Dosing regimen for Anti-DLL3 agents

Abstract

To provide a therapeutic method for the treatment of small cell lung cancer (SCLC).SOLUTION: A method for treating Delta-like 3 (DLL3)-positive cancer comprises administering to a subject in need thereof an anti-DLL3 agent at a dose of 3 mg to 200 mg once every two weeks.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of European Patent Application No. 19208214, filed November 10, 2019, and U.S. Provisional Patent Application No. 63 / 078,131, filed September 14, 2020, the contents of both applications being incorporated herein by reference in their entirety.

[0002] Submitting a sequence listing as an ASCII text file The contents of the following ASCII text file submission are incorporated herein by reference in their entirety: Sequence Listing in Computer Readable Form (CRF) (Filename: A-2520-WO-PCT_ST25.txt, Creation Date: October 28, 2020, Size: 1,218,887 bytes).

[0003] This application relates to the dosage and administration of anti-DLL3 agents for the treatment of cancer. [Background technology]

[0004] Small cell lung cancer (SCLC) is an aggressive form of lung cancer with a poor prognosis and limited treatment options, accounting for approximately 10-15% of lung cancers. Survival rates have remained low for decades, with only 5% of SCLC patients surviving five years, largely due to the lack of new treatments for this form of lung cancer. Approximately one-third of patients present with limited-stage disease. Most patients present with extensive-stage disease, defined as tumor in only one breast and confined to a single radiation field. These stages influence the available treatment regimens, with some stages treated with chemotherapy and radiation and others treated with chemotherapy alone. Disseminated metastatic tumors with lymphoma-like features are characteristic of SCLC.

[0005] Although patients typically respond well to current state-of-the-art treatments, including etoposide and cisplatin, they invariably relapse with chemotherapy-resistant disease, for which no currently available treatment options are available. The prognosis in the relapsed, refractory setting is extremely poor, with rapidly progressing disease and a short median survival of less than six months. Furthermore, patients with SCLC have a high incidence of comorbidities, including hypertension, heart disease, diabetes, and paraneoplastic syndromes. These, combined with the typical advanced age of SCLC patients, impact a patient's ability to tolerate demanding chemotherapy regimens, further limiting treatment options. Delta-like 3 (DLL3) is a type 1 transmembrane protein and non-canonical Notch ligand differentially expressed in SCLC. Using immunohistochemistry (IHC), 85% of SCLC tumors stained positive for CLL3, a pattern consistent with both membrane and cytoplasmic expression. In contrast, low levels of DLL3 protein expression were detected in normal brain, pancreatic islets, and pituitary gland with a cytoplasmic staining pattern (Saunders et al., Sci Transl Med. 7:302ra136 (2015)). DLL3 is a novel and promising target for the development of T cell-targeted therapy for SCLC. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Saunders et al, Sci Transl Med.7:302ra136(2015) Summary of the Invention [Problem to be solved by the invention]

[0007] There is an unmet medical need for the development of therapeutics for the treatment of SCLC. [Means for solving the problem]

[0008] Based on the disclosure provided herein, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by embodiment (E) below. In an embodiment of the present invention, for example, the following items are provided: (Item 1) 1. A method for treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent comprising the amino acid sequence of SEQ ID NOs: 437 and 431, wherein the anti-DLL3 agent is administered at a dose of 3 mg to 200 mg once every two weeks. (Item 2) Item 1. The method according to Item 1, wherein the anti-DLL3 agent is administered once every two weeks at a dose of 3 mg to 100 mg, 10 mg to 150 mg, 30 mg to 200 mg, 30 mg to 100 mg, 50 mg to 150 mg, 70 mg to 120 mg, 90 mg to 120 mg, or 100 mg to 200 mg. (Item 3) 10. The method of claim 1, wherein the anti-DLL3 agent is administered at a dose of 3 mg, 10 mg, 30 mg, or 100 mg once every two weeks. (Item 4) 4. The method of any one of items 1 to 3, wherein the anti-DLL3 agent is administered on days 1 and 15 of a 28-day cycle. (Item 5) 1. A method for treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent comprising the amino acid sequence of SEQ ID NOs: 437 and 431, wherein the anti-DLL3 agent is administered according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) of 3 mg to 200 mg on day 8, and c) one or more subsequent doses (target dose) of 3 mg to 200 mg starting on day 15 and every two weeks thereafter, wherein the second dose and subsequent doses are the same and higher than the first dose. (Item 6) 6. The method of claim 5, wherein the second and subsequent doses are at least 3 times, at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, at least 120 times, at least 150 times, or at least 200 times higher than the first dose. (Item 7) the first dose is 0.5 mg to 8 mg, 0.5 mg to 6 mg, 0.5 mg to 4 mg, 0.5 mg to 2 mg, or 1 mg; 7. The method according to item 5 or 6, wherein the second dose or the subsequent dose is 3 mg to 100 mg, 10 mg to 150 mg, 30 mg to 200 mg, 30 mg to 100 mg, 50 mg to 150 mg, 70 mg to 120 mg, 90 mg to 120 mg, or 100 mg to 200 mg. (Item 8) 8. The method of any one of items 5 to 7, wherein the first dose is 1 mg, and the second and subsequent doses are 3 mg, 10 mg, 30 mg, or 100 mg, respectively. (Item 9) 1. A method of treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent comprising the amino acid sequence of SEQ ID NOs: 437 and 431, wherein the anti-DLL3 agent is administered according to one of the following two schedules: Schedule I: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) of 3 mg to 100 mg on day 4, c) a third dose (step-up dose) of 3 mg to 200 mg on day 8, and d) one or more subsequent doses (target dose) of 3 mg to 200 mg starting on day 15 and every two weeks thereafter, wherein the second dose is higher than the first dose, and the third and subsequent doses are the same and higher than the second dose; or Schedule II: a) a first dose of 0.5 mg to 10 mg on day 1 (induction dose), b) a second dose of 3 mg to 100 mg on day 8 (step-up dose), c) a third dose of 3 mg to 200 mg on day 15 (step-up dose), and d) one or more subsequent doses of 3 mg to 200 mg starting on day 29 and every two weeks thereafter (target dose), wherein the second dose is higher than the first dose, and the third and subsequent doses are the same and higher than the second dose. The method comprises administering the compound according to one of the following methods. (Item 10) The first dose for each schedule is 0.5 mg to 8 mg, 0.5 mg to 6 mg, 0.5 mg to 4 mg, 0.5 mg to 2 mg, or 1 mg; The second dose for each schedule is 3 mg to 10 mg, 10 mg to 80 mg, 10 mg to 60 mg, 20 mg to 80 mg, 20 mg to 60 mg, 25 mg to 50 mg, 30 mg to 80 mg, 40 mg to 60 mg, 25 mg, or 50 mg; and The third dose and subsequent doses for each schedule are 3 mg to 100 mg, 10 mg to 150 mg, 30 mg to 200 mg, 30 mg to 100 mg, 50 mg to 150 mg, 70 mg to 120 mg, 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg. Item 9. The method according to item 9. (Item 11) Item 10. The method of item 9, wherein the second dose is 20 to 90 times, 20 to 70 times, or 25 to 50 times higher than the first dose, and the third dose and the subsequent doses are 2 to 10 times higher than the second dose. (Item 12) 1. A method of treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent comprising the amino acid sequence of SEQ ID NOs: 437 and 431, wherein the anti-DLL3 agent is administered according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) of 3 mg to 100 mg on day 4, c) a third dose (step-up dose) of 3 mg to 100 mg on day 8, d) a fourth dose (step-up dose) of 3 mg to 200 mg on day 15, and e) one or more subsequent doses (target doses) of 3 mg to 200 mg starting on day 29 and every two weeks thereafter, wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and the subsequent doses are the same and higher than the third dose. (Item 13) the first dose is 0.5 mg to 8 mg, 0.5 mg to 6 mg, 0.5 mg to 4 mg, 0.5 mg to 2 mg, or 1 mg; the second dose is 3 mg to 10 mg, 10 mg to 80 mg, 10 mg to 60 mg, 20 mg to 80 mg, 20 mg to 60 mg, 20 mg to 40 mg, or 25 mg; the third dose is 3 mg to 10 mg, 10 mg to 80 mg, 10 mg to 60 mg, 20 mg to 80 mg, 20 mg to 60 mg, 30 mg to 80 mg, 30 mg to 60 mg, 40 mg to 80 mg, 40 mg to 60 mg, or 50 mg; and Item 13. The method of item 12, wherein the fourth dose and the subsequent doses are 3 mg to 100 mg, 10 mg to 150 mg, 30 mg to 200 mg, 30 mg to 100 mg, 50 mg to 150 mg, 70 mg to 120 mg, 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg. (Item 14) Item 13. The method according to item 12, wherein the second dose is 5 to 30 times, 20 to 70 times, or 25 to 50 times higher than the first dose, the third dose is 0.5 to 3 times higher than the second dose, and the fourth dose and the subsequent doses are 2 to 4 times higher than the third dose. (Item 15) 15. The method of any one of items 1 to 14, wherein the anti-DLL3 agent comprises the amino acid sequence of SEQ ID NO: 438 or 520. (Item 16) Item 17. The method according to any one of Items 1 to 15, wherein the anti-DLL3 agent is administered in a 28-day cycle, and the method further comprises administering to the subject saline, an anti-inflammatory agent, tocilizumab, or etanercept during the first cycle of administering the anti-DLL3 agent. 17. The method of claim 16, wherein after the induction dose and the ramping doses of the anti-DLL3 agent, the subject is administered 1 liter of saline via IV infusion. (Item 18) Item 17. The method of item 16, wherein the anti-inflammatory agent is a corticosteroid or acetaminophen. (Item 19) 19. The method of claim 18, wherein the corticosteroid is dexamethasone. (Item 20) 20. The method of claim 16, 18, or 19, wherein the subject is administered the anti-inflammatory agent or tocilizumab prior to the induction dose and the ramping doses of the anti-DLL3 agent. (Item 21) 21. The method of claim 20, wherein the corticosteroid is administered to the subject 6 to 16 hours prior to the induction dose and the ramping doses of the anti-DLL3 agent. (Item 22) 21. The method of claim 20, wherein the subject is administered acetaminophen or tocilizumab 1 hour prior to the induction dose and ramping doses of the anti-DLL3 agent. (Item 23) Item 17. The method of item 16, wherein etanercept is administered 36 to 60 hours before the induction dose and ramping doses of the anti-DLL3 agent, excluding the ramping dose on day 4. (Item 24) 24. The method of claim 23, wherein etanercept is administered two days prior to the loading dose and loading doses of the anti-DLL3 agent, excluding the loading dose on day 4. (Item 25) 1. A method of treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent comprising the amino acid sequence of SEQ ID NOs: 437 and 431, wherein the anti-DLL3 agent is administered according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) of 3 mg to 200 mg on day 4, c) a third dose (target dose) of 3 mg to 200 mg on day 8, and d) one or more subsequent doses (target doses) of 3 mg to 200 mg starting on day 15 and every two weeks thereafter, wherein the second dose is higher than the first dose, and the third and subsequent doses are identical to and are the same as the second dose. (Item 26) Item 25. The method according to Item 25, wherein the first dose is 0.5 mg to 8 mg, 0.5 mg to 6 mg, 0.5 mg to 4 mg, 0.5 mg to 2 mg, or 1 mg, and the second dose, the third dose, and the subsequent doses are 3 mg to 100 mg, 10 mg to 150 mg, 30 mg to 200 mg, 30 mg to 100 mg, 50 mg to 150 mg, 70 mg to 120 mg, 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg, respectively. How to post. (Item 27) 28. A method for treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 437 and 431, wherein the anti-DLL3 agent is administered according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) of 3 mg to 100 mg on day 4, c) a third dose (step-up dose) of 3 mg to 200 mg on day 8, d) a fourth dose (target dose) of 3 mg to 200 mg on day 15, and e) one or more subsequent doses (target doses) of 3 mg to 200 mg starting on day 29 and every two weeks thereafter, wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and the subsequent doses are the same and are the same as the third dose. 28. The method of item 27, wherein the first dose is 0.5 mg to 8 mg, 0.5 mg to 6 mg, 0.5 mg to 4 mg, 0.5 mg to 2 mg, or 1 mg; the second dose is 3 mg to 10 mg, 10 mg to 80 mg, 10 mg to 60 mg, 20 mg to 80 mg, 20 mg to 60 mg, 20 mg to 40 mg, 25 mg, or 50 mg; and the third dose, the fourth dose, and subsequent doses are 3 mg to 100 mg, 10 mg to 150 mg, 30 mg to 200 mg, 30 mg to 100 mg, 50 mg to 150 mg, 70 mg to 120 mg, 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg, respectively. (Item 29) 29. The method of any one of Items 25 to 28, wherein the anti-DLL3 agent comprises the amino acid sequence of SEQ ID NO: 438 or 520. (Item 30) 30. The method of any one of items 25 to 29, wherein the anti-DLL3 agent is administered in a 28-day cycle, and the method further comprises administering to the subject saline, acetaminophen, dexamethasone, tocilizumab, or etanercept during a first cycle of administering the anti-DLL3 agent. (Item 31) 27. The method of item 25 or 26, wherein saline, acetaminophen, dexamethasone, or tocilizumab is administered to the subject on days 1 and 4, or days 1, 4, and 8, of a first cycle of administration of the anti-DLL3 agent. (Item 32) 27. The method of item 25 or 26, wherein etanercept is administered to the subject two days before day 1 and two days before day 8, or two days before day 1, of a first cycle of administration of the anti-DLL3 agent. (Item 33) 29. The method of item 27 or 28, wherein saline, acetaminophen, dexamethasone, or tocilizumab is administered to the subject on days 1, 4, and 8, or on days 1, 4, 8, and 15, of a first cycle of administration of the anti-DLL3 agent. (Item 34) 29. The method of item 27 or 28, wherein etanercept is administered to the subject two days prior to days 1, 8, and 15, or two days prior to days 1 and 8, of a first cycle of administration of the anti-DLL3 agent. (Item 35) 35. The method of any one of items 1 to 34, further comprising administering a corticosteroid prior to administering the anti-DLL3 agent during the first cycle. (Item 36) Item 3, wherein the corticosteroid is dexamethasone administered by IV infusion. 5. The method described in 5. (Item 37) 37. The method of any one of items 1 to 36, wherein the cancer is small cell lung cancer (SCLC). (Item 38) 38. The method of any one of items 1 to 37, wherein the cancer is relapsed / refractory SCLC (RR SCLC) or extensive-stage SCLC (ED SCLC). (Item 39) 39. The method of any one of items 1 to 38, wherein the anti-DLL3 agent is administered by IV infusion. (Item 40) 40. The method according to any one of items 1 to 39, wherein the subject is a human.

