuzumab and Lenalidomide

[0087] The present invention relates to methods of treating subjects with previously untreated follicular lymphoma (FL) by administering mosulatuzumab and lenalidomide as a combination therapy. Specifically, the present invention relates to methods of treating subjects with previously untreated FL by subcutaneous administration of mosulatuzumab and oral administration of lenalidomide.

[0088] In one aspect, the invention features a method of treating a subject having previously untreated follicular lymphoma (FL), the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and a second 28-day (±1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 (±1 day), and day 15 (±1 day) of the first dosing cycle, respectively, wherein C1D1 is about 5 mg (e.g., 5 The amount of C1D2 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), and the amount of C1D2 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg). 3 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg) g, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, e.g., 45 mg), and (c) the second dosing cycle further comprises oral administration of about 5 mg to about 20 mg (e.g., about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, or about 5 mg to about 15 mg, e.g., about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg) of lenalidomide daily on days 1 to 21 of the second dosing cycle. In some embodiments, the first dosing cycle is a three-dose dosing cycle (i.e., comprising three doses of mosulimab).

[0089] In some embodiments, the dosing regimen includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) additional dosing cycles. In some embodiments, the dosing regimen includes one to ten (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) additional dosing cycles. In some aspects, the dosing regimen includes ten additional dosing cycles. In some embodiments, the length of any one of the one or more additional dosing cycles is about 28 days (± 1 day). In some embodiments, each of the one or more additional dosing cycles is about 28 days (± 1 day).

[0090] In some embodiments, any one of the one or more additional dosing cycles includes an additional single dose of mosunetuzumab. In some embodiments, each of the one or more additional dosing cycles includes an additional single dose of mosunetuzumab. In some embodiments, the method includes administering each additional single dose of mosunetuzumab to the subject subcutaneously on the first day of each of the one or more additional dosing cycles. In some embodiments, the additional single dose of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg). In some embodiments, each additional single dose of mosulatuzumab is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg, or ± 9 mg, e.g., 45 mg).

[0091] In some embodiments, lenalidomide is not administered during the first dosing cycle. In some embodiments, lenalidomide is orally administered during any one of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) additional dosing cycles. In some embodiments, lenalidomide is orally administered during any one of ten additional dosing cycles. In some embodiments, lenalidomide is orally administered during each of ten additional dosing cycles. In some embodiments, lenalidomide is orally administered on the 1st to 21st day of each of the additional dosing cycles including the administration of lenalidomide. In some embodiments, lenalidomide is not administered in the last 7 days (± 1 day) of any dosing cycle including the administration of lenalidomide. In some embodiments, lenalidomide is administered at a dose of about 10 mg (e.g., 10 mg ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg or ± 2 mg, such as 10 mg). In some embodiments, lenalidomide is administered at a dose of about 20 mg (e.g., 20 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg or ± 4 mg, e.g., 20 mg).

[0092] In one aspect, the invention features a method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and a second 28-day (±1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 (±1 day), and day 15 (±1 day) of the first dosing cycle, respectively, wherein C1D1 is about 5 mg (e.g., 5 mg±0 .01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg or ±1 mg, for example, 5 mg), C1D2 is about 45 mg (for example, 45 mg ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, for example, 45 mg), and C1D 3 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, e.g., 45 mg), and (c) the second dosing cycle further comprises oral administration of about 10 mg (e.g., 10 mg ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ±1 mg or ±2 mg, e.g., 10 mg) of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0093] In one aspect, the invention features a method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and a second 28-day (±1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 (±1 day), and day 15 (±1 day) of the first dosing cycle, respectively, wherein C1D1 is about 5 mg (e.g., 5 mg±0 .01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg or ±1 mg, for example, 5 mg), C1D2 is about 45 mg (for example, 45 mg ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, for example, 45 mg), and C1D 3 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, e.g., 45 mg), and (c) the second dosing cycle further comprises oral administration of about 20 mg (e.g., 20 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg or ±4 mg, e.g., 20 mg) of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0094] In one aspect, the invention features a method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and eleven subsequent 28-day (±1 day) dosing cycles, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 (±1 day), and day 15 (±1 day) of the first dosing cycle, respectively, wherein C1D1 is about 5 mg (e.g., 5 mg±0.01 The invention relates to a pharmaceutical composition comprising: ... , 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab administered subcutaneously on day 1 of each dosing cycle, wherein C2D1 to C12D1 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg , ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, for example, 45 mg), and (c) the second to twelfth dosing cycles further comprise oral administration of about 10 mg (e.g., 10 mg ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ±1 mg or ±2 mg, for example 10 mg) of lenalidomide per day on days 1 to 21 of each dosing cycle.

[0095] In one aspect, the invention features a method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and eleven subsequent 28-day (±1 day) dosing cycles, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 (±1 day), and day 15 (±1 day) of the first dosing cycle, respectively, wherein C1D1 is about 5 mg (e.g., 5 mg±0.01 m g, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg or ±1 mg, e.g., 5 mg), C1D2 is about 45 mg (e.g., 45 mg ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, e.g., 45 mg), and C1D3 is about 45 mg (e.g., 45 (a) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), The invention relates to a method for orally administering lenalidomide of at least 20 mg, for example, 45 mg, ±0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, for example, 45 mg), and (c) the second to twelfth dosing cycles further comprise oral administration of about 20 mg (e.g., 20 mg ±0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg or ±4 mg, for example, 20 mg) of lenalidomide per day on days 1 to 21 of each dosing cycle.

[0096] In some embodiments, the FL is histologically documented as grade 1, 2, or 3a, but not grade 3b, according to the World Health Organization classification of lymphoid neoplasms (as cited in Swerdlow SH et al. Blood 2016; 127: 2375-90).

[0097] In some embodiments, the subject has been previously determined to require systemic therapy for treatment of the previously untreated FL based on the Follicular Lymphoma Group (GELF) criteria (Brice et al. J Clin Oncol. 15(3): 1110-1117, 1997).

[0098] In some embodiments, the subject is a human.

[0099] For all methods described herein, mosunetuzumab and lenalidomide are formulated, dosed and applied in a manner consistent with good medical practice. Factors to be considered in this case include the specific illness being treated, the specific mammal being treated, the clinical condition of the individual subject, the cause of the illness, the delivery site of the agent, the method of administration, the administration regimen, and other factors known to the doctor. Mosunetuzumab and lenalidomide do not need (but are optionally used with) one or more additional agents (e.g., therapeutic agents) currently used to prevent or treat the illness in question and / or reduce the rate of adverse events, reduce the severity of adverse events, treat or prevent adverse events and / or symptoms associated with adverse events to be formulated, combined or used together. The effective amount of such other agents depends on the amount of mosunetuzumab and / or lenalidomide present in the preparation, the type of illness or treatment, the type of adverse event, and other factors discussed herein. Mosunetuzumab and lenalidomide can be appropriately administered to the subject through a series of treatments. When mosulatuzumab and lenalidomide are administered on the same day, lenalidomide is administered to the subject prior to administration of mosulatuzumab.

[0100] B. Dosing Strategies to Mitigate Adverse Events

[0101] The present invention relates to methods of treating subjects with previously untreated follicular lymphoma (FL) by administering mosulatuzumab and lenalidomide as a combination therapy. In some embodiments, the therapies and dosing regimens described herein provide an acceptable safety profile for treating subjects with previously untreated FL with the described dosing regimens.

[0102] 1. CRS symptoms and grading

[0103] Any method described herein may involve monitoring the cytokine release syndrome (CRS) of the subject, such as CRS events after starting any of the above methods.Current clinical management focuses on treating subject symptoms and symptoms, providing supportive care, and attempting to use high-dose corticosteroids to suppress inflammatory responses.However, the method is not always successful, especially in the case of late intervention.The CRS grading criteria used by the method described herein are issued by the American Society of Transplantation and Cellular Therapy (ASTCT) for defining mild, moderate, severe or life-threatening CRS and coordinating reports across clinical trials, to allow rapid identification and treatment of CRS (Lee et al. Biol Blood Marrow Transplantation.25 (4): 625-638, 2019).The ASTCT criteria are intended to be objective, easy to apply and more accurately classify the severity of CRS.The CRS grading system is shown in Table 2 below.

[0104] Table 2. CRS grading system

[0105]

[0106] ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = biphasic positive airway pressure; CPAP = continuous positive airway pressure; CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events.

[0107] Fever was defined as a body temperature ≥ 38°C not attributable to any other cause. For subjects who had CRS and then received antipyretic or anticytokine therapy such as tocilizumab or corticosteroids, fever was no longer required to grade the subsequent severity of CRS. In this setting, CRS grade was determined by hypotension and / or hypoxia.

[0108] The CRS grade was determined by the more severe event, hypotension or hypoxia not attributable to any other cause. For example, a subject with a temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring a low-flow nasal cannula was classified as Grade 3 CRS.

[0109] Low flow nasal cannula is defined as delivering oxygen at ≤6 L / min. Low flow also includes blow-by delivery of oxygen, which is sometimes used in pediatrics. High flow nasal cannula is defined as delivering oxygen at >6 L / min.

[0110] CRS is associated with a wide range of cytokine elevations, including significant increases in IFN-γ, IL-6, and TNF-α levels. Emerging evidence in particular suggests that IL-6 serves as a central mediator in CRS. IL-6 is a proinflammatory multifunctional cytokine produced by a variety of cell types that has been shown to participate in a wide range of physiological processes, including T cell activation. Regardless of the stimulatory agent, CRS is associated with high IL-6 levels (Nagorsen et al., Cytokine. 25(1):31-5, 2004; Lee et al., Blood. 124(2):188-95, 2014; Doesegger et al., Clin. Transl. Immunology. 4(7):e39, 2015), and IL-6 is correlated with the severity of CRS, with subjects who experienced grade 4 or 5 CRS events having much higher IL-6 levels than those who did not experience CRS or experienced milder CRS (grades 0 to 3) (Chen et al., J. Immunol. Methods. 434:1-8, 2016).

[0111] Therefore, blocking the inflammatory effects of IL-6 using drugs that inhibit IL-6-mediated signaling to manage CRS observed in subjects during a two-step fractionated, dose-escalating dosing regimen is an alternative to steroid therapy that is not expected to negatively affect T cell function or reduce the efficacy or clinical benefit of mosulatuzumab therapy in the treatment of CD20-positive cell proliferative diseases (e.g., B cell proliferative diseases).

[0112] If the subject has a CRS event that does not resolve or worsens within 24 hours of administering an IL-6R antagonist to treat the symptoms of the CRS event, and the method may further include administering one or more additional doses of an IL-6R antagonist to the subject to manage the CRS event. If the CRS event cannot be managed by administering an IL-6R antagonist, a corticosteroid such as methylprednisolone or dexamethasone may be administered to the subject.

[0113] 2. Other adverse events and classification

[0114] Any of the methods described herein may involve monitoring subjects for additional non-CRS adverse events. The incidence, nature, and severity of physical findings and adverse events were determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5 (NCI CTCAE v5.0). In addition to CRS, the most common adverse event reported in patients receiving mosulatuzumab and / or lenalidomide was neutropenia (e.g., febrile neutropenia).

