Method for the treatment of previously untreated follicular lymphoma with mosunetuzumab and lenalidomide

Abstract

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

Description

Technical Field

[0001] Sequence Listing This application includes a sequence listing submitted electronically in XML format, which is hereby incorporated by reference in its entirety. The name of the XML copy created on June 2, 2023 is 50474-298WO2_Sequence_Listing_6_2_23, and the size is 34,004 bytes.

[0002] The present invention relates to the treatment of subjects having previously untreated follicular lymphoma (FL). More specifically, the present invention relates to the combination treatment of subjects having previously untreated FL by administration of mosunetuzumab and lenalidomide.

Background Art

[0003] Cancer is characterized by the uncontrolled growth of a subset of cells. Cancer is the leading cause of death in developed countries and the second most common cause of death in developing countries, with over 14 million new cancer cases diagnosed and over 8 million cancer deaths occurring each year. Low-grade cancers can also have a profound impact on quality of life. Therefore, cancer care has become an increasingly significant social burden.

[0004] B-cell proliferative disorders are a major cause of cancer-related death. For example, non-Hodgkin lymphoma (NHL) progresses rapidly and is fatal if untreated. Lymphomas of B-cell origin constitute a diverse series of neoplasms within the broader context of non-Hodgkin lymphoma (NHL). Follicular lymphoma (FL) is the most common subtype of low-grade NHL (Al-Hamandi et al. 2015). There is no standard treatment for the initial management of FL, and questions regarding the optimal anti-CD20 monoclonal antibody, the optimal chemotherapy backbone, and additional maintenance treatments remain unclear. Despite promising responses to first-line therapies based on currently available immunotherapies, most patients ultimately relapse. Relapse is characterized by increasing refractoriness, several important needs remain unmet, the therapies are not yet curative, and the majority of patients experience disease progression. Therefore, there is a need for novel therapies to increase antitumor activity and to prolong remission in patients with previously untreated FL.

Summary of the Invention

[0005] The present invention relates to a method of treating a subject having previously untreated follicular lymphoma (FL) by administration of mosunetuzumab and lenalidomide as a combination therapy. In particular, the present invention relates to a method of treating a subject having previously untreated FL by subcutaneous administration of mosunetuzumab and oral administration of lenalidomide.

[0006] In one aspect, the present invention is a method of treating a subject having previously untreated follicular lymphoma (FL), comprising administering mosunetuzumab and lenalidomide to the subject 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 mosunetuzumab administered subcutaneously on days 1, 8 (±1 day), and 15 (±1 day), respectively, of the first dosing cycle, wherein the 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; e.g., 5 mg), the 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 C1D3 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 (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein the 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; for example, 45 mg), and (c) the second dosing cycle comprises orally administering lenalidomide at about 5 mg to about 20 mg (for example, 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; for example, about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg) daily on days 1 to 21 of the second dosing cycle. In some embodiments, the first dosing cycle is a 3-dose dosing cycle (i.e., comprising three doses of mosunetuzumab)..

[0007] In some embodiments, the dosing regimen comprises 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 comprises 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) additional dosing cycles. In some embodiments, the dosing regimen comprises 10 additional dosing cycles. In some embodiments, the length of each of the one or more additional dosing cycles is about 28 days (±1 day).

[0008] In some embodiments, each of the one or more additional dosing cycles comprises an additional single dose of mosunetuzumab. In some embodiments, the method comprises subcutaneously administering to the subject each additional single dose of mosunetuzumab on day 1 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 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).

[0009] In some embodiments, lenalidomide is not administered during the first dosing cycle. In some embodiments, lenalidomide is orally administered during any 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 10 additional dosing cycles. In some embodiments, lenalidomide is orally administered on days 1 to 21 of each of the additional dosing cycles that include the administration of lenalidomide. In some embodiments, lenalidomide is not administered during the last 7 (±1 day) days of any dosing cycle that includes 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; e.g., 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).

[0010] In one aspect, the present invention is a method of treating a subject having previously untreated FL, comprising administering mosunetuzumab and lenalidomide to the subject 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 mosunetuzumab administered subcutaneously on days 1, 8 (±1 day), and 15 (±1 day), respectively, of the first dosing cycle, 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; 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 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 dosing cycle comprises a single dose (C2D1) of mosunetuzumab 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 orally administering 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 daily from days 1 to 21 of the second dosing cycle.

[0011] In one aspect, the present invention is a method of treating a subject having previously untreated FL, comprising administering mosunetuzumab and lenalidomide to the subject 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 mosunetuzumab administered subcutaneously on days 1, 8 (±1 day), and 15 (±1 day) of the first dosing cycle, 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; 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 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 dosing cycle comprises a single dose (C2D1) of mosunetuzumab 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 orally administering 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 daily from days 1 to 21 of the second dosing cycle.

[0012] In one aspect, the present invention is a method of treating a subject having previously untreated FL, comprising administering mosunetuzumab and lenalidomide to the subject according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and 11 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 mosunetuzumab administered subcutaneously on days 1, 8 (±1 day), and 15 (±1 day), respectively, of the first dosing cycle, 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; 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 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-C12D1) of mosunetuzumab administered subcutaneously on day 1 of each dosing cycle, and each single dose C2D1-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), and (c) the second to twelfth dosing cycles each comprise 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.Further comprising orally administering lenalidomide at a dose of 75 mg, ±1 mg, or ±2 mg; for example, 10 mg). The method is characterized by this.

[0013] In one aspect, the present invention is a method of treating a subject having previously untreated FL, comprising administering mosunetuzumab and lenalidomide to the subject according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and 11 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 mosunetuzumab administered subcutaneously on days 1, 8 (±1 day), and 15 (±1 day), respectively, of the first dosing cycle, 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; 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 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-C12D1) of mosunetuzumab administered subcutaneously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 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 to twelfth dosing cycles each comprise, daily from days 1 to 21 of each dosing cycle, 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.Characterized by a method further comprising orally administering lenalidomide at a dose of 5 mg, ±2 mg, ±3 mg, or ±4 mg; for example, 20 mg).

[0014] In some embodiments, FL is histologically demonstrated to be grade 1, 2 or 3a according to the World Health Organization classification of lymphoid neoplasms (as referenced in Swerdlow SH, et al. Blood 2016;127:2375-90), but not 3b.

[0015] In some embodiments, the subject has previously been determined to require systemic therapy to treat previously untreated FL based on the follicular lymphoma research group (GELF) criteria (Brice et al., J Clin Oncol. 15(3):1110-1117, 1997).

[0016] In some embodiments, the first dosing cycle further comprises administration of a corticosteroid. In some embodiments, the second dosing cycle further comprises administration of a corticosteroid. In some embodiments, any of one or more additional dosing cycles comprises administration of a corticosteroid. In some embodiments, a single dose of corticosteroid is administered to the subject prior to administration of any dose of mosunetuzumab. In some embodiments, the corticosteroid comprises dexamethasone or methylprednisolone. In some embodiments, the corticosteroid is administered intravenously or orally. In some embodiments, the corticosteroid comprises dexamethasone and 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). 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).

[0017] In some embodiments, the first dosing cycle further includes administration of an antihistamine. In some embodiments, the second dosing cycle further includes administration of an antihistamine. In some embodiments, any of one or more additional dosing cycles includes administration of an antihistamine. In some embodiments, a single dose of an antihistamine is administered to a subject prior to (e.g., 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, or more prior to) administration of any dose of mosunetuzumab. In some embodiments, the antihistamine is administered to a subject at least 30 minutes (e.g., 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, or more) prior to administration of any dose of mosunetuzumab. In some embodiments, the antihistamine is administered orally or intravenously. In some embodiments, the antihistamine comprises diphenhydramine hydrochloride and is administered at a dose of about 50 - 100 mg (e.g., 50 - 90 mg, 50 - 80 mg, 50 - 70 mg, 50 - 60 mg, 60 - 100 mg, 70 - 100 mg, 80 - 100 mg, 90 - 100 mg, 70 - 80 mg, 60 - 90 mg, 60 - 80 mg, 70 - 90 mg, or 65 - 85 mg; e.g., 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).

[0018] In some embodiments, the first dosing cycle further comprises administration of an antipyretic. In some embodiments, the second dosing cycle further comprises administration of an antipyretic. In some embodiments, any of one or more additional dosing cycles comprises administration of an antipyretic. In some embodiments, a single dose of an antipyretic is administered to the subject prior to administration of any dose of mosunetuzumab. In some embodiments, the antipyretic is administered to the subject at least 30 minutes (e.g., 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, or more) prior to administration of any dose of mosunetuzumab. In some embodiments, the antipyretic is administered orally. In some embodiments, the antipyretic comprises acetaminophen and is administered in a dose of about 500 - 1000 mg (e.g., 500 - 900 mg, 500 - 800 mg, 500 - 700 mg, 500 - 600 mg, 600 - 1000 mg, 700 - 1000 mg, 800 - 1000 mg, 900 - 1000 mg, 700 - 800 mg, 600 - 900 mg, 600 - 800 mg, 700 - 900 mg, or 650 - 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).

[0019] In some embodiments, the first dosing cycle further includes administration of a first dose of a prophylactic agent against tumor lysis syndrome (TLS). In some embodiments, the second dosing cycle further includes administration of a first dose of a prophylactic agent against TLS. In some embodiments, any one of one or more additional dosing cycles includes administration of a first dose of a prophylactic agent against TLS. In some embodiments, a first dose of a prophylactic agent against TLS is administered to the subject prior to administration of any dose of mosunetuzumab. In some embodiments, the prophylactic agent against TLS comprises allopurinol. In some embodiments, the first dose of allopurinol is administered approximately 72 hours (e.g., 72 ± 0.5 hours, ± 1 hour, ± 2 hours, ± 3 hours, ± 4 hours, ± 8 hours, ± 12 hours, or ± 16 hours; e.g., 72 hours) prior to administration of any dose of mosunetuzumab. In some embodiments, an additional single dose of allopurinol is administered daily for 6 - 10 days (± 1 day) after administration of the first dose. In some embodiments, the first 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 prophylactic agent against TLS comprises rasburicase. In some embodiments, the first dose of rasburicase is administered approximately 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 administration of any dose of mosunetuzumab. In some embodiments, an additional single dose of rasburicase is administered daily for 1 - 5 days (± 1 day) after administration of the first dose. In some embodiments, the first 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 razumab 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, razumab is administered intravenously.

Brief Description of the Drawings

[0020]

Figure 1

Modes for Carrying Out the Invention

[0021] The present invention relates to a method of treating a subject having previously untreated follicular lymphoma (FL) by administration of mosunetuzumab and lenalidomide as a combination therapy. The methods described herein include subcutaneously administering mosunetuzumab to a subject and orally administering lenalidomide according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab, and (b) the second dosing cycle comprises a first dose (C2D1) of mosunetuzumab and a daily dose of lenalidomide. In particular, the first dosing cycle is a 21-day (±1 day) dosing cycle, and the C1D1, C1D2 and C1D3 doses are administered on days 1, 8 (±1 day) and 15 (±1 day), respectively, or on approximately day 1, approximately day 8 (±1 day) and approximately day 15 (±1 day), and the second dosing cycle is a 28-day (±1 day) dosing cycle, and C2D1 is administered on day 1. Further, lenalidomide is administered on days 1 to 21 of the second dosing cycle. The methods of the present invention further include administration of additional therapeutic agents, such as premedication (e.g., using corticosteroids, antihistamines, antipyretics, or prophylactic agents for tumor lysis syndrome (TLS)).

[0022] I. General Technology The technologies and procedures described or referenced in this specification are generally well understood. For example, Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.I. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993 - 8) J.Wiley and Sons; Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M.Conventional methodologies such as those widely used methodologies described in Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 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, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993) are commonly used by those skilled in the art.

[0023] II. Definitions It is understood that the aspects and embodiments of the invention described herein include those aspects and embodiments "comprising", "consisting of", and "consisting essentially of".

[0024] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated.

[0025] As used herein, the term "about" refers to the normal error range of each value that would be readily understood by one of ordinary skill in the art. References to a value or parameter following "about" in this specification include (and describe) embodiments that are directed to that value or parameter itself. In some embodiments, the term "about" value or parameter refers to that value or parameter ±10%.

[0026] "Disorder" includes any condition for which treatment would be beneficial, including, but not limited to, chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to the disorder in question.

[0027] The terms "cell proliferative disorder" and "proliferative disorder" refer to disorders that involve 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.

[0028] The terms "cancer" and "cancerous" refer to or describe physiological conditions in mammals typically characterized by uncontrolled cell growth. Examples of cancers include, but are not limited to, blood cancers such as mature B-cell cancers including non-Hodgkin lymphomas (NHL) such as diffuse large B-cell lymphoma (DLBCL) which can be Richter's transformation except Hodgkin lymphoma. Other specific examples of cancers 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 (PMLBCL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), transformed LL, Waldenström macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt lymphoma (BL), B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, unclassifiable, splenic diffuse red pulp small B-cell lymphoma, hairy cell leukemia variant, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasmacytic myeloma, solitary plasmacytoma of bone, extramedullary plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodal 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, lower extremity type, EBV-positive DLBCL in the elderly, DLBCL associated with chronic inflammation, lymphomatoid granulomatosis, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma resulting from HHV8-related multicentric Castleman disease, primary effusion lymphoma: an unclassifiable B-cell lymphoma with intermediate features between DLBCL and Burkitt lymphoma, and an unclassifiable B-cell lymphoma with intermediate features between DLBCL and classical Hodgkin lymphoma are also included.Further examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and lymphoid malignancies including leukemia or B-cell lymphoma. Even more specific examples of such cancers include 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-cleaved cell NHL; large tumor lesion NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myelogenous leukemia; and post-transplant lymphoproliferative disorder (PTLD).

[0029] As used herein, the term "tumor" refers to the growth and proliferation of all neoplastic cells, whether malignant or benign, as well as all precancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive as used herein.

[0030] The term "B-cell proliferative disorder" or "B-cell malignancy" refers to disorders involving some abnormal B-cell proliferation, including, for example, lymphomas, leukemias, myelomas, and myelodysplastic syndromes. In some examples, a B-cell proliferative disorder is a lymphoma such as non-Hodgkin lymphoma (NHL), including, for example, follicular lymphoma (FL) (e.g., previously untreated FL). In certain embodiments, a subject having previously untreated FL is determined to require systemic therapy to treat the previously untreated FL based on the follicular lymphoma prognostic index (FLIPI) criteria (Brice et al., J Clin Oncol. 15(3):1110-1117, 1997).

[0031] The terms "Follicular Lymphoma Study Group (Groupe d’Etude des Lymphomes Folliculaires) criteria" and "GELF criteria" refer to criteria for determining whether immediate treatment is required for follicular lymphoma. In particular, a subject or individual who meets one or more GELF criteria is determined to require treatment. The GELF criteria include: (i) any nodal or extranodal tumor mass with a diameter of 7 cm or more; (ii) metastases to at least three nodal sites each with a diameter exceeding 3 cm; (iii) the presence of B symptoms (e.g., fever, night sweats, and weight loss); (iv) splenomegaly (exceeding 16 cm on computed tomography (CT) scan); (v) the risk of local compressive symptoms that can cause organ damage; (vi) pleural effusion or ascites; (vii) leukemic phase (>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.

[0032] The "Follicular Lymphoma International Prognostic Index" or "FLIPI" refers to a scoring system or index for determining the prognostic risk of patients (having, for example, cancer; for example, NHL; for example, follicular lymphoma (FL)). The FLIPI score ranges from 0 to 5 depending on how many of the following five symptoms or risk factors a patient may have: (i) age 60 years or older; (ii) Ann Arbor stage III-IV; hemoglobin level ≤ 120 g / L; serum lactate dehydrogenase (LDH) level ≥ upper limit of normal value (ULN) (for example, > 280 units / L); and (v) number of nodal sites > 4. The FLIPI risk groups are defined as follows. (a) 0 or 1 FLIPI risk factors = low risk group; (b) 2 FLIPI risk factors = intermediate risk group; (c) 3 - 5 FLIPI risk factors = high risk group. See, for example, Solal-Celigny et al. Blood. 2004;104(5):1258-1265, Table 4.

