Methods for treatment of B cell proliferative disorders with anti-CD20/anti-CD3 bispecific antibodies

1 . A method of treating an elderly or unfit subject having a previously untreated B cell proliferative disorder comprising intravenously administering to the subject, as a monotherapy, mosunetuzumab in 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 the mosunetuzumab, wherein the C1D1 is 1 mg, the C1D2 is 2 mg, and the C1D3 is 13.5 or 30 mg; and

(b) the second dosing cycle comprises a single dose (C2D1) of the mosunetuzumab, wherein the C2D1 is the same dose as the C1D3, wherein:

(a) the elderly subject is at least 80-years old; or

(b) the unfit subject is at least 60-years old, and wherein the unfit subject exhibits:

(i) an impairment in at least one activity of daily living (ADL) component;

(ii) an impairment in at least one instrumental activity of daily living (IADL) component;

(iii) an impairment in at least one of cardiac function, vascular function, renal function, and/or liver function; and/or

(iv) diabetes.

2 . The method of claim 1 , wherein:

(i) the impairment in cardiac function comprises heart arrhythmia, congestive heart failure (CHF), myocardial infarction, and/or cardiac-related symptoms of hypothyroidism;

(ii) the impairment in vascular function comprises anemia, cerebrovascular accident (CVA), cerebrovascular disease (CVD), chronic obstructive pulmonary disease not otherwise specified (COPD: NOS), hyperlipidemia, peripheral vascular disease, stroke, and/or ischemic attack (TIA);

(iii) the impairment in renal function comprises acute kidney disease and/or chronic kidney disease; and/or

(iv) diabetes comprises type 2 diabetes, diabetes with end organ damage (EOD), and/or diabetes without EOD.

3 . The method of claim 1 , wherein the subject is unsuitable for treatment with R-CHOP therapy.

4 . A method of treating a subject having a previously untreated B cell proliferative disorder comprising intravenously administering to the subject, as a monotherapy, mosunetuzumab in 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 the mosunetuzumab, wherein the C1D1 is 1 mg, the C1D2 is 2 mg, and the C1D3 is 13.5 or 30 mg; and

(b) the second dosing cycle comprises a single dose (C2D1) of the mosunetuzumab, wherein the C2D1 is the same dose as the C1D3,

wherein the subject is unsuitable for treatment with R-CHOP therapy.

5 . The method of claim 3 , wherein the R-CHOP therapy comprises rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, and further wherein the rituximab is administered to the subject at a dose of 375 mg/m 2 every three weeks.

6 . The method of claim 1 , wherein:

(a) the first and second dosing cycles are 21-day dosing cycles;

(b) the method comprises administering the C2D1 on Day 1 of the second dosing cycle;

(c) the dosing regimen further comprises one or more additional dosing cycles; and/or

(d) the method further comprises administering to the subject one or more additional therapeutic agents to treat or reduce the likelihood of a cytokine release syndrome (CRS) event or a tumor lysis syndrome (TLS) event.

7 . The method of claim 6 , wherein the method comprises administering the C1D1, the C1D2, and the C1D3 on Days 1, 8, and 15, respectively, of the first dosing cycle.

8 . The method of claim 6 , wherein:

(a) the dosing regimen comprises six or 15 additional dosing cycles;

(b) the additional dosing cycles are 21-day dosing cycle; and/or

(c) one or more of the additional dosing cycles comprise an additional single dose of the mosunetuzumab.

9 . The method of claim 8 , wherein the additional single dose of the mosunetuzumab is:

(a) administered to the subject on Day 1 of each additional dosing cycle; and/or

(b) the same dose as the C1D3.

10 . The method of claim 6 , wherein the one or more additional therapeutic agents is:

(a) tocilizumab;

(b) an antihistamine;

(c) allopurinol or rasburicase; and/or

(d) a corticosteroid.

11 . The method of claim 10 , wherein:

(a) the antihistamine is diphenhydramine; and/or

(b) the corticosteroid comprises prednisone, prednisolone, methylprednisolone, and dexamethasone.

12 . The method of claim 11 , wherein the corticosteroid comprises prednisone, and wherein prednisone is administered to the subject:

(a) on each of the seven days prior to the administration of the C1D1; and/or

(b) at a dose of 100 mg/day.

13 . The method of claim 1 wherein the previously untreated B cell proliferative disorder is a previously untreated high-grade B-cell lymphoma and/or a previously untreated non-Hodgkin's lymphoma (NHL).

14 . The method of claim 13 , wherein the previously untreated NHL is a previously untreated DLBCL.

15 . A method of treating a population of subjects having a previously untreated DLBCL comprising intravenously administering to the subjects, as a monotherapy, mosunetuzumab in a dosing regimen comprising eight 21-day dosing cycles, wherein:

(a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the mosunetuzumab administered on Days 1, 8, and 15, respectively, of the first dosing cycle, wherein the C1D1 is 1 mg, the C1D2 is 2 mg, and the C1D3 is 13.5 or 30 mg; and

(b) the second to eighth dosing cycles each comprises a single dose (C2D1-C8D1) of the mosunetuzumab administered on Day 1 of each dosing cycle, wherein each single dose C2D1-C8D1 is the same dose as the C1D3,

wherein the subjects are at least 65-years old, and wherein the subjects are unsuitable for treatment with R-CHOP therapy.