[0009] E1: A method for treating DLL3-positive cancer, comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered once every two weeks at a dose of 0.3 mg to 100 mg, 3 mg to 200 mg, or 100 mg.

[0010] E2: A method for treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent, wherein the anti-DLL3 agent is administered according to the following schedule: a) a first dose of 0.3 mg to 100 mg, 0.5 mg to 10 mg, or 1 mg on day 1, b) a second dose of 0.3 mg to 100 mg, 3 to 200 mg, or 100 mg on day 8, and c) one or more subsequent doses of 0.3 mg to 100 mg, 3 to 200 mg, or 100 mg starting on day 15 and once every two weeks thereafter, wherein the second dose and the subsequent doses are the same and higher than the first dose.

[0011] E3: A method of treating DLL3-positive cancer, comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered according to one of the following two schedules: Schedule I: a) a first dose of 0.5 mg to 10 mg or 1 mg on day 1 (run-in dose), b) a second dose of 3 mg to 100 mg or 25 mg to 50 mg on day 4 (step-in dose), c) a third dose of 3 mg to 200 mg or 100 mg on day 8 (step-in dose), and d) one or more subsequent doses of 3 mg to 200 mg or 100 mg starting on day 15 and every two weeks thereafter (target dose), where the second dose is higher than the first dose, and the third and subsequent doses are the same as and greater than or equal to the second dose; or Schedule II: a) a first dose (induction dose) of 0.5 mg to 10 mg or 1 mg on day 1, b) a second dose (step-up dose) of 3 mg to 100 mg or 25 mg to 50 mg on day 8, c) a third dose (step-up dose) of 3 mg to 200 mg or 100 mg on day 15, and d) one or more subsequent doses (target dose) of 3 mg to 200 mg or 100 mg starting on day 29 and every two weeks thereafter, where the second dose is higher than the first dose and the third and subsequent doses are the same and higher than the second dose. The method comprises administering the compound according to one of the following methods.

[0012] E4: A method of treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent, wherein the anti-DLL3 agent is administered according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg or 1 mg on day 1, b) a second dose (step-up dose) of 3 mg to 100 mg or 25 mg on day 4, c) a third dose (step-up dose) of 3 mg to 100 mg or 50 mg on day 8, d) a fourth dose (step-up dose) of 3 mg to 200 mg or 100 mg on day 15, and e) one or more subsequent doses (target doses) of 3 mg to 200 mg or 100 mg starting on day 29 and every two weeks thereafter, wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and any subsequent doses are the same as and greater than or equal to the third dose.

[0013] E5: A method of treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent, wherein the anti-DLL3 agent is administered according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) of 3 mg to 200 mg on day 4, c) a third dose (target dose) of 3 mg to 200 mg on day 8, and d) one or more subsequent doses (target doses) of 3 mg to 200 mg starting on day 15 and every two weeks thereafter, wherein the second dose is higher than the first dose, and the third dose and subsequent doses are identical and are identical to the second dose.

[0014] E6: A method of treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent, wherein the anti-DLL3 agent is administered according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) of 3 mg to 100 mg on day 4, c) a third dose (step-up dose) of 3 mg to 200 mg on day 8, d) a fourth dose (target dose) of 3 mg to 200 mg on day 15, and e) one or more subsequent doses (target doses) of 3 mg to 200 mg starting on day 29 and every two weeks thereafter, wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and subsequent doses are identical and are identical to the third dose.

[0015] E7: The method according to any one of E1 to E6, wherein the DLL3-positive cancer is small cell lung cancer (SCLC).

[0016] E8: The method according to any one of E1 to E7, wherein the DLL3-positive cancer is relapsed / refractory (RR) SCLC or extensive disease (ED) SCLC.

[0017] E9: The method of any one of E1 to E8, wherein the anti-DLL3 agent is a bispecific antibody construct comprising two binding domains: a first domain that binds to human DLL3, and a second domain that binds to human CD3.

[0018] E10: The method of E9, wherein the DLL3-binding domain binds to an epitope of human DLL3 contained within the amino acid sequence of SEQ ID NO:258.

[0019] E11: The method described in E9 or E10, wherein the DLL3-binding domain comprises: (a) a heavy chain variable region (VH) comprising: (i) a VH complementarity-determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 31; (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 32; and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 33; and (b) a light chain variable region (VL) comprising: (i) a VL complementarity-determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 34; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 36.

[0020] E12: A method described in any one of E9 to E11, wherein the DLL3-binding domain comprises (1) a VH comprising the amino acid sequence of SEQ ID NO: 37 and a VL comprising the amino acid sequence of SEQ ID NO: 38, or (2) a VH comprising the amino acid sequence of SEQ ID NO: 435 and a VL comprising the amino acid sequence of SEQ ID NO: 436.

[0021] E13: The method according to any one of E9 to E12, wherein the VH and VL of the DLL3-binding domains are linked by a linker to form a single-chain Fv (scFv).

[0022] E14: The method according to E13, wherein the linker comprises a sequence selected from any one of SEQ ID NOs: 285 to 293.

[0023] E15: The method of E13 or E14, wherein the linker comprises (Gly4Ser)x, where x is an integer greater than or equal to 1 (eg, 1, 2, 3, or 4).

[0024] E16: The method according to any one of E9 to E15, wherein the DLL3-binding domain comprises the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 437.

[0025] E17: A method described in any one of E9 to E16, wherein the CD3-binding domain comprises (a) a VH comprising CDR-H1 having the amino acid sequence of SEQ ID NO: 426, CDR-H2 having the amino acid sequence of SEQ ID NO: 427, and CDR-H3 having the amino acid sequence of SEQ ID NO: 428, and a VL comprising CDR-L1 having the amino acid sequence of SEQ ID NO: 423, CDR-L2 having the amino acid sequence of SEQ ID NO: 424, and CDR-L3 having the amino acid sequence of SEQ ID NO: 425.

[0026] E18. The method according to any one of E9 to E17, wherein the CD3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 429 and a VL comprising the amino acid sequence of SEQ ID NO: 430.

[0027] E19. The method according to E17 or E18, wherein the VH and VL of the CD3-binding domains are linked by a linker to form a single-chain Fv (scFv).

[0028] E20: The method according to E19, wherein the linker comprises a sequence selected from any one of SEQ ID NOs: 285 to 293.

[0029] E21: The method of E19 or E20, wherein the linker comprises (Gly4Ser)x, where x is an integer greater than or equal to 1 (for example, 1, 2, 3, or 4).

[0030] E22: The method according to any one of E17 to E21, wherein the CD3-binding domain comprises the amino acid sequence of SEQ ID NO: 431.

[0031] E23: The method according to any one of E9 to E22, wherein the DLL3-binding domain and the CD3-binding domain are linked by a linker.

[0032] E24: The method according to E23, wherein the linker is a peptide linker comprising a sequence selected from any one of SEQ ID NOs: 285 to 293.

[0033] E25: The method of E23 or E24, wherein the linker is a peptide linker comprising (Gly4Ser)x, where x is an integer equal to or greater than 1 (eg, 1, 2, 3, or 4).

[0034] E26: The method of any one of E9 to E25, wherein the anti-DLL3 agent comprises a DLL3-binding domain and a CD3-binding domain. The DLL3-binding domain comprises: (a) a heavy chain variable region (VH) comprising: (i) a VH complementarity-determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 31; (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 32; and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 33; and (b) a light chain variable region (VL) comprising: (i) a VL complementarity-determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 34; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 36. This CD3-binding domain comprises (a) a VH comprising (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 426, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 427, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 428, and (b) a VL comprising (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 423, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 424, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 425.

[0035] E27: A method described in any one of E9 to E26, wherein the DLL3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 37 and a VL comprising the amino acid sequence of SEQ ID NO: 38, and the CD3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 429 and a VL comprising the amino acid sequence of SEQ ID NO: 430.

[0036] E28: A method described in any one of E9 to E26, wherein the DLL3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 435 and a VL comprising the amino acid sequence of SEQ ID NO: 436, and the CD3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 429 and a VL comprising the amino acid sequence of SEQ ID NO: 430.

[0037] E29: The method according to any one of E9 to E27, wherein the DLL3-binding domain comprises the amino acid sequence of SEQ ID NO: 39, and the CD3-binding domain comprises the amino acid sequence of SEQ ID NO: 431.

[0038] E30: The method according to any one of E9 to E26 or E28, wherein the DLL3-binding domain comprises the amino acid sequence of SEQ ID NO: 437 and the CD3-binding domain comprises the amino acid sequence of SEQ ID NO: 431.

[0039] E31: The method of E29, wherein the anti-DLL3 agent comprises the amino acid sequence of SEQ ID NO:40.

[0040] E32: The method of E30, wherein the anti-DLL3 agent comprises the amino acid sequence of SEQ ID NO:438.

[0041] E33: The method of any one of E9 to E32, wherein the anti-DLL3 agent further comprises a third domain that extends or enhances the serum half-life of the anti-DLL3 agent.

[0042] E34: The method according to E33, wherein the third domain comprises an amino acid sequence selected from any one of SEQ ID NOs: 541 to 548.