[0033] As used herein, the term "Ann Arbor staging" or "Ann Arbor stage" refers to a system for classifying the stage of lymphoma (e.g., NHL, e.g., FL, e.g., previously untreated FL). Lymphoma (e.g., NHL) can be classified as one of four Ann Arbor stages. Stage I refers to lymphoma with involvement of a single lymph node region or a single extranodal organ or site. Stage II refers to lymphoma with involvement of two or more lymph node regions on the same side of the diaphragm. Stage III refers to lymphoma with involvement of lymph node regions on both sides of the diaphragm (III) that may be associated with limited involvement of an extranodal organ or site, involvement of the spleen, or both. Stage IV refers to lymphoma with diffuse or disseminated involvement of one or more extranodal organs or tissues, with or without associated lymphadenopathy. Liver metastases are always considered to be diffuse and are therefore always considered to be Ann Arbor stage IV. Lymphoid structures include lymph nodes, thymus, spleen, appendix, Waldeyer's ring, and Peyer's patches. See Carbone, P.P. et al., Cancer Res. 1971, 31(11):1860-1861.

[0034] As used herein, "treatment" (and its grammatical variations such as "treat" or "treating") refers to a clinical intervention in an attempt to alter the natural course of the subject being treated, and can be implemented for prophylaxis or during the course of a clinical condition. Desirable effects of treatment include, but are not limited to, preventing the onset or recurrence of a disease, alleviating symptoms, attenuating the direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, improving or alleviating the condition, and achieving remission or improving the prognosis. In some embodiments, the antibodies of the invention are used to delay the onset of a disease or to delay the progression of a disease.

[0035] As used herein, "retarding the progression" of a disorder or disease refers to delaying, preventing, slowing, deferring, stabilizing, and / or postponing the onset of a disease or disorder (e.g., previously untreated FL). This delay can be for varying lengths of time depending on the medical history and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can, in effect, encompass prevention in that the individual does not develop the disease. For example, it can retard the onset of advanced cancers such as metastases.

[0036] "Extending survival" means increasing the overall survival or progression-free survival in a treated patient / animal compared to an untreated patient / animal (e.g., compared to a patient / animal not treated with a medicament), and / or compared to a patient / animal not expressing a biomarker at a specified level, and / or compared to a patient / animal treated with an approved anti-tumor agent. Objective response refers to a measurable response including a complete response (CR) or a partial response (PR).

[0037] "Reduce" or "inhibit" means, for example, the ability to cause an overall decrease of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more. For clarity, this term also includes a reduction to zero (or below the detection limit of the assay method), i.e., complete disappearance or elimination. In certain embodiments, "reduce" or "inhibit" refers to a decrease or inhibition of undesirable events such as cytokine-induced 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 after treatment with mosunetuzumab using the step-up dosing regimen of the present invention compared to a preset dosing without modification of the target dose of mosunetuzumab. In other embodiments, "reduce" or "inhibit" can refer to the effector functions of an antibody mediated by the Fc region of the antibody, and such effector functions specifically include complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP). In other embodiments, "reduce" or "inhibit" can refer to the symptoms of FL, the presence or size of metastases, or the size of the primary tumor that have not been treated prior to treatment. In yet other embodiments, reducing or inhibiting cancer recurrence means reducing or inhibiting tumor or cancer recurrence, or tumor or cancer progression (e.g., reducing the risk of progression and / or recurrence of FL or preventing progression and / or recurrence of FL).

[0038] As used herein, "administering" means a method of giving a dosage 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 prophylactic agent for tumor lysis syndrome (TLS)) or a composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition containing a bispecific antibody (e.g., mosunetuzumab) or other therapeutic agent) to a subject. The compounds and / or compositions utilized in the methods described herein can be administered subcutaneously (e.g., by injection), intravenously (e.g., by intravenous infusion), or orally.

[0039] As used herein, a "fixed" or "constant" dosage of a therapeutic agent (e.g., a bispecific antibody) refers to a dosage that is administered to a patient / animal subject regardless of the patient / animal subject's body weight or body surface area (BSA). Thus, this fixed or constant dosage is provided as an absolute amount (e.g., mg) of the therapeutic agent rather than as a mg / kg dosage or mg / m 2 dosage.

[0040] A "subject" or "individual" is a mammal. Mammals include, but are not limited to, primates (e.g., humans and non-human primates, e.g., monkeys), livestock (e.g., cows, sheep, cats, dogs, and horses), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the subject or individual is a human.

[0041] "Individual response" or "response" can be evaluated using any endpoint that indicates a benefit to a subject, including but not limited to: (1) some inhibition of disease progression (e.g., progression of previously untreated FL) including deceleration and complete cessation, (2) reduction in tumor size, (3) inhibition (i.e., reduction, deceleration or complete cessation) of cancer cell invasion into adjacent peripheral organs and / or tissues, (4) inhibition of metastasis (i.e., reduction, deceleration or complete cessation), (5) some alleviation of one or more symptoms associated with previously untreated FL, (6) increase or prolongation of the length of survival including overall survival and progression-free survival, and / or (7) decrease in mortality at a given time point after treatment. In some embodiments, the efficacy of treatment of previously untreated FL is evaluated using the Lugano response criteria for malignant lymphoma (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0042] As used herein, the "Lugano criteria" or "Lugano response criteria" for malignant lymphoma are a set of criteria for evaluating response assessment (e.g., of a PET / CT scan) to the methods of treatment described herein. The Lugano criteria are set forth in Table 1 below. [Table 1] TIFF2025521501000002.tif252170TIFF2025521501000003.tif88170

[0043] For evaluation, target lesions should include up to the six largest target lymph nodes, lymph node tumors, or other lymphomatous lesions measurable in two diameters, identified from different body regions representing the overall disease burden of the patient / animal, including mediastinal and retroperitoneal disease if metastatic. At baseline, measurable lymph nodes must have a longest diameter (LDi) greater than 15 mm. Measurable extranodal disease may be included in the six representative measured lesions. At baseline, measurable extranodal lesions must have an LDi greater than 10 mm. All other lesions (including lymph node, extranodal, and evaluable disease) should be observed as non-measurable disease as non-target lesions (e.g., skin, gastrointestinal, bone, spleen, liver, kidney, pleural or pericardial fluid collections, ascites, bone, bone marrow). Lesions may divide or coalesce over time. In the case of divided lesions, the individual products of the perpendicular diameters (PPDs) of the lymph nodes should be added together to represent the PPD of the divided lesion, and for measuring response, this PPD is added to the sum of the PPDs of the remaining lesions. If growth occurs in any or all of these separated lymph nodes, the nadir of each individual lymph node is used to determine progression. In the case of coalesced lesions, the PPD of the coalesced tumor should be compared to the sum of the PPDs of the individual lymph nodes, and for progressive disease to be indicated, the PPD of the coalesced tumor must increase by more than 50% compared to the sum of the individual lymph nodes. LDi and shortest diameter (SDi) are no longer required to determine progression.

[0044] As used herein, “objective response rate” (ORR) refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0045] As used herein, “duration of objective response” (DOR) is defined as the time from the first occurrence of an objective response documented in the record until disease progression, recurrence, or death from any cause (whichever occurs first).

[0046] As used herein, "duration of complete response" (DOCR) is defined as the time from the first occurrence of complete response recorded in the document until disease progression, recurrence, or death from any cause (whichever occurs first).

[0047] As used herein, "tumor burden" refers to the total amount of tumors (e.g., tumor cells or tumor masses) in a subject (e.g., a human subject) having cancer, such as NHL, such as FL. In some embodiments, tumor burden is defined as the sum of the diameters of the target lesions or the sum of products of the target lesions. In certain embodiments, tumor burden is defined as the sum of products of the diameters of the (SPD) target lesions. In some embodiments, the diameters of the target lesions are quantified by computed tomography (CT).

[0048] "Sustained response" refers to a sustained effect on reducing tumor growth after a treatment break. For example, the tumor size can remain the same or be smaller compared to the size at the start of the dosing phase. In some embodiments, the sustained response has a length of at least the same period as the treatment period, at least 1.5 times, 2.0 times, 2.5 times, or 3.0 times the length of the treatment period.

[0049] "Effective response" of a subject to treatment with a medicament or "responsiveness" of a subject and similar terms refer to the clinical or therapeutic benefit conferred on a subject at risk of a disease or disorder such as cancer or suffering from a disease or disorder such as cancer. In one embodiment, such benefits include any one or more of extending the survival period (including overall survival period and progression-free survival period), bringing about an objective response (including complete response or partial response), or improving the signs or symptoms of cancer.

[0050] A subject "not having an effective response" to a treatment refers to a subject who does not have any one of extending the survival period (including overall survival period and progression-free survival period), bringing about an objective response (including complete response or partial response), or improving the signs or symptoms of cancer.

[0051] As used herein, "survival" refers to a patient / animal being alive and includes overall survival and progression-free survival.

[0052] As used herein, "overall survival" (OS) refers to the proportion of subjects in a group who are alive at a specific time period, e.g., 1 year or 5 years after the time of diagnosis or treatment.

[0053] As used herein, "progression-free survival" (PFS) refers to the length of time during and after treatment during which the treated disease (e.g., previously untreated FL) does not worsen. Progression-free survival can include the amount of time a patient / animal experiences a complete response or partial response, and the amount of time a patient / animal experiences stable disease.

[0054] The term "antibody" as used herein is used in the broadest sense and encompasses various antibody structures including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0055] "Antibody fragment" refers to a molecule other than an intact antibody that includes a portion of an intact antibody that binds an antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab’, Fab’-SH, F(ab’)2, diabody, linear antibodies, single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0056] 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 a heavy chain that contains an Fc region as defined herein.

[0057] The term "surface antigen classification 3" or "CD3", as used herein, unless otherwise indicated, refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), and includes, for example, the CD3ε, CD3γ, CD3α, and CD3β chains. This term encompasses "full-length" unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ), and any form of CD3 resulting from intracellular processing. This term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, the human CD3ε protein that is 207 amino acids in length (NCBI reference sequence number NP_000724), and the human CD3γ protein that is 182 amino acids in length (NCBI reference sequence number NP_000064).

[0058] The term "surface antigen classification 20" or "CD20", as used herein, unless otherwise indicated, refers to any native CD20 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). This term encompasses "full-length" unprocessed CD20, and any form of CD20 resulting from intracellular processing. This term also encompasses naturally occurring variants of CD20, including, for example, splice variants or allelic variants. CD20 includes, for example, the human CD20 protein (see, e.g., NCBI reference sequence numbers NP_068769.2 and NP_690605.1), which is 297 amino acids in length and can be produced from, for example, a variant mRNA transcript that lacks a portion of the 5'UTR (see, e.g., NCBI reference sequence number NM_021950.3), or a longer variant mRNA transcript (see, e.g., NCBI reference sequence number NM_152866.2).

[0059] 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 mosunetuzumab.

[0060] As used herein, the term "mosunetuzumab" refers to an anti-CD20 / anti-CD3 bispecific antibody having the International Nonproprietary Name (INN) listed in List 117 (WHO Drug Information, Vol. 31, No. 2, 2017, p. 304 - 305) or the CAS Registry Number 1905409-39-3.

[0061] As used herein, the term "lenalidomide" refers to a compound having the CAS Registry Number 191732-72-6 and the 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 REVLIMID®, Lenamide, and Lenalid. Lenalidomide has the DrugBank accession number DB00480, PubChem CID 216326, and the chemical formula C 13 H 13 N3O3.

[0062] As used herein, the terms "bind", "specifically bind to", or "is specific for" refer to a measurable and reproducible interaction such as the binding between a target and an antibody, which 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 can be an epitope) binds to this target with a higher affinity, binding activity, more readily, and / or for a longer period than to other targets. In one embodiment, the degree to which the antibody binds to an irrelevant target is, for example, less than about 10% of the binding of the antibody to the target as measured by radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds to a target has a dissociation constant (K D) It has. In certain embodiments, the antibody specifically binds to an epitope on a protein that is conserved between proteins from different species. In another embodiment, specific binding can include, but does not require, exclusive binding. As used herein, the term, for example, 10 -4 M or less, or 10 -5 M or less, or 10 -6 M or less, or 10 -7 M or less, or 10 -8 M or less, or 10 -9 M or less, or 10 -10 M or less, or 10 -11 M or less, or 10 -12 M or less for a target of K D , or 10 -4 M to 10 -6 M or 10 -6 M to 10 -10 M or 10 -7 M to 10 -9 M of K D can be shown by a molecule having. As will be understood by those skilled in the art, affinity and K D values are inversely correlated. High affinity for an antigen is measured by a low K D value. In one embodiment, the term "specific binding" refers to a binding in which a molecule binds to a particular polypeptide or an epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

[0063] 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 constituent that is unduly toxic to the subject to which the preparation is administered.

[0064] "Pharmaceutically acceptable carrier" refers to a component in a pharmaceutical formulation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers or preservatives.

[0065] As used herein, the term "chemotherapeutic agent" refers to a compound useful in the treatment of cancers such as previously untreated FL. Examples of chemotherapeutic agents include EGFR inhibitors (including small molecule inhibitors (e.g., erlotinib (TARCEVA®, Genentech / OSI Pharm.); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 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-quinolyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); and dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolineamine)); tyrosine kinase inhibitors (e.g., EGFR inhibitors;Low molecular weight HER2 tyrosine kinase inhibitors, such as TAK165 (Takeda); CP-724,714 (Pfizer and OSI), an oral selective inhibitor of the ErbB2 receptor tyrosine kinase; dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but inhibits both cells overexpressing HER2 and cells overexpressing EGFR; PKI-166 (Novartis); pan-HER inhibitors, such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors, such as the antisense agent ISIS-5132 (ISIS Pharmaceuticals) that inhibits Raf-1 signaling; non-HER target tyrosine kinase inhibitors, such as imatinib mesylate (GLEEVEC®, Glaxo Smithkline); multi-target tyrosine kinase inhibitors, such as sunitinib (SUTENT®, Pfizer); VEGF receptor tyrosine kinase inhibitors, such as bevacizumab (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 CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tilorone containing a nitrothiophene moiety; PD-0183805 (Warner-Lambert); antisense molecules (e.g., those that bind to nucleic acids encoding HER); quinoxalines (U.S. Patent No. 5,804,396); tilorone (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering); 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, RAPAMUNE®); proteasome inhibitors such as bortezomib (VELCADE®, Millennium Pharm.); disulfiram; epigallocatechin gallate; salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; lactate dehydrogenase A (LDH-A); fulvestrant (FASLODEX®, AstraZeneca); letrozole (FEMARA®, Novartis), finasunate (VATALANIB®, Novartis); oxaliplatin (ELOXATIN®, Sanofi); 5-FU (5-fluorouracil); leucovorin; lonafarnib (SCH 66336); sorafenib (NEXAVAR®, Bayer Labs); AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carbocone, meturedopa and uredopa; altretamine, ethyleneimine and methylamelamine including triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; acetogenins (particularly bratasin and bratasinone); camptothecin (including topotecan and irinotecan); bryostatin; calistatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, dacostat;Aldesleukin, talc duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); erythrobicin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chloroozotocin, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γ1 and calicheamicin ω1); dynemicin including dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophore and related pigment proteins enediyne antibiotic chromophores), aclacinomycin, actinomycin, anthramycin, azaserine, cactinomycin, carabicin, caminomycin, cardinophilin, chromomycin, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;Pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, drostanolone propionate, epithioestanol, mepitiostane, testolactone; anti-adrenergic drugs, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid; aceglutamide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demeclocycline; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products); razoxane; rizoxin; schizophyllan; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2’’-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); thiotepa; chlorambucil; GEMZAR (registered trademark) (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; etoposide (VP-16); ifosfamide; mitoxantrone; novantrone; teniposide; edatraxate; daunomycin; aminopterin; capecitabine (XELODA (registered trademark)); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid;and any of the above pharmaceutically acceptable salts, acids, prodrugs and derivatives are included;

[0066] Chemotherapeutic agents also include: (i) antihormonal agents that act to modulate or inhibit the hormonal action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), for example, tamoxifen (NOLVADEX®; including tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone and FARESTON® (toremifene citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase that regulates estrogen production in the adrenal glands, for example, 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestane, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprorelin and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, Premarin, fluoxymesterone, all-trans retinoic acid, fenretinide, and troxacitabine (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 involved in abnormal cell proliferation, such as PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) gene therapy vaccines, such as ALLOVECTIN®, LEUVECTIN® and VAXID® vaccines;(ix) Growth inhibitors including vinca (e.g., vincristine and vinblastine), NAVELBINE® (vinorelbine), taxanes (e.g., paclitaxel, nab-paclitaxel, and docetaxel), topoisomerase II inhibitors (e.g., doxorubicin, epirubicin, daunorubicin, etoposide and bleomycin), and DNA alkylating agents (e.g., tamoxifen, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C); and (x) pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the foregoing are included.;

[0067] The term "chemoimmunotherapy" refers to a combination therapy that includes both chemotherapeutic agents and immunotherapeutic agents. In some embodiments, chemoimmunotherapy is used to treat cancer, such as CD20-positive cancer, such as NHL, such as FL. In some embodiments, immunotherapeutic agents include antibodies, such as anti-CD20 antibodies (e.g., anti-CD20 monoclonal antibodies). In some embodiments, the anti-CD20 antibody or anti-CD20 monoclonal antibody is rituximab or obinutuzumab. In some embodiments, chemoimmunotherapy includes R-CHOP.