[0115] Neutropenia is characterized by an abnormally low blood count of neutrophils, which are a type of white blood cell. Neutropenia may lead to an increased risk of infection. The generally accepted reference range for the absolute neutrophil count (ANC) in adults is 1,500 to 8,000 cells / μL of blood. Mild neutropenia is characterized by an ANC between 1,000 and 1,500 cells / μL (grades 1 to 2); moderate neutropenia is characterized by an ANC between 500 and 1,000 cells / μL (grade 3), and severe neutropenia is characterized by an ANC below 500 cells / μL (grade 4). Febrile neutropenia (grade 3+ neutropenia) is characterized by an ANC below 1,000 cells / μL, in addition to a single temperature measurement above 38.3°C or a continuous temperature measurement above 38°C for more than one hour.

[0116] Tumor lysis syndrome (TLS) is a risk of antineoplastic therapy for hematologic malignancies, including NHL. Metabolic abnormalities associated with TLS (Howard Criteria; Howard et al. N. Engl. J. Med. 364 (19) 1844-1854, 2011) are described in Table 3 below:

[0117] Table 3. Metabolic abnormalities associated with laboratory and clinical tumor lysis syndrome

[0118]

[0119] TLS = tumor lysis syndrome; ULN = upper limit of normal. Note: TLS should be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

[0120] In laboratory TLS, two or more metabolic abnormalities must be present during the same 24-hour period within 3 days before or up to 7 days after the start of therapy. Clinical TLS requires the presence of laboratory TLS plus an increase in creatinine level, seizure, arrhythmia, or death. Acute kidney injury is defined as an increase in creatinine level of 0.3 mg / dL (26.5 μmol / L) or an oliguric period lasting 6 or more hours. By definition, if acute kidney injury is present, the patient has clinical TLS (Levin et al. Am. J. Kidney Dis. 50(1): 1-4, 2007).

[0121] Because mosulatuzumab and lenalidomide have the potential to kill B cells, the potential risk of TLS development and the need for TLS prophylaxis before initiating mosulatuzumab must be considered in all patients.

[0122] All patients received TLS prophylaxis prior to study drug administration during dosing cycles 1 and 2. Prophylaxis guidelines included the following:

[0123] Hydration, including approximately 2 to 3 L / day of fluid intake starting 24 to 48 hours before the first dose of mosulatuzumab

[0124] – If patients are hospitalized for study treatment, IV hydration at a rate of 150 to 200 mL / hour should be initiated at the end of mosulatuzumab administration and continued for at least 24 hours thereafter.

[0125] - If patients receive study treatment in the outpatient setting, fluid intake should be maintained at approximately 2 to 3 L / day for at least 24 hours after mosulatuzumab administration.

[0126] – Modification of fluid rates should be considered for individuals with specific medical needs.

[0127] ·Use of drugs to lower uric acid:

[0128] – Allopurinol (eg, 300 mg / day orally starting 72 hours before the dose and continued for 3 to 7 days thereafter) should be self-administered by the investigator.

[0129] – For patients with elevated uric acid levels prior to study treatment or considered at high risk for TLS: Rasburicase should be administered (eg, 0.2 mg / kg IV within 30 minutes before the first dose of mosulatuzumab and daily thereafter for up to 5 days).

[0130] days), unless contraindicated ( [rasburicase] U.S. package insert).

[0131] – Treatment with allopurinol / rasburicase should be continued as above or, if laboratory evidence of TLS is observed, until normalization of serum uric acid or other laboratory parameters.

[0132] Patients at high risk for TLS should continue to receive prophylaxis with allopurinol or rasburicase and adequate hydration with each subsequent dose of mosulatuzumab and lenalidomide until the patient is no longer considered at risk for TLS. Patients who develop clinical or laboratory TLS during Cycle 1 should be considered for hospitalization during subsequent cycles to allow for optimal hydration and monitoring.

[0133] If the Howard criteria for TLS (see Table 3 above) are met at any time during the study (coexistence of two or more electrolyte laboratory abnormalities), or if there are medically relevant laboratory abnormalities in TLS-related parameters or clinical signs of TLS (e.g., elevated serum creatinine or cardiac arrhythmias), study treatment should be withheld and the patient should be hospitalized and adequately treated until normalization of the laboratory abnormalities before restarting study treatment.

[0134] 3. Dosing regimen with an acceptable safety profile

[0135] In one aspect, the invention features a method of treating a subject having previously untreated follicular lymphoma (FL), the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and a second 28-day (±1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 (±1 day), and day 15 (±1 day) of the first dosing cycle, respectively, wherein C1D1 is about 5 mg (e.g., 5 The amount of C1D2 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), and the amount of C1D2 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg). 3 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg), (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg) g, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, ±3 mg, ±4 mg, ±5 mg, ±6 mg, ±7 mg, ±8 mg or ±9 mg, e.g., 45 mg), and (c) the second dosing cycle further comprises oral administration of about 5 mg to about 20 mg (e.g., about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, or about 5 mg to about 15 mg, e.g., about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg) of lenalidomide daily on days 1 to 21 of the second dosing cycle. In some embodiments, the first dosing cycle is a three-dose dosing cycle (i.e., comprising three doses of mosulimab).

[0136] In some embodiments, the dosing regimen includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) additional dosing cycles. In some embodiments, the dosing regimen includes one to ten (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) additional dosing cycles. In some aspects, the dosing regimen includes ten additional dosing cycles. In some embodiments, the length of any one of the one or more additional dosing cycles is about 28 days (± 1 day). In some embodiments, each of the one or more additional dosing cycles is about 28 days (± 1 day).

[0137] In some embodiments, any one of the one or more additional dosing cycles includes an additional single dose of mosunetuzumab. In some embodiments, each of the one or more additional dosing cycles includes an additional single dose of mosunetuzumab. In some embodiments, the method includes administering each additional single dose of mosunetuzumab to the subject subcutaneously on the first day of each of the one or more additional dosing cycles. In some embodiments, the additional single dose of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg or ± 9 mg, e.g., 45 mg). In some embodiments, each additional single dose of mosulatuzumab is about 45 mg (e.g., 45 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg, or ± 9 mg, e.g., 45 mg).

[0138] In some embodiments, lenalidomide is not administered during the first dosing cycle. In some embodiments, lenalidomide is orally administered during any one of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) additional dosing cycles. In some embodiments, lenalidomide is orally administered during any one of ten additional dosing cycles. In some embodiments, lenalidomide is orally administered during each of ten additional dosing cycles. In some embodiments, lenalidomide is orally administered on the 1st to 21st day of each of the additional dosing cycles including the administration of lenalidomide. In some embodiments, lenalidomide is not administered in the last 7 days (± 1 day) of any dosing cycle including the administration of lenalidomide. In some embodiments, lenalidomide is administered at a dose of about 10 mg (e.g., 10 mg ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg or ± 2 mg, such as 10 mg). In some embodiments, lenalidomide is administered at a dose of about 20 mg (e.g., 20 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg or ± 4 mg, e.g., 20 mg).

[0139] In certain embodiments, the first dosing cycle further includes the use of corticosteroids.In certain embodiments, the second dosing cycle further includes the use of corticosteroids.In certain embodiments, any one of one or more additional dosing cycles includes the use of corticosteroids.In certain embodiments, a single dose of corticosteroids is applied to the subject before the use of any dose of mosunetuzumab.In certain embodiments, corticosteroids include dexamethasone or methylprednisolone.In certain embodiments, corticosteroids are administered intravenously or orally.In certain embodiments, corticosteroids include dexamethasone and are administered at a dosage of about 20mg (e.g., 20mg ± 0.05mg, ± 0.1mg, ± 0.2mg, ± 0.3mg, ± 0.4mg, ± 0.5mg, ± 0.75mg, ± 1mg, ± 1.5mg, ± 2mg, ± 3mg or ± 4mg, e.g., 20mg). In some embodiments, the corticosteroid comprises methylprednisolone and is administered at a dose of about 80 mg (e.g., 80 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg, ± 10 mg, ± 12 mg, ± 14 mg, or ± 16 mg, e.g., 80 mg).

[0140] In some embodiments, the first dosing cycle further includes the use of antihistamines. In some embodiments, the second dosing cycle further includes the use of antihistamines. In some embodiments, any one of one or more additional dosing cycles includes the use of antihistamines. In some embodiments, before the use of any dose of mosunetuzumab (e.g., 30, 35, 40, 45, 50, 60, 70, 80, 90, 120, 150, 180 minutes or longer), a single dose of antihistamines is administered to the subject. In some embodiments, before the use of any dose of mosunetuzumab (e.g., 30, 35, 40, 45, 50, 60, 70, 80, 90, 120, 150, 180 minutes or longer), antihistamines are administered to the subject. In some embodiments, antihistamines are administered orally or intravenously. In some embodiments, the antihistamine comprises diphenhydramine hydrochloride and is administered at a dose of about 50 to 100 mg (e.g., 50 to 90 mg, 50 to 80 mg, 50 to 70 mg, 50 to 60 mg, 60 to 100 mg, 70 to 100 mg, 80 to 100 mg, 90 to 100 mg, 70 to 80 mg, 60 to 90 mg, 60 to 80 mg, 70 to 90 mg, or 65 to 85 mg, such as about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg).

[0141] In some embodiments, the first dosing cycle further includes the use of an antipyretic. In some embodiments, the second dosing cycle further includes the use of an antipyretic. In some embodiments, any one of one or more additional dosing cycles includes the use of an antipyretic. In some embodiments, a single dose of an antipyretic is administered to a subject before the administration of any dose of mosunetuzumab. In some embodiments, an antipyretic is administered to a subject at least 30 minutes (e.g., 30, 35, 40, 45, 50, 60, 70, 80, 90, 120, 150, 180 minutes or longer) before the administration of any dose of mosunetuzumab. In some embodiments, an antipyretic is administered orally. In some embodiments, the antipyretic comprises acetaminophen and is administered at a dose of about 500 to 1000 mg (e.g., 500 to 900 mg, 500 to 800 mg, 500 to 700 mg, 500 to 600 mg, 600 to 1000 mg, 700 to 1000 mg, 800 to 1000 mg, 900 to 1000 mg, 700 to 800 mg, 600 to 900 mg, 600 to 800 mg, 700 to 900 mg, or 650 to 850 mg, e.g., about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg).