[0043] E35: The method of any one of E9 to E26, E28, E30, E32, E33, or E35, wherein the anti-DLL3 agent comprises the amino acid sequence of SEQ ID NO: 520.

[0044] E36: Approximately 0.3 mg to approximately 90 mg, approximately 0.3 mg to approximately 80 mg, approximately 0.3 mg to approximately 70 mg, approximately 0.3 mg to approximately 60 mg, approximately 0.3 mg to approximately 50 mg, approximately 0.3 mg to approximately 40 mg, approximately 0. 3mg to about 30mg, about 0.3mg to about 20mg, about 0.3mg to about 10mg, about 0.3mg to about 3mg, about 0.3mg to about 1mg, about 1mg to about 100mg, about 1mg to about 90mg, about 1mg to about 80mg, Approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 50 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 30 mg, approximately 1 mg to approximately 20 mg, approximately 1 mg to approximately 10 mg, approximately 1 mg to approximately 3 mg, approximately 3 mg to approximately 1 00mg, about 3mg to about 90mg, about 3mg to about 80mg, about 3mg to about 70mg, about 3mg to about 60mg, about 3mg to about 50mg, about 3mg to about 40mg, about 3mg to about 30mg, about 3mg to about 20mg, about 3mg to about 10mg, about 3mg to about 12mg, about 3mg to about 15mg, about 10mg to about 100mg, about 10mg to about 90mg, about 10mg to about 80mg, about 10mg to about 70mg, about 10mg to about 60mg, about 10mg to about 50mg, about 10mg to about 40mg, about 10mg to about 30mg, about 10mg to about 20mg, about 10mg to about 15mg, about 20mg to about 100mg, about 20mg to about 90mg, about 20mg to about 80m g, about 20 mg to about 70 mg, about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 20 mg to about 30 mg, about 30 mg to about 100 mg, about 30 mg to about 90 mg, about 30 mg to about 80 mg, about 30 mg to about 70 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, or about 30 mg to about 40 mg, administered once every two weeks.

[0045] E37: anti-DLL3 agent, about 3 mg to about 100 mg, about 10 to about 180 mg, about 10 to about 150 mg, about 30 mg to about 200 mg, about 30 mg to about 180 mg, about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 50 mg to about 200 mg, about 50 mg to about 180 mg, about 50 mg to about 150 mg, about 50 mg to about 120 mg, about 70 mg to about 200 mg, about 70 mg to about 180 mg, about 70 mg to about 150 mg, about 70 mg the method of any one of E1 and E7 to E35, wherein the anti-DLL3 agent is administered once every two weeks at a dose of 3 mg, 10 mg, 30 mg, or 100 mg.

[0046] E38: The method of any one of E1 or E7 to E37, wherein the anti-DLL3 agent is administered on days 1 and 15 of a 28-day cycle.

[0047] E39: The method of any one of E2 or E7-E35, wherein the second dose and the one or more subsequent doses are identical and are at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times, at least 65 times, at least 70 times, at least 75 times, at least 80 times, at least 85 times, at least 90 times, at least 95 times, at least 100 times, at least 120 times, at least 150 times, at least 200 times higher than the first dose.

[0048] E40: The first dose of the anti-DLL3 agent is about 0.5 mg to about 10 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 2 mg, or about 1 mg, and the second and subsequent doses of the anti-DLL3 agent are about 0.3 mg to about 90 mg, about 0.3 mg to about 80 mg, about 0.3 mg to about 70 mg, about 0.3 mg to about 60 mg, about 0.3 mg to about 50 mg, about 0.3 mg to about 40 mg, about 0.3 mg to about 30 mg, about 0.3 mg to about 20 mg, about 0.3 mg to about 10 mg, about 0.3 mg to about 3 mg, or about 0.3 mg.3mg to about 1mg, about 1mg to about 100mg, about 1mg to about 90mg, about 1mg to about 80mg, about 1mg to about 70mg, about 1mg to about 60mg, about 1mg to about 50mg, about 1mg to about 40mg, about 1mg to about 30mg, about 1mg to about 20mg, about 1m g ~ about 10mg, about 1mg - about 3mg, about 3mg - about 100mg, about 3mg - about 90mg, about 3mg - about 80mg, about 3mg - about 70mg, about 3mg - about 60mg, about 3mg - about 50mg, about 3mg - about 40mg, about 3mg - about 30mg, about 3mg - about 20mg, about 3mg to about 10mg, about 3mg to about 12mg, about 3mg to about 15mg, about 10mg to about 100mg, about 10mg to about 90mg, about 10mg to about 80mg, about 10mg to about 70mg, about 10mg to about 60mg, about 10mg to about 50mg, about 10mg to about 40mg, about 10mg to about 30mg, about 10mg to about 20mg, about 10mg to about 15mg, about 20mg to about 100mg, about 20mg to about 90mg, about 20mg to about 80mg, about 20mg to about 70mg, about 20mg to about 60mg, about 20mg ~50mg, 20mg~40mg, 20mg~30mg, 30mg~100mg, 30mg~90mg, 30mg~80mg, 30mg~70mg, 30mg~60mg, 30mg~50mg, 30mg~4 0mg, about 10mg to about 180mg, about 10mg to about 150mg, about 10mg to about 120mg, about 30mg to about 200mg, about 30mg to about 180mg, about 30mg to about 150mg, about 30mg to about 120mg, about 50mg to about 200mg, about 50mg The method according to any one of E2, E7 to E35, and E39, wherein the dose may be any one of about 100 mg to about 180 mg, about 50 mg to about 150 mg, about 50 mg to about 120 mg, about 70 mg to about 200 mg, about 70 mg to about 180 mg, about 70 mg to about 150 mg, about 70 mg to about 120 mg, about 90 mg to about 200 mg, about 90 mg to about 180 mg, about 90 mg to about 150 mg, about 90 mg to about 120 mg, about 100 mg to about 180 mg, about 100 mg to about 150 mg, and about 100 mg to about 120 mg.

[0049] E41: The method of any one of E2, E7 to E35, E39, or E40, wherein the first dose of the anti-DLL3 agent is 1 mg, and the second and subsequent doses of the anti-DLL3 agent are 3 mg, 10 mg, 30 mg, or 100 mg, respectively.

[0050] E42: The first dose of the anti-DLL3 agent is about 0.5 mg to about 8 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 2 mg, or about 1 mg; the second dose of the anti-DLL3 agent is about 3 mg to about 10 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 25 mg to about 50 mg, about 30 mg to about 80 mg, about 30 mg to about 60 mg, about 30 mg to about 40 mg, about 40 mg to about 80 mg, or about 40 mg to about 60 mg; and the third and subsequent doses of the anti-DLL3 agent are about 3 mg to about 100 mg, about 10 mg to about 180 mg, about 10 mg to about 150 mg. The method according to any one of E3 and E7 to E35, wherein the amount of hydroxybenzoate may be any one of about 10 mg to about 120 mg, about 30 mg to about 200 mg, about 30 mg to about 180 mg, about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 50 mg to about 200 mg, about 50 mg to about 180 mg, about 50 mg to about 150 mg, about 70 mg to about 200 mg, about 70 mg to about 180 mg, about 70 mg to about 150 mg, about 70 mg to about 120 mg, about 90 mg to about 200 mg, about 90 mg to about 180 mg, about 90 mg to about 150 mg, about 90 mg to about 120 mg, about 100 mg to about 180 mg, about 100 mg to about 150 mg, about 100 mg to about 120 mg, and about 100 mg.

[0051] E43: The method of any one of E3, E7 to E35, or E42, wherein the first dose of the anti-DLL3 agent is 1 mg, the second dose of the anti-DLL3 agent is 25 mg to 50 mg or 45 mg to 70 mg, and the third and subsequent doses of the anti-DLL3 agent are 100 mg.

[0052] E44: A method according to any one of E3, E7 to E35, or E42, wherein the first dose of the anti-DLL3 agent is 1 mg on day 1, the second dose of the anti-DLL3 agent is 25 mg or 50 mg on day 4, the third dose of the anti-DLL3 agent is 100 mg on day 8, and subsequent doses of the anti-DLL3 agent are 100 mg starting on day 15 and every two weeks thereafter.

[0053] E45: The first dose of the anti-DLL3 agent is about 0.5 mg to about 8 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 2 mg, or 1 mg, and the second dose of the DLL3 agent is about 3 mg to about 10 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 20 mg to about 80 mg, about The third dose of the DLL3 agent is about 3 mg to about 10 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, 10 mg to about 60 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 30 mg to about 100 mg, about 30 mg to about 80 mg, about 30 mg to about 30 mg The fourth dose and subsequent doses of the anti-DLL3 agent are about 3 mg to about 100 mg, about 10 mg to about 150 mg, about 30 mg to about 200 mg, about 30 mg to about 150 mg, about 30 mg to about 100 mg, about 50 mg to about 200 mg, about 50 mg to about 180 mg. The method according to any one of E4 and E7 to E35, wherein the amount of the steroid hormone administered is any one of about 50 mg to about 150 mg, about 50 mg to about 120 mg, about 70 mg to about 200 mg, about 70 mg to about 180 mg, about 70 mg to about 120 mg, about 90 mg to about 200 mg, about 90 mg to about 180 mg, about 90 mg to about 150 mg, about 90 mg to about 120 mg, or about 100 mg.

[0054] E46: The method of any one of E4, E7 to E35, or E45, wherein the first dose of the anti-DLL3 agent is 1 mg, the second dose of the anti-DLL3 agent is 25 mg, the third dose of the anti-DLL3 agent is 50 mg, and the fourth and subsequent doses of the anti-DLL3 agent are 100 mg.

[0055] E47: The method of any one of E5 or E7 to E35, wherein the first dose of the anti-DLL3 agent is 0.5 mg to 8 mg, 0.5 mg to 6 mg, 0.5 mg to 4 mg, 0.5 mg to 2 mg, or 1 mg, and the second dose, the third dose, and subsequent doses are 3 mg to 100 mg, 10 mg to 150 mg, 30 mg to 200 mg, 30 mg to 100 mg, 50 mg to 150 mg, 70 mg to 120 mg, 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg, respectively.

[0056] E48: The method of any one of E6 or E7 to E35, wherein the first dose is 0.5 mg to 8 mg, 0.5 mg to 6 mg, 0.5 mg to 4 mg, 0.5 mg to 2 mg, or 1 mg, the second dose is 3 mg to 10 mg, 10 mg to 80 mg, 10 mg to 60 mg, 20 mg to 80 mg, 20 mg to 60 mg, 20 mg to 40 mg, 25 mg, or 50 mg, and the third dose, the fourth dose, and subsequent doses are 3 mg to 100 mg, 10 mg to 150 mg, 30 mg to 200 mg, 30 mg to 100 mg, 50 mg to 150 mg, 70 mg to 120 mg, 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg, respectively.

[0057] E49: The method of any one of E1-E48, wherein the method comprises administering to the subject one or more additional therapeutic agents.

[0058] E50: The method of E49, wherein the one or more additional therapeutic agents is a steroid.

[0059] E51: The method of E49 or E50, wherein the additional therapeutic agent is dexamethasone.

[0060] E52: The method of any one of E49-E51, wherein the additional therapeutic agent is administered prior to treatment with the anti-DLL3 agent.

[0061] E53: The method of any one of E48 to E51, wherein an additional therapeutic agent is administered simultaneously with the anti-DLL3 agent.

[0062] E54: The method of any one of E2 to E53, wherein the anti-DLL3 agent is administered in a 28-day cycle, and the method further comprises administering to the subject a fluid (e.g., saline), an anti-inflammatory agent, tocilizumab, or etanercept during the first cycle of administering the anti-DLL3 agent.

[0063] E55: The method of E54, wherein one liter of saline is administered to the subject by IV infusion after the loading dose and ramp-up doses of the anti-DLL3 agent.

[0064] E56: The method of E55, in which 1 liter of saline is administered over approximately 4 to 5 hours.