[0068] As used herein, the term "cytotoxic agent" refers to any agent that is harmful to cells (e.g., causes cell death, inhibits proliferation, or otherwise interferes with cell function). Cytotoxic agents include radioisotopes (e.g., 211 At, 131 I, 125 I, 90 Y, 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P, 212Radioisotopes of Pb and Lu; chemotherapeutic agents; enzymes such as nucleolytic enzymes and fragments thereof; and toxins, such as small molecule toxins or enzymatically active toxins (including fragments and / or variants thereof) of bacterial, fungal, plant or animal origin, are included but not limited thereto. Exemplary cytotoxic agents can be selected from antimicrotubule 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, apoptosis promoters, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signal transduction inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. In one example, the cytotoxic agent is a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin). In one example, the cytotoxic agent is an antagonist of EGFR, such as N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (e.g., erlotinib). In one example, the cytotoxic agent is a RAF inhibitor, such as a BRAF and / or CRAF inhibitor. In one example, the RAF inhibitor is vemurafenib. In one example, the cytotoxic agent is a PI3K inhibitor.

[0069] The term "package insert" is used to refer to the instructions customarily included in the commercial package of a therapeutic product, which contains information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings regarding the use of such therapeutic product.

[0070] III. Treatment Methods Provided herein is a method of treating a subject having previously untreated follicular lymphoma (FL) by administration of mosunetuzumab and lenalidomide as combination therapy. In particular, the invention relates to a method of treating a subject having 1 / L FL by subcutaneous administration of mosunetuzumab and oral administration of lenalidomide. In some embodiments, the FL is grade-classified FL (e.g., grade 1, 2, or 3a, but not grade 3b FL). In some embodiments, the FL of each subject is histologically demonstrated to be grade 1, 2, or 3a, but not 3b, according to the World Health Organization classification of lymphoid neoplasms (as referenced in Swerdlow SH, et al. Blood 2016;127:2375-90).

[0071] In some instances, the subject has not been treated by any standard or investigational anti-cancer therapy, including but not limited to: (i) lenalidomide exposure within 12 months prior to administration of the first dose of mosunetuzumab (e.g., the C1D1 dose) of the method of the invention; (ii) fludarabine or alemtuzumab within 12 months prior to administration of the first dose of mosunetuzumab (e.g., the C1D1 dose) of the method of the invention; (iii) a radioimmunoconjugate within 12 weeks prior to administration of the first dose of mosunetuzumab (e.g., the C1D1 dose) of the method of the invention; (iv) a prior anti-lymphoma treatment with a monoclonal antibody or antibody-drug conjugate within 4 weeks prior to administration of the first dose of mosunetuzumab (e.g., the C1D1 dose) of the method of the invention; and (v) treatment with any chemotherapeutic agent or any other anti-cancer agent (investigational or otherwise) within 4 weeks or within 5 half-lives of the drug (whichever is shorter) prior to administration of the first dose of mosunetuzumab (e.g., the C1D1 dose) of the method of the invention.

[0072] In some embodiments, the subject has been previously determined to require systemic therapy to treat previously untreated FL based on follicular lymphoma study group (GELF) criteria (Brice et al., J Clin Oncol. 15(3):1110-1117, 1997).

[0073] A. Therapeutic method for the administration of mosunetuzumab and lenalidomide The present invention relates to a method of treating a subject having previously untreated follicular lymphoma (FL) by administration of mosunetuzumab and lenalidomide as a combination therapy. In particular, the present invention relates to a method of treating a subject having previously untreated FL by subcutaneous administration of mosunetuzumab and oral administration of lenalidomide.

[0074] In one aspect, the present invention is a method of treating a subject having previously untreated follicular lymphoma (FL), comprising administering mosunetuzumab and lenalidomide to the subject 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 mosunetuzumab administered subcutaneously on days 1, 8 (±1 day), and 15 (±1 day), respectively, of the first dosing cycle, 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; 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 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 (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab 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; for example, 45 mg), and (c) the second dosing cycle comprises orally administering lenalidomide at about 5 mg to about 20 mg (for example, 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; for example, about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg) daily on days 1 to 21 of the second dosing cycle. In some embodiments, the first dosing cycle is a 3-dose dosing cycle (i.e., comprising three doses of mosunetuzumab)..

[0075] In some embodiments, the dosing regimen comprises 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 comprises 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) additional dosing cycles. In some embodiments, the dosing regimen comprises 10 additional dosing cycles. In some embodiments, the length of any one or more of the additional dosing cycles is about 28 days (±1 day). In some embodiments, the length of each of the one or more additional dosing cycles is about 28 days (±1 day).

[0076] In some embodiments, any one of the one or more additional dosing cycles comprises an additional single dose of mosunetuzumab. In some embodiments, each of the one or more additional dosing cycles comprises an additional single dose of mosunetuzumab. In some embodiments, the method comprises subcutaneously administering to the subject each additional single dose of mosunetuzumab on day 1 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 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).

[0077] 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 10 additional dosing cycles. In some embodiments, lenalidomide is orally administered during each of 10 additional dosing cycles. In some embodiments, lenalidomide is orally administered on days 1 to 21 of each of the additional dosing cycles that include administration of lenalidomide. In some embodiments, lenalidomide is not administered during the last 7 (±1 day) days of any dosing cycle that includes 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; e.g., 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).

[0078] In one aspect, the present invention is a method of treating a subject having previously untreated FL, comprising administering mosunetuzumab and lenalidomide to the subject 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 mosunetuzumab administered subcutaneously on days 1, 8 (±1 day), and 15 (±1 day), respectively, of the first dosing cycle, 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; 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 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 dosing cycle comprises a single dose (C2D1) of mosunetuzumab 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 orally administering 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 daily from days 1 to 21 of the second dosing cycle.

[0079] In one aspect, the present invention is a method of treating a subject having previously untreated FL, comprising administering mosunetuzumab and lenalidomide to the subject 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 mosunetuzumab administered subcutaneously on days 1, 8 (±1 day), and 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; 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 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 dosing cycle comprises a single dose (C2D1) of mosunetuzumab 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 orally administering 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 daily from days 1 to 21 of the second dosing cycle.

[0080] In one aspect, the present invention is a method of treating a subject having previously untreated FL, comprising administering mosunetuzumab and lenalidomide to the subject according to a dosing regimen comprising a first 21-day (±1 day) dosing cycle and 11 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 mosunetuzumab administered subcutaneously on days 1, 8 (±1 day), and 15 (±1 day), respectively, of the first dosing cycle, 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; 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 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-C12D1) of mosunetuzumab administered subcutaneously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 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 to twelfth dosing cycles each comprise, daily, 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.The method further comprises orally administering lenalidomide at a dose of 75 mg, ±1 mg, or ±2 mg; for example, 10 mg).

[0081] In one aspect, the present invention is a method of treating a subject having previously untreated FL, comprising administering mosunetuzumab and lenalidomide to the subject according to a dosing regimen comprising a first dosing cycle of 21 days (±1 day) and 11 subsequent dosing cycles of 28 days (±1 day), wherein (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered subcutaneously on days 1, 8 (±1 day), and 15 (±1 day), respectively, of the first dosing cycle, 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; 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 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 - C12D1) of mosunetuzumab administered subcutaneously on day 1 of each dosing cycle, each single dose C2D1 - C12D1 being 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 to twelfth dosing cycles each comprise, daily on days 1 - 21 of each dosing cycle, 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.Characterized by a method further comprising orally administering lenalidomide at 5 mg, ±2 mg, ±3 mg, or ±4 mg; for example, 20 mg).

[0082] In some embodiments, FL is histologically demonstrated to be grade 1, 2, or 3a according to the World Health Organization classification of lymphoid neoplasms (referenced in Swerdlow SH, et al. Blood 2016;127:2375-90), but not 3b.

[0083] In some embodiments, the subject has previously been determined to require systemic therapy to treat previously untreated FL based on the follicular lymphoma prognostic index (FLIPI) criteria (Brice et al., J Clin Oncol. 15(3):1110-1117, 1997).

[0084] In some embodiments, the subject is human.

[0085] For all of the methods described herein, mosunetuzumab and lenalidomide are formulated, dosed, and administered in a manner consistent with the principles of good medical care. Factors to be considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual subject, the cause of the disorder, the site of drug delivery, the method of administration, the scheduling of administration, and other factors known to the medical practitioner. Mosunetuzumab and lenalidomide are currently used to prevent or treat the disorder in question and / or to reduce the rate, severity, and treat or prevent adverse events and / or symptoms associated with adverse events, and may be formulated, administered in combination, or used together with one or more additional agents (e.g., therapeutic agents) currently in use, but need not be, and optionally may be formulated, administered in combination, or used together with said one or more additional agents (e.g., therapeutic agents). The effective amount of such other agent depends on the amount of mosunetuzumab and / or lenalidomide present in the formulation, the type of disorder or treatment, the type of adverse event, and other factors discussed herein. Mosunetuzumab and lenalidomide may be appropriately administered to the subject during a series of treatments. If mosunetuzumab and lenalidomide are administered on the same day, lenalidomide is administered to the subject prior to the administration of mosunetuzumab.

[0086] B. Dosage Strategies for Reducing Adverse Events The present invention relates to a method of treating a subject having previously untreated follicular lymphoma (FL) by administering mosunetuzumab and lenalidomide as a combination therapy. In some embodiments, the treatment and dosing regimens described herein provide an acceptable safety profile in subjects having previously untreated FL treated with the described dosing regimens.

[0087] 1. Symptoms and Grade Classification of CRS Any of the methods described herein may include monitoring a subject for cytokine release syndrome (CRS), e.g., CRS events after initiation of any of the above methods. Current clinical responses focus on treating individual signs and symptoms, providing supportive care, and attempting to attenuate the inflammatory response using high doses of corticosteroids. However, this approach does not always succeed, especially in cases of late intervention. The CRS grading criteria used by the methods described herein define mild, moderate, severe, or life-threatening CRS and are published by the American Society for Transplantation and Cellular Therapy (ASTCT) (Lee et al. Biol Blood Marrow Transplantation. 25(4):625-638, 2019) to harmonize reporting across clinical trials and enable rapid recognition and treatment of CRS. The ASTCT criteria are objective, easy to apply, and intended to more accurately classify the severity of CRS. This CRS grading system is shown in Table 2 below.

Table 2

[0088] Fever is defined as a body temperature of 38°C or higher not due to other causes. In subjects with CRS who then receive antipyretic or anti-cytokine therapy such as tocilizumab or corticosteroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is determined by hypotension and / or hypoxia.

[0089] The CRS grade is determined by more severe events not due to other causes, hypotension, or hypoxia. For example, a subject with a body temperature of 39.5°C, hypotension requiring one pressor agent, and hypoxia requiring a low-flow nasal cannula is classified as having grade 3 CRS.

[0090] A low-flow nasal cannula is defined as oxygen delivered at ≤6 L / min. Low flow also includes blow-by oxygen delivery, which is sometimes used in pediatrics. A high-flow nasal cannula is defined as oxygen delivered at >6 L / min.

[0091] CRS is accompanied by an increase in various cytokines, including marked increases in IFN-γ, IL-6, and TNF-α levels. Emerging evidence implicates IL-6 in particular as a central mediator in CRS. IL-6 is a pro-inflammatory multifunctional cytokine produced by various cell types and has been shown to be involved in a wide variety of physiological processes, including T cell activation. Irrespective of the inducing factor, 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. Immunol. 4(7):e39, 2015), and IL-6 correlates with the severity of CRS. Subjects experiencing grade 4 or 5 CRS events have much higher IL-6 levels compared to those who do not experience CRS or who experience milder CRS (grades 0-3) (Chen et al. J. Immunol. Methods. 434:1-8, 2016).

[0092] Therefore, blocking the inflammatory action of IL-6 using an agent that inhibits IL-6-mediated signaling to manage CRS observed in subjects during a two-step split-dose escalation dosing regimen is an alternative to steroid treatment that is not expected to adversely affect T cell function in the treatment of CD20-positive cell proliferative disorders (such as B cell proliferative disorders) or attenuate the efficacy or clinical benefit of mosunetuzumab therapy.

[0093] If the subject has a CRS event that does not resolve within 24 hours or worsens after administration of an IL-6R antagonist to treat the symptoms of the CRS event, the method may further include administering one or more additional doses of the IL-6R antagonist to the subject to manage the CRS event. If the CRS event is not managed through administration of the IL-6R antagonist, the subject may be administered a corticosteroid such as methylprednisolone or dexamethasone.

[0094] 2. Other Adverse Events and Grade Classification Any of the methods described herein may include monitoring the subject for additional non-CRS adverse events. Physical findings and the incidence, nature, and severity of adverse events, as determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5 (NCI CTCAE v5.0). One of the most common adverse events reported in patients treated with mosunetuzumab and / or lenalidomide, other than CRS, is neutropenia (e.g., febrile neutropenia).

[0095] Neutropenia is characterized by an abnormally low blood cell count of neutrophils, a type of white blood cell. Neutropenia can lead to an increased risk of infection. The generally recognized reference range for the absolute neutrophil count (ANC) in adults is 1,500 - 8,000 cells / μL of blood. Mild neutropenia is characterized by an ANC of 1,000 - 1,500 cells / μL (Grade 1 - 2); moderate neutropenia is characterized by an ANC of 500 - 1,000 cells / μL (Grade 3), and severe neutropenia is characterized by an ANC of less than 500 cells / μL (Grade 4). Febrile neutropenia (Grade 3+ neutropenia) is characterized by an ANC of less than 1,000 cells / μL in addition to either a single temperature measurement above 38.3°C or a sustained temperature measurement above 38°C for more than 1 hour.

[0096] Tumor lysis syndrome (TLS) is a risk of antitumor therapy in hematologic malignancies, including NHL. The 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.