16 . A method of treating a population of subjects having a previously untreated DLBCL comprising intravenously administering to the subjects, as a monotherapy, mosunetuzumab in a dosing regimen comprising seventeen 21-day dosing cycles, wherein:

(a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the mosunetuzumab administered on Days 1, 8, and 15, respectively, of the first dosing cycle, wherein the C1D1 is 1 mg, the C1D2 is 2 mg, and the C1D3 is 13.5 or 30 mg; and

(b) the second to seventeenth dosing cycles each comprises a single dose (C2D1-C17D1) of the mosunetuzumab administered on Day 1 of each dosing cycle, wherein each single dose C2D1-C17D1 is the same dose as the C1D3,

wherein the subjects are at least 65-years old, and wherein the subjects are unsuitable for treatment with R-CHOP therapy.

17 . The method of claim 15 , wherein

(a) the overall response rate is greater than 56%;

(b) the complete response rate is greater than 38%; and/or

(c) the rate of cytokine release syndrome having a grade of 3 or higher is less than 5%.

18 . The method of claim 16 , wherein:

(a) the overall response rate is greater than 56%;

(b) the complete response rate is greater than 38%; and/or

(c) the rate of cytokine release syndrome having a grade of 3 or higher is less than 5%.

19 . The method of claim 17 , wherein greater than 42% of subjects having a complete response maintained complete remission for 12 months.

20 . The method of claim 18 , wherein greater than 42% of subjects having a complete response maintained complete remission for 12 months.

21 . A method of treating a subject having a previously untreated DLBCL comprising intravenously administering to the subject, as a monotherapy, mosunetuzumab in a dosing regimen comprising eight 21-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 on Days 1, 8, and 15, respectively, of the first dosing cycle, wherein the C1D1 is 1 mg, the C1D2 is 2 mg, and the C1D3 is 30 mg; and

(b) the second to eighth dosing cycles each comprises a single dose (C2D1-C8D1) of mosunetuzumab administered on Day 1 of each dosing cycle, wherein each single dose C2D1-C8D1 is the same dose as the C1D3,

wherein the subject is at least 65-years old, and wherein the subject is unsuitable for treatment with standard R-CHOP therapy.

22 . A method of treating a subject having a previously untreated DLBCL comprising intravenously administering to the subject, as a monotherapy, mosunetuzumab in a dosing regimen comprising seventeen 21-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 on Days 1, 8, and 15, respectively, of the first dosing cycle, wherein the C1D1 is 1 mg, the C1D2 is 2 mg, and the C1D3 is 30 mg; and

(b) the second to seventeenth dosing cycles each comprises a single dose (C2D1-C17D1) of mosunetuzumab administered on Day 1 of each dosing cycle, wherein each single dose C2D1-C17D1 is the same dose as the C1D3,

wherein the subject is at least 65-years old, and wherein the subject is unsuitable for treatment with standard R-CHOP therapy.

23 . A method of treating an elderly subject having a previously untreated DLBCL comprising intravenously administering to the subject, as a monotherapy, mosunetuzumab in a dosing regimen comprising eight 21-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 on Days 1, 8, and 15, respectively, of the first dosing cycle, wherein the C1D1 is 1 mg, the C1D2 is 2 mg, and the C1D3 is 30 mg; and

(b) the second to eighth dosing cycles each comprises a single dose (C2D1-C8D1) of mosunetuzumab administered on Day 1 of each dosing cycle, wherein each single dose C2D1-C8D1 is the same dose as the C1D3,

wherein the subject is at least 80-years old.

24 . A method of treating an elderly subject having a previously untreated DLBCL comprising intravenously administering to the subject, as a monotherapy, mosunetuzumab in a dosing regimen comprising seventeen 21-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 on Days 1, 8, and 15, respectively, of the first dosing cycle, wherein the C1D1 is 1 mg, the C1D2 is 2 mg, and the C1D3 is 30 mg; and

(b) the second to seventeenth dosing cycles each comprises a single dose (C2D1-C17D1) of mosunetuzumab administered on Day 1 of each dosing cycle, wherein each single dose C2D1-C17D1 is the same dose as the C1D3,

wherein the subject is at least 80-years old.

25 . A method of treating an unfit subject having a previously untreated DLBCL comprising intravenously administering to the subject, as a monotherapy, mosunetuzumab in a dosing regimen comprising eight 21-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 on Days 1, 8, and 15, respectively, of the first dosing cycle, wherein the C1D1 is 1 mg, the C1D2 is 2 mg, and the C1D3 is 30 mg; and

(b) the second to eighth dosing cycles each comprises a single dose (C2D1-C8D1) of mosunetuzumab administered on Day 1 of each dosing cycle, wherein each single dose C2D1-C8D1 is the same dose as the C1D3,

wherein the subject is at least 60-years old, and wherein the subject exhibits:

(i) an impairment in at least one ADL component;

(ii) an impairment in at least one IADL component;

(iii) an impairment in at least one of cardiac function, vascular function, renal function, and/or liver function; and/or

(iv) diabetes.

26 . A method of treating an unfit subject having a previously untreated DLBCL comprising intravenously administering to the subject, as a monotherapy, mosunetuzumab in a dosing regimen comprising seventeen 21-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 on Days 1, 8, and 15, respectively, of the first dosing cycle, wherein the C1D1 is 1 mg, the C1D2 is 2 mg, and the C1D3 is 30 mg; and

(b) the second to seventeenth dosing cycles each comprises a single dose (C2D1-C17D1) of mosunetuzumab administered on Day 1 of each dosing cycle, wherein each single dose C2D1-C17D1 is the same dose as the C1D3,

wherein the subject is at least 60-years old, and wherein the subject exhibits:

(i) an impairment in at least one ADL component;

(ii) an impairment in at least one IADL component;

(iii) an impairment in at least one of cardiac function, vascular function, renal function, and/or liver function; and/or

(iv) diabetes.