[0065] E57: The method according to E54, wherein the anti-inflammatory agent is a corticosteroid or acetaminophen.

[0066] E58: The method according to E57, wherein the corticosteroid is dexamethasone.

[0067] E59: The method of any one of E54, E57, or E58, wherein an anti-inflammatory agent or tocilizumab is administered to the subject prior to the induction dose and ramp-up doses of the anti-DLL3 agent.

[0068] E60: The method of E59, wherein the corticosteroid is administered to the subject about 6 to 16 hours prior to the induction dose and ramp-up doses of the anti-DLL3 agent.

[0069] E61: The method of E59, wherein tocilizumab or acetaminophen is administered to the subject about 1 hour prior to the induction dose and ramp-up doses of the anti-DLL3 agent.

[0070] E62: The method of E54, wherein etanercept is administered to the subject about 36 to 60 hours before the induction dose and ramp-up doses, excluding the ramp-up dose on day 4, of the anti-DLL3 agent.

[0071] E63: The method of E62, wherein etanercept is administered two days before the induction dose and ramp-up doses of the anti-DLL3 agent, excluding the ramp-up dose on day 4.

[0072] E64: The method according to any one of E1 to E63, wherein the subject is a human.

[0073] E65: An anti-DLL3 agent for use in the method according to any one of embodiments E1 to E64.

[0074] E66: An anti-DLL3 agent for use in the treatment of a DLL3-positive cancer (eg, SCLC), wherein the anti-DLL3 agent is administered as described in any one of embodiments E1 to E64.

[0075] E67: Use of an anti-DLL3 agent for the manufacture of a medicament for the treatment of SCLC, wherein the medicament is prepared for administration as described in any one of embodiments E1 to E64.

[0076] E68: Use of an anti-DLL3 agent in the preparation of a medicament for the treatment of a DLL3-positive cancer, wherein the anti-DLL3 agent is administered as described in any one of embodiments E1 to E64. [Brief explanation of the drawings]

[0077] [Figure 1] Figure 1 shows the predicted serum concentration-time profile of a single cycle of AMG757 in humans after administration of a short IV infusion once every two weeks. The dashed lines represent the concentrations required for 50% and 90% maximal efficacy of AMG757-mediated CD69 upregulation (EC50 and EC90 values ​​of 0.61 ng / mL and 4.6 ng / mL, respectively), which was identified as the most sensitive marker of AMG757 activity (Study 123564). [Figure 2] Figure 1 shows the predicted lung concentration-time profile of a single cycle of AMG757 in humans after administration of short IV infusions once every two weeks. The dashed lines represent the concentrations required for 50% and 90% maximal efficacy of AMG757-mediated cell killing in SHP-77 cells (EC50 and EC90 values ​​of 2.8 ng / mL and 5.7 ng / mL, respectively). [Figure 3] An example of step-dose administration is shown below, assuming that adverse events related to the first dose effect occur at 0.03 mg. [Figure 4] 1 shows confirmed partial responses (PRs) in SCLC patients treated with AMG757. [Figure 5] 5 shows the mean steady state serum AMG 757 Concentration-Time profile of SCLC patients treated with the molecule. In Figure 5, * indicates step dosing, and the data shown is after the cycle 2 day 15 dose during the 2-week dosing interval. Data from the only patient enrolled in the 0.1 mg group were not available because this patient dropped out during cycle 1. [Figure 6] 1 shows a summary of objective responses in patients with SLCL treated with AMG757. DETAILED DESCRIPTION OF THE INVENTION

[0078] As disclosed and exemplified herein, a bispecific protein (AMG757) targeting DLL3 and CD3 was used in a Phase 1 clinical trial for the treatment of SCLC.

[0079] AMG757 is a half-life extended BiTE® (bispecific T cell engager) molecule developed for the treatment of SCLC. The activity of AMG757 involves the activation of target cells (DLL3 + The pharmacological effect of AMG757 is to bind to both DLL3 and T cells simultaneously. + Cytotoxic CD8 already primed to kill cells+ or CD4 + The selection of the starting dose for the first-in-human (FIH) study was based on the EC value of AMG757-mediated CD69 upregulation in SHP-77 cells. 50 The initial dose was based on the estimated minimum effective dose (MABEL) identified as the MABEL (Study 123564). Based on human PK predictions, a starting dose of 0.003 mg once every two weeks (Q2W) was selected, which is predicted to achieve a maximum serum concentration equal to the MABEL (0.61 ng / mL). This regimen is expected to achieve adequate exposure in target tissues (e.g., lung) throughout the dosing interval while minimizing the peak-to-trough ratio after multiple treatment cycles of AMG757. Based on clinical experience in this FIH study, a dose of at least 0.3 mg Q2W is preferred.

[0080] 1.Definition Some exemplary bispecific anti-DLL3 agents disclosed herein (e.g., BiTE® molecules) are recombinant protein constructs comprising two binding domains, each derived from an antigen-binding fragment of a full-length antibody. Such antigen-binding fragments retain the ability to specifically bind to antigen (preferably with substantially the same binding affinity). Examples of antigen-binding fragments include: (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) an F(ab')2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single antibody arm; and (v) a dAb fragment consisting of the VH domain (Ward et al., 1989 Nature 341:544-546). Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker that allows them to be produced as a single protein chain in which the VL and VH regions pair to form a monovalent molecule (known as a single-chain Fv (scFv)); see, e.g., Bird et al. Science 242:423-426 (1988) and Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883.

[0081] "Variable domain" refers to the variable region of an antibody light chain (VL) or the variable region of an antibody heavy chain (VH), either alone or in combination. As is known in the art, the heavy and light chain variable regions each consist of four framework regions (FR) connected by three complementarity-determining regions (CDRs), which contribute to the formation of the antigen-binding site of an antibody.

[0082] The "complementarity determining regions" (CDRs) of exemplary DLL3-binding domains and CD3-binding domains are set forth in the sequence listing. CDRs may be determined according to Kabat, Chothia, both Kabat and Chothia, AbM, contact, North, and / or conformation definitions, or any method of CDR determination known in the art. See, e.g., Kabat et al., 1991, Sequences of See Proteins of Immunological Interest, 5th ed. (hypervariable regions); Chothia et al., 1989, Nature 342:877-883 (structural loop structures). The AbM definition of CDRs is a compromise between Kabat and Chothia and uses Oxford Molecular's AbM antibody modeling software (Accelrys®). The identity of the amino acid residues in a particular antibody that make up a CDR can be determined using methods known in the art.

[0083] The term "treatment" includes prophylactic and / or therapeutic treatment. Treatment is considered prophylactic if administered prior to clinical manifestation of a condition. Therapeutic treatment includes, for example, amelioration or lessening of disease severity or shortening of disease duration.

[0084] "About" or "approximately," when used in connection with a measurable numerical variable, refers to the stated value of the variable and all values ​​of the variable that are within experimental error of the stated value (e.g., within a 95% confidence interval of the mean) or ±10% of the stated value, whichever is greater. Numerical ranges are inclusive of the numbers defining the range.

[0085] An "induction dose," when used in reference to administration of an anti-DLL3 agent for the treatment of cancer (e.g., small cell lung cancer (SCLC)), refers to an initial dose of the anti-DLL3 agent that is equal to or less than the dose at which a first-dose effect (e.g., cytokine release syndrome (CRS)) is observed. As is known in the art, the induction dose can be determined by modeling and simulation of safety and pharmacokinetic data. For example, the induction dose can be the maximum tolerated dose (MTD) of the anti-DLL3 agent at which no CRS or CRS of less than a certain grade (e.g., grade 2) is observed.

[0086] "Target dose," when used in connection with administration of an anti-DLL3 agent for the treatment of cancer (e.g., SCLC), refers to the dose at which the target effect of the anti-DLL3 agent (e.g., remission or reduction in the severity of SCLC or shortening the duration of SCLC) is achieved.

[0087] A "step-up dose," when used in reference to administration of an anti-DLL3 agent for the treatment of cancer (e.g., SCLC), refers to a higher dose than the previous dose at which the anti-DLL3 agent is administered. A step-up dose includes one or more doses that increase from an induction dose until a target dose is reached.

[0088] 2. Anti-DLL3 agents DLL3 is a non-canonical Notch ligand expressed primarily during embryonic development that functions during somitogenesis. In contrast to other Notch ligands expressed on the cell surface, DLL3 accumulates in the Golgi in normal tissues (Geffers et al., J Cell Biol. 178:465-476 (2007)). DLL3 was identified as a tumor-associated antigen and a potential target for T cell-based therapy by analyzing the differential expression of this target in 28 SCLC tumors and a large panel of normal tissues (Study 123658).

[0089] The human DLL3 protein contains eight extracellular domains: a signal peptide, an N-terminus, a DSL, EGF1, EGF2, EGF3, EGF4, EGF5, and EGF6. The amino acid sequences of human DLL3, the EGF3 domain, the EGF4 domain, and the combined EGF3 and EGF4 domains are shown in the Sequence Listing as SEQ ID NOs: 252, 258, 259, and 260, respectively.

[0090] An exemplary anti-DLL3 agent is a bispecific molecule that binds to DLL3 and CD3 (e.g., a BiTE® (bispecific T cell engager) molecule). BiTE® molecules are recombinant protein constructs formed from two flexibly linked binding domains, each derived from an antibody. One binding domain of a BiTE® molecule is specific for a tumor-associated surface antigen (e.g., DLL3), and the other binding domain is specific for CD3, a subunit of the T cell receptor complex on T cells. These designs make BiTE® molecules uniquely suited to transiently link T cells to target cells while simultaneously potently activating the intrinsic cytolytic potential of T cells against target cells. See, e.g., WO 99 / 54440, WO 2005 / 040220, and WO 2008 / 119567.

[0091] Thus, in some embodiments, the described anti-DLL3 agents comprise two binding domains: a first domain that binds to DLL3 (preferably human DLL3), and a second domain that binds to CD3 (preferably human CD3). Preferably, the first domain binds to an epitope of DLL3 contained in the amino acid sequence of SEQ ID NO: 260. More preferably, the first domain binds to an epitope of DLL3 contained in the amino acid sequence of SEQ ID NO: 258.

[0092] In certain embodiments, the DLL3-binding domain comprises: (a) a heavy chain variable region (VH) comprising: (i) a VH complementarity-determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 31; (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 32; and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 33; and (b) a light chain variable region (VL) comprising: (i) a VL complementarity-determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 34; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 36.

[0093] In certain embodiments, the DLL3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 37 and a VL comprising the amino acid sequence of SEQ ID NO: 38. In certain preferred embodiments, the DLL3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 435 and a VL comprising the amino acid sequence of SEQ ID NO: 436.

[0094] In some embodiments, the VH and VL are linked by a linker to form a single-chain Fv (scFv). In some embodiments, the linker is a peptide linker comprising a sequence selected from any one of SEQ ID NOs: 285-293. In some embodiments, the linker is a GS linker (e.g., Gly-Gly-Gly-Gly-Ser (G4S, SEQ ID NO: 286)) or a polymer thereof (i.e., (Gly4Ser)x, where x is an integer equal to or greater than 1, such as 2 or 3) (e.g., SEQ ID NOs: 292, 293).

[0095] In certain embodiments, the DLL3 binding domain comprises the amino acid sequence of SEQ ID NO: 39. In certain preferred embodiments, the DLL3 binding domain comprises the amino acid sequence of SEQ ID NO: 437.

[0096] In certain embodiments, the CD3-binding domain comprises (a) a VH comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 426, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 427, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 428, and a VL comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 423, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 424, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 425.

[0097] In certain embodiments, the CD3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 429 and a VL comprising the amino acid sequence of SEQ ID NO: 430. In some embodiments, the VH and VL are linked by a linker to form a single-chain Fv (scFv). In some embodiments, the linker is a peptide linker comprising a sequence selected from any one of SEQ ID NOs: 285-293. In some embodiments, the linker is a GS linker (e.g., Gly-Gly-Gly-Gly-Ser (G4S, SEQ ID NO: 286)) or a polymer thereof (i.e., (Gly4Ser)x, where x is an integer equal to or greater than 1 (e.g., 2 or 3)).