Table 3

[0097] For laboratory TLS, two or more metabolic abnormalities must be present within the same 24-hour period, either within 3 days before the start of treatment or up to 7 days after the start. Clinical TLS requires, in addition to the presence of laboratory TLS, an increase in creatinine level, seizures, arrhythmia, or death. Acute kidney injury is defined as an increase in creatinine level of 0.3 mg / dL (26.5 μmol / L) or a period of oliguria lasting more than 6 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).

[0098] Since mosunetuzumab and lenalidomide have the potential for B-cell killing, the potential risk of TLS in all patients must be considered, along with the need for TLS prophylaxis before the start of mosunetuzumab.

[0099] All patients will receive prophylaxis against TLS before the administration of the investigational drug during cycles 1 and 2 of dosing. Prophylaxis guidelines include the following: · Hydration consisting of approximately 2 to 3 L / day starting 24 to 48 hours before the first dose of mosunetuzumab. - If the patient is hospitalized for the administration of the test procedure, IV hydration at a rate of 150 to 200 mL / hour should begin at the end of mosunetuzumab administration and continue for at least 24 hours thereafter. - If the patient receives the test procedure in the outpatient setting, hydration should be maintained at approximately 2 to 3 L / day for at least 24 hours after mosunetuzumab administration. - For individuals with special medical needs, the rate of water supply should be considered for change. · Administration of agents to reduce uric acid: - At the discretion of the principal investigator of the clinical trial, allopurinol (e.g., orally initiate at 300 mg / day 72 hours before dosing and continue for 3 - 7 days thereafter) should be administered. - For patients who have elevated uric acid levels before the test procedure or are considered to have a high risk of TLS, unless contraindicated, rasburicase (e.g., 0.2 mg / kg IV over 30 minutes before the first dose of mosunetuzumab and then daily for up to 5 days) should be administered (Elitek® [rasburicase] US prescribing information). - Treatment with allopurinol / rasburicase should be continued as described above or until normalization of serum uric acid or other test parameters if TLS laboratory findings are observed.

[0100] Patients at high risk of TLS should continue to receive prophylaxis with allopurinol or rasburicase and adequate hydration with each subsequent dose of mosunetuzumab and lenalidomide until the patient is no longer considered to be at risk of TLS. Patients who develop clinical or laboratory TLS during cycle 1 should be considered for hospitalization during subsequent cycles for optimal hydration and monitoring.

[0101] If the Howard criteria for TLS (see Table 3 above) are met at any point during the trial (two or more electrolyte test abnormalities are present simultaneously), or if there are medically relevant test abnormalities or signs of clinical TLS in TLS-related parameters (e.g., increased serum creatinine or arrhythmia), the test procedure should be withheld and the patient should be hospitalized and adequately treated until normalization of the test abnormalities before the test procedure is restarted.

[0102] 3. Dosage regimens with an acceptable safety profile In one aspect, the present invention is a method of treating a subject having previously untreated follicular lymphoma (FL), comprising administering mosunetuzumab and lenalidomide to the subject 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 mosunetuzumab administered subcutaneously on days 1, 8 (±1 day), and 15 (±1 day) of the first dosing cycle, wherein the 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; e.g., 5 mg), the 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 C1D3 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 (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein the 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; for example, 45 mg), and (c) the second dosing cycle comprises orally administering lenalidomide at about 5 mg to about 20 mg (for example, 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; for example, about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg) daily on days 1 to 21 of the second dosing cycle. In some embodiments, the first dosing cycle is a 3-dose dosing cycle (i.e., comprising three doses of mosunetuzumab)..

[0103] In some embodiments, the dosing regimen comprises 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 comprises 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) additional dosing cycles. In some embodiments, the dosing regimen comprises 10 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, the length of each of the one or more additional dosing cycles is about 28 days (±1 day).

[0104] In some embodiments, any one of the one or more additional dosing cycles comprises an additional single dose of mosunetuzumab. In some embodiments, each of the one or more additional dosing cycles comprises an additional single dose of mosunetuzumab. In some embodiments, the method comprises subcutaneously administering to the subject each additional single dose of mosunetuzumab on day 1 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 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).

[0105] 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 10 additional dosing cycles. In some embodiments, lenalidomide is orally administered during each of 10 additional dosing cycles. In some embodiments, lenalidomide is orally administered on days 1 to 21 of each of the additional dosing cycles that include administration of lenalidomide. In some embodiments, lenalidomide is not administered during the last 7 (±1 day) days of any dosing cycle that includes 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; e.g., 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).

[0106] In some embodiments, the first dosing cycle further comprises administration of a corticosteroid. In some embodiments, the second dosing cycle further comprises administration of a corticosteroid. In some embodiments, any one of the one or more additional dosing cycles comprises administration of a corticosteroid. In some embodiments, a single dose of corticosteroid is administered to the subject prior to administration of any dose of mosunetuzumab. In some embodiments, the corticosteroid comprises dexamethasone or methylprednisolone. In some embodiments, the corticosteroid is administered intravenously or orally. In some embodiments, the corticosteroid comprises dexamethasone and 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). 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).

[0107] In some embodiments, the first dosing cycle further comprises administration of an antihistamine. In some embodiments, the second dosing cycle further comprises administration of an antihistamine. In some embodiments, any one of one or more additional dosing cycles comprises administration of an antihistamine. In some embodiments, a single dose of the antihistamine is administered to the subject prior to (e.g., 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, or more prior to) administration of any dose of mosunetuzumab. In some embodiments, the antihistamine is administered to the subject at least 30 minutes (e.g., 30, 35, 40, 45, 50, 60, 70, 80, 90, 120, 150, 180 minutes, or more) prior to administration of any dose of mosunetuzumab. In some embodiments, the antihistamine is administered orally or intravenously. In some embodiments, the antihistamine comprises diphenhydramine hydrochloride and is administered at a dose of about 50 - 100 mg (e.g., 50 - 90 mg, 50 - 80 mg, 50 - 70 mg, 50 - 60 mg, 60 - 100 mg, 70 - 100 mg, 80 - 100 mg, 90 - 100 mg, 70 - 80 mg, 60 - 90 mg, 60 - 80 mg, 70 - 90 mg, or 65 - 85 mg; e.g., 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).

[0108] In some embodiments, the first dosing cycle further comprises administration of an antipyretic. In some embodiments, the second dosing cycle further comprises administration of an antipyretic. In some embodiments, any one of the one or more additional dosing cycles comprises administration of an antipyretic. In some embodiments, a single dose of an antipyretic is administered to the subject prior to administration of any dose of mosunetuzumab. In some embodiments, the antipyretic is administered to the subject at least 30 minutes (e.g., 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, or more) prior to administration of any dose of mosunetuzumab. In some embodiments, the antipyretic is administered orally. In some embodiments, the antipyretic comprises acetaminophen and is administered in a dose of about 500-1000 mg (e.g., 500-900 mg, 500-800 mg, 500-700 mg, 500-600 mg, 600-1000 mg, 700-1000 mg, 800-1000 mg, 900-1000 mg, 700-800 mg, 600-900 mg, 600-800 mg, 700-900 mg, or 650-850 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).

[0109] In some embodiments, the first dosing cycle further includes administration of a first dose of a prophylactic agent against tumor lysis syndrome (TLS). In some embodiments, the second dosing cycle further includes administration of a first dose of a prophylactic agent against TLS. In some embodiments, any one of the one or more additional dosing cycles includes administration of a first dose of a prophylactic agent against TLS. In some embodiments, a first dose of a prophylactic agent against TLS is administered to the subject prior to administration of any dose of mosunetuzumab. In some embodiments, the prophylactic agent against TLS includes allopurinol. In some embodiments, the first dose of allopurinol is administered about 72 hours (e.g., 72 ± 0.5 hours, ± 1 hour, ± 2 hours, ± 3 hours, ± 4 hours, ± 8 hours, ± 12 hours, or ± 16 hours; e.g., 72 hours) prior to administration of any dose of mosunetuzumab. In some embodiments, an additional single dose of allopurinol is administered daily for 6 - 10 days (± 1 day) after administration of the first dose. In some embodiments, the first 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 prophylactic agent against TLS includes rasburicase. In some embodiments, the first 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 administration of any dose of mosunetuzumab. In some embodiments, an additional single dose of rasburicase is administered daily for 1 - 5 days (± 1 day) after administration of the first dose. In some embodiments, the first 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 lasubricase 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, lasubricase is administered intravenously.

[0110] In some embodiments, for example, after any dose of mosunetuzumab has been administered, for example, if the subject exhibits CRS, an IL-6R antagonist may be administered to a subject treated by the methods of the invention. In some embodiments, the IL-6R antagonist is tocilizumab. In some embodiments, tocilizumab is administered to the subject as 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 the single dose does not exceed 800 mg. In some embodiments, tocilizumab is administered to the subject as 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 the single dose does not exceed 800 mg. In some embodiments, tocilizumab is administered intravenously.

[0111] The methods described herein can provide an acceptable safety profile for subjects having previously untreated follicular lymphoma (FL) being treated with a combination therapy of mosunetuzumab and lenalidomide. In some examples, treatment using the methods described herein, including subcutaneous administration of mosunetuzumab in the context of a dose-escalating dosing regimen and oral administration of lenalidomide, results in a reduction (e.g., by 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more; e.g., 20% - 100%, 20% - 90%, 20% - 80%, 20% - 70%, 20% - 60%, 20% - 50%, 20% - 40%, 20% - 30%, 40% - 100%, 60% - 100%, 80% - 100%, 30% - 70%, 40% - 60%, 30% - 50%, 50% - 80%, or 90% - 100%; e.g., about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 99%, or about 100%) or complete inhibition (100% reduction) of undesirable adverse events such as cytokine-induced toxicities (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), macrophage activation syndrome (MAS), neurotoxicity, tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes and / or hepatotoxicity compared to treatment with mosunetuzumab using a non-divided dosing regimen.

[0112] IV. Therapeutic Agents A. Mosunetuzumab The present invention provides mosunetuzumab, a bispecific antibody that binds to CD20 and CD3, which is useful for treating previously untreated follicular lymphoma (FL).

[0113] Mosunetuzumab has an anti-CD20 arm with a first binding domain that includes the following six hypervariable regions (HVRs): (a) HVR-H1 that includes the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1); (b) HVR-H2 that includes the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) HVR-H3 that includes the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3); (d) HVR-L1 that includes the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4); (e) HVR-L2 that includes the amino acid sequence of APSNLAS (SEQ ID NO: 5); and (f) HVR-L3 that includes the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6). Mosunetuzumab includes an anti-CD20 arm with a first binding domain that includes heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 that include the sequences of SEQ ID NOs: 17-20, respectively, and light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 that include the sequences of SEQ ID NOs: 21-24, respectively. Mosunetuzumab includes an anti-CD20 arm with a first binding domain that includes (a) a heavy chain variable (VH) domain that includes the amino acid sequence of SEQ ID NO: 7 and (b) a light chain variable (VL) domain that includes the amino acid sequence of SEQ ID NO: 8.

[0114] Mosunetuzumab has an anti-CD3 arm with a second binding domain that includes the following six HVRS: (a) HVR-H1 containing the amino acid sequence of NYYIH (SEQ ID NO: 9); (b) HVR-H2 containing the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 10); (c) HVR-H3 containing the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 11); (d) HVR-L1 containing the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 containing the amino acid sequence of WASTRES (SEQ ID NO: 13); and (f) HVR-L3 containing the amino acid sequence of TQSFILRT (SEQ ID NO: 14). Mosunetuzumab includes an anti-CD3 arm with a second binding domain that includes heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, each containing the sequences of SEQ ID NOS: 25-28, respectively, and light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4, each containing the sequences of SEQ ID NOS: 29-32, respectively. Mosunetuzumab includes an anti-CD3 arm with a second binding domain that includes a VH domain containing an amino acid sequence having the amino acid sequence of SEQ ID NO: 15 and a VL domain containing the amino acid sequence of SEQ ID NO: 16.

[0115] Mosunetuzumab has an International Nonproprietary Name (INN) in List 117 (WHO Drug Information, Vol. 31, No. 2, 2017, p. 304-305), or a CAS Registry Number of 1905409-39-3, and has (1) an anti-CD20 arm containing a heavy chain sequence and a light chain sequence of SEQ ID NOS: 33 and 34, respectively, and (2) an anti-CD3 arm containing a heavy chain and a light chain sequence of SEQ ID NOS: 35 and 36, respectively. Mosunetuzumab includes (1) an anti-CD20 arm with a first binding domain containing a heavy chain containing the amino acid sequence of SEQ ID NO: 33 and a light chain containing the amino acid sequence of SEQ ID NO: 34, and (2) an anti-CD3 arm with a second binding domain containing a heavy chain containing the amino acid sequence of SEQ ID NO: 35 and a light chain containing the amino acid sequence of SEQ ID NO: 36.

[0116] The amino acid sequence of mosunetuzumab is summarized in Table 4 below.

Table 4

[0117] Mosunetuzumab can be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567.

[0118] B. Lenalidomide 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, but 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).

[0119] Lenalidomide has the CAS registration number 191732 - 72 - 6 and the 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 REVLIMID®, lenamide, and lenalid. Lenalidomide has the DrugBank accession number DB00480, PubChem CID 216326, and the chemical formula C 13 H 13 N3O3.

[0120] C. Additional Therapeutic Agents In some examples, the methods described herein include administering mosunetuzumab and lenalidomide in combination with one or more additional therapeutic agents.

[0121] In some examples, one or more additional therapeutic agents can prevent, reduce the rate of, or reduce the severity of cytokine release syndrome (CRS) and / or symptoms associated with CRS. In certain examples, the additional therapeutic agent used to reduce the rate or severity of CRS or to prevent symptoms associated with CRS is a corticosteroid (e.g., dexamethasone (CAS number: 50-02-2), prednisone (CAS number: 53-03-2), prednisolone (CAS number: 50-42-8) or methylprednisolone (CAS number: 83-43-2)), an antihistamine (e.g., diphenhydramine (CAS number: 58-73-1) and pharmaceutically acceptable salts thereof, e.g., diphenhydramine hydrochloride (CAS number: 147-24-0)) or an interleukin-6 receptor (IL-6R) antagonist (e.g., tocilizumab (CAS number: 375823-41-9), sarilumab (CAS number: 1189541-98-7), balilixizumab (ALX-0061; CAS number: 1628814-88-9), satralizumab (SA-237; CAS number: 1535963-91-7), and alternatives thereof). In some examples, the additional therapeutic agent is a corticosteroid. In certain examples, the corticosteroid is dexamethasone or methylprednisolone. In certain examples, the antihistamine is diphenhydramine hydrochloride. In certain examples, the antipyretic is acetaminophen (i.e., paracetamol) or a pharmaceutically acceptable salt thereof. In certain examples, the IL-6R antagonist is tocilizumab.

[0122] In some examples, one or more additional therapeutic agents may be used in the treatment of neutropenia. In some examples, the additional therapeutic agent may prevent symptoms associated with neutropenia. In some examples, the additional therapeutic agent may reduce the rate or severity of neutropenia. In certain examples, the additional therapeutic agent is granulocyte colony-stimulating factor (G-CSF or GCSF) or colony-stimulating factor 3 (CSF3). The mRNA sequences of human G-CSF / CSF3 include, for example, NCBI reference sequence numbers NM_000759, NM_001178147, NM_172219, and NM_172220, and the protein amino acid sequences of human G-CSF / CSF3 include, for example, NCBI reference sequence numbers NP_000750, NP_001171618, NP_757373 and NP_757374.

[0123] In some examples, one or more additional therapeutic agents are prophylactic agents for preventing, reducing the rate of, or reducing the severity of, for example, tumor lysis syndrome (TLS). In some examples, prophylactic agents for TLS are allopurinol (CAS number: 315-30-0), rasburicase (Elitek™; CAS number: 134774-45-1), or suitable alternatives and / or pharmaceutically acceptable salts thereof. In some examples, prophylactic agents for TLS reduce serum uric acid (e.g., reduce elevated uric acid levels compared to, for example, a baseline or reference value).