[0142] In some embodiments, the first dosing cycle further includes the administration of a pre-dose of a preventive agent for tumor lysis syndrome (TLS). In some embodiments, the second dosing cycle further includes the administration of a pre-dose of a preventive agent for TLS. In some embodiments, any one of one or more additional dosing cycles includes the administration of a pre-dose of a preventive agent for TLS. In some embodiments, a pre-dose of a preventive agent for TLS is administered to a subject before the administration of any dose of mosunetuzumab. In some embodiments, the preventive agent for TLS includes allopurinol. In some embodiments, a pre-dose of allopurinol is administered about 72 hours (e.g., 72 ± 0.5 hours, ± 1 hours, ± 2 hours, ± 3 hours, ± 4 hours, ± 8 hours, ± 12 hours or ± 16 hours, e.g., 72 hours) before the administration of any dose of mosunetuzumab. In some embodiments, an additional single dose of allopurinol is administered every day after the administration of the pre-dose for 6 to 10 days (± 1 day). In some embodiments, the initial dose of allopurinol is about 300 mg (e.g., 300 mg ± 5 mg, ± 10 mg, ± 15 mg, ± 20 mg, ± 25 mg, ± 30 mg, ± 45 mg, or ± 60 mg, e.g., 300 mg). In some embodiments, each additional single dose of allopurinol is about 300 mg (e.g., 300 mg ± 5 mg, ± 10 mg, ± 15 mg, ± 20 mg, ± 25 mg, ± 30 mg, ± 45 mg, or ± 60 mg, e.g., 300 mg). In some embodiments, allopurinol is administered orally. In some embodiments, the preventive agent for TLS includes rasburicase. In some embodiments, the initial dose of rasburicase is administered about 30 minutes (e.g., 30 ± 0.5 minutes, 1 minute, ± 2 minutes, ± 3 minutes, ± 4 minutes, ± 5 minutes, or ± 6 minutes, e.g., 30 minutes) prior to the administration of any dose of mosunetuzumab. In some embodiments, an additional single dose of rasburicase is administered daily for 1 to 5 days (±1 day) after administration of the initial dose. In some embodiments, the initial dose of rasburicase is about 0.2 mg / kg (e.g., 0.2±0.005 mg / kg, ±0.01 mg / kg, ±0.02 mg / kg, ±0.03 mg / kg, or ±0.04 mg / kg, e.g., 0.2 mg / kg). In some embodiments, each additional single dose of rasburicase is about 0.2 mg / kg (e.g., 0.2±0.005 mg / kg, ±0.01 mg / kg, ±0.02 mg / kg, ±0.03 mg / kg, or ±0.04 mg / kg, e.g., 0.2 mg / kg). In some embodiments, rasburicase is administered intravenously.

[0143] In some embodiments, an IL-6R antagonist may be administered to a subject treated with the methods of the present invention, for example, when the subject exhibits CRS, for example, after administration of any dose of mosunetuzumab. In some embodiments, the IL-6R antagonist is tocilizumab. In some embodiments, tocilizumab is administered to a subject in a single dose of about 8 mg / kg (e.g., 8 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, ± 1 mg / kg, ± 1.5 mg / kg, or ± 2 mg / kg; e.g., 8 mg / kg), and wherein the single dose does not exceed 800 mg. In some embodiments, tocilizumab is administered to a subject at a single dose of about 12 mg / kg (e.g., 12 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, ± 1 mg / kg, ± 1.5 mg / kg, or ± 2 mg / kg; e.g., 12 mg / kg), and wherein the single dose does not exceed 800 mg. In some embodiments, tocilizumab is administered intravenously.

[0144] The methods described herein can produce an acceptable safety profile for subjects with previously untreated follicular lymphoma (FL) treated with combination therapy of mosulatuzumab and lenalidomide. In some instances, treatment with the methods described herein comprising subcutaneous administration of mosulatuzumab in the context of a dose-escalating dosing regimen and oral administration of lenalidomide results in a decrease (e.g., a decrease of 20% or greater, 25% or greater, 30% or greater, 35% or greater, 40% or greater, 45% or greater, 50% or greater, 55% or greater, 60% or greater, 65% or greater, 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater) in undesirable adverse events such as cytokine-driven toxicities (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRRs), macrophage activation syndrome (MAS), neurological toxicities, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and / or hepatotoxicity following treatment with mosulatuzumab using the fractionated, dose-escalating dosing regimens of the invention, relative to treatment with mosulatuzumab using a non-fractionated dosing regimen. or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater; for example, between 20% and 100%, between 20% and 90%, between 20% and 80%, between 20% and 70%, between 20% and 60%, between 20% and 50%, between 20% and 40%, between 20% and 30%, between 40% and 100%, between 60% and 100%, between 80% and 100%, between %, about 95%, about 97%, about 99%, or about 100%), or completely inhibit (100% reduction).

[0145] IV. Therapeutic Agents

[0146] A. Mosunituzumab

[0147] The present invention provides mosulatuzumab, a bispecific antibody that binds to CD20 and CD3, that can be used to treat previously untreated follicular lymphoma (FL).

[0148] Mosunituzumab has an anti-CD20 arm having a first binding domain comprising the following six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and (f) HVR-L3 comprising the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6). Mosunetuzumab comprises an anti-CD20 arm comprising a first binding domain comprising heavy chain framework regions FR-H1, FR-H2, FR-H3 and FR-H4 comprising the sequences of SEQ ID NOs: 17 to 20, respectively, and light chain framework regions FR-L1, FR-L2, FR-L3 and FR-L4 comprising the sequences of SEQ ID NOs: 21 to 24, respectively. Mosunetuzumab comprises an anti-CD20 arm comprising a first binding domain comprising: (a) a heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 7; and (b) a light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 8.

[0149] Mosulatuzumab has an anti-CD3 arm having a second binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO:9); (b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO:10); (c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO:11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO:12); (e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO:13); and (f) HVR-L3 comprising the amino acid sequence of TQSFILRT (SEQ ID NO:14). Mosunetuzumab comprises an anti-CD3 arm comprising a second binding domain comprising heavy chain framework regions FR-H1, FR-H2, FR-H3 and FR-H4 comprising the sequences of SEQ ID NOs: 25 to 28, respectively, and light chain framework regions FR-L1, FR-L2, FR-L3 and FR-L4 comprising the sequences of SEQ ID NOs: 29 to 32, respectively. Mosunetuzumab comprises an anti-CD3 arm comprising a second binding domain comprising: (a) a VH domain comprising an amino acid sequence having the amino acid sequence of SEQ ID NO: 15; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 16.

[0150] Mosulatuzumab has International Nonproprietary Name (INN) List 117 (WHO Drug Information, Vol. 31, No. 2, 2017, pp. 304-305) or CAS Registry Number 1905409-39-3, and has (1) an anti-CD20 arm comprising the heavy chain and light chain sequences of SEQ ID NOs: 33 and 34, respectively; and (2) an anti-CD3 arm comprising the heavy chain and light chain sequences of SEQ ID NOs: 35 and 36, respectively. Mosunituzumab comprises: (1) an anti-CD20 arm comprising a first binding domain, the first binding domain comprising a heavy chain and a light chain, the heavy chain comprising the amino acid sequence of SEQ ID NO:33, and the light chain comprising the amino acid sequence of SEQ ID NO:34; and (2) an anti-CD3 arm comprising a second binding domain, the second binding domain comprising a heavy chain and a light chain, the heavy chain comprising the amino acid sequence of SEQ ID NO:35, and the light chain comprising the amino acid sequence of SEQ ID NO:36.

[0151] The amino acid sequence of mosulatuzumab is summarized in Table 4 below.

[0152] Table 4. Sequence ID of mosunetuzumab

[0153]

[0154] Mosunituzumab can be produced using recombinant methods and compositions, for example, as described in U.S. Pat. No. 4,816,567.

[0155] B. Lenalidomide

[0156] Lenalidomide is an immunomodulatory (IMiD) imide drug that binds to cereblon, an E3 ubiquitin ligase protein (Gribben et al. J. Clin. Oncol. 33(25):2803-2811, 2015). The immunomodulatory activity of lenalidomide is not fully understood; however, lenalidomide has been shown to enhance CD4+ and CD8+ T cell co-stimulation, induce T cell proliferation, and enhance IL-2 and IFN-γ (Haslett et al. J. Exp. Med. 187(11):1885-1892, 1998; Davies et al. Blood 98(1):210-216, 2001).

[0157] The CAS registry number of lenalidomide is 191732-72-6 and the IUPAC name is (3RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. Lenalidomide is also known by trade names including Linamid and lenalid. The DrugBank accession number of lenalidomide is DB00480, PubChem CID216326, and the chemical formula is C 13 H 13 N3O3.

[0158] C. Additional therapeutic agents

[0159] In some instances, the methods described herein comprise administering mosunituzumab and lenalidomide in combination with one or more additional therapeutic agents.

[0160] In some cases, one or more additional therapeutic agents can prevent, reduce the incidence, or reduce the severity of cytokine release syndrome (CRS) and / or symptoms associated with CRS. In certain cases, the additional therapeutic agent used to reduce the incidence or severity of CRS or prevent symptoms associated with CRS is a corticosteroid (e.g., dexamethasone (CAS No.: 50-02-2), prednisone (CAS No.: 53-03-2), prednisolone (CAS No.: 50-42-8), or methylprednisolone (CAS No.: 83-43-2)), an antihistamine (e.g., diphenhydramine (CAS No.: 58-73-1) and its pharmaceutically acceptable salts, for example, diphenhydramine hydrochloride In some cases, the additional therapeutic agent is a corticosteroid. In certain cases, the corticosteroid is dexamethasone or methylprednisolone. In certain cases, the antihistamine is diphenhydramine hydrochloride. In certain cases, the antipyretic is acetaminophen (ie, paracetamol) or a pharmaceutically acceptable salt thereof. In certain cases, the IL-6R antagonist is tocilizumab.

[0161] In some cases, one or more additional therapeutic agents can be used to treat neutropenia. In some cases, the additional therapeutic agent can prevent symptoms associated with neutropenia. In some cases, the additional therapeutic agent can reduce the incidence or severity of neutropenia. In certain cases, the additional therapeutic agent is granulocyte colony stimulating factor (G-CSF or GCSF) or colony stimulating factor 3 (CSF 3). The mRNA sequence of human G-CSF / CSF 3 includes, for example, NCBI RefSeq No.NM_000759, NM_001178147, NM_172219 and NM_172220, and the protein amino acid sequence of human G-CSF / CSF3 includes, for example, NCBI RefSeq No.NP_000750, NP_001171618, NP_757373 and NP_757374.

[0162] In some cases, one or more additional therapeutic agents are preventive agents for, for example, preventing tumor lysis syndrome (TLS), reducing its incidence, or reducing its severity. In some cases, the preventive agent for TLS is allopurinol (CAS No.: 315-30-0), rasburicase (ElitekTM; CAS No.: 134774-45-1), or a suitable substitute and / or a pharmaceutically acceptable salt thereof. In some cases, the preventive agent for TLS reduces serum uric acid (e.g., reduces elevated uric acid levels, e.g., relative to a baseline or reference value).

[0163] In some cases, additional therapeutic agents useful in the present invention include therapeutic antibodies, such as alemtuzumab Bevacizumab ( Genentech); Cetuximab ( Imclone; Panitumumab ( Amgen), rituximab ( Genentech / Biogen Idec), Pertuzumab ( 2C4, Genentech), trastuzumab ( Genentech), tositumomab ( Corixia) and antibody-drug conjugates, gemtuzumab ozogamicin ( Wyeth)。Additional humanized monoclonal antibodies with therapeutic potential for use as medicaments in combination with the compounds of the invention include: apolizumab, aselizumab, alizumab, barbituruzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, inotuzumab ozogamicin), ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab , pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sirolimusumab, cilizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, tafasitamab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, uzumab, ustekinumab, visilizumab, and briakinumab.