[0098] In certain embodiments, the CD3 binding domain comprises the amino acid sequence of SEQ ID NO:431.

[0099] In certain embodiments, the DLL3-binding domain and the CD3-binding domain are linked by a linker. In some embodiments, the linker is a peptide linker comprising a sequence selected from any one of SEQ ID NOs: 285-293. In some embodiments, the linker is a GS linker (e.g., Gly-Gly-Gly-Gly-Ser (G4S, SEQ ID NO: 286)) or a polymer thereof (i.e., (Gly4Ser)x, where x is an integer equal to or greater than 1 (e.g., 2 or 3)).

[0100] In certain embodiments, the anti-DLL3 agents disclosed herein comprise two domains: a first domain binds to DLL3 (preferably human DLL3) and comprises: (a) a heavy chain variable region (VH) comprising: (i) a VH complementarity-determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 31; (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 32; and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 33; and (b) a light chain variable region (VL) comprising: (i) a VL complementarity-determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 34; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 36. The second domain binds to CD3 (preferably human CD3) and comprises (a) a VH comprising (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 426, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 427, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 428, and (b) a VL comprising (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 423, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 424, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 425.

[0101] In certain embodiments, the anti-DLL3 agents described herein comprise two domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises a VH comprising the amino acid sequence of SEQ ID NO: 37 and a VL comprising the amino acid sequence of SEQ ID NO: 38, and (b) a second domain that binds to CD3 (preferably human CD3) and comprises a VH comprising the amino acid sequence of SEQ ID NO: 429 and a VL comprising the amino acid sequence of SEQ ID NO: 430. In certain preferred embodiments, the anti-DLL3 agents described herein comprise two domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises a VH comprising the amino acid sequence of SEQ ID NO: 435 and a VL comprising the amino acid sequence of SEQ ID NO: 436, and (b) a second domain that binds to CD3 (preferably human CD3) and comprises a VH comprising the amino acid sequence of SEQ ID NO: 429 and a VL comprising the amino acid sequence of SEQ ID NO: 430.

[0102] In certain embodiments, the anti-DLL3 agents described herein comprise two domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises the amino acid sequence of SEQ ID NO: 39, and (b) a second domain that binds to CD3 (preferably human CD3) and comprises the amino acid sequence of SEQ ID NO: 431. In certain embodiments, the anti-DLL3 agents described herein comprise two domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises the amino acid sequence of SEQ ID NO: 437, and (b) a second domain that binds to CD3 (preferably human CD3) and comprises the amino acid sequence of SEQ ID NO: 431.

[0103] In certain embodiments, the anti-DLL3 agents described herein comprise the amino acid sequence of SEQ ID NO: 40. In certain embodiments, the anti-DLL3 agents described herein comprise the amino acid sequence of SEQ ID NO: 438.

[0104] In certain embodiments, the anti-DLL3 agents described herein further comprise a third domain that extends or enhances the serum half-life of the anti-DLL3 agent. In certain embodiments, the third domain comprises two polypeptides linked by a linker, each peptide comprising the hinge, CH2, and CH3 domains of human IgG. In certain embodiments, the third domain comprises, from N- to C-terminus, hinge-CH2-CH3-linker-hinge-CH2-CH3. In some embodiments, the linker is a GS linker (e.g., Gly-Gly-Gly-Gly-Ser (G4S, SEQ ID NO: 286)) or a polymer thereof (i.e., (Gly4Ser)x, where x is an integer equal to or greater than 1 (e.g., 6)). In certain embodiments, the third domain comprises an amino acid sequence selected from any one of SEQ ID NOs: 541-548.

[0105] In certain embodiments, the DLL3-binding domain and the CD3-binding domain are linked by a first linker to form a peptide, and the peptide is linked to a third domain by a second linker. In certain embodiments, the first peptide linker is a peptide linker comprising a sequence selected from any one of SEQ ID NOs: 285-293, and the second linker comprises a sequence selected from any one of SEQ ID NOs: 285, 286, 288, 289, 290, 292, and 293. In some embodiments, the first linker is a GS linker (e.g., Gly-Gly-Gly-Gly-Ser (G4S, SEQ ID NO: 286)) or a polymer thereof (i.e., (Gly4Ser)x, where x is an integer equal to or greater than 1 (e.g., 2 or 3)), and the second linker comprises a sequence selected from any one of SEQ ID NOs: 285, 286, 288, 289, 290, 292, and 293.

[0106] In certain embodiments, the anti-DLL3 agents described herein comprise three domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises the amino acid sequence of SEQ ID NO: 39, (b) a second domain that binds to CD3 (preferably human CD3) and comprises the amino acid sequence of SEQ ID NO: 431, and (c) a third domain that comprises an amino acid sequence selected from any one of SEQ ID NOs: 541 to 548. In certain embodiments, the anti-DLL3 agents described herein comprise three domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises the amino acid sequence of SEQ ID NO: 437, (b) a second domain that binds to CD3 (preferably human CD3) and comprises the amino acid sequence of SEQ ID NO: 431, and (c) a third domain that comprises any one of the amino acid sequences selected from SEQ ID NOs: 541 to 548.

[0107] In certain embodiments, the anti-DLL3 agents described herein comprise the amino acid sequence of SEQ ID NO:520.

[0108] 3. Administration of anti-DLL3 agents Disclosed herein are methods for treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent at a dose of about 0.3 mg to about 100 mg, about 3 mg to about 200 mg, or about 100 mg once every two weeks. In certain embodiments, the DLL3-positive cancer is small cell lung cancer (SCLC). In certain embodiments, the SCLC is relapsed / refractory SCLC (RR SCLC) or extensive-stage SCLC (ED SCLC). In certain embodiments, the subject is a human with SCLC (e.g., RR SCLC or ED SCLC).

[0109] In certain embodiments, the anti-DLL3 agent is administered in a dose of about 0.3 mg to about 100 mg, about 0.3 mg to about 90 mg, about 0.3 mg to about 80 mg, about 0.3 mg to about 70 mg, about 0.3 mg to about 60 mg, about 0.3 mg to about 50 mg, about 0.3 mg to about 40 mg, about 0.3 mg to about 30 mg, about 0.3 mg to about 20 mg, about 0.3 mg to about 10 mg, about 0.3 mg to about 3 mg, about 0.3 mg to about 1 mg, about 1 mg to about 100 mg, Approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 50 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 30 mg, approximately 1 mg to approximately 20 mg, approximately 1 mg to approximately About 10mg, about 1mg to about 3mg, about 3mg to about 100mg, about 3mg to about 90mg, about 3mg to about 80mg, about 3mg to about 70mg, about 3mg to about 60mg, about 3mg to about 50mg, about 3mg to about 40mg, Approximately 3mg to approximately 30mg, approximately 3mg to approximately 20mg, approximately 3mg to approximately 10mg, approximately 3mg to approximately 12mg, approximately 3mg to approximately 15mg, approximately 10mg to approximately 100mg, approximately 10mg to approximately 90mg, approximately 10mg to approximately 80mg, approximately 10mg to about 70mg, about 10mg to about 60mg, about 10mg to about 50mg, about 10mg to about 40mg, about 10mg to about 30mg, about 10mg to about 20mg, about 10mg to about 15mg, about 20mg to about 100m g, about 20 mg to about 90 mg, about 20 mg to about 80 mg, about 20 mg to about 70 mg, about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 20 mg to about 30 mg, about 30 mg to about 100 mg, about 30 mg to about 90 mg, about 30 mg to about 80 mg, about 30 mg to about 70 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, or about 30 mg to about 40 mg, and administered once every two weeks.

[0110] In certain embodiments, the anti-DLL3 agent is administered in a dose of about 3 mg to about 100 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 150 mg, about 10 mg to about 120 mg, about 30 mg to about 200 mg, about 30 mg to about 180 mg, about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 50 mg to about 200 mg, about 50 mg to about 180 mg, about 50 mg to about 150 mg, It is administered once every two weeks at a dose of about 50 mg to about 120 mg, about 70 mg to about 200 mg, about 70 mg to about 180 mg, about 70 mg to about 150 mg, about 70 mg to about 120 mg, about 90 mg to about 200 mg, about 90 mg to about 180 mg, about 90 mg to about 150 mg, about 90 mg to about 120 mg, about 100 mg to about 180 mg, about 100 mg to about 150 mg, or about 100 mg to about 120 mg.

[0111] In certain embodiments, the anti-DLL3 agent is administered once every two weeks at a dose of about 3 mg, 10 mg, 30 mg, or 100 mg.

[0112] In certain embodiments, the anti-DLL3 agent is administered on days 1 and 15 of a 28-day cycle.

[0113] As described in Example 2, the starting dose in the FIH study was based on the estimated minimum effective dose (MABEL), identified as the EC50 for AMG757-mediated CD69 upregulation in SHP-77 cells (Study 123564). Based on human PK predictions, a starting dose of 0.003 mg was selected, which is predicted to achieve a maximum serum concentration equivalent to the MABEL (0.61 ng / mL). The dose of AMG757 in the Phase 1 clinical trial is ≥0.003 mg and is administered as an intravenous (IV) infusion once every two weeks (Q2W) to patients with SCLC. This regimen is believed to achieve adequate exposure in target tissues (e.g., lungs) throughout the dosing interval while minimizing the peak-to-trough ratio after multiple treatment cycles of AMG757.

[0114] Predicted human PK parameters were used to predict AMG757 concentrations in the lung, designated as the representative site of action and expected to achieve approximately 1% of serum exposure (Vugmeyster et al., 2010). Early indications of efficacy were assessed by the mean EC50 of cell killing in SHP-77 cells. 90 was projected at 10 mg every 2 weeks based on trough coverage of 10 mg every 2 weeks (assuming 1% lung exposure, see Example 2).

[0115] In clinical trials, one confirmed response was observed at 0.3 mg (Cohort 5) administered as an IV infusion every two weeks. This observed efficacy of AMG757 is surprising because it is significantly lower than the 10 mg Q2W dose predicted to be effective based on preclinical results. Additional confirmed responses were observed in higher dose cohorts. It is believed that an effective dose of AMG757 may be at least 0.3 mg (e.g., about 0.3 mg to about 100 mg or about 3 mg to about 200 mg) administered every two weeks.

[0116] The anti-DLL3 agent may be administered by any suitable means, for example, parenterally, subcutaneously, intraperitoneally, intrapulmonary, intranasally, and / or intralesionally. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the anti-DLL3 agent is administered by intravenous (IV) infusion (e.g., a short IV infusion (about 60 minutes)) once every two weeks.

[0117] 3.1 Stepwise administration Due to the mechanism of action, subjects may be at increased risk of first-dose effects (e.g., cytokine release syndrome) after the first infusion of AMG757. It is believed that an optimal maximum tolerated dose (MTD) may require a step-dose approach (e.g., an initial dose on day 1, a step-up dose on day 8, and subsequent doses starting on day 15 and thereafter). In certain embodiments, two MTDs may be estimated or established: one for the first dose (MTD1, induction dose) and one for subsequent doses (MTD2). In certain embodiments, multiple MTDs may be estimated or established, if applicable: one for the initial induction dose (MTD1), and one for each step-up and follow-up dose.

[0118] If a subject experiences a first dose effect (e.g., cytokine release syndrome (CRS)), an appropriate first dose (MTD1) that does not exceed the dose at which a CRS event is observed can be determined and administered. A second dose and subsequent doses can also be determined and administered. In addition, depending on the number of stages in the step-administration schedule, a second dose, a third dose, a fourth dose, and subsequent doses can be determined and administered. In certain embodiments, the second dose and subsequent doses are the same and higher than the first dose. In certain embodiments, the second dose is higher than the first dose, and the third dose and subsequent doses are the same and higher than the second dose. In certain embodiments, the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and subsequent doses are the same and higher than the third dose. These doses and dosing schedules may be derived by modeling and simulating clinical data (e.g., pharmacokinetics, safety data, etc.) to ensure that systemic exposure of AMG 757 does not exceed that associated with the dose at which first-dose effects were observed (e.g., CRS) due to the high dosing frequency of the stepped dosing regimen and the potential for drug accumulation.