[0124] In some examples, additional therapeutic agents useful in the present invention include therapeutic antibodies such as alemtuzumab (CAMPATH®), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (BEXXAR®, Corixia), and gemtuzumab ozogamicin (MYLOTARG®, Wyeth), which is an antibody-drug conjugate. Additional humanized monoclonal antibodies having therapeutic potential as agents in combination with the compounds of the present invention include apolizumab, aselizumab, atorizumab, bapineuzumab, bevacizumab mertansine, canertinib mertansine, cedelizumab, certolizumab pegol, cidfostuximab, cidtuzumab, daclizumab, eclizumab, efalizumab, epratuzumab, elotuzumab, felvizumab, fontolizumab, inotuzumab ozogamicin, ipilimumab, labelizumab, lintuzumab, matuzumab, mapolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, norovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfostuximab, pecfuzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, recevizumab, rovelizumab, rupelizumab, sibrotuzumab, siprilizumab, sonrozumab, takatsizumab tetraxetan, tadocizumab, tafasitamab, talizumab, tefibazumab, tocilizumab, tralizumab, tucotuzumab celmoleukin, tucusitumab, umavizumab, ultuxizumab, ustekinumab, visilizumab, and briakinumab.

[0125] IV. Pharmaceutical Compositions and Formulations The mosunetuzumab, lenalidomide, and other therapeutic agents described herein can be used in pharmaceutical compositions and formulations. The pharmaceutical compositions and formulations of the mosunetuzumab, lenalidomide, and / or other agents (e.g., corticosteroids, antihistamines, antipyretics, prophylactic agents for TLS and / or IL-6R antagonists) described herein can be in the form of a lyophilized formulation or an aqueous solution and can be prepared by mixing one, two, three, or more of all of the agents having the desired purity with one or more pharmaceutically acceptable carriers (Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)) which may optionally be present. Corticosteroids, antihistamines, antipyretics, prophylactic agents for TLS, and / or IL-6R antagonists can also be formulated according to standard formulation and / or manufacturing practices.Pharmaceutically acceptable carriers are usually non-toxic to the recipient 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 (e.g., octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinyl pyrrolidone; 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., Zn-protein complexes); and / or nonionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersants such as soluble neutral active hyaluronidase glycoprotein (sHASEGP), such as human soluble PH-20 hyaluronidase glycoprotein such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGP and methods of use including rHuPH20 are described in U.S. Patent Publication Nos. 2005 / 0260186 and 2006 / 0104968. In one aspect, the sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinase.

[0126] Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958. Aqueous antibody formulations include those described in U.S. Patent No. 6,171,586 and International Publication No. 2006 / 044908, the latter of which includes a histidine-acetate buffer.

[0127] The formulations herein may also contain two or more active ingredients, if necessary for the particular indication being treated, preferably two or more active ingredients having 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 antihormonal agents, such as those mentioned above herein). Such active ingredients are suitably present in combination in an amount effective for the intended purpose.

[0128] The active ingredients can be encapsulated, for example, in microcapsules prepared by coacervation techniques or by interfacial polymerization, such as in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions, in hydroxyethylmethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively. Such techniques are disclosed in Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0129] Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, and these matrices are in the form of shaped articles, such as films or microcapsules.

[0130] Formulations for in vivo administration are generally sterile. Sterility can be readily achieved, for example, by filtration through sterile filtration membranes.

[0131] 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.

[0132] V. Kits and Manufactured Articles In another aspect of the invention, a kit or a manufactured article is provided that includes a material useful for treating, preventing, and / or diagnosing the above-described disorders. The kit or manufactured article comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV infusion bags, and the like. The container can be formed from various materials such as glass or plastic. The container holds a single composition or a composition combined with another composition effective to treat, prevent, and / or diagnose a condition and can have a sterile access port (e.g., the container can be a vial having a stopper pierceable by a hypodermic needle). At least one active agent in the composition is the 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 / animal. Further, the kit or manufactured article can comprise (a) a first container containing the composition therein, wherein the composition comprises mosunetuzumab, lenalidomide, or both mosunetuzumab and lenalidomide, and (b) a second container containing the composition therein, wherein the composition comprises a further cytotoxic agent or other therapeutic agent. Alternatively or additionally, the kit or manufactured article can further comprise a second (or third) container containing a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. The kit or manufactured article can further include other materials desirable from a commercial and user perspective, such as other buffers, diluents, filters, needles, and syringes.

Example

[0133] The following are examples of the methods and compositions of the invention. It is understood that various other embodiments can be practiced, given the general description provided above.

[0134] Example 1. A Phase Ib / II open-label, non-randomized, multi-center trial to evaluate the safety, tolerability, and pharmacokinetics of subcutaneous mosunetuzumab in combination with lenalidomide in patients with previously untreated follicular lymphoma Study design Study CO41942 is an ongoing Phase Ib / II open-label, multi-center trial that includes an evaluation of the safety, tolerability, and pharmacokinetics of subcutaneous mosunetuzumab administration in combination with lenalidomide in patients with previously untreated follicular lymphoma (FL). The study design of this trial is summarized in Figure 1.

[0135] This study includes an expanded cohort of approximately 20 to 40 patients who will be dosed at the recommended Phase 2 dose (RP2D) of mosunetuzumab.

[0136] The study treatment will be administered for 12 cycles. The duration of dosing cycle 1 is 21 days, and the duration of cycles 2 to 12 is 28 days. Mosunetuzumab will be administered together with lenalidomide in cycle 2 after the patient has completed the step-up dosing in cycle 1.

[0137] Inclusion criteria · 18 years of age or older · Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (see Table 5 below) · Patients with previously untreated follicular lymphoma (FL) must require systemic therapy as evaluated by the treating investigator based on the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria (Brice et al. J Clin Oncol. 15(3):1110-1117, 1997). · Histologically proven FL expressing CD20 of grade 1, 2, or 3a (Swerdlow SH, et al. Blood 2016;127:2375-90) · Fluorodeoxyglucose-avid lymphoma (i.e., positron emission tomography (PET)-positive lymphoma) · At least one two-dimensionally measurable lymph node lesion (maximum dimension > 1.5 cm by PET-computed tomography (CT) scan), or at least one two-dimensionally measurable extranodal lesion (maximum dimension > 1.0 cm by PET-CT scan) · Adequate hematologic function (without growth factor or blood product transfusions within 14 days of the first dose of investigational drug) is defined as follows: - Hemoglobin ≥ 9 g / dL - Absolute neutrophil count (ANC) ≥ 1.0 × 10 9 / L - Platelet count ≥ 75 × 10 9 / L · Measured or estimated creatinine clearance ≥ 50 mL / min by the facility's standard method · Aspartate aminotransferase (AST) or alanine transaminase (ALT) < 2.5 × upper limit of normal (ULN) · Serum total bilirubin < 1.5 × ULN (or < 3 × ULN in patients with Gilbert syndrome) · For women of childbearing potential: agreement to maintain abstinence (refrain from heterosexual intercourse) or use at least two appropriate contraceptive methods, including at least one method with a failure rate of less than 1% per year, for at least 28 days before day 1 of cycle 1, during the treatment period (including treatment interruption periods), and for at least 28 days after the last dose of lenalidomide, 3 months after the last dose of tocilizumab, and 3 months after the last dose of mosunetuzumab. Women must refrain from donating eggs during the same period. · For men: agreement to maintain abstinence (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating sperm.

Table 5

[0138] Exclusion Criteria · History of grade 3b FL · History of transformation and / or diffuse large B-cell lymphoma (DLBCL) · Activity or history of central nervous system (CNS) lymphoma or leptomeningeal infiltration · Documented refractoriness to lenalidomide (defined as no response (PR or CR) within 6 months of treatment) · Prior standard or investigational anti-cancer therapy as specified below: - Lenalidomide exposure within 12 months prior to Day 1 of Cycle 1 - Fludarabine or alemtuzumab within 12 months prior to Day 1 of Cycle 1 - Radioactive immunoconjugate within 12 weeks prior to Day 1 of Cycle 1 - Prior anti-lymphoma treatment with monoclonal antibody or antibody-drug conjugate within 4 weeks prior to Day 1 of Cycle 1 - Treatment with any chemotherapeutic agent or any other anti-cancer agent (investigational drug or otherwise) within 4 weeks prior to the first dose of the study treatment or within 5 half-lives of the drug (whichever is shorter) · Clinically significant toxicity (other than alopecia) attributable to prior treatment that had not recovered to Grade 2 or less (by NCI CTCAE, v5.0) prior to Day 1 of Cycle 1 · Known history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced interstitial pneumonia or evidence of active interstitial pneumonia on screening chest CT scan · Treatment with systemic immunosuppressive drugs 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 - Use of inhaled corticosteroids is permitted. - Use of mineralocorticoids for the management of orthostatic hypotension is permitted. - Use of physiological doses of corticosteroids for the management of adrenal insufficiency is permitted. - If corticosteroid treatment is urgently required for the control of lymphoma symptoms prior to the start of the study treatment, 100 mg of prednisone or equivalent may be given for up to 5 days. · History of solid organ transplantation · History of severe allergic or anaphylactic reaction to humanized, chimeric or murine monoclonal antibodies · Known hypersensitivity to any component of mosunetuzumab, lenalidomide or thalidomide formulations, including biologic agents produced in Chinese hamster ovary cells or mannitol · History of polymorphous erythema, grade 3 or higher rash, or vesicle formation after previous treatment with immunomodulatory derivatives · Known active bacterial, viral, fungal or other infections requiring treatment with IV antibiotics within 4 weeks of day 1 of cycle 1, or onset of any major symptoms of an infection · Known or suspected chronic active Epstein-Barr virus (EBV) infection · Known or suspected hemophagocytic syndrome · Active hepatitis B infection: Patients who are hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (HBcAb) positive must have a negative hepatitis B virus (HBV) polymerase chain reaction (PCR) to be eligible to participate in the study. · Active hepatitis C infection: Patients who are hepatitis C virus (HCV) antibody positive must be HCV negative by PCR to be eligible to participate in the study. · Known history of human immunodeficiency virus (HIV) positive status: For patients with unknown HIV status, an HIV test will be performed at screening if required by local regulations. · History of progressive multifocal leukoencephalopathy (PML) · Administration of live attenuated vaccines within 4 weeks prior to the first dose of the study treatment or prediction that such live attenuated vaccines will be required during the study - Patients should not receive live attenuated vaccines (e.g., FluMist®) while receiving the study treatment or after the last dose until B cells have recovered to the normal range. Inactivated vaccines or toxoids should be administered at least 4 weeks before the first dose of the study treatment to allow for adequate immune development. - Approved non-live COVID-19 vaccines are allowed - Inactivated influenza vaccination should only be performed during the influenza epidemic period. · History of other malignancies that may affect compliance with the protocol or interpretation of the results, except for the following: - Any of the following malignancies that have been previously treated curatively: cervical intraepithelial neoplasia, intraductal carcinoma of the breast with a favorable prognosis, basal cell or squamous cell skin cancer - Stage I melanoma, low-grade localized prostate cancer at an early stage, or any other previously treated malignancy that has been in remission for more than 2 years prior to registration and has not been treated · Active autoimmune diseases requiring treatment - Patients with a history of autoimmune-related hypothyroidism receiving a stable dose of thyroid replacement hormone may be eligible. - Patients with controlled type 1 diabetes receiving an insulin regimen are eligible to participate in the study. - Patients with a history of disease-related immune thrombocytopenic purpura, or autoimmune hemolytic anemia, or other stable autoimmune diseases may be eligible. - Patients with a history of autoimmune diseases including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis, and who have had a 12-month interval without treatment from immunosuppressive therapy may be eligible. · Previous allogeneic hematopoietic stem cell transplantation · Grade 2 or higher neuropathy · Evidence of significant uncontrolled complications that may affect compliance with the protocol or interpretation of the results, including, but not limited to, significant cardiovascular diseases (e.g., New York Heart Association class III or IV heart diseases, myocardial infarction within the past 6 months, unstable arrhythmias or unstable angina) or significant pulmonary diseases (such as a history of obstructive pulmonary disease or bronchospasm) · Major surgical procedures expected during the course of major surgical procedures or tests other than for diagnostic purposes within 28 days before the first day of Cycle 1 · Clinically significant history of liver disease, including viral or other hepatitis, current alcohol dependence or cirrhosis · Pregnant or breastfeeding, or planning to become pregnant during the trial

[0139] Test procedure Moxetumomab administration Moxetumomab is administered subcutaneously (SC) according to a step-up dosing regimen: In Cycle 1 (a 21-day dosing cycle), patients receive 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 - 12 (a 28-day dosing cycle), patients receive 45 mg on Day 1 (C2D1 - C12D1 doses). (Based on previous clinical experience in the GO29781 trial) Hospitalization is not required for patients receiving subcutaneous moxetumomab unless clinically necessary.

[0140] Prior to the dose on Day 8 of Cycle 1, if the patient has toxicity requiring interruption of SC moxetumomab for more than 7 days, the patient needs to repeat the 5 mg dose before resuming the planned treatment schedule (7 days after administration of the 5 mg dose). If a dosing delay results in a treatment-free interval of more than 6 weeks, after the dosing delay, for Cycle 1, step-up dosing of SC moxetumomab is required on Day 1 (5 mg) and Day 8 (45 mg). Corticosteroid prophylaxis should be administered on the day of repeated doses to reduce the risk of cytokine release syndrome (CRS).

[0141] A corticosteroid premedication consisting of 20 mg of dexamethasone or 80 mg of methylprednisolone is administered orally or intravenously (IV) prior to the administration of each dose of mosunetuzumab. Additionally, a premedication with an oral or IV analgesic / antipyretic (e.g., 500 - 1,000 mg of acetaminophen or paracetamol) and / or an oral or IV antihistamine (e.g., 50 - 100 mg of diphenhydramine) is administered according to the standard institutional practice prior to the administration of mosunetuzumab. The premedication with the analgesic / antipyretic and antihistamine is performed at least 30 minutes before the administration of mosunetuzumab. The premedication is administered to all patients in cycle 1 and may be optional from cycle 2 onwards. However, if a patient experiences CRS at an earlier dose, premedication with corticosteroids is administered for subsequent doses.

[0142] Furthermore, for patients at risk of tumor lysis syndrome (TLS; e.g., due to bulky disease or renal dysfunction (creatinine clearance < 60 mL / min)), appropriate alternatives such as allopurinol or rasburicase are used as premedication.

[0143] Lenalidomide Administration Lenalidomide is administered orally (PO) once daily at a dose of 20 mg on days 1 - 21 of cycles 2 - 12 (28 - day cycles). Lenalidomide is not administered during the last 7 days of each of cycles 2 - 12 of the 28 - day cycle. If the creatinine clearance is < 60 mL / min, start lenalidomide at a dose of 10 mg / day instead.

[0144] On the day of administering lenalidomide together with mosunetuzumab, after initially administering lenalidomide, subcutaneous mosunetuzumab injection is performed. Lenalidomide is administered at approximately the same time every day. If a dose of lenalidomide is not taken, the patient can take the missed dose within 12 hours from the scheduled dose time. If it exceeds 12 hours, the dose is skipped and the next dose is taken regularly at the scheduled time. Two doses should not be taken simultaneously. If a dose is vomited, that dose is not taken again.

[0145] Granulocyte colony-stimulating factor (G-CSF) can be administered according to the guidelines of the American Society of Clinical Oncology, the European Organization for Research and Treatment of Cancer (EORTC), and the European Society for Medical Oncology (Smith et al. J. Clin. Oncol. 33(28):3199 - 3212; 2015).

[0146] Prophylactic treatment with antibiotics should be administered according to standard practice.