[0164] IV. Pharmaceutical Compositions and Formulations

[0165] Mosunetuzumab, lenalidomide, and other therapeutic agents described herein can be used in pharmaceutical compositions and preparations. Pharmaceutical compositions and preparations of mosunetuzumab, lenalidomide, and other therapeutic agents described herein (e.g., corticosteroids, antihistamines, antipyretics, preventive agents for TLS, and / or IL-6R antagonists) can be prepared in the form of a lyophilized formulation or an aqueous solution by mixing one, two, three or more agents with a desired purity with one or more optional pharmaceutical carriers (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. Editor (1980)). Corticosteroids, antihistamines, antipyretics, preventive agents for TLS, and / or IL-6R antagonists can also be formulated according to standard formulations and / or manufacturing practices. Pharmaceutical carriers are generally nontoxic to subjects at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol); low molecular weight (less than about 10 residues) Polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., zinc protein complexes); and / or nonionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutical carriers herein further include interstitial drug dispersants such as soluble neutral active hyaluronidase glycoprotein (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoprotein, such as rHuPH20 ( Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in U.S. Patent Publication Nos. 2005 / 0260186 and 2006 / 0104968. In one aspect, sHASEGP is combined with one or more additional glycosaminoglycanases, such as chondroitinases.

[0166] Exemplary lyophilized antibody formulations are described in US Pat. No. 6,267,958. Aqueous antibody formulations include those described in US Pat. No. 6,171,586 and WO 2006 / 044908, the latter of which includes a histidine-acetate buffer.

[0167] The preparations herein may also contain more than one active ingredient necessary for the particular indication being treated, preferably active ingredients with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide additional therapeutic agents (e.g., chemotherapeutic agents, cytotoxic agents, growth inhibitors and / or anti-hormonal agents, such as those described above). Such active ingredients are appropriately present in an amount combination effective for the intended purpose.

[0168] The active ingredient can be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively); embedded in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules); or embedded in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. ed. (1980).

[0169] Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, eg, films or microcapsules.

[0170] Preparations for in vivo administration are generally sterile. For example, sterility can be easily achieved by filtration through sterile filtration membranes.

[0171] In some embodiments, mosunetuzumab is formulated for subcutaneous administration. In some embodiments, lenalidomide is formulated for oral administration. In some embodiments, dexamethasone is formulated for oral or intravenous administration. In some embodiments, methylprednisolone is formulated for oral or intravenous administration. In some embodiments, allopurinol is formulated for oral administration. In some embodiments, rasburicase is formulated for intravenous administration. In some embodiments, tocilizumab is formulated for intravenous administration.

[0172] V. Kits and Products

[0173] In another aspect of the present invention, a kit or article is provided, which contains materials that can be used to treat, prevent and / or diagnose the above-mentioned diseases. The kit or article includes a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The container can be formed of a variety of materials such as glass or plastic. The container holds a composition, which itself or in combination with another composition can effectively treat, prevent and / or diagnose the disease, and the container can have a sterile access port (for example, the container can be a vial with a stopper that can be pierced by a hypodermic needle). At least one active agent in the composition is mosunetuzumab or lenalidomide described herein. The label or package insert indicates that the composition is used to treat previously untreated follicular lymphoma (FL), and further includes information related to at least one of the dosing regimens described herein. In some embodiments, the label or package insert indicates that the composition is used to treat previously untreated FL in a patient. In addition, the kit or article may include (a) a first container having a composition contained therein, wherein the composition comprises mosunetuzumab, lenalidomide, or both mosunetuzumab and lenalidomide; and (b) a second container having a composition contained therein, wherein the composition comprises an additional cytotoxic agent or other therapeutic agent. Alternatively or additionally, the kit or article may further include a second (or third) container, which contains a pharmaceutical buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. The article may also include other substances required from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0174] Examples

[0175] The following are examples of methods and compositions of the invention. It is understood that various other embodiments may be practiced given the general description provided above.

[0176] Example 1. A Phase Ib / II, Open-label, Non-randomized, Multicenter Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Subcutaneous Mosulatuzumab in Combination with Lenalidomide in Patients with Previously Untreated Follicular Lymphoma

[0177] Study Design

[0178] Study CO41942 is an ongoing Phase Ib / II, open-label, multicenter study and includes the evaluation of the safety, tolerability, and pharmacokinetics of subcutaneously administered mosulatuzumab in combination with lenalidomide in patients with previously untreated follicular lymphoma (FL). Figure 1 Overview.

[0179] The study includes an expansion cohort of approximately 20 to 40 patients who receive the recommended phase 2 dosing (RP2D) of mosulatuzumab.

[0180] Study treatment was administered for 12 cycles; the duration of dosing Cycle 1 was 21 days, and the duration of Cycles 2 to 12 was 28 days. Mosulatuzumab was administered with lenalidomide in Cycle 2 after patients completed the step-wise dosing of Cycle 1.

[0181] Inclusion criteria

[0182] Age ≥ 18 years

[0183] Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 (see table below)

[0184] 5).

[0185] Previously untreated patients with follicular lymphoma (FL) must require systemic therapy as assessed by the investigator based on the Follicular Lymphoma Group (GELF) criteria (Brice et al., J

[0186] Clin Oncol.15(3):1110-1117,1997)

[0187] Histologically documented grade 1, 2, or 3a FL (Swerdlow SH et al. Blood 2016;

[0188] 127:2375-90), and it expresses CD20

[0189] Fluorodeoxyglucose lymphoma (ie, positron emission tomography (PET)-positive lymphoma)

[0190] At least one two-dimensionally measurable nodular lesion (by PET-computed tomography (CT)

[0191] scan, with its greatest dimension >1.5 cm), or at least one extranodal lesion measurable in two dimensions

[0192] (>1.0 cm in greatest dimension by PET-CT scan)

[0193] Adequate hematologic function (no growth factor or blood product transfusions within 14 days after the first dose of study drug) was defined as follows:

[0194] – Hemoglobin ≥9 g / dL

[0195] – Absolute neutrophil count (ANC) ≥1.0 × 10 9 / L

[0196] – Platelet count ≥75 × 10 9 / L

[0197] Creatinine clearance ≥ 50 mL / min measured or estimated according to institutional standard methods

[0198] Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 × upper limit of normal (ULN)

[0199] Total serum bilirubin <1.5×ULN (or, for patients with Gilbert's syndrome, <3×ULN)

[0200] For women of childbearing potential: agree to remain abstinent (avoid heterosexual intercourse) or use two adequate methods of contraception, including at least one method with a failure rate of <1% per year, before Day 1 of Cycle 1, for at least 28 days during the treatment period (including treatment breaks), and for at least 28 days after the last dose of lenalidomide, for 3 months after the last dose of tocilizumab, and for 3 months after the last dose of mosunimumab. Women must refrain from donating eggs during this same period.

[0202] For men: agree to abstinence (avoid heterosexual intercourse) or use contraceptive methods and refrain from sperm donation.

[0203] Table 5. ECOG performance status score

[0204]

[0205]

[0206] Exclusion criteria

[0207] Any history of grade 3b FL

[0208] Any history of transformed and / or diffuse large B-cell lymphoma (DLBCL)

[0209] Active central nervous system (CNS) lymphoma or leptomeningeal infiltration or history of such disease.

[0210] Document refractoryness to lenalidomide, defined as no response (PR or

[0211] CR)

[0212] · Prior standard or investigational anticancer therapy as specified below:

[0213] – Exposure to lenalidomide within 12 months prior to Day 1 of Cycle 1.

[0214] – Fludarabine or alemtuzumab administered within 12 months prior to Day 1 of Cycle 1.

[0215] - Administer radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1.

[0216] – Prior anti-lymphoma therapy with monoclonal antibodies or antibody-drug conjugates within 4 weeks before Cycle 1 Day 1

[0217] – Patients must not have received any chemotherapeutic agent or any other anticancer drug (investigational or otherwise) within 4 weeks or 5 half-lives of the drug (whichever is shorter) prior to the first dose of study treatment, with the following exceptions:

[0218] Clinically significant toxicity (other than alopecia) from previous treatment that has not resolved to ≤ Grade 2 (per NCI CTCAE v5.0) by Day 1 of Cycle 1.

[0219] Known idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolar obliterans)

[0220] history of pulmonary inflammation), drug-induced pulmonary inflammation, or active pulmonary CT scan on screening chest

[0221] evidence of lung inflammation;

[0222] Treatment with systemic immunosuppressive medications (including but not limited to prednisone, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to Day 1 of Cycle 1

[0223] – Inhaled corticosteroids are permitted.

[0224] – Mineralocorticoids are permitted for the management of orthostatic hypotension.

[0225] – Physiologic doses of corticosteroids are permitted for the management of adrenal insufficiency.

[0226] – If corticosteroid therapy is urgently needed to control lymphoma symptoms before the start of study treatment, 100 mg of prednisone or equivalent may be given for up to 5 days.

[0227] History of solid organ transplantation

[0228] · History of severe allergic or anaphylactic reaction to humanized, chimeric, or murine monoclonal antibodies · Known hypersensitivity to biologic drugs produced in Chinese hamster ovary cells or to any component of mosulatuzumab, lenalidomide, or thalidomide formulations (including mannitol)

[0229] History of erythema multiforme, grade ≥ 3 rash, or blistering following previous treatment with immunomodulatory derivatives

[0230] · Need for IV antibiotics for known active bacterial, viral, fungal, or other infection, or any significant infection episode within 4 weeks of Cycle 1 Day 1

[0231] Known or suspected chronic active Epstein-Barr virus (EBV) infection

[0232] Known or suspected hemophagocytic syndrome

[0233] Active Hepatitis B Infection: Patients who are hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (HBcAb) positive must be negative for hepatitis B virus (HBV) polymerase chain reaction (PCR) to be eligible for study participation.

[0234] Active Hepatitis C Infection: Patients who are positive for hepatitis C virus (HCV) antibodies must be negative for HCV by PCR to be eligible for study participation.

[0235] Known history of human immunodeficiency virus (HIV)-positive status: For patients with unknown HIV status, HIV testing should be performed at screening if required by local regulations.

[0236] History of progressive multifocal leukoencephalopathy (PML).

[0237] Administered a live attenuated vaccine within 4 weeks prior to the first dose of study treatment or anticipates the need for such a live attenuated vaccine during the study

[0238] – Patients must not receive live attenuated vaccines while receiving study treatment or after the last dose

[0239] (For example, ) until B cells return to the normal range. Inactivated vaccines or toxoids should be given at least 4 weeks before the first dose of study treatment to allow for the development of adequate immunity.

[0240] – Allowing the use of approved non-live COVID-19 vaccines

[0241] – Inactivated influenza vaccination should only be given during flu season.