[0119] An exemplary phased dosing schedule for an anti-DLL3 agent (eg, AMG757) in a 28-day cycle is shown in the table below (first cycle only), after which the anti-DLL3 agent is administered once every two weeks.

[0120] [Table 1]

[0121] Accordingly, disclosed herein is a method of treating a DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent, wherein the anti-DLL3 agent is administered according to a single-phase dosing schedule.

[0122] In certain embodiments, disclosed herein are methods of treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent according to the following schedule: a) a first dose of 0.3 mg to 100 mg on day 1 (induction dose), b) a second dose of 0.3 mg to 100 mg on day 8 (step-up dose), and c) one or more subsequent doses of 0.3 mg to 100 mg starting on day 15 and every two weeks thereafter (target dose), wherein the second dose and subsequent doses are the same and higher than the first dose.

[0123] In certain embodiments, disclosed herein are methods of treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent according to the following schedule: a) a first dose of 0.5 mg to 10 mg on day 1 (induction dose), b) a second dose of 3 mg to 200 mg on day 8 (step-up dose), and c) one or more subsequent doses of 3 mg to 200 mg starting on day 15 and every two weeks thereafter (target dose), wherein the second dose and subsequent doses are the same and higher than the first dose.

[0124] In certain embodiments of a one-step dosing schedule, the second dose and subsequent doses are the same and are at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times, at least 65 times, at least 70 times, at least 75 times, at least 80 times, at least 85 times, at least 90 times, at least 95 times, at least 100 times, or at least 120 times, at least 150 times, or at least 200 times higher than the first dose.

[0125] In certain embodiments of a one-step dosing schedule, the second dose and subsequent doses are the same and are at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times, at least 65 times, at least 70 times, The first dose, second dose, and subsequent doses of the anti-DLL3 agent are each at least 75 times, at least 80 times, at least 85 times, at least 90 times, at least 95 times, or at least 100 times higher, and the ...5 times, or at least 100 times higher, and the second dose, second dose, and subsequent doses of the anti-DLL3 agent are each at least 75 times, at least 85 times, at least 90 times, at least 95 times, or at least 100 times higher, and the first dose, second dose, and subsequent doses of the anti-DLL3 agent are each at least 75 times, at least 85 times, at least 90 times, at least 90 times, at least 90 times, at least 90 times, at3mg to about 1mg, about 1mg to about 100mg, about 1mg to about 90mg, about 1mg to about 80mg, about 1mg to about 70mg, about 1mg to about 60mg, about 1mg to about 5 0mg, about 1mg to about 40mg, about 1mg to about 30mg, about 1mg to about 20mg, about 1mg to about 10mg, about 1mg to about 3mg, about 3mg to about 100mg, about 3m g ~ about 90mg, about 3mg - about 80mg, about 3mg - about 70mg, about 3mg - about 60mg, about 3mg - about 50mg, about 3mg - about 40mg, about 3mg - about 30mg , about 3 mg to about 20 mg, about 3 mg to about 10 mg, about 3 mg to about 12 mg, about 3 mg to about 15 mg, about 10 mg to about 100 mg, about 10 mg to about 90 mg, about 10 The dosage may be any one of about 10 mg to about 80 mg, about 10 mg to about 70 mg, about 10 mg to about 60 mg, about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 100 mg, about 20 mg to about 90 mg, about 20 mg to about 80 mg, about 20 mg to about 70 mg, about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 20 mg to about 30 mg, about 30 mg to about 100 mg, about 30 mg to about 90 mg, about 30 mg to about 80 mg, about 30 mg to about 70 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, and about 30 mg to about 40 mg.

[0126] In certain embodiments of the one-step dosing schedule, the first dose of the anti-DLL3 agent is about 0.5 mg to about 10 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 2 mg, or about 1 mg; the second dose and subsequent doses are the same and are at least 3-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, at least 120-fold, at least 150-fold, or at least 200-fold greater than the first dose. At most, each of the second dose and subsequent doses may be any one of about 3 mg to about 200 mg, about 3 mg to about 100 mg, about 10 mg to about 180 mg, about 10 mg to about 150 mg, about 30 mg to about 200 mg, about 30 mg to about 180 mg, about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 50 mg to about 200 mg, about 50 mg to about 180 mg, about 50 mg to about 150 mg, about 50 mg to about 120 mg, about 70 mg to about 200, about 70 mg to about 180, about 70 mg to about 150, about 70 mg to about 120 mg, about 90 mg to about 200, about 90 mg to about 180, about 90 mg to about 120 mg, or about 100 mg.

[0127] In certain embodiments of a one-step dosing schedule, the first dose of the anti-DLL3 agent is 1 mg, and the second and subsequent doses are the same and are 3 mg, 10 mg, 30 mg, or 100 mg.

[0128] In certain embodiments, disclosed herein are methods of treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent, wherein the anti-DLL3 agent is administered according to a two-stage dosing schedule.

[0129] In certain embodiments, disclosed herein are methods of treating DLL3-positive cancer, comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered according to one of two schedules: Schedule I: a) a first dose of 0.5 mg to 10 mg on day 1 (induction dose), b) a second dose of 3 mg to 100 mg on day 4 (step-up dose), c) a third dose of 3 mg to 200 mg on day 8 (step-up dose), and d) one or more subsequent doses of 3 mg to 200 mg starting on day 15 and every two weeks thereafter (target dose), with the second dose being higher than the first dose and the third and subsequent doses being the same and higher than the second dose; or Schedule II: a) a first dose of 0.5 mg to 10 mg on day 1 (induction dose), b) a second dose of 3 mg to 100 mg on day 8 (step-up dose), c) a third dose of 3 mg to 200 mg on day 15 (step-up dose), and d) one or more subsequent doses of 3 mg to 200 mg starting on day 29 and every two weeks thereafter (target dose), with the second dose being higher than the first dose and the third and subsequent doses being the same and higher than the second dose. The method is to administer the compound according to one of the following methods.

[0130] In certain embodiments of a two-stage dosing schedule, the second dose is at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, or at least 90-fold higher than the first dose, and the third dose and subsequent doses are identical and are at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold higher than the second dose.

[0131] In certain embodiments of the two-step administration schedule, the second dose is about 20-fold to about 100-fold, about 20-fold to about 90-fold, about 20-fold to about 70-fold, about 20-fold to about 50-fold, about 25-fold to about 50-fold, about 30-fold to about 100-fold, about 30-fold to about 90-fold, about 30-fold to about 70-fold, or about 30-fold to about 50-fold higher than the first dose, and the third dose and any subsequent doses are the same and are about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 2-fold to about 6-fold, about 2-fold to about 4-fold, about 4-fold to about 8-fold, or about 4-fold to about 6-fold higher than the second dose.

[0132] In certain embodiments of a two-step administration schedule, the first dose is about 0.5 mg to about 10 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 2 mg, or 1 mg; the second dose is about 3 mg to about 10 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 25 mg to about 50 mg, about 30 mg to about 80 mg, about 30 mg to about 60 mg, about 30 mg to about 40 mg, about 40 mg to about 80 mg, or about 40 mg to about 60 mg; and the third dose and subsequent doses are the same and are about 3 mg to about 100 mg, about 10 mg to about 60 mg, or about 10 mg to about 60 mg. mg ~ about 200mg, about 10mg - about 180mg, about 10mg - about 150mg, about 10mg - about 120mg, about 30mg - about 200mg, about 30mg - about 180mg , about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 50 mg to about 200 mg, about 50 mg to about 180 mg, about 50 mg to about 150 mg, about 70 mg to about 20 0 mg, about 70 mg to about 180 mg, about 70 mg to about 150 mg, about 70 mg to about 120 mg, about 90 mg to about 200 mg, about 90 mg to about 180 mg, about 90 mg to about 150 mg, about 90 mg to about 120 mg, about 100 mg to about 180 mg, about 100 mg to about 150 mg, about 100 mg to about 120 mg, or about 100 mg.

[0133] In certain embodiments of a two-stage dosing schedule, the first dose is 1 mg, the second dose is about 25 mg to about 50 mg, and the third and subsequent doses are the same and 100 mg. In certain embodiments of a two-stage dosing schedule, the first dose is 1 mg, the second dose is about 45 mg to about 70 mg, and the third and subsequent doses are the same and 100 mg.

[0134] In certain embodiments of a two-stage dosing schedule, the first dose is 1 mg on day 1, the second dose is 25 mg or 50 mg on day 4, the third dose is 100 mg on day 8, and one or more subsequent doses of 100 mg starting on day 15 and every two weeks thereafter.

[0135] In certain embodiments of Schedule I, the target dose is administered on day 4. In such embodiments, the anti-DLL3 agent is administered according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose, equal to the target dose) of 3 mg to 200 mg on day 4, c) a third dose (target dose) of 3 mg to 200 mg on day 8, and d) one or more subsequent doses (target doses) of 3 mg to 200 mg starting on day 15 and every two weeks thereafter, where the second dose is higher than the first dose, and the third and subsequent doses are identical and are the same as the second dose. In certain embodiments, the first dose is 0.5 mg to 8 mg, 0.5 mg to 6 mg, 0.5 mg to 4 mg, 0.5 mg to 2 mg, or 1 mg, and the second, third, and subsequent doses are 3 mg to 100 mg, 10 mg to 150 mg, 30 mg to 200 mg, 30 mg to 100 mg, 50 mg to 150 mg, 70 mg to 120 mg, 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg, respectively. Such a dosing schedule (target doses administered on days 4, 8, and 15 of the first cycle) is believed to be advantageous in that it helps to rapidly reach desired serum levels of the anti-DLL3 agent.

[0136] In certain embodiments, disclosed herein are methods of treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent, wherein the anti-DLL3 agent is administered according to a three-phase administration schedule.

[0137] In certain embodiments, disclosed herein are methods of treating DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent, wherein the anti-DLL3 agent is administered according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) of 3 mg to 100 mg on day 4, c) a third dose (step-up dose) of 3 mg to 100 mg on day 8, d) a fourth dose (step-up dose) of 3 mg to 200 mg on day 15, and e) one or more subsequent doses (target doses) of 3 mg to 200 mg starting on day 29 and every two weeks thereafter, wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and subsequent doses are the same and higher than the third dose.

[0138] In certain embodiments of a three-stage dosing schedule, the second dose is at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, or at least 50-fold higher than the first dose; the third dose is at least 0.5-fold, at least 1-fold, at least 2-fold, at least 3-fold, or at least 5-fold higher than the second dose; and the fourth dose and subsequent doses are identical and at least 1-fold, at least 2-fold, at least 3-fold, or at least 5-fold higher than the third dose.

[0139] In certain embodiments of a three-step administration schedule, the second dose is about 5 to about 70 times, about 20 to about 70 times, about 20 to about 60 times, or about 25 to about 50 times higher than the first dose; the third dose is about 0.5 to about 4 times, about 0.5 to about 2.5 times, about 1 to about 4 times, or about 1 to about 2 times higher than the second dose; and the fourth dose and any subsequent doses are identical and about 1 to about 4 times, or about 2 to about 3 times higher than the third dose.