[0147] Lenalidomide increases the risk of thromboembolism (TE). Anticoagulation prophylaxis can be carried out after careful assessment of the patient's potential risk factors. All patients are recommended to receive low-dose aspirin (81 - 100 mg) daily during lenalidomide treatment and up to 28 days after the last dose of lenalidomide. Patients with no tolerance to aspirin, a history of TE, and a high risk of TE can be given warfarin or low-molecular-weight heparin or a novel oral anticoagulant according to the facility's practice.

[0148] Tocilizumab Administration Tocilizumab is administered to patients who experience CRS events if necessary. Tocilizumab is administered at a dose of 8 mg / kg IV (for participants with a body weight of 30 kg or more only) or 12 mg / kg (for participants with a body weight of less than 30 kg) for up to 4 doses. Doses exceeding 800 mg per infusion are not recommended.

[0149] Dose Modification The dosing of Mosunetuzumab has not been changed in this trial. Patients receiving Mosunetuzumab who experience Grade 4 related non-hematological adverse events discontinue the study treatment.

[0150] Lenalidomide dosing is individualized for each patient based on the toxicity rules described below and further detailed in Table 6. The dose of lenalidomide can be decreased by 5 mg each time (for example, from 20 mg to 15 mg; from 15 mg to 10 mg; from 10 mg to 5 mg). There is no more than one dose reduction per dosing cycle. If the dose of lenalidomide is decreased, re-increase is not permitted. If creatinine clearance is 50 or more but less than 60 mL / min, lenalidomide is initiated at a dose of 10 mg / day, and if the creatinine clearance is still above 50 mL / min after 2 cycles and the patient tolerates the treatment, the dose of lenalidomide can be increased to 15 mg. Doses not taken due to toxicity or any other reason will not be rescheduled or re-administered.

Table 6

[0151] Prohibited Treatments The use of treatments including but not limited to those listed below is prohibited during this trial. · Investigational drugs or unapproved / untested drugs · Administration of live vaccines · Cytotoxic chemotherapy other than study treatments for the treatment of lymphoma · Radiation therapy for the treatment of lymphoma (except for pre-planned radiation therapy) · Immunotherapy other than study treatments for the treatment of lymphoma · Immunosuppressive therapy (except for drugs required according to the protocol, including corticosteroids and tocilizumab) · Hormone therapy (except for contraceptives, hormone replacement therapy, or megestrol acetate). · Adjuvant endocrine therapy for non-metastatic hormone receptor-positive breast cancer is acceptable. · Biologics or targeted agents for the treatment of lymphoma · Herbal medicine therapy for the treatment of lymphoma · Any therapy for the treatment of lymphoma, whether approved by the local regulatory authorities or under clinical trial

[0152] Patients who require the use of any of these agents shall discontinue the test treatment. Patients who discontinue the test treatment shall be followed up for safety outcomes for 90 days after the last dose of the test treatment or until the patient receives another anti-cancer therapy, whichever is earlier.

[0153] Safety Safety is evaluated through a summary of adverse events and a summary of changes in clinical laboratory results. All adverse events, serious adverse events, adverse events leading to death, particularly notable adverse events, and adverse events leading to discontinuation of the test treatment that occur after the first test treatment shall be summarized using mapped terms, appropriate synonym levels, and the NCI CTCAE v5.0 toxicity grades (cancer.gov). All serious adverse events shall be listed and summarized separately.

[0154] Adverse Event (AE) According to the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines (ich.org) for Good Clinical Practice, an adverse event is any untoward medical occurrence in a clinical trial subject who has received a medicinal product, regardless of the attribution of the cause. Thus, an adverse event can be any of the following: · Any unfavorable and unexpected sign (including abnormal clinical findings), symptom, or disease that temporarily accompanies the use of a medicinal product, whether or not considered related to the medicinal product · Worsening of a new or existing disease (worsening of the nature, frequency, or severity of known symptoms) · Recurrence of intermittent medical symptoms (e.g., headache) that were not present at baseline · Worsening of clinical laboratory values or other clinical tests (e.g., electrocardiogram (ECG), X-ray) related to the syndrome or leading to a change in the test procedure or concomitant treatment or discontinuation of the investigational drug · Adverse events related to protocol-required interventions (e.g., screening invasive procedures such as biopsies), including those occurring before the assignment of the test procedure

[0155] Serious adverse event (SAE) A serious adverse event is any adverse event that meets any of the following criteria: · Fatal (i.e., the adverse event actually causes death or leads to death) · Life-threatening (i.e., the adverse event exposes the patient to an immediate risk of death) This does not include adverse events that occurred in a more severe form or, if continued, would have been likely to cause death. · Requires or prolongs hospitalization of an inpatient · Results in persistent or significant disability / incapacity (i.e., the adverse event results in substantial disruption of the patient's ability to perform normal life functions) · Congenital anomalies / congenital defects in a neonate / infant born to a mother exposed to the investigational drug · May place the patient at risk or may require medical / surgical intervention to prevent one of the outcomes listed above

[0156] The terms "severe" and "serious" are not synonymous. Severe refers to the intensity of the adverse event (e.g., rated as mild, moderate, or severe, or evaluated according to NCI CTCAE; cancer.gov), and the event itself may have relatively minor medical significance (e.g., severe headache without further findings).

[0157] Severity and seriousness need to be assessed independently for each adverse event.

[0158] Adverse events of special interest (AESI) The adverse events that should be particularly noted in this trial are as follows: · Cases that may have drug-induced liver injury, including an increase in alanine transaminase (ALT) or aspartate aminotransferase (AST) accompanied by either an increase in bilirubin or clinical jaundice as defined by Hy's law (an increase in ALT or AST (more than 3 times the upper limit of normal (ULN)) accompanied by either an increase in total bilirubin (>2×ULN) or clinical jaundice in the absence of other causes of cholestasis or hyperbilirubinemia is considered an indicator of severe liver injury). · Suspected transmission of infectious agents by the investigational drug as defined below: Regardless of pathogenicity or non-pathogenicity, any organism, virus, or infectious particle (e.g., prion protein that transmits transmissible spongiform encephalopathy) is considered an infectious pathogen. Transmission of an infectious pathogen may be suspected from clinical symptoms or laboratory findings indicating infection in patients exposed to the pharmaceutical product. This term applies only when contamination of the investigational drug is suspected.

[0159] The adverse events that should be particularly noted regarding mosunetuzumab include the following: · Cytokine release syndrome (CRS) of grade 2 or higher; · Neurological adverse events of grade 2 or higher · Injection site reactions of grade 2 or higher (in the case of subcutaneous (SC) mosunetuzumab) · Any suspected hemophagocytic lymphohistiocytosis (HLH) · Tumor lysis syndrome (TLS; grade 3 or higher by definition) · Febrile neutropenia (grade 3 minimum by definition) · Increase in AST, ALT, or total bilirubin of grade 2 or higher · Disseminated intravascular coagulation syndrome of any grade (grade 2 minimum by definition) · Tumor inflammation or flare of grade 2 or higher (e.g., manifestation of signs / symptoms associated with an increase in the size of known lymph node lesions or extranodal lesions, new onset, or worsening of existing pleural effusion as determined by clinical or radiological assessment) ·All grades of pneumonitis / interstitial lung disease (excluding pneumonia with infectious etiology)

[0160] Particularly notable adverse events related to lenalidomide include the following: ·Embryo-fetal toxicity ·Febrile neutropenia (grade 3 minimum by definition) ·Venous and arterial thromboembolic events ·Severe skin reactions of grade 3 or higher ·Renal dysfunction of grade 3 or higher ·Thyroid disorders of grade 3 or higher ·Peripheral neuropathy of grade 3 or higher ·Second primary malignancies

[0161] Efficacy analysis The efficacy of treatment with mosunetuzumab and lenalidomide in previously untreated FL is assessed based on the following endpoints using the standard criteria for NHL as reviewed by the principal investigator of the trial using the Lugano classification (Cheson BD, et al. J Clin Oncol 2014;32:1-9). Response is assessed based on positron emission tomography / computed tomography (PET-CT) scans.

[0162] CRR is defined as the proportion of patients with a best overall response of CR in the trial. An exact 95% confidence interval using the Clopper-Pearson method is provided.

[0163] ORR is defined as the proportion of patients with a best overall response of CR or PR in the trial. An exact 95% confidence interval using the Clopper-Pearson method is provided.

[0164] DOR is defined as the time from the first occurrence of objective response documented in the medical record to disease progression or recurrence or death from any cause (whichever occurs first). Kaplan-Meier estimates are provided. The Brookmeyer-Crowley method is used to construct 95% confidence intervals for the median DOR. The response duration includes all patients with CR or PR by the treating investigator.

[0165] DOCR is defined as the time from the first occurrence of complete response documented in the medical record to disease progression or recurrence or death from any cause (whichever occurs first). Kaplan-Meier estimates are provided. The Brookmeyer-Crowley method is used to construct 95% confidence intervals for the median DOR. DOCR includes all patients with CR by the treating investigator.

[0166] Pharmacokinetics (PK) analysis The time-versus-data for individual serum mosunetuzumab concentrations and mean serum mosunetuzumab concentrations are tabulated and plotted. As appropriate, C max 、C min and AUC are estimated to summarize the plasma PK of mosunetuzumab. These parameters are tabulated and summarized (mean, standard deviation, coefficient of variation, median, minimum, and maximum).

[0167] Additional PK analyses are performed as appropriate. Furthermore, these data are analyzed using population PK modeling.

[0168] The serum concentration of lenalidomide is measured. The concentration of lenalidomide is summarized using the descriptive statistics described above.

[0169] Embodiments Some embodiments of the technology described herein may be defined according to any of the following numbered embodiments.

[0170] 1. A method of treating a subject having previously untreated follicular lymphoma (FL), comprising administering mosunetuzumab and lenalidomide to the subject according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, (a) said first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab administered subcutaneously on days 1, 8 and 15, respectively, of said first dosing cycle, said C1D1 being about 5 mg, said C1D2 being about 45 mg, and said C1D3 being about 45 mg, (b) said second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered subcutaneously on day 1 of said second dosing cycle, said C2D1 being about 45 mg, and (c) said second dosing cycle further comprises orally administering lenalidomide at about 5 mg to about 20 mg daily from days 1 to 21 of said second dosing cycle, A method.

[0171] 2. Mosunetuzumab for use in combination with lenalidomide for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled 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, (a) said first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab scheduled to be administered subcutaneously on days 1, 8 and 15, respectively, of said first dosing cycle, said C1D1 being about 5 mg, said C1D2 being about 45 mg, and said C1D3 being about 45 mg, (b) said second dosing cycle comprises a single dose (C2D1) of mosunetuzumab scheduled to be administered subcutaneously on day 1 of said second dosing cycle, said C2D1 being about 45 mg, and (c) The second dosing cycle further includes lenalidomide at about 5 mg to about 20 mg, which is scheduled to be orally administered daily on days 1 to 21 of the second dosing cycle. Mosunetuzumab.

[0172] 3. Lenalidomide for use in combination with mosunetuzumab to treat subjects with previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled 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. (a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, which are scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle. The C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg. (b) The second dosing cycle includes a single dose (C2D1) of mosunetuzumab, which is scheduled to be administered subcutaneously on day 1 of the second dosing cycle. The C2D1 is about 45 mg, and (c) The second dosing cycle further includes lenalidomide at about 5 mg to about 20 mg, which is scheduled to be orally administered daily on days 1 to 21 of the second dosing cycle. Lenalidomide.

[0173] 4. Use of mosunetuzumab in combination with lenalidomide to treat subjects with previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled 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. (a) The first dosing cycle includes the first dose (C1D1), the second dose (C1D2), and the third dose (C1D3) of mosunetuzumab that are scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle. The C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg. (b) The second dosing cycle includes a single dose (C2D1) of mosunetuzumab that is scheduled to be administered subcutaneously on day 1 of the second dosing cycle. The C2D1 is about 45 mg, and (c) The second dosing cycle further includes lenalidomide at about 5 mg to about 20 mg that is scheduled to be administered orally daily from days 1 to 21 of the second dosing cycle. Use of mosunetuzumab.

[0174] 5. Use of lenalidomide in combination with mosunetuzumab for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled to be administered to the subject according to a dosing regimen including a first 21-day dosing cycle and a second 28-day dosing cycle. (a) The first dosing cycle includes the first dose (C1D1), the second dose (C1D2), and the third dose (C1D3) of mosunetuzumab that are scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle. The C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg. (b) The second dosing cycle includes a single dose (C2D1) of mosunetuzumab that is scheduled to be administered subcutaneously on day 1 of the second dosing cycle. The C2D1 is about 45 mg, and (c) The second dosing cycle further includes lenalidomide at about 5 mg to about 20 mg that is scheduled to be administered orally daily from days 1 to 21 of the second dosing cycle. Use of lenalidomide.

[0175] 6. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating a subject having previously untreated FL, wherein mosunetuzumab 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, (a) The first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, which are each scheduled to be administered subcutaneously on days 1, 8, and 15 of the first dosing cycle, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg, (b) The second dosing cycle comprises a single dose (C2D1) of mosunetuzumab, which is scheduled to be 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 about 5 mg to about 20 mg of lenalidomide, which is scheduled to be administered orally daily from days 1 to 21 of the second dosing cycle, Use of lenalidomide.

[0176] 7. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab for treating a subject having previously untreated FL, wherein mosunetuzumab 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, (a) The first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, which are each scheduled to be administered subcutaneously on days 1, 8, and 15 of the first dosing cycle, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg, (b) The second dosing cycle includes a single dose of mosunetuzumab (C2D1) scheduled to be administered subcutaneously on day 1 of the second dosing cycle, where C2D1 is about 45 mg, and (c) The second dosing cycle further includes about 5 mg to about 20 mg of lenalidomide scheduled to be administered orally daily from days 1 to 21 of the second dosing cycle, Use of lenalidomide.

[0177] 8. The method according to any one of embodiments 1 to 7, mosunetuzumab for use, lenalidomide for use, or use, wherein the dosing regimen comprises one or more additional dosing cycles.

[0178] 9. The method according to embodiment 8, mosunetuzumab for use, lenalidomide for use, or use, wherein the dosing regimen comprises 1 to 10 additional dosing cycles.

[0179] 10. The method according to embodiment 8 or 9, mosunetuzumab for use, lenalidomide for use, or use, wherein the dosing regimen comprises 10 additional dosing cycles.

[0180] 11. The method according to any one of embodiments 8 to 10, mosunetuzumab for use, lenalidomide for use, or use, wherein each of the one or more additional dosing cycles is about 28 days in length.

[0181] 12. The method according to any one of embodiments 8 to 11, mosunetuzumab for use, lenalidomide for use, or use, wherein each of the one or more additional dosing cycles comprises an additional single dose of mosunetuzumab.

[0182] 13. The method according to embodiment 12, mosunetuzumab for use, lenalidomide for use, or use, wherein the additional single dose of mosunetuzumab is about 45 mg.

[0183] 14. The method according to embodiment 12 or 13, wherein the method comprises subcutaneously administering to the subject each additional single dose of mosunetuzumab on day 1 of each of the one or more additional dosing cycles.

[0184] 15. Mosunetuzumab for use according to embodiment 12 or 13, lenalidomide for use, or use, wherein each additional single dose of mosunetuzumab is scheduled to be subcutaneously administered to the subject on day 1 of each of the one or more additional dosing cycles.

[0185] 16. The method according to any one of embodiments 1 to 15, mosunetuzumab for use, lenalidomide for use, or use, wherein lenalidomide is not administered or not scheduled to be administered during the first dosing cycle.

[0186] 17. The method according to any one of embodiments 8 to 16, mosunetuzumab for use, lenalidomide for use, or use, wherein lenalidomide is orally administered or scheduled to be orally administered during any of the one or more additional dosing cycles.

[0187] 18. The method according to any one of embodiments 10 to 17, mosunetuzumab for use, lenalidomide for use, or use, wherein lenalidomide is orally administered or scheduled to be orally administered during each of the 10 additional dosing cycles.