[0242] Other malignancies that may affect protocol compliance or interpretation of results, except for the following:

[0243] – Any of the following malignancies that have been previously treated with curative intent: carcinoma in situ of the cervix, favorable prognosis ductal carcinoma in situ of the breast, basal cell carcinoma, or squamous cell skin cancer

[0244] – Stage I melanoma, low-grade early localized prostate cancer, or any other previously treated malignancy that has been in remission without treatment for ≥ 2 years prior to enrollment

[0245] Active autoimmune disease requiring treatment

[0246] – Patients with a history of autoimmune-related hypothyroidism receiving stable doses of thyroid replacement hormone may be eligible.

[0247] – Patients with type 1 diabetes who are on an insulin regimen are eligible for the study.

[0248] – Patients with a history of disease-associated immune thrombocytopenic purpura or autoimmune hemolytic anemia or other stable autoimmune diseases may be eligible.

[0249] - Have autoimmune diseases (including but not limited to: myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,

[0250] Patients with a history of vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis) and a 12-month treatment-free interval from immunosuppressive therapy may be eligible.

[0251] Prior allogeneic hematopoietic stem cell transplantation

[0252] ≥Grade 2 neuropathy

[0253] Evidence of any serious, uncontrolled concomitant illness that may affect regimen compliance or interpretation of results, including but not limited to severe cardiovascular disease (e.g., New York Heart Association class III or IV heart disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or unstable angina) or severe pulmonary disease (such as history of obstructive pulmonary disease or bronchospasm).

[0254] Major surgery other than diagnostic surgery within 28 days prior to Day 1 of Cycle 1, or anticipated major surgery during the study

[0255] History of clinically significant liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis

[0256] Pregnant or breastfeeding, or planning to become pregnant during the study

[0257] Study Treatment

[0258] Mosunituzumab administration

[0259] Mosulatuzumab was administered subcutaneously (SC) following an ascending dosing schedule: in Cycle 1 (21-day dosing cycle), patients received 5 mg on Day 1 (C1D1 dose); 45 mg on Day 8 (C1D2 dose); and 45 mg on Day 15 (C1D3 dose). In Cycles 2 to 12 (28-day dosing cycles), patients received 45 mg on Day 1 (C2D1 to C12D1 doses). Patients receiving subcutaneous mosulatuzumab did not require hospitalization unless clinically indicated (based on prior clinical experience from Study GO29781).

[0260] If a patient experiences toxicity, an interruption of SC mosulatuzumab for >7 days prior to the Cycle 1 Day 8 dose is required, and the patient needs to repeat the 5 mg dose upon resumption of planned treatment (7 days after the 5 mg dose). If a dose delay results in a treatment-free interval of 6 weeks or longer, a step-up of SC mosulatuzumab is required on Day 1 (5 mg) and Day 8 (45 mg) of the first cycle following the dose delay. Corticosteroid prophylaxis should be administered on days when repeat doses are administered to mitigate the risk of cytokine release syndrome (CRS).

[0261] Prior to the administration of each dose of mosunetuzumab, a corticosteroid premedication consisting of dexamethasone 20 mg or methylprednisolone 80 mg was administered orally or intravenously (IV). In addition, before the administration of mosunetuzumab, oral or IV analgesics / antipyretics (e.g., 500 to 1,000 mg acetaminophen or paracetamol) and / or oral or IV antihistamines (e.g., 50 to 100 mg diphenhydramine) were administered premedication according to standard institutional practice. Premedication with analgesics / antipyretics and antihistamines occurred at least 30 minutes before the administration of mosunetuzumab. All patients were premedicated in cycle 1, and premedication was optional in cycle 2 and beyond. However, if the patient experienced CRS in an earlier dose, corticosteroids were administered premedication in subsequent doses.

[0262] In addition, allopurinol or an appropriate alternative such as rasburicase can be used as premedication for patients at risk for tumor lysis syndrome (TLS; for example, due to larger lesions or impaired renal function (creatinine clearance <60 mL / min)).

[0263] Lenalidomide administration

[0264] Lenalidomide was administered orally (PO) at 20 mg once daily on Days 1 to 21 of Cycles 2 to 12 (28-day dosing cycles). Lenalidomide was not administered on the last 7 days of each of Cycles 2 to 12. If creatinine clearance was <60 mL / min, lenalidomide was instead initiated at a dose of 10 mg / day.

[0265] On days when lenalidomide is administered with mosulatuzumab, lenalidomide is administered first, followed by subcutaneous mosulatuzumab. Lenalidomide is administered at approximately the same time each day. If a dose of lenalidomide is missed, and it has been ≤12 hours since the scheduled dose, the patient is allowed to take the missed dose. If it has been >12 hours, skip the dose and take the next dose at the regularly scheduled time. Two doses should not be taken at the same time. If a dose is vomited, it does not need to be repeated.

[0266] Granulocyte colony stimulating factor (G-CSF) can be administered according to the American Society of Clinical Oncology, the European Organization for Research and Treatment of Cancer (EORTC), and the European Society for Medical Oncology guidelines (Smith et al. J. Clin. Oncol. 33(28):3199-3212; 2015).

[0267] Antibiotic prophylaxis should be administered according to standard practice.

[0268] Lenalidomide increases the risk of thromboembolism (TE). Anticoagulation prophylaxis may be given after careful evaluation of the patient's underlying risk factors. It is recommended that all patients receive low-dose aspirin (81 to 100 mg) daily during lenalidomide treatment and until 28 days after the last dose of lenalidomide. Patients who cannot tolerate aspirin, have a history of TE, and are at high risk for TE may receive warfarin or low molecular weight heparin or novel oral anticoagulants based on institutional practice.

[0269] Tocilizumab administration

[0270] Tocilizumab was administered as necessary to patients who experienced a CRS event. Tocilizumab was administered at a dose of 8 mg / kg IV (only for participants weighing 30 kg or more) or 12 mg / kg (for participants weighing less than 30 kg) for up to 4 doses; doses exceeding 800 mg per infusion were not recommended.

[0271] Dosage Considerations

[0272] Mosulatuzumab dosing was not modified in this study. For patients receiving mosulatuzumab who experienced a grade 4 related non-hematologic adverse event, study treatment was discontinued.

[0273] Based on the toxicity rules described below and further detailed in Table 6, the patient's lenalidomide dosing is modified individually. The lenalidomide dose can be reduced in 5 mg increments (e.g., 20 mg to 15 mg; 15 mg to 10 mg, 10 mg to 5 mg). No more than one dose reduction per dosing cycle. If the lenalidomide dose is reduced, re-increase of the dose is not allowed. If lenalidomide is started at a dose of 10 mg / day, the creatinine clearance is ≥50 but <60 mL / min, and the creatinine clearance remains above 50 mL / min after 2 cycles, the lenalidomide dose can be increased to 15 mg if the patient tolerates therapy. Doses missed due to toxicity or any other reason will not be rescheduled or re-administered.

[0274] Table 6. Lenalidomide dose modifications based on toxicity

[0275]

[0276]

[0277] AE = adverse event; NSAID = nonsteroidal anti-inflammatory drug; TLS = tumor lysis syndrome; ULN = upper limit of normal.

[0278] a Dose modifications were only applied for events considered to be related to lenalidomide.

[0279] b Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5 (NCI CTCAE version 5.0; cancer.gov).

[0280] Prohibited therapies

[0281] The following therapies are prohibited during the study, including but not limited to:

[0282] Investigational drugs or unlicensed / unapproved drugs

[0283] Administration of live vaccines

[0284] Cytotoxic chemotherapy other than investigational therapy for the treatment of lymphoma

[0285] Radiation therapy for lymphoma (except pre-planned radiation therapy)

[0286] Immunotherapy other than investigational therapy for the treatment of lymphoma

[0287] Immunosuppressive therapy (except for drugs specified per protocol, including corticosteroids and tocilizumab)

[0288] Hormone therapy (other than birth control pills, hormone replacement therapy, or megestrol acetate).

[0289] Adjuvant endocrine therapy is allowed for non-metastatic hormone receptor-positive breast cancer.

[0290] Biological or targeted drugs for the treatment of lymphoma

[0291] Herbal remedies intended to treat lymphoma

[0292] Any therapy intended to treat lymphoma, whether approved by local regulatory authorities or investigational

[0293] Patients who required use of any of these agents would discontinue study treatment. For patients who discontinued study treatment, safety outcomes were followed until 90 days after the patient's last dose of study treatment or until the patient received another anticancer therapy, whichever occurred first.

[0294] Security

[0295] Safety was assessed by an overview of adverse events and a summary of changes in laboratory test results. All adverse events occurring on or after the first day of study treatment, serious adverse events, adverse events leading to death, adverse events of special interest, and adverse events leading to discontinuation of study treatment were summarized using mapped terms, appropriate vocabulary level, and NCI CTCAE v5.0 toxicity scale. All serious adverse events were listed and summarized separately.

[0296] Adverse events (AEs)

[0297] According to the International Conference on Harmonisation (ICH) Good Clinical Practice (ich.org) guidelines, an adverse event is any untoward medical occurrence, regardless of causality, that occurs during the use of a medicinal product in clinical investigation subjects. Thus, an adverse event can be any of the following:

[0298] Any adverse and unexpected sign (including abnormal laboratory test results), symptom, or illness temporally associated with the use of a medicinal product, whether or not believed to be related to the medicinal product

[0299] Any new illness or exacerbation of an existing illness (worsening of the character, frequency, or severity of a known illness)

[0300] Recurrence of an intermittent medical condition (e.g., headache) that was not present at baseline

[0301] Any worsening of laboratory values ​​or other clinical tests (e.g., electrocardiogram (ECG), X-ray) associated with symptoms or leading to a change in study treatment or concomitant therapy or discontinuation of study drug

[0302] Adverse events related to protocol-specified interventions, including those occurring prior to assignment of study treatment (e.g., screening invasive procedures such as biopsy)

[0303] Serious Adverse Events (SAEs)

[0304] A critical adverse event is any adverse event that meets any of the following criteria:

[0305] Is fatal (i.e., the adverse event actually causes or contributes to death)

[0306] Is life-threatening (i.e. the adverse event puts the patient at immediate risk of death)

[0307] This does not include any adverse events that could have resulted in death if they occurred in a more severe form or were allowed to continue.

[0308] Requirement or prolonged hospitalization

[0309] · Resulting in persistent or significant disability / incapacity (i.e., the adverse event results in a substantial disruption in the patient's ability to carry out normal life functions)

[0310] Congenital anomalies / birth defects in newborns / infants born to mothers exposed to the study drug

[0311] May endanger the patient or may require medical / surgical intervention to prevent one of the above outcomes

[0312] The terms "serious" and "critical" are not synonymous. Severity refers to the intensity of the adverse event (e.g., graded as mild, moderate, or severe, or according to NCI CTCAE; cancer.gov); the event itself may be of relatively minor medical significance (such as a severe headache without any further findings).

[0313] For each adverse event, severity and seriousness need to be assessed individually.

[0314] Adverse Events of Special Interest (AESI)

[0315] Adverse events of particular interest in this study are as follows:

[0316] Cases of potential drug-induced liver injury (including elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST), combined with elevated bilirubin or clinical jaundice as defined by Hy's law (elevated ALT or AST (>3× upper limit of normal (ULN)) combined with elevated total bilirubin (>2× ULN) or clinical jaundice in the absence of cholestasis or other causes of hyperbilirubinemia)) are considered indicators of severe liver injury.