[0140] In certain embodiments of the three-step administration schedule, the first dose is about 0.5 mg to about 10 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 2 mg, or 1 mg, and the second dose is about 3 mg to about 10 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 100 mg. The first dose is about 3 mg to about 10 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, or about 25 mg, and the second dose is about 3 mg to about 10 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, 10 mg to about 60 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 30 mg to about 100 mg, or about The fourth dose and subsequent doses are the same and are about 3 mg to about 10 mg, about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 30 mg to about 200 mg, about 30 mg to about 150 mg, about 30 mg to about 150 mg, about 30 mg to about 50 mg, about 30 mg to about 80 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, or about 50 mg. The dose is about 100 mg, about 50 mg to about 200 mg, about 50 mg to about 180 mg, about 50 mg to about 150 mg, about 50 mg to about 120 mg, about 70 mg to about 200 mg, about 70 mg to about 180 mg, about 70 mg to about 120 mg, about 90 mg to about 200 mg, about 90 mg to about 180 mg, about 90 mg to about 150 mg, about 90 mg to about 120 mg, or about 100 mg.

[0141] In certain embodiments of a three-step dosing schedule, the first dose is 1 mg, the second dose is 25 mg, the third dose is 50 mg, and the fourth and subsequent doses are the same and are 100 mg.

[0142] In certain embodiments of the three-step dosing schedule, the target dose is administered on day 8. In such embodiments, the anti-DLL3 agent is administered according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (stepping dose) of 3 mg to 100 mg on day 4, c) a third dose (stepping dose, equal to the target dose) of 3 mg to 200 mg on day 8, d) a fourth dose (target dose) of 3 mg to 200 mg on day 15, and e) one or more subsequent doses (target doses) of 3 mg to 200 mg starting on day 29 and every two weeks thereafter, where the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and subsequent doses are identical and are identical to the third dose. In certain embodiments, the first dose is 0.5 mg to 8 mg, 0.5 mg to 6 mg, 0.5 mg to 4 mg, 0.5 mg to 2 mg, or 1 mg, the second dose is 3 mg to 10 mg, 10 mg to 80 mg, 10 mg to 60 mg, 20 mg to 80 mg, 20 mg to 60 mg, 20 mg to 40 mg, 25 mg, or 50 mg, and the third dose, fourth dose, and subsequent doses are 3 mg to 100 mg, 10 mg to 150 mg, 30 mg to 200 mg, 30 mg to 100 mg, 50 mg to 150 mg, 70 mg to 120 mg, 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg, respectively. Such dosing schedules are believed to be advantageous in that they help rapidly achieve desired serum levels of the anti-DLL3 agent.

[0143] The anti-DLL3 agent may be administered by any suitable means, for example, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intranasal, and / or intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the anti-DLL3 agent is administered by intravenous (IV) infusion.

[0144] In certain embodiments, the DLL3-positive cancer is small cell lung cancer (SLCL). In certain embodiments, the SLCL is relapsed / refractory SCLC (RR SCLC) or extensive-stage SCLC (ED SCLC). In certain embodiments, the subject is a human with SCLC (e.g., RR SCLC or ED SCLC).

[0145] 3.2 Co-administration In some embodiments, the compositions and methods of the present invention provide for the use of an anti-DLL3 agent in combination with one or more additional therapeutic agents. In certain embodiments, the one or more additional therapeutic agents are agents that alleviate CRS, such as the anti-DLL3 agent (e.g., AMG757). In certain embodiments, the one or more additional therapeutic agents include an anti-inflammatory agent, a fluid (e.g., saline), an anti-IL6 antibody (e.g., tocilizumab), or an anti-TNF agent (e.g., etanercept). In certain embodiments, the methods disclosed herein include administering an anti-DLL3 agent (e.g., AMG757) in combination with one or more of an anti-inflammatory agent, a fluid (e.g., saline), an anti-IL6 antibody (e.g., tocilizumab), and an anti-TNF agent (e.g., etanercept).

[0146] In some embodiments, the one or more additional therapeutic agents can be an anti-inflammatory agent (e.g., an anti-inflammatory agent for prophylactically treating CRS). The anti-inflammatory agent can be administered prior to, concurrently with, or after administration of the anti-DLL3 agent. Exemplary anti-inflammatory agents include acetaminophen, naproxen sodium, ibuprofen, tramadol, aspirin, celecoxib, valdecoxib, indomethacin, or other nonsteroidal anti-inflammatory drugs (NSAIDs). Other anti-inflammatory agents include, for example, beclomethasone, hydroxycortisone, betamethasone, methylprednisolone, budesonide, prednisolone, cortisone, prednisone, dexamethasone, and triamcinolone, or other glucocorticoids. In certain embodiments, the anti-inflammatory agent is a corticosteroid. In certain embodiments, the corticosteroid is dexamethasone. In certain embodiments, the anti-inflammatory agent is acetaminophen. In certain embodiments, an anti-inflammatory agent (e.g., a corticosteroid such as dexamethasone, or acetaminophen) is administered prior to administration of the anti-DLL3 agent. In certain embodiments, dexamethasone is administered intravenously, e.g., prior to the first cycle dose of AMG757. In certain embodiments, dexamethasone is administered orally.

[0147] In some embodiments, the one or more additional therapeutic agents that alleviate CRS are a fluid (e.g., saline), an anti-IL6 antibody (e.g., tocilizumab), or an anti-TNF agent (e.g., etanercept). Each of these agents may be administered before, simultaneously with, or after the administration of the anti-DLL3 agent. In certain embodiments, saline is administered after the administration of the anti-DLL3 agent (e.g., by IV administration). In certain embodiments, the anti-IL6 antibody (e.g., tocilizumab) or anti-TNF agent (e.g., etanercept) is administered before the administration of the anti-DLL3 agent.

[0148] Higher doses of the anti-DLL3 agent may be required if steroids (eg, dexamethasone) are used. Accordingly, in some aspects, the present invention provides a method of treating SCLC or DLL3-positive cancer, comprising administering a steroid (e.g., a corticosteroid such as dexamethasone) and an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered once every two weeks at a dose of about 0.3 mg to 100 mg (e.g., once every two weeks, about 0.3 mg to about 90 mg, about 0.3 mg to about 80 mg, about 0.3 mg to about 70 mg, about 0.3 mg to about 60 mg, about 0.3 mg to about 50 mg, about 0.3 mg to about 40 mg, about 0.3 mg to about 30 mg, about 0.3 mg to about 20 mg, about 0.3 mg to about 10 mg, about 0.3 mg to about 3 mg, about 0.3 mg to about 1 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 3 mg to about 15 mg, or about 3 mg to about 12 mg).

[0149] In some aspects, the invention provides a method of treating SCLC or DLL3-positive cancer, comprising administering to a subject in need thereof a steroid (e.g., a corticosteroid such as dexamethasone) and an anti-DLL3 agent, wherein the anti-DLL3 agent is administered once every two weeks at a dose of about 0.3 mg to 100 mg or about 3 mg to about 200 mg (e.g., about 3 mg to about 100 mg, about 10 mg to about 180 mg, about 10 mg to about 150 mg, about 10 mg to about 120 mg, about 30 mg to about 200 mg, The present invention provides methods for administering an anti-DLL3 agent at a dose of about 30 mg to about 180 mg, about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 50 mg to about 200 mg, about 50 mg to about 180 mg, about 50 mg to about 150 mg, about 50 mg to about 120 mg, about 70 mg to about 180 mg, about 70 mg to about 150 mg, about 70 mg to about 120 mg, about 90 mg to about 180 mg, about 90 mg to about 150 mg, about 90 mg to about 120 mg, or about 3 mg, 10 mg, 30 mg, or 100 mg. In certain embodiments, the anti-DLL3 agent is administered in a 28-day cycle. In certain embodiments, the steroid is administered in the first cycle of administering the anti-DLL3 agent.

[0150] In some aspects, the present invention provides a method for treating SCLC or DLL3-positive cancer, comprising administering to a subject in need thereof a steroid (e.g., a corticosteroid such as dexamethasone) and an anti-DLL3 agent, wherein the anti-DLL3 agent is administered according to the following schedule: (a) on day 1, 0.3 mg to 100 mg (e.g., about 0.3 mg to about 90 mg, about 0.3 mg to about 80 mg, about 0.3 mg to about 70 mg, about 0.3 mg to about 60 mg, about 0.3 mg to about 50 mg, about 0.3 mg to about 40 mg) on ​​day 2; (b) a first dose of about 0.3 mg to about 30 mg, about 0.3 mg to about 20 mg, about 0.3 mg to about 10 mg, about 0.3 mg to about 3 mg, about 0.3 mg to about 1 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 3 mg to about 15 mg, or about 3 mg to about 12 mg on the 8th day, and (c) a second dose of about 0.3 mg to about 100 mg on the 8th day (e.g., about 0.3 mg to about 90 mg, about 0.3 mg to about 80 mg, about 0.3 mg to about 70 mg, about 0.3 mg to about 60 mg, about 0.3 mg to about 50 mg, about 0.3 mg to about 12 mg on the 8th day). (c) a second dose of 0.3 mg to about 40 mg, about 0.3 mg to about 30 mg, about 0.3 mg to about 20 mg, about 0.3 mg to about 10 mg, about 0.3 mg to about 3 mg, about 0.3 mg to about 1 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 3 mg to about 15 mg, or about 3 mg to about 12 mg starting on day 15 and once every two weeks thereafter; and (c) a second dose of 0.3 mg to about 100 mg (e.g., about 0.3 mg to about 90 mg, about 0.3 mg to about 80 mg, about 0.3 mg to about 70 mg, about 0.3 mg to about and one or more subsequent doses of about 60 mg, about 0.3 mg to about 50 mg, about 0.3 mg to about 40 mg, about 0.3 mg to about 30 mg, about 0.3 mg to about 20 mg, about 0.3 mg to about 10 mg, about 0.3 mg to about 3 mg, about 0.3 mg to about 1 mg, or about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 3 mg to about 15 mg, or about 3 mg to about 12 mg), wherein the second dose and the one or more subsequent doses are the same and higher than the first dose.In certain embodiments, the second dose and one or more subsequent doses are at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times, at least 65 times, at least 70 times, at least 75 times, at least 80 times, at least 85 times, at least 90 times, at least 95 times, or at least 100 times higher than the first dose.

[0151] In certain embodiments, an anti-DLL3 agent (e.g., AMG757) is administered to a subject with a DLL3-positive cancer (e.g., SCLC) in 28-day cycles, and the anti-DLL3 agent is administered in the first cycle together with an anti-inflammatory agent, fluid (e.g., saline), an anti-IL6 antibody (e.g., tocilizumab), an anti-TNF agent (e.g., etanercept), or a combination thereof. In certain embodiments, a corticosteroid (e.g., dexamethasone) is further administered in the first cycle together with the anti-DLL3 agent and the anti-inflammatory agent, fluid (e.g., saline), an anti-IL6 antibody (e.g., tocilizumab), an anti-TNF agent (e.g., etanercept), or a combination thereof. In certain embodiments, the corticosteroid (e.g., dexamethasone) is administered by IV infusion during the first cycle of AMG757 administration.

[0152] In certain embodiments, the first cycle of anti-DLL3 administration is followed by an IV infusion of fluid, such as saline. In certain embodiments, the first cycle of anti-DLL3 agent administration is followed by an IV infusion of 1 liter of saline. In certain embodiments, the first cycle of anti-DLL3 agent administration is followed by an induction dose and ramp-up doses of the anti-DLL3 agent by an IV infusion of 1 liter of saline. In some embodiments, the first cycle of anti-DLL3 agent administration is followed by an IV infusion of 1 liter of saline over approximately 4-5 hours.

[0153] In certain embodiments, an anti-inflammatory agent is administered prior to the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, the anti-inflammatory agent is a corticosteroid (e.g., dexamethasone) and is administered about 6 to about 16 hours prior to the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 8 mg of dexamethasone is administered about 6 to about 16 hours prior to the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 8 mg of dexamethasone is administered about 6 to about 16 hours prior to the induction dose and ramp-up doses of the anti-DLL3 agent in the first cycle. In some embodiments, dexamethasone is administered orally, and in other embodiments, dexamethasone is administered intravenously.

[0154] In certain embodiments, the anti-inflammatory agent is acetaminophen and is administered about 1 hour before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 650 mg of acetaminophen is administered about 1 hour before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 650 mg of acetaminophen is administered about 1 hour before the induction dose and ramp-up doses of the anti-DLL3 agent in the first cycle. In some embodiments, acetaminophen is administered orally.