[0188] 19. The method according to embodiment 17 or 18, mosunetuzumab for use, lenalidomide for use, or use, wherein lenalidomide is orally administered or scheduled to be orally administered on days 1 to 21 of each of the additional dosing cycles comprising administration of lenalidomide.

[0189] 20. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 1 to 19, wherein lenalidomide is not administered or not scheduled to be administered during the last 7 days of any dosing cycle including the administration of lenalidomide.

[0190] 21. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 1 to 20, wherein lenalidomide is administered or scheduled to be administered at a dose of about 10 mg.

[0191] 22. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 1 to 21, wherein lenalidomide is administered or scheduled to be administered at a dose of about 20 mg.

[0192] 23. A method of treating a subject having previously untreated FL, comprising administering mosunetuzumab and lenalidomide to the subject according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg, and C1D3 is about 45 mg, (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg, and (c) the second dosing cycle further comprises orally administering about 10 mg of lenalidomide daily from days 1 to 21 of the second dosing cycle. Method.

[0193] 24. Mosunetuzumab for use in combination with lenalidomide to treat a subject having previously untreated F), wherein mosunetuzumab 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, (a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, which are each scheduled to be administered subcutaneously on days 1, 8, and 15 of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg, and C1D3 is about 45 mg, (b) The second dosing cycle includes a single dose (C2D1) of mosunetuzumab, which is scheduled to be administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg, and (c) The second dosing cycle further includes about 10 mg of lenalidomide, which is scheduled to be administered orally daily on days 1 to 21 of the second dosing cycle, Mosunetuzumab.

[0194] 25. Lenalidomide for use in combination with mosunetuzumab to treat a subject having previously untreated FL, wherein mosunetuzumab 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, (a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, which are each scheduled to be administered subcutaneously on days 1, 8, and 15 of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg, and C1D3 is about 45 mg, (b) The second dosing cycle includes a single dose (C2D1) of mosunetuzumab, which is scheduled to be administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg, and (c) The second dosing cycle further comprises about 10 mg of lenalidomide that is scheduled to be orally administered daily on days 1 to 21 of the second dosing cycle. Lenalidomide.

[0195] 26. Use of mosunetuzumab in combination with lenalidomide for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled 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. (a) The first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab that are scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg, and C1D3 is about 45 mg. (b) The second dosing cycle comprises a single dose (C2D1) of mosunetuzumab that is scheduled to be administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg, and (c) The second dosing cycle further comprises about 10 mg of lenalidomide that is scheduled to be orally administered daily on days 1 to 21 of the second dosing cycle. Use of mosunetuzumab.

[0196] 27. Use of lenalidomide in combination with mosunetuzumab for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled 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. (a) The first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab that are scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg, and C1D3 is about 45 mg. (b) The second dosing cycle includes a single dose of mosunetuzumab (C2D1) that is scheduled to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and (c) The second dosing cycle further includes about 10 mg of lenalidomide that is scheduled to be administered orally daily on days 1 to 21 of the second dosing cycle, Use of lenalidomide.

[0197] 28. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled 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, (a) The first dosing cycle includes a first dose of mosunetuzumab (C1D1), a second dose of mosunetuzumab (C1D2), and a third dose of mosunetuzumab (C1D3) that are scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg, (b) The second dosing cycle includes a single dose of mosunetuzumab (C2D1) that is scheduled to be administered subcutaneously on day 1 of the second dosing cycle, wherein the C2D1 is about 45 mg, and (c) The second dosing cycle further includes about 10 mg of lenalidomide that is scheduled to be administered orally daily on days 1 to 21 of the second dosing cycle, Use of lenalidomide.

[0198] 29. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled 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, (a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab that are scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle. The C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg. (b) The second dosing cycle includes a single dose (C2D1) of mosunetuzumab that is scheduled to be administered subcutaneously on day 1 of the second dosing cycle. The C2D1 is about 45 mg, and (c) The second dosing cycle further includes about 10 mg of lenalidomide that is scheduled to be administered orally daily from days 1 to 21 of the second dosing cycle. Use of lenalidomide.

[0199] 30. A method of treating a subject having previously untreated FL, comprising administering mosunetuzumab and lenalidomide to the subject according to a dosing regimen including a first 21-day dosing cycle and a second 28-day dosing cycle. (a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab that are administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle. The C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg. (b) The second dosing cycle includes a single dose (C2D1) of mosunetuzumab that is administered subcutaneously on day 1 of the second dosing cycle. The C2D1 is about 45 mg, and (c) The second dosing cycle further includes administering about 20 mg of lenalidomide orally daily from days 1 to 21 of the second dosing cycle. Method.

[0200] Moxetumomab pasudotox for use in combination with lenalidomide for treating a subject having previously untreated F), wherein moxetumomab pasudotox 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, (a) the first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of moxetumomab pasudotox, which are each scheduled to be administered subcutaneously on days 1, 8, and 15 of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg, and C1D3 is about 45 mg, (b) the second dosing cycle includes a single dose (C2D1) of moxetumomab pasudotox, which is scheduled to be administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg, and (c) the second dosing cycle further includes about 20 mg of lenalidomide, which is scheduled to be administered orally daily on days 1 to 21 of the second dosing cycle, Moxetumomab pasudotox.

[0201] Lenalidomide for use in combination with moxetumomab pasudotox for treating a subject having previously untreated FL, wherein moxetumomab pasudotox 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, (a) the first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of moxetumomab pasudotox, which are each scheduled to be administered subcutaneously on days 1, 8, and 15 of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg, and C1D3 is about 45 mg, (b) the second dosing cycle includes a single dose (C2D1) of moxetumomab pasudotox, which is scheduled to be administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg, and (c) The second dosing cycle further comprises about 20 mg of lenalidomide, which is scheduled to be orally administered daily on days 1 to 21 of the second dosing cycle. Lenalidomide.

[0202] 33. Use of mosunetuzumab in combination with lenalidomide for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled 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. (a) The first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab, which are scheduled to be subcutaneously administered on days 1, 8 and 15, respectively, of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg and C1D3 is about 45 mg. (b) The second dosing cycle comprises a single dose (C2D1) of mosunetuzumab, which is scheduled to be subcutaneously administered on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg, and (c) The second dosing cycle further comprises about 20 mg of lenalidomide, which is scheduled to be orally administered daily on days 1 to 21 of the second dosing cycle. Use of mosunetuzumab.

[0203] 34. Use of lenalidomide in combination with mosunetuzumab for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled 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. (a) The first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab, which are scheduled to be subcutaneously administered on days 1, 8 and 15, respectively, of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg and C1D3 is about 45 mg. (b) The second dosing cycle includes a single dose of mosunetuzumab (C2D1) that is scheduled to be administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg, and (c) The second dosing cycle further includes about 20 mg of lenalidomide that is scheduled to be administered orally daily from days 1 to 21 of the second dosing cycle, Use of lenalidomide.

[0204] 35. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled 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, (a) The first dosing cycle includes a first dose of mosunetuzumab (C1D1), a second dose of mosunetuzumab (C1D2), and a third dose of mosunetuzumab (C1D3) that are scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg, and C1D3 is about 45 mg, (b) The second dosing cycle includes a single dose of mosunetuzumab (C2D1) that is scheduled to be administered subcutaneously on day 1 of the second dosing cycle, wherein C2D1 is about 45 mg, and (c) The second dosing cycle further includes about 20 mg of lenalidomide that is scheduled to be administered orally daily from days 1 to 21 of the second dosing cycle, Use of lenalidomide.

[0205] 36. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled 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, (a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab that are scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle. The C1D1 is about 5 mg, the C1D2 is about 45 mg, and the C1D3 is about 45 mg. (b) The second dosing cycle includes a single dose (C2D1) of mosunetuzumab that is scheduled to be administered subcutaneously on day 1 of the second dosing cycle. The C2D1 is about 45 mg, and (c) The second dosing cycle further includes about 20 mg of lenalidomide that is scheduled to be administered orally daily from days 1 to 21 of the second dosing cycle. Use of lenalidomide.

[0206] 37. A method of treating a subject having previously untreated FL, comprising administering mosunetuzumab and lenalidomide to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles. (a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab that are administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle. 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 include a single dose (C2D1 - C12D1) of mosunetuzumab that is administered subcutaneously on day 1 of each dosing cycle. Each single dose C2D1 - C12D1 is about 45 mg, and (c) The second to twelfth dosing cycles each further include administering about 10 mg of lenalidomide orally daily from days 1 to 21 of each dosing cycle. Method.

[0207] 38. Mosunetuzumab for use in combination with lenalidomide to treat a subject having previously untreated F), wherein mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, which are each scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg, and C1D3 is about 45 mg, (b) the second to twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of mosunetuzumab, which is scheduled to be administered subcutaneously on day 1 of each dosing cycle, and each single dose C2D1-C12D1 is about 45 mg, and (c) the second to twelfth dosing cycles each further comprise about 10 mg of lenalidomide, which is scheduled to be administered orally daily from days 1 to 21 of each dosing cycle, Mosunetuzumab.

[0208] 39. Lenalidomide for use in combination with mosunetuzumab to treat a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, which are each scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg, and C1D3 is about 45 mg, (b) The second to twelfth dosing cycles each include a single dose of mosunetuzumab (C2D1 - C12D1) scheduled to be administered subcutaneously on day 1 of each dosing cycle, each single dose C2D1 - C12D1 being about 45 mg, and (c) The second to twelfth dosing cycles each further include about 10 mg of lenalidomide scheduled to be administered orally daily on days 1 - 21 of each dosing cycle, Lenalidomide.

[0209] 40. Use of mosunetuzumab in combination with lenalidomide for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 - day dosing cycle and 11 subsequent 28 - day dosing cycles, (a) The first dosing cycle includes a first dose of mosunetuzumab (C1D1), a second dose (C1D2), and a third dose (C1D3) scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle, C1D1 being about 5 mg, C1D2 being about 45 mg, and C1D3 being about 45 mg, (b) The second to twelfth dosing cycles each include a single dose of mosunetuzumab (C2D1 - C12D1) scheduled to be administered subcutaneously on day 1 of each dosing cycle, each single dose C2D1 - C12D1 being about 45 mg, and (c) The second to twelfth dosing cycles each further include about 10 mg of lenalidomide scheduled to be administered orally daily on days 1 - 21 of each dosing cycle, Use of mosunetuzumab.

[0210] 41. Use of lenalidomide in combination with mosunetuzumab for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 - day dosing cycle and 11 subsequent 28 - day dosing cycles, (a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab that are scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle. 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 include a single dose (C2D1 - C12D1) of mosunetuzumab that is scheduled to be administered subcutaneously on day 1 of each dosing cycle. Each single dose C2D1 - C12D1 is about 45 mg, and (c) The second to twelfth dosing cycles each further include about 10 mg of lenalidomide that is scheduled to be administered orally daily from days 1 to 21 of each dosing cycle. Use of lenalidomide.

[0211] 42. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled to be administered to the subject according to a dosing regimen comprising a first 21 - day dosing cycle and 11 subsequent 28 - day dosing cycles. (a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab that are scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle. 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 include a single dose (C2D1 - C12D1) of mosunetuzumab that is scheduled to be administered subcutaneously on day 1 of each dosing cycle. Each single dose C2D1 - C12D1 is about 45 mg, and (c) The second to twelfth dosing cycles each further include about 10 mg of lenalidomide that is scheduled to be administered orally daily from days 1 to 21 of each dosing cycle. Use of lenalidomide.

[0212] 43. Use of lenalidomide in the manufacture of a medicament for use in combination with ofatumumab for treating a subject having previously untreated FL, wherein ofatumumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, (a) said first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of ofatumumab, which are each scheduled to be administered subcutaneously on days 1, 8 and 15 of said first dosing cycle, said C1D1 being about 5 mg, said C1D2 being about 45 mg, and said C1D3 being about 45 mg, (b) said second to twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of ofatumumab, which is scheduled to be administered subcutaneously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being about 45 mg, and (c) said second to twelfth dosing cycles each further comprise about 10 mg of lenalidomide, which is scheduled to be administered orally daily on days 1 to 21 of each dosing cycle, Use of lenalidomide.

[0213] 44. A method of treating a subject having previously untreated FL, comprising administering ofatumumab and lenalidomide to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, (a) said first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of ofatumumab, which are administered subcutaneously on days 1, 8 and 15 of said first dosing cycle, said C1D1 being about 5 mg, said C1D2 being about 45 mg, and said C1D3 being about 45 mg, (b) The second to twelfth dosing cycles each include a single dose of mosunetuzumab (C2D1-C12D1) administered subcutaneously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being about 45 mg, and (c) The second to twelfth dosing cycles each further include oral administration of about 20 mg of lenalidomide daily on days 1-21 of each dosing cycle, Method.

[0214] 45. Mosunetuzumab for use in combination with lenalidomide to treat a subject having previously untreated F), wherein mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, (a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle, C1D1 being about 5 mg, C1D2 being about 45 mg, and C1D3 being about 45 mg, (b) The second to twelfth dosing cycles each include a single dose of mosunetuzumab (C2D1-C12D1) scheduled to be administered subcutaneously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being about 45 mg, and (c) The second to twelfth dosing cycles each further include about 20 mg of lenalidomide scheduled to be administered orally daily on days 1-21 of each dosing cycle, Mosunetuzumab.

[0215] 46. Lenalidomide for use in combination with mosunetuzumab to treat a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, (a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab that are scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg, and C1D3 is about 45 mg, (b) The second to twelfth dosing cycles each include a single dose (C2D1 - C12D1) of mosunetuzumab that is scheduled to be administered subcutaneously on day 1 of each dosing cycle, and each single dose C2D1 - C12D1 is about 45 mg, and (c) The second to twelfth dosing cycles each further include about 20 mg of lenalidomide that is scheduled to be administered orally daily on days 1 to 21 of each dosing cycle, Lenalidomide.

[0216] 47. Use of mosunetuzumab in combination with lenalidomide for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled to be administered to the subject according to a dosing regimen comprising a first 21 - day dosing cycle and 11 subsequent 28 - day dosing cycles, (a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab that are scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is about 5 mg, C1D2 is about 45 mg, and C1D3 is about 45 mg, (b) The second to twelfth dosing cycles each include a single dose (C2D1 - C12D1) of mosunetuzumab that is scheduled to be administered subcutaneously on day 1 of each dosing cycle, and each single dose C2D1 - C12D1 is about 45 mg, and (c) The second to twelfth dosing cycles each further include about 20 mg of lenalidomide that is scheduled to be administered orally daily on days 1 to 21 of each dosing cycle, Use of mosunetuzumab.

[0217] 48. Use of lenalidomide in combination with ofatumumab for treating a subject having previously untreated FL, wherein ofatumumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, (a) said first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of ofatumumab, which are each scheduled to be administered subcutaneously on days 1, 8 and 15 of said first dosing cycle, said C1D1 being about 5 mg, said C1D2 being about 45 mg, and said C1D3 being about 45 mg, (b) said second to twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of ofatumumab, which is scheduled to be administered subcutaneously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being about 45 mg, and (c) said second to twelfth dosing cycles each further comprise about 20 mg of lenalidomide, which is scheduled to be administered orally daily on days 1-21 of each dosing cycle, Use of lenalidomide.

[0218] 49. Use of ofatumumab in the manufacture of a medicament for use in combination with lenalidomide for treating a subject having previously untreated FL, wherein ofatumumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, (a) said first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of ofatumumab, which are each scheduled to be administered subcutaneously on days 1, 8 and 15 of said first dosing cycle, said C1D1 being about 5 mg, said C1D2 being about 45 mg, and said C1D3 being about 45 mg, (b) The second to twelfth dosing cycles each include a single dose of mosunetuzumab (C2D1 - C12D1) scheduled to be administered subcutaneously on day 1 of each dosing cycle, each single dose C2D1 - C12D1 being about 45 mg, and (c) The second to twelfth dosing cycles each further include about 20 mg of lenalidomide scheduled to be administered orally daily on days 1 - 21 of each dosing cycle, Use of lenalidomide.