[0317] Suspected transmission of an infectious agent via the investigational drug, as defined below:

[0318] Any pathogenic or nonpathogenic organism, virus, or infectious particle (e.g., prion-transmitted spongiform encephalopathies) is considered an infectious agent. Transmission of an infectious agent may be suspected based on clinical symptoms or laboratory test results that indicate infection in a patient exposed to a drug product. This term is only used when contamination of the investigational drug is suspected.

[0319] For mosunituzumab, adverse events of particular interest include the following:

[0320] ≥Grade 2 cytokine release syndrome (CRS)

[0321] ≥Grade 2 neurological adverse events

[0322] ≥Grade 2 injection site reactions (for subcutaneous (SC) mosulatuzumab)

[0323] Any suspected hemophagocytic hyperplasia (HLH)

[0324] Tumor lysis syndrome (TLS; grade ≥3 by definition)

[0325] Febrile neutropenia (minimum grade 3 by definition)

[0326] ≥ Grade 2 elevation of AST, ALT, or total bilirubin

[0327] Disseminated intravascular coagulation of any grade (minimum grade 2 by definition)

[0328] ≥ Grade 2 tumor inflammation or erythema (e.g., development of signs / symptoms associated with an increase in size of a known nodal or extranodal lesion, new onset or worsening of a pre-existing pleural effusion as assessed clinically or radiologically)

[0329] Pneumonia / interstitial lung disease of any grade (except infectious pneumonia)

[0330] For lenalidomide, adverse events of particular interest include the following:

[0331] Embryo-fetal toxicity

[0332] Febrile neutropenia (minimum grade 3 by definition)

[0333] Venous and arterial thromboembolic events

[0334] ≥Grade 3 severe skin reactions

[0335] ≥ Grade 3 renal impairment

[0336] ≥Grade 3 thyroid disease

[0337] ≥Grade 3 peripheral neuropathy

[0338] Second primary malignant tumor

[0339] Efficacy analysis

[0340] The efficacy of mosulatuzumab and lenalidomide in the treatment of previously untreated FL was assessed based on the following endpoints using standard criteria for NHL, as assessed by the investigator using the Lugano classification (Cheson BD et al. J Clin Oncol 2014;32:1-9). Response was assessed based on positron emission tomography / computed tomography (PET-CT) scans.

[0341] CRR, defined as the proportion of patients whose best overall response was CR during the study period, is provided with exact 95% confidence intervals using the Clopper-Pearson method.

[0342] ORR, defined as the proportion of patients with a best overall response of CR or PR during the study, is provided with exact 95% CIs using the Clopper-Pearson method.

[0343] DOR, defined as the time from the first documented objective response to disease progression or relapse or death from any cause, whichever occurred first. Kaplan-Meier estimates are provided. The 95% CI for the median DOR was constructed using the Brookmeyer-Crowley method. Duration of response included all patients with a CR or PR, according to the investigators.

[0344] DOCR, defined as the time from the first documented complete response to disease progression or relapse or death from any cause, whichever occurred first. Kaplan-Meier estimates are provided. The 95% CI for median DOR was constructed using the Brookmeyer-Crowley method. According to the investigators, DOCR included all patients with a CR.

[0345] Pharmacokinetic (PK) analysis

[0346] Individual and mean serum mosulatuzumab concentrations versus time data were tabulated and plotted. If appropriate, C max , C min The plasma PK of mosulatuzumab was summarized by using the AUC and AUC. These parameters were tabulated and summarized (mean, standard deviation, coefficient of variation, median, minimum and maximum).

[0347] Additional PK analyses were performed as appropriate. In addition, these data were analyzed using population PK modeling.

[0348] Serum concentrations of lenalidomide were measured. Descriptive statistics as described above were used to summarize lenalidomide concentrations.

[0349] Example

[0350] Some embodiments of the technology described herein may be defined according to any of the following numbered embodiments:

[0351] 1. A method of treating a subject with previously untreated follicular lymphoma (FL), the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0352] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0353] (b) a second dosing cycle comprising a single dose (C2D1) of mosulatuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0354] (c) the second dosing cycle further comprises orally administering between about 5 mg and about 20 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0355] 2. Mosulatuzumab in combination with lenalidomide for the treatment of a subject with previously untreated F), wherein the subject will be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0356] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0357] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0358] (c) the second dosing cycle further comprises between about 5 mg and about 20 mg of lenalidomide administered orally daily on days 1 to 21 of the second dosing cycle.

[0359] 3. Lenalidomide in combination with mosulatuzumab for the treatment of a subject with previously untreated FL, wherein mosulatuzumab and lenalidomide will be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0360] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0361] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0362] (c) the second dosing cycle further comprises between about 5 mg and about 20 mg of lenalidomide administered orally daily on days 1 to 21 of the second dosing cycle.

[0363] 4. The use of mosulatuzumab in combination with lenalidomide for treating a subject with previously untreated FL, wherein mosulatuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0364] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0365] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0366] (c) the second dosing cycle further comprises between about 5 mg and about 20 mg of lenalidomide administered orally daily on days 1 to 21 of the second dosing cycle.

[0367] 5. The use of lenalidomide in combination with mosulatuzumab for treating a subject with previously untreated FL, wherein mosulatuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0368] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0369] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0370] (c) the second dosing cycle further comprises between about 5 mg and about 20 mg of lenalidomide administered orally daily on days 1 to 21 of the second dosing cycle.

[0371] 6. Use of mosulatuzumab in the manufacture of a medicament for treating a subject with previously untreated FL in combination with lenalidomide, wherein mosulatuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0372] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0373] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0374] (c) the second dosing cycle further comprises between about 5 mg and about 20 mg of lenalidomide administered orally daily on days 1 to 21 of the second dosing cycle.

[0375] 7. Use of lenalidomide in the manufacture of a medicament for treating a subject with previously untreated FL in combination with mosulatuzumab, wherein mosulatuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0376] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0377] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0378] (c) the second dosing cycle further comprises between about 5 mg and about 20 mg of lenalidomide administered orally daily on days 1 to 21 of the second dosing cycle.

[0379] 8. The method, mosunituzumab for use, lenalidomide for use or the use according to any one of embodiments 1 to 7, wherein the dosing regimen comprises one or more additional dosing cycles.

[0380] 9. The method, mosulatuzumab for use, lenalidomide for use or the use according to any one of Embodiment 8, wherein the dosing regimen comprises one to ten additional dosing cycles.

[0381] 10. The method, mosunituzumab for use, lenalidomide for use or the use according to embodiment 8 or 9, wherein the dosing regimen comprises ten additional dosing cycles.

[0382] 11. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 8 to 10, wherein each of the one or more additional dosing cycles is about 28 days in length.

[0383] 12. The method, mosulatuzumab for use, lenalidomide for use or the use according to any one of embodiments 8 to 11, wherein each of the one or more additional dosing cycles comprises an additional single dose of mosulatuzumab.

[0384] 13. The method, mosulatuzumab for use, lenalidomide for use or the use according to embodiment 12, wherein the additional single dose of mosulatuzumab is about 45 mg.

[0385] 14. The method of embodiment 12 or 13, wherein the method comprises subcutaneously administering to the subject each additional single dose of mosulatuzumab on day 1 of each of the one or more additional dosing cycles.

[0386] 15. The method, mosulatuzumab for use, lenalidomide for use or the use according to embodiment 12 or 13, wherein each additional single dose of mosulatuzumab is administered subcutaneously to the subject on day 1 of each of the one or more additional dosing cycles.

[0387] 16. The method, mosulatuzumab for use, lenalidomide for use or the use according to embodiments 1 to 15, wherein lenalidomide is not or will not be administered during the first dosing cycle.

[0388] 17. The method, mosulatuzumab for use, lenalidomide for use or the use according to embodiments 8 to 16, wherein lenalidomide is or is to be administered orally during each of said one or more additional dosing cycles.

[0389] 18. The method, mosulatuzumab for use, lenalidomide for use or the use according to embodiments 10 to 17, wherein lenalidomide is or is to be administered orally during each of said ten additional dosing cycles.

[0390] 19. The method, mosulatuzumab for use, lenalidomide for use, or the use according to embodiment 17 or 18, wherein lenalidomide is or is to be administered orally on days 1 to 21 of each of said additional dosing cycles comprising the administration of lenalidomide.

[0391] 20. The method, mosulatuzumab for use, lenalidomide for use or the use according to embodiments 1 to 19, wherein lenalidomide is not or will not be administered in the last 7 days of any dosing cycle comprising the administration of lenalidomide.

[0392] 21. The method, mosunituzumab for use, lenalidomide for use or the use according to embodiments 1 to 20, wherein lenalidomide is or is to be administered in a dose of about 10 mg.

[0393] 22. The method, mosunituzumab for use, lenalidomide for use or the use according to embodiments 1 to 21, wherein lenalidomide is or is to be administered in a dose of about 20 mg.

[0394] 23. A method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0395] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0396] (b) a second dosing cycle comprising a single dose (C2D1) of mosulatuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0397] (c) the second dosing cycle further comprises orally administering about 10 mg of lenalidomide daily on days 1 to 21 of the second dosing cycle.

[0398] 24. Mosulatuzumab in combination with lenalidomide for use in treating a subject with previously untreated F), wherein the subject is administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0399] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0400] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0401] (c) the second dosing cycle further comprises orally administering about 10 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0402] 25. Lenalidomide in combination with mosulatuzumab for use in treating a subject with previously untreated FL, wherein mosulatuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0403] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0404] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0405] (c) the second dosing cycle further comprises orally administering about 10 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0406] 26. Use of mosulatuzumab in combination with lenalidomide for treating a subject with previously untreated FL, wherein the subject is to be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0407] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0408] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0409] (c) the second dosing cycle further comprises orally administering about 10 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0410] 27. Use of lenalidomide in combination with mosulatuzumab for treating a subject with previously untreated FL, wherein mosulatuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0411] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0412] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0413] (c) the second dosing cycle further comprises orally administering about 10 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0414] 28. Use of mosulatuzumab in the manufacture of a medicament for treating a subject with previously untreated FL in combination with lenalidomide, wherein mosulatuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0415] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0416] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0417] (c) the second dosing cycle further comprises orally administering about 10 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0418] 29. Use of lenalidomide in the manufacture of a medicament for treating a subject with previously untreated FL in combination with mosulatuzumab, wherein the subject is to be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0419] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0420] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0421] (c) the second dosing cycle further comprises orally administering about 10 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0422] 30. A method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0423] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0424] (b) a second dosing cycle comprising a single dose (C2D1) of mosulatuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0425] (c) the second dosing cycle further comprises orally administering about 20 mg of lenalidomide daily on days 1 to 21 of the second dosing cycle.