[0155] In certain embodiments, the anti-IL6 antibody is tocilizumab and is administered prior to administration of the anti-DLL3 agent in cycle 1. In certain embodiments, about 8 mg / kg of tocilizumab is administered to the subject by IV infusion about 1 hour prior to administration of the anti-DLL3 agent in cycle 1. In certain embodiments, about 8 mg / kg of tocilizumab is administered to the subject by IV infusion about 1 hour prior to the induction dose and ramp-up doses of the anti-DLL3 agent in cycle 1.

[0156] In certain embodiments, the anti-TNF agent is etanercept (e.g., Enbrel®) and is administered prior to the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, etanercept is administered about 36 hours to about 60 hours prior to the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, etanercept is administered about 36 hours to about 60 hours prior to the induction dose and ramping doses of the anti-DLL3 agent in the first cycle. In certain embodiments, etanercept is administered two days prior to the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 50 mg of etanercept is administered subcutaneously two days prior to the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 50 mg of etanercept is administered subcutaneously two days prior to the induction dose and ramping doses of the anti-DLL3 agent in the first cycle, excluding the ramping dose on day 4 of a two-stage or three-stage schedule.

[0157] Exemplary CRS mitigation strategies for anti-DLL3 agents (e.g., AMG757) using anti-inflammatory agents (e.g., dexamethasone or acetaminophen), saline, anti-IL6 antibodies (e.g., tocilizumab), or anti-TNF agents (e.g., etanercept) are shown in the table below. In certain embodiments, in addition to the CRS mitigation strategies listed below, a corticosteroid (e.g., dexamethasone) is further administered (e.g., by IV infusion) during the first cycle of AMG757 administration (e.g., administered before the first dose of AMG757).

[0158] [Table 2]

[0159] [Table 3]

[0160] [Table 4]

[0161]

Table 5

[0162] In some aspects, the present invention provides a method for treating SCLC or DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent and an anti-inflammatory agent (e.g., a corticosteroid such as dexamethasone, or acetaminophen), saline, an anti-IL6 antibody (e.g., tocilizumab), or an anti-TNF agent (e.g., etanercept), wherein the anti-DLL3 agent is administered according to the following one-stage schedule: a) on day 1, 0.5 mg to 10 mg (e.g., about 0.5 mg to about 8 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 2 mg) on ​​day 2; a) a first dose (induction dose) of 3 mg to 200 mg (e.g., about 3 mg to about 100 mg, about 10 mg to about 180 mg, about 10 mg to about 150 mg, about 30 mg to about 200 mg, about 30 mg to about 180 mg, about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 50 mg to about 200 mg, about 50 mg to about 180 mg, about 50 mg to about 150 mg, about 50 mg to about 120 mg, about 70 mg to about 200, about 70 mg to about 180, about 70 mg to about 150, about 70 mg to about 120 mg, about 90 mg to about 2 a) a first dose (step dose) of 3 mg to 200 mg (e.g., about 3 mg to about 100 mg, about 10 mg to about 180 mg, about 10 mg to about 150 mg, about 30 mg to about 200 mg, about 30 mg to about 180 mg, about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 50 mg to about 200 mg, about 50 mg to about 180 mg, about 50 mg to about 150 mg, about 50 mg to about 120 mg, about 50 mg to about 120 mg, about 50 mg to about 150 mg, about 50 mg to about 120 mg, about 50 mg to about 120 mg, about 50 mg to about 120 mg, about 50 mg to about 180 mg, about 50 mg to about 150 mg, about 50 mg to about 12 ... the second dose and the subsequent doses are the same but higher than the first dose, and an anti-inflammatory agent, saline, an anti-IL6 antibody, or an anti-TNF agent is administered in the first cycle of administering the anti-DLL3 agent.In certain embodiments, the second dose and subsequent doses are the same and are at least 3-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, at least 120-fold, at least 150-fold, or at least 200-fold higher than the first dose.

[0163] In some embodiments of a one-stage schedule, the method includes administering an anti-DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept, wherein a first dose of the anti-DLL3 agent is 1 mg, and a second and subsequent doses of the anti-DLL3 agent are the same and are 3 mg, 10 mg, 30 mg, or 100 mg, and the dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered during a first cycle of administration of the anti-DLL3 agent. In some embodiments of such a one-stage schedule, dexamethasone is further administered by IV infusion during the first cycle of AMG757 administration.

[0164] In some aspects, the present invention provides a method for treating SLCL or DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent and an anti-inflammatory agent (e.g., a corticosteroid such as dexamethasone, or acetaminophen), saline, an anti-IL6 antibody (e.g., tocilizumab), or an anti-TNF agent (e.g., etanercept), wherein the anti-DLL3 agent is administered according to the following two-stage schedule: Schedule I: a) Day 1, 0.5 mg to 10 mg (e.g., about 0.5 mg to about 8 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 7 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 9 mg, about 0.5 mg to about 10 ... b) a first dose (induction dose) of 3 mg to about 2 mg, or 1 mg) on ​​day 4, a second dose (tiered dose) of 3 mg to 100 mg (e.g., about 3 mg to about 10 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 25 mg to about 50 mg, about 30 mg to about 80 mg, about 30 mg to about 60 mg, about 30 mg to about 40 mg, about 40 mg to about 80 mg, or about 40 mg to about 60 mg), c) a third dose (tiered dose) of 3 mg to 200 mg on day 8, and d) starting on day 15 and every 2 weeks thereafter. The drug is administered in a 28-day cycle according to one or more subsequent doses (target doses) of 3 mg to 200 mg at a time, where the second dose is higher than the first dose, and the third dose and subsequent doses are the same and higher than the second dose, and the third dose and subsequent doses are about 3 mg to about 100 mg, about 10 mg to about 180 mg, about 10 mg to about 150 mg, about 10 mg to about 120 mg, about 30 mg to about 200 mg, about 30 mg to about 180 mg, about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 50 mg to about 200 mg, and about 50 mg to about 180 mg. g, about 50 mg to about 150 mg, about 70 mg to about 200 mg, about 70 mg to about 180 mg, about 70 mg to about 150 mg, about 70 mg to about 120 mg, about 90 mg to about 200 mg, about 90 mg to about 180 mg, about 90 mg to about 150 mg, about 90 mg to about 120 mg, about 100 mg to about 180 mg, about 100 mg to about 150 mg, about 100 mg to about 120 mg, or about 100 mg, and an anti-inflammatory agent, saline, an anti-IL6 antibody, or an anti-TNF agent is administered in the first cycle of administering the anti-DLL3 agent.In some embodiments of such a two-phase schedule, dexamethasone is additionally administered by IV infusion during the first cycle of AMG757 administration.

[0165] In certain embodiments, the method includes administering to a subject in need thereof an anti-DLL3 agent (e.g., AMG757) and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept, wherein the anti-DLL3 agent is administered in 28-day cycles according to the following two-phase schedule: a first dose of 1 mg on day 1, a second dose of 25 mg or 50 mg on day 4, a third dose of 100 mg on day 8, and one or more subsequent doses of 100 mg starting on day 15 and every two weeks thereafter, wherein the dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered during the first cycle in which the anti-DLL3 agent is administered. In certain embodiments, dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered on the same day as or prior to the induction and ramping doses of AMG 757 in Cycle 1. In certain embodiments, dexamethasone is additionally administered by IV infusion during Cycle 1 of AMG 757 administration.

[0166] In certain embodiments of Schedule I, the target dose is administered on day 4. In such embodiments, the method comprises administering to a subject in need thereof an anti-DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept, wherein the anti-DLL3 agent is administered according to the following two-phase schedule: Schedule I: a) Day 1, a first dose of 0.5 mg to 10 mg (e.g., about 0.5 mg to about 8 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 2 mg, or 1 mg); (induction dose), b) a second dose of 3 mg to 200 mg on day 4 (step-up dose), c) a third dose of 3 mg to 200 mg on day 8 (target dose), and d) one or more subsequent doses of 3 mg to 200 mg starting on day 15 and every two weeks thereafter (target dose), wherein the second dose is higher than the first dose, and the third and subsequent doses are the same and identical to the second dose, The third dose and subsequent doses are about 3 mg to about 100 mg, about 10 mg to about 180 mg, about 10 mg to about 150 mg, about 10 mg to about 120 mg, about 30 mg to about 200 mg, about 30 mg to about 180 mg, about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 50 mg to about 200 mg, about 50 mg to about 180 mg, about 50 mg to about 150 mg, about 70 mg to about 200 mg, about 70 mg to about 180 mg, about 70 mg to about 150 mg, The dose may be any one of about 70 mg to about 120 mg, about 90 mg to about 200 mg, about 90 mg to about 180 mg, about 90 mg to about 150 mg, about 90 mg to about 120 mg, about 100 mg to about 180 mg, about 100 mg to about 150 mg, about 100 mg to about 120 mg, or about 100 mg. Dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered in the first cycle of administration of the anti-DLL3 agent. In certain embodiments, dexamethasone, acetaminophen, saline, or tocilizumab is administered on days 1 and 4 or on days 1, 4, and 8 of AMG757 administration in the first cycle. In certain embodiments, etanercept is administered two days before days 1 and 8 of AMG757 administration in the first cycle.In certain embodiments, etanercept is administered two days prior to day 1 of AMG757 administration in cycle 1. In certain embodiments, the method further comprises administering dexamethasone by IV infusion during cycle 1 of AMG757 administration.

[0167] In some aspects, the present invention provides a method for treating SCLC or DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent and an anti-inflammatory agent (e.g., a corticosteroid such as dexamethasone, or acetaminophen), saline, an anti-IL6 antibody (e.g., tocilizumab), or an anti-TNF agent (e.g., etanercept), wherein the anti-DLL3 agent is administered according to the following two-phase schedule: Schedule II: a) Day 1, 0.5 mg to 10 mg (e.g., about 0.5 mg to about 8 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 4 mg, about 0.5 mg a) a first dose (induction dose) of 3 mg to about 2 mg, or 1 mg, on day 8; b) a second dose (tiered dose) of 3 mg to about 100 mg (e.g., about 3 mg to about 10 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 25 mg to about 50 mg, about 30 mg to about 80 mg, about 30 mg to about 60 mg, about 30 mg to about 40 mg, about 40 mg to about 80 mg, or about 40 mg to about 60 mg); c) a third dose (tiered dose) of 3 mg to about 200 mg on day 15; and d) a second dose (tiered dose) of 3 mg to about 200 mg starting on day 29 and every 2 weeks thereafter. The drug is administered in a 28-day cycle according to one or more subsequent doses (target doses) of 3 mg to 200 mg at a time, the second dose being higher than the first dose, the third dose and subsequent doses being the same and higher than the second dose, and the third dose and subsequent doses being about 3 mg to about 100 mg, about 10 mg to about 180 mg, about 10 mg to about 150 mg, about 10 mg to about 120 mg, about 30 mg to about 200 mg, about 30 mg to about 180 mg, about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 50 mg to about 200 mg, about 50 mg to about 180 mg mg, about 50 mg to about 150 mg, about 70 mg to about 200 mg, about 70 mg to about 180 mg, about 70 mg to about 150 mg, about 70 mg to about 120 mg, about 90 mg to about 200 mg, about 90 mg to about 180 mg, about 90 mg to about 150 mg, about 90 mg to about 120 mg, about 100 mg to about 180 mg, about 100 mg to about 150 mg, about 100 mg to about 120 mg, or about 100 mg, and an anti-inflammatory agent, saline, an anti-IL6 antibody, or an anti-TNF agent is administered in the first cycle of administering the anti-DLL3 agent.In some embodiments of such a two-phase schedule, dexamethasone is additionally administered by IV infusion during the first cycle of AMG757 administration.

[0168] In some embodiments of a two-stage administration schedule, the method includes administering to a subject an anti-DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept, wherein a first dose of the DLL3