[0219] 50. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab for treating a subject having previously untreated FL, wherein mosunetuzumab and lenalidomide are scheduled to be administered to the subject according to a dosing regimen comprising a first 21 - day dosing cycle and 11 subsequent 28 - day dosing cycles, (a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab scheduled to be administered subcutaneously on days 1, 8, and 15, respectively, of the first dosing cycle, C1D1 being about 5 mg, C1D2 being about 45 mg, and C1D3 being about 45 mg, (b) The second to twelfth dosing cycles each include a single dose of mosunetuzumab (C2D1 - C12D1) scheduled to be administered subcutaneously on day 1 of each dosing cycle, each single dose C2D1 - C12D1 being about 45 mg, and (c) The second to twelfth dosing cycles each further include about 20 mg of lenalidomide scheduled to be administered orally daily on days 1 - 21 of each dosing cycle, Use of lenalidomide.

[0220] 51. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 1-50, wherein the FL is histologically demonstrated to be grade 1, 2, or 3a according to the World Health Organization classification of lymphoid neoplasms (as referenced in Swerdlow SH, et al. Blood 2016;127:2375-90), but not 3b.

[0221] 52. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 1-51, wherein the subject has previously been determined to require systemic therapy to treat previously untreated FL based on the follicular lymphoma research group (GELF) criteria (Brice et al., J Clin Oncol. 15(3):1110-1117, 1997).

[0222] 53. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 1-52, wherein the first dosing cycle further comprises administration of a corticosteroid.

[0223] 54. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 1-53, wherein the second dosing cycle further comprises administration of a corticosteroid.

[0224] 55. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 8-54, wherein any one of the one or more additional dosing cycles comprises administration of a corticosteroid.

[0225] 56. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 53-55, wherein a single dose of the corticosteroid is administered to or is scheduled to be administered to the subject prior to administration of any dose of mosunetuzumab.

[0226] 57. The method according to any one of embodiments 53 to 56, mosunetuzumab for use, lenalidomide for use, or use, wherein the corticosteroid comprises dexamethasone or methylprednisolone.

[0227] 58. The method according to any one of embodiments 53 to 57, mosunetuzumab for use, lenalidomide for use, or use, wherein the corticosteroid is administered intravenously or orally, or is scheduled to be administered intravenously or orally.

[0228] 59. The method according to any one of embodiments 53 to 58, mosunetuzumab for use, lenalidomide for use, or use, wherein the corticosteroid comprises dexamethasone and is administered or is scheduled to be administered in a dose of about 20 mg.

[0229] 60. The method according to any one of embodiments 53 to 27, mosunetuzumab for use, lenalidomide for use, or use, wherein the corticosteroid comprises methylprednisolone and is administered or is scheduled to be administered in a dose of about 58 mg.

[0230] 61. The method according to any one of embodiments 1 to 60, mosunetuzumab for use, lenalidomide for use, or use, wherein the first dosing cycle further comprises administration of an antihistamine.

[0231] 62. The method according to any one of embodiments 1 to 61, mosunetuzumab for use, lenalidomide for use, or use, wherein the second dosing cycle further comprises administration of an antihistamine.

[0232] 63. The method according to any one of embodiments 8 to 62, mosunetuzumab for use, lenalidomide for use, or use, wherein any one of the one or more additional dosing cycles comprises administration of an antihistamine.

[0233] 64. Prior to administration of any dose of mosunetuzumab, the method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 61 to 63, wherein a single dose of the antihistamine is administered or is scheduled to be administered to the subject.

[0234] 65. The method, mosunetuzumab for use, lenalidomide for use, or use according to embodiment 64, wherein the antihistamine is administered or is scheduled to be administered to the subject at least 30 minutes prior to administration of any dose of mosunetuzumab.

[0235] 66. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 61 to 65, wherein the antihistamine is administered or is scheduled to be administered orally or intravenously.

[0236] 67. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 61 to 66, wherein the antihistamine comprises diphenhydramine hydrochloride and is administered or is scheduled to be administered in a dose of about 50 to 100 mg.

[0237] 68. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 1 to 67, wherein the first dosing cycle further comprises administration of an antipyretic.

[0238] 69. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 1 to 68, wherein the second dosing cycle further comprises administration of an antipyretic.

[0239] 70. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 8 to 69, wherein any one of the one or more additional dosing cycles comprises administration of an antipyretic.

[0240] 71. Before administration of any dose of mosunetuzumab, the method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 68 to 70, wherein a single dose of the antipyretic is administered to or is scheduled to be administered to the subject.

[0241] 72. The method, mosunetuzumab for use, lenalidomide for use, or use according to embodiment 71, wherein the antipyretic is administered to or is scheduled to be administered to the subject at least 30 minutes before administration of any dose of mosunetuzumab.

[0242] 73. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 68 to 72, wherein the antipyretic is administered orally or is scheduled to be administered orally.

[0243] 74. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 68 to 73, wherein the antipyretic contains acetaminophen and is administered or is scheduled to be administered at a dose of about 500 - 1000 mg.

[0244] 75. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 1 to 74, wherein the first dosing cycle further includes administration of a first dose of a prophylactic agent against tumor lysis syndrome (TLS).

[0245] 76. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 1 to 75, wherein the second dosing cycle further includes administration of a first dose of a prophylactic agent against TLS.

[0246] 77. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 8 to 76, wherein any one of said one or more additional dosing cycles comprises administration of a first dose of a prophylactic agent against TLS.

[0247] 78. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 75 to 77, wherein prior to administration of any dose of mosunetuzumab, said first dose of said prophylactic agent against TLS is administered or is scheduled to be administered to said subject.

[0248] 79. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 75 to 78, wherein said prophylactic agent against TLS comprises allopurinol.

[0249] 80. The method, mosunetuzumab for use, lenalidomide for use, or use according to embodiment 79, wherein said first dose of allopurinol is administered or is scheduled to be administered approximately 72 hours prior to administration of any dose of mosunetuzumab.

[0250] 81. The method, mosunetuzumab for use, lenalidomide for use, or use according to embodiment 80, wherein after administration of said first dose, an additional single dose of allopurinol is administered or is scheduled to be administered daily for 6 to 10 days.

[0251] 82. The method, mosunetuzumab for use, lenalidomide for use, or use according to any one of embodiments 79 to 81, wherein said first dose of allopurinol is approximately 300 mg.

[0252] 83. The method, mosunetuzumab for use, lenalidomide for use, or use according to embodiment 81 or 82, wherein each additional single dose of allopurinol is approximately 300 mg.

[0253] The method according to any one of embodiments 79 to 83, mosunetuzumab for use, lenalidomide for use, or use, wherein allopurinol is administered orally or is scheduled to be administered orally.

[0254] The method according to any one of embodiments 75 to 78, mosunetuzumab for use, lenalidomide for use, or use, wherein the prophylactic agent against TLS comprises rasburicase.

[0255] The method according to embodiment 85, mosunetuzumab for use, lenalidomide for use, or use, wherein the first dose of rasburicase is administered or is scheduled to be administered approximately 30 minutes before the administration of any dose of mosunetuzumab.

[0256] The method according to embodiment 86, mosunetuzumab for use, lenalidomide for use, or use, wherein after the administration of the first dose, an additional single dose of rasburicase is administered or is scheduled to be administered daily for 1 to 5 days.

[0257] The method according to any one of embodiments 85 to 87, mosunetuzumab for use, lenalidomide for use, or use, wherein the first dose of rasburicase is about 0.2 mg / kg.

[0258] The method according to embodiment 87 or 88, mosunetuzumab for use, lenalidomide for use, or use, wherein each additional single dose of rasburicase is about 0.2 mg / kg.

[0259] The method according to any one of embodiments 85 to 89, mosunetuzumab for use, lenalidomide for use, or use, wherein rasburicase is administered intravenously or is scheduled to be administered intravenously.

[0260] 91. The method according to any one of embodiments 1 to 90, the mosunetuzumab for use, the lenalidomide for use, or the use, wherein the first dosing cycle is a three-dose dosing cycle.

[0261] 92. The method according to any one of embodiments 1 to 91, the mosunetuzumab for use, the lenalidomide for use, or the use, wherein the subject is human.

[0262] Other embodiments The above invention has been described in some detail by way of illustration and example for the purpose of clarity of understanding, but these illustration and examples should not be construed as limiting the scope of the invention. The disclosures of all patents and scientific literature cited herein are hereby expressly incorporated by reference in their entirety.

Claims

**Claim 1** A medicament for treating a subject having previously untreated follicular lymphoma (FL) and comprising mosunetuzumab, wherein mosunetuzumab is formulated for administration to said subject in combination with lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, (a) said first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab administered subcutaneously on days 1, 8 and 15 respectively of said first dosing cycle, said C1D1 being about 5 mg, said C1D2 being about 45 mg and said C1D3 being about 45 mg, (b) said second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered subcutaneously on day 1 of said second dosing cycle, said C2D1 being about 45 mg, and (c) said second dosing cycle further comprises oral administration of about 10 mg of lenalidomide per day or about 20 mg of lenalidomide per day on days 1 to 21 of said second dosing cycle, a medicament. **Claim 2** A medicament for treating a subject having previously untreated FL and comprising lenalidomide, wherein lenalidomide is formulated for administration to said subject in combination with mosunetuzumab according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, (a) said first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab administered subcutaneously on days 1, 8 and 15 respectively of said first dosing cycle, said C1D1 being about 5 mg, said C1D2 being about 45 mg and said C1D3 being about 45 mg, (b) said second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered subcutaneously on day 1 of said second dosing cycle, said C2D1 being about 45 mg, and (c) said second dosing cycle further comprises oral administration of about 10 mg of lenalidomide per day or about 20 mg of lenalidomide per day on days 1 to 21 of said second dosing cycle, a medicament. **Claim 3** A medicament for treating a subject having previously untreated FL and comprising mosunetuzumab and lenalidomide, Moxetumomab and lenalidomide are formulated for administration to said subject according to a dosing regimen comprising a first 21-day dosing cycle and a second 28-day dosing cycle, where (a) said first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of moxetumomab administered subcutaneously on days 1, 8, and 15, respectively, of said first dosing cycle, said C1D1 being about 5 mg, said C1D2 being about 45 mg, and said C1D3 being about 45 mg, where (b) said second dosing cycle comprises a single dose (C2D1) of moxetumomab administered subcutaneously on day 1 of said second dosing cycle, said C2D1 being about 45 mg, and where (c) said second dosing cycle further comprises oral administration of about 10 mg of lenalidomide per day or about 20 mg of lenalidomide per day on days 1 to 21 of said second dosing cycle, a medicament.

4. The medicament according to any one of claims 1 to 3, wherein said dosing regimen comprises one or more additional dosing cycles.

5. The medicament according to claim 4, wherein said dosing regimen comprises 1 to 10 additional dosing cycles.

6. (a) said dosing regimen comprises 10 additional dosing cycles; where (b) the length of each of said one or more additional dosing cycles is 28 days; where (c) each of said one or more additional dosing cycles comprises an additional single dose of moxetumomab; where (d) lenalidomide is not administered during the first dosing cycle; and / or, where (e) lenalidomide is orally administered during any of said one or more additional dosing cycles, the medicament according to claim 4.

7. (a) said additional single dose of moxetumomab is about 45 mg; where (b) moxetumomab is administered subcutaneously to said subject on day 1 of each of said one or more additional dosing cycles; where (c) lenalidomide is orally administered on days 1 to 21 of each of said additional dosing cycles comprising administration of lenalidomide; where (d) lenalidomide is not administered during the last 7 days of any dosing cycle comprising administration of lenalidomide; and / or, where (e) the second dosing cycle where (i) comprises administration of about 10 mg of lenalidomide per day, and lenalidomide is administered at a dose of about 10 mg of lenalidomide per day during any of said one or more additional dosing cycles; or, (ii) including administration of about 20 mg of lenalidomide per day, and lenalidomide is administered at a dose of about 20 mg of lenalidomide per day during any of the one or more additional dosing cycles The medicament according to claim 6.

8. The medicament according to any one of claims 1 to 3, wherein the FL is histologically demonstrated to be grade 1, 2 or 3a according to the World Health Organization classification of lymphoid neoplasms (referenced in Swerdlow SH, et al. Blood 2016; 127: 2375-90), but not 3b.

9. The medicament according to any one of claims 1 to 3, wherein the subject has been previously determined to require systemic therapy to treat previously untreated FL based on the follicular lymphoma research group (GELF) criteria (Brice et al., J Clin Oncol. 15(3): 1110-1117, 1997).

10. Any one of the first dosing cycle, the second dosing cycle, and / or the one or more additional dosing cycles is (a) corticosteroid; (b) antihistamine; (c) antipyretic; and / or (d) first dose of a prophylactic agent for tumor lysis syndrome (TLS) further comprising administration of The medicament according to any one of claims 1 to 3.

11. (a) A single dose of the corticosteroid is administered to the subject prior to administration of any dose of mosunetuzumab; (b) the corticosteroid comprises dexamethasone or methylprednisolone; and / or (c) the corticosteroid is administered intravenously or orally, The medicament according to claim 10.

12. The corticosteroid is (a) including dexamethasone and administered at a dose of about 20 mg; or (b) including methylprednisolone and administered at a dose of about 80 mg, The medicament according to claim 11.

13. (a) A single dose of the antihistamine is administered to the subject prior to administration of any dose of mosunetuzumab; (b) the antihistamine is administered orally or intravenously; and / or (c) the antihistamine comprises diphenhydramine hydrochloride and is administered at a dose of about 50-100 mg, The medicament according to claim 10.

14. The pharmaceutical according to claim 13, wherein the antihistamine agent is administered to the subject at least 30 minutes before administration of any dose of mosunetuzumab.

15. (a) A single dose of the antipyretic agent is administered to the subject before administration of any dose of mosunetuzumab; (b) The antipyretic agent is administered orally; and / or (c) The antipyretic agent contains acetaminophen and is administered at a dose of about 500 to 1000 mg, The pharmaceutical according to claim 10.

16. The pharmaceutical according to claim 15, wherein the antipyretic agent is administered to the subject at least 30 minutes before administration of any dose of mosunetuzumab.

17. (a) The first dose of the prophylactic agent against TLS is administered to the subject before administration of any dose of mosunetuzumab; and / or (b) The prophylactic agent against TLS contains allopurinol or rasburicase, The pharmaceutical according to claim 10.

18. The prophylactic agent against TLS contains allopurinol, (a) The first dose of allopurinol is administered about 72 hours before administration of any dose of mosunetuzumab; (b) An additional single dose of allopurinol is administered daily for 6 to 10 days after administration of the first dose of allopurinol; (c) The first dose of allopurinol is about 300 mg; and / or (d) Allopurinol is administered orally, The pharmaceutical according to claim 17.

19. The pharmaceutical according to claim 18, wherein each additional single dose of allopurinol is about 300 mg.

20. The prophylactic agent against TLS contains rasburicase, (a) The first dose of rasburicase is administered about 30 minutes before administration of any dose of mosunetuzumab; (b) An additional single dose of rasburicase is administered daily for 1 to 5 days after administration of the first dose of rasburicase; (c) The first dose of rasburicase is about 0.2 mg / kg; and / or (d) Rasburicase is administered intravenously, The pharmaceutical according to claim 17.

21. The pharmaceutical according to claim 20, wherein each additional single dose of rasburicase is about 0.2 mg / kg.

22. Mosunetuzumab is administered by subcutaneous injection, The pharmaceutical according to any one of claims 1 to 3. The medicament according to any one of claims 1 to 3, wherein on the day including the administration of mosunetuzumab and lenalidomide, lenalidomide is administered before the administration of mosunetuzumab.

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