[0426] 31. Mosulatuzumab in combination with lenalidomide for use in treating a subject with previously untreated F), wherein the subject is to be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0427] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0428] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0429] (c) the second dosing cycle further comprises orally administering about 20 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0430] 32. Lenalidomide in combination with mosulatuzumab for use in treating a subject with previously untreated FL, wherein the subject will be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0431] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0432] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0433] (c) the second dosing cycle further comprises orally administering about 20 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0434] 33. Use of mosulatuzumab in combination with lenalidomide for treating a subject with previously untreated FL, wherein the subject is to be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0435] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0436] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0437] (c) the second dosing cycle further comprises orally administering about 20 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0438] 34. Use of lenalidomide in combination with mosulatuzumab for treating a subject with previously untreated FL, wherein mosulatuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0439] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0440] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0441] (c) the second dosing cycle further comprises orally administering about 20 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0442] 35. Use of mosulatuzumab in the manufacture of a medicament for treating a subject with previously untreated FL in combination with lenalidomide, wherein mosulatuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein:

[0443] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0444] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0445] (c) the second dosing cycle further comprises orally administering about 20 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0446] 36. Use of lenalidomide in the manufacture of a medicament for treating a subject with previously untreated FL in combination with mosulatuzumab, wherein mosulatuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 day dosing cycle and a second 28 day dosing cycle, wherein:

[0447] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0448] (b) a second dosing cycle comprises a single dose (C2D1) of mosulatuzumab to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and

[0449] (c) the second dosing cycle further comprises orally administering about 20 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

[0450] 37. A method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:

[0451] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0452] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0453] (c) the second to twelfth dosing cycles each further comprise oral administration of about 10 mg of lenalidomide per day on days 1 to 21 of each dosing cycle.

[0454] 38. Mosulatuzumab in combination with lenalidomide for use in treating a subject with previously untreated F), wherein the subject is to be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:

[0455] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0456] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab to be administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0457] (c) the second to twelfth dosing cycles each further comprise about 10 mg of lenalidomide to be orally administered daily on days 1 to 21 of each dosing cycle.

[0458] 39. Lenalidomide in combination with mosulatuzumab for use in treating a subject with previously untreated FL, wherein the subject will be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:

[0459] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0460] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab to be administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0461] (c) the second to twelfth dosing cycles each further comprise about 10 mg of lenalidomide to be orally administered daily on days 1 to 21 of each dosing cycle.

[0462] 40. The use of mosulatuzumab in combination with lenalidomide for treating a subject with previously untreated FL, wherein the subject is to be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:

[0463] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0464] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab to be administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0465] (c) the second to twelfth dosing cycles each further comprise about 10 mg of lenalidomide to be orally administered daily on days 1 to 21 of each dosing cycle.

[0466] 41. The use of lenalidomide in combination with mosulatuzumab for treating a subject with previously untreated FL, wherein the subject is to be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:

[0467] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0468] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab to be administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0469] (c) the second to twelfth dosing cycles each further comprise about 10 mg of lenalidomide to be orally administered daily on days 1 to 21 of each dosing cycle.

[0470] 42. Use of mosulatuzumab in the manufacture of a medicament for treating a subject with previously untreated FL in combination with lenalidomide, wherein mosulatuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 day dosing cycle and eleven subsequent 28 day dosing cycles, wherein:

[0471] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0472] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab to be administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0473] (c) the second to twelfth dosing cycles each further comprise about 10 mg of lenalidomide to be orally administered daily on days 1 to 21 of each dosing cycle.

[0474] 43. Use of lenalidomide in the manufacture of a medicament for treating a subject with previously untreated FL in combination with mosulatuzumab, wherein the subject is to be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21 day dosing cycle and eleven subsequent 28 day dosing cycles, wherein:

[0475] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0476] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab to be administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0477] (c) the second to twelfth dosing cycles each further comprise about 10 mg of lenalidomide to be orally administered daily on days 1 to 21 of each dosing cycle.

[0478] 44. A method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:

[0479] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0480] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0481] (c) the second to twelfth dosing cycles each further comprise oral administration of about 20 mg of lenalidomide per day on days 1 to 21 of each dosing cycle.

[0482] 45. Mosulatuzumab in combination with lenalidomide for use in treating a subject with previously untreated F), wherein the subject is to be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:

[0483] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0484] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab to be administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0485] (c) the second to twelfth dosing cycles each further comprise about 20 mg of lenalidomide to be orally administered daily on days 1 to 21 of each dosing cycle.

[0486] 46. ​​Lenalidomide in combination with mosulatuzumab for use in treating a subject with previously untreated FL, wherein the subject will be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:

[0487] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0488] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab to be administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0489] (c) the second to twelfth dosing cycles each further comprise about 20 mg of lenalidomide to be orally administered daily on days 1 to 21 of each dosing cycle.

[0490] 47. Use of mosulatuzumab in combination with lenalidomide for treating a subject with previously untreated FL, wherein the subject is to be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:

[0491] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0492] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab to be administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0493] (c) the second to twelfth dosing cycles each further comprise about 20 mg of lenalidomide to be orally administered daily on days 1 to 21 of each dosing cycle.

[0494] 48. The use of lenalidomide in combination with mosulatuzumab for treating a subject with previously untreated FL, wherein the subject is to be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:

[0495] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0496] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab to be administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0497] (c) the second to twelfth dosing cycles each further comprise about 20 mg of lenalidomide to be orally administered daily on days 1 to 21 of each dosing cycle.

[0498] 49. Use of mosulatuzumab in the manufacture of a medicament for treating a subject with previously untreated FL in combination with lenalidomide, wherein mosulatuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:

[0499] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0500] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab to be administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0501] (c) the second to twelfth dosing cycles each further comprise about 20 mg of lenalidomide to be orally administered daily on days 1 to 21 of each dosing cycle.

[0502] 50. Use of lenalidomide in the manufacture of a medicament for treating a subject with previously untreated FL in combination with mosulatuzumab, wherein the subject is to be administered mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21 day dosing cycle and eleven subsequent 28 day dosing cycles, wherein:

[0503] (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab to be administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg,

[0504] (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab to be administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and

[0505] (c) the second to twelfth dosing cycles each further comprise about 20 mg of lenalidomide to be orally administered daily on days 1 to 21 of each dosing cycle.

[0506] 51. The method, mosulatuzumab for use, lenalidomide for use or the use according to any one of embodiments 1 to 50, wherein the FL is histologically recorded as grade 1, 2 or 3a, but not grade 3b, according to the World Health Organization Classification of Lymphoid Neoplasms (as cited in Swerdlow SH et al. Blood 2016; 127: 2375-90).

[0507] 52. The method, mosulatuzumab for use, lenalidomide for use or the use according to any one of embodiments 1 to 51, wherein the subject has previously been determined to require systemic therapy to treat the previously untreated FL based on the Follicular Lymphoma Group (GELF) criteria (Brice et al. J Clin Oncol. 15(3): 1110-1117, 1997).

[0508] 53. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 1 to 52, wherein the first dosing cycle further comprises administration of a corticosteroid.

[0509] 54. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 1 to 53, wherein the second dosing cycle further comprises administration of a corticosteroid.

[0510] 55. The method, mosunituzumab for use, lenalidomide for use, or the use according to any one of embodiments 8 to 54, wherein any of the one or more additional dosing cycles comprises administration of a corticosteroid.

[0511] 56. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 53 to 55, wherein said corticosteroid is administered to said subject prior to or to said subject being administered a single dose of said corticosteroid.

[0512] 57. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 53 to 56, wherein the corticosteroid comprises dexamethasone or methylprednisolone.

[0513] 58. The method, mosunituzumab for use, lenalidomide for use or the use according to embodiments 53 to 57, wherein the corticosteroid is or is to be administered intravenously or orally.

[0514] 59. The method, mosunituzumab for use, lenalidomide for use, or the use according to embodiments 53 to 58, wherein the corticosteroid comprises dexamethasone and is or is to be administered at a dose of about 20 mg.

[0515] 60. The method, mosulatuzumab for use, lenalidomide for use, or the use according to embodiments 53 to 27, wherein the corticosteroid comprises methylprednisolone and is or is to be administered at a dose of about 58 mg.

[0516] 61. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 1 to 60, wherein the first dosing cycle further comprises administration of an antihistamine.

[0517] 62. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 1 to 61, wherein the second dosing cycle further comprises administration of an antihistamine.

[0518] 63. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 8 to 62, wherein any of the one or more additional dosing cycles comprises administration of an antihistamine.

[0519] 64. The method, mosulatuzumab for use, lenalidomide for use or the use according to any one of embodiments 61 to 63, wherein a single dose of the antihistamine is or will be administered to the subject prior to administration of any dose of mosulatuzumab.

[0520] 65. The method, mosulatuzumab for use, lenalidomide for use, or the use according to embodiment 64, wherein the antihistamine is or is to be administered to the subject at least 30 minutes prior to administration of any dose of mosulatuzumab.

[0521] 66. The method, mosunituzumab for use, lenalidomide for use, or the use according to any one of embodiments 61 to 65, wherein the antihistamine is or is to be administered intravenously or orally.

[0522] 67. The method, mosulatuzumab for use, lenalidomide for use or the use according to embodiments 61 to 66, wherein the antihistamine comprises diphenhydramine hydrochloride and is or is to be administered at a dose of about 50 to 100 mg.

[0523] 68. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 1 to 67, wherein the first dosing cycle further comprises the administration of an antipyretic.

[0524] 69. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 1 to 68, wherein the second dosing cycle further comprises administration of an antipyretic.

[0525] 70. The method, mosunituzumab for use, lenalidomide for use, or the use according to any one of embodiments 8 to 69, wherein any of the one or more additional dosing cycles comprises administration of an antipyretic.

[0526] 71. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 68 to 70, wherein a single dose of the antipyretic is or will be administered to the subject prior to administration of any dose of mosulatuzumab.

[0527] 72. The method, mosulatuzumab for use, lenalidomide for use, or the use according to embodiment 71, wherein the antipyretic is or is to be administered to the subject at least 30 minutes prior to administration of any dose of mosulatuzumab.

[0528] 73. The method, mosunituzumab for use, lenalidomide for use, or the use according to any one of embodiments 68 to 72, wherein the antipyretic is or is to be administered orally.

[0529] 74. The method, mosulatuzumab for use, lenalidomide for use or the use according to embodiments 68 to 73, wherein the antipyretic comprises acetaminophen and is or is to be administered at a dose of about 500 to 1000 mg.

[0530] 75. The method, mosulatuzumab for use, lenalidomide for use or the use according to embodiments 1 to 74, wherein the first dosing cycle further comprises the administration of an initial dose of a prophylactic agent against tumor lysis syndrome (TLS).

[0531] 76. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 1 to 75, wherein the second dosing cycle further comprises administration of an initial dose of a prophylactic agent against TLS.

[0532] 77. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 8 to 76, wherein any of the one or more additional dosing cycles comprises administration of an initial dose of a prophylactic agent against TLS.

[0533] 78. The method, mosulatuzumab for use, lenalidomide for use or the use according to any one of embodiments 75 to 77, wherein the initial dose of the prophylactic agent against TLS is or will be administered to the subject prior to administration of any dose of mosulatuzumab.

[0534] 79. The method, mosulatuzumab for use, lenalidomide for use, or the use according to any one of embodiments 75 to 78, wherein the prophylactic agent against TLS comprises allopurinol.

[0535] 80. The method, mosulatuzumab for use, lenalidomide for use, or the use according to embodiment 79, wherein the initial dose of allopurinol is or is to be administered about 72 hours prior to administration of any dose of mosulatuzumab.

[0536] 81. The method, mosunituzumab for use, lenalidomide for use, or the use according to embodiment 80, wherein an additional single dose of allopurinol is or will be administered daily for 6 to 10 days after administration of said initial dose.

[0537] 82. The method, mosunituzumab for use, lenalidomide for use, or the use according to any one of embodiments 79 to 81, wherein the initial dose of allopurinol is about 300 mg.

[0538] 83. The method, mosunituzumab for use, lenalidomide for use, or the use according to embodiment 81 or 82, wherein each additional single dose of allopurinol is about 300 mg.

[0539] 84. The method, mosunituzumab for use, lenalidomide for use, or the use according to any one of embodiments 79 to 83, wherein allopurinol is or is to be administered orally.

[0540] 85. The method, mosunituzumab for use, lenalidomide for use, or the use according to any one of embodiments 75 to 78, wherein the prophylactic agent against TLS comprises rasburicase.

[0541] 86. The method, mosulatuzumab for use, lenalidomide for use, or the use according to embodiment 85, wherein the initial dose of rasburicase is or is to be administered about 30 minutes prior to administration of any dose of mosulatuzumab.

[0542] 87. The method, mosulatuzumab for use, lenalidomide for use, or the use according to embodiment 86, wherein an additional single dose of rasburicase is or will be administered daily for 1 to 5 days after administration of said initial dose.

[0543] 88. The method, mosunituzumab for use, lenalidomide for use, or the use according to any one of embodiments 85 to 87, wherein the initial dose of rasburicase is about 0.2 mg / kg.

[0544] 89. The method, mosunituzumab for use, lenalidomide for use, or the use according to embodiment 87 or 88, wherein each additional single dose of rasburicase is about 0.2 mg / kg.

[0545] 90. The method, mosunituzumab for use, lenalidomide for use, or the use according to any one of embodiments 85 to 89, wherein rasburicase is or is to be administered intravenously.

[0546] 91. The method, mosunituzumab for use, lenalidomide for use, or the use according to any one of embodiments 1 to 90, wherein the first dosing cycle is a three-dose dosing cycle.

[0547] 92. The method, mosunituzumab for use, lenalidomide for use, or the use according to any one of embodiments 1 to 91, wherein the subject is a human.

[0548] Other embodiments

[0549] Although the present invention has been previously described in considerable detail by way of illustration and example for purposes of clarity of understanding, these descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated by reference in their entirety.

Claims

1. A method of treating a subject with previously untreated follicular lymphoma (FL), the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein: (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg, (b) a second dosing cycle comprising a single dose (C2D1) of mosulatuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and (c) the second dosing cycle further comprises orally administering between about 5 mg and about 20 mg of lenalidomide per day on days 1 to 21 of the second dosing cycle.

2. The method of claim 1, wherein the dosing regimen comprises one or more additional dosing cycles.

3. The method of claim 2, wherein the dosing regimen comprises one to ten additional dosing cycles.

4. The method of claim 2 or 3, wherein the dosing regimen comprises ten additional dosing cycles.

5. The method of any one of claims 2 to 4, wherein each of the one or more additional dosing cycles is about 28 days in length.

6. The method according to any one of claims 2 to 5, wherein each of the one or more additional dosing cycles comprises an additional single dose of mosulatuzumab.

7. The method of claim 6, wherein the additional single dose of mosulatuzumab is about 45 mg.

8. The method of claim 6 or 7, wherein the method comprises subcutaneously administering to the subject each additional single dose of mosulatuzumab on day 1 of each of the one or more additional dosing cycles.

9. The method according to any one of claims 1 to 8, wherein lenalidomide is not administered during the first dosing cycle.

10. The method according to any one of claims 2 to 9, wherein lenalidomide is administered orally during any of the one or more additional dosing cycles.

11. The method according to any one of claims 4 to 10, wherein lenalidomide is administered orally during each of the ten additional dosing cycles.

12. The method according to claim 10 or 11, wherein lenalidomide is administered orally on days 1 to 21 of each of the additional dosing cycles comprising administration of lenalidomide.

13. The method according to any one of claims 1 to 12, wherein lenalidomide is not administered in the last 7 days of any dosing cycle comprising administration of lenalidomide.

14. The method according to any one of claims 1 to 13, wherein lenalidomide is administered at a dose of about 10 mg.

15. The method according to any one of claims 1 to 13, wherein lenalidomide is administered at a dose of about 20 mg.

16. A method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein: (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8, and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg, (b) a second dosing cycle comprising a single dose (C2D1) of mosulatuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and (c) the second dosing cycle further comprises orally administering about 10 mg of lenalidomide daily on days 1 to 21 of the second dosing cycle.

17. A method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, wherein: (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, The C1D2 is about 45 mg, and the C1D3 is about 45 mg, (b) a second dosing cycle comprising a single dose (C2D1) of mosulatuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and (c) the second dosing cycle further comprises orally administering about 20 mg of lenalidomide daily on days 1 to 21 of the second dosing cycle.

18. A method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles, wherein: (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, The C1D2 is about 45 mg, and the C1D3 is about 45 mg, (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and (c) the second to twelfth dosing cycles each further comprise oral administration of about 10 mg of lenalidomide per day on days 1 to 21 of each dosing cycle.

19. A method of treating a subject having previously untreated FL, the method comprising administering to the subject mosulatuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles, wherein: (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosulatuzumab administered subcutaneously on day 1, day 8 and day 15 of the first dosing cycle, respectively, wherein the C1D1 is about 5 mg, The C1D2 is about 45 mg, and the C1D3 is about 45 mg, (b) the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosulatuzumab administered subcutaneously on day 1 of each dosing cycle, wherein each single dose C2D1 to C12D1 is about 45 mg, and (c) the second to twelfth dosing cycles each further comprise oral administration of about 20 mg of lenalidomide per day on days 1 to 21 of each dosing cycle.

20. The method according to any one of claims 1 to 19, wherein the FL is histologically recorded as grade 1, 2 or 3a, but not grade 3b, according to the World Health Organization Classification of Lymphoid Neoplasms (as cited in Swerdlow SH et al. Blood 2016; 127: 2375-90).

21. The method of any one of claims 1 to 20, wherein the subject has been previously determined to require systemic therapy for treatment of the previously untreated FL based on the Follicular Lymphoma Group (GELF) criteria (Brice et al. J Clin Oncol. 15(3): 1110-1117, 1997).

22. The method of any one of claims 1 to 21, wherein the first dosing cycle further comprises administration of a corticosteroid.

23. The method of any one of claims 1 to 22, wherein the second dosing cycle further comprises administration of a corticosteroid.

24. The method of any one of claims 2 to 23, wherein any of the one or more additional dosing cycles comprises administration of a corticosteroid.

25. The method of any one of claims 22 to 24, wherein a single dose of the corticosteroid is administered to the subject prior to administration of any dose of mosunituzumab.

26. The method of any one of claims 22 to 25, wherein the corticosteroid comprises dexamethasone or methylprednisolone.

27. The method of any one of claims 22 to 26, wherein the corticosteroid is administered intravenously or orally.

28. The method of any one of claims 22 to 27, wherein the corticosteroid comprises dexamethasone and is administered at a dose of about 20 mg.

29. The method of any one of claims 22 to 27, wherein the corticosteroid comprises methylprednisolone and is administered at a dose of about 80 mg.

30. The method of any one of claims 1 to 29, wherein the first dosing cycle further comprises administration of an antihistamine.

31. The method of any one of claims 1 to 30, wherein the second dosing cycle further comprises administration of an antihistamine.

32. The method of any one of claims 2 to 31, wherein any of the one or more additional dosing cycles comprises administration of an antihistamine.

33. The method of any one of claims 30 to 32, wherein a single dose of the antihistamine is administered to the subject prior to administration of any dose of mosulatuzumab.

34. The method of claim 33, wherein the antihistamine is administered to the subject at least 30 minutes prior to administration of any dose of mosulatuzumab.

35. The method of any one of claims 30 to 34, wherein the antihistamine is administered orally or intravenously.

36. The method of any one of claims 30 to 35, wherein the antihistamine comprises diphenhydramine hydrochloride and is administered at a dose of about 50-100 mg.

37. The method of any one of claims 1 to 36, wherein the first dosing cycle further comprises administration of an antipyretic drug.

38. The method of any one of claims 1 to 37, wherein the second dosing cycle further comprises administration of an antipyretic drug.

39. The method of any one of claims 2 to 38, wherein any of the one or more additional dosing cycles comprises administration of an antipyretic drug.

40. The method of any one of claims 37 to 39, wherein a single dose of the antipyretic is administered to the subject prior to administration of any dose of mosunituzumab.

41. The method of claim 40, wherein the antipyretic is administered to the subject at least 30 minutes prior to administration of any dose of mosulatuzumab.

42. The method of any one of claims 37 to 41, wherein the antipyretic is administered orally.

43. The method of any one of claims 37 to 42, wherein the antipyretic comprises acetaminophen and is administered at a dose of about 500-1000 mg.

44. The method of any one of claims 1 to 43, wherein the first dosing cycle further comprises administration of an initial dose of a prophylactic agent against tumor lysis syndrome (TLS).

45. The method of any one of claims 1 to 44, wherein the second dosing cycle further comprises administration of an initial dose of a prophylactic agent against TLS.

46. ​​The method of any one of claims 2 to 45, wherein any of the one or more additional dosing cycles comprises administration of an initial dose of a prophylactic agent against TLS.

47. The method of any one of claims 44 to 46, wherein the initial dose of the prophylactic agent against TLS is administered to the subject prior to administration of any dose of mosulatuzumab.

48. The method of any one of claims 44 to 47, wherein the prophylactic agent against TLS comprises allopurinol.

49. The method of claim 48, wherein the initial dose of allopurinol is administered about 72 hours prior to administration of any dose of mosunituzumab.

50. The method of claim 49, wherein additional single doses of allopurinol are administered daily for 6 to 10 days following administration of the initial dose.

51. The method of any one of claims 48 to 50, wherein the initial dose of allopurinol is about 300 mg.

52. The method of claim 50 or 51, wherein each additional single dose of allopurinol is about 300 mg.

53. The method of any one of claims 48 to 52, wherein allopurinol is administered orally.

54. The method of any one of claims 44 to 47, wherein the prophylactic agent against TLS comprises rasburicase.

55. The method of claim 54, wherein the initial dose of rasburicase is administered about 30 minutes prior to administration of any dose of mosunituzumab.

56. The method of claim 55, wherein additional single doses of rasburicase are administered daily for 1 to 5 days following administration of the initial dose.

57. The method of any one of claims 54 to 56, wherein the initial dose of rasburicase is about 0.2 mg / kg.

58. The method of claim 56 or 57, wherein each additional single dose of rasburicase is about 0.2 mg / kg.

59. The method of any one of claims 54 to 58, wherein rasburicase is administered intravenously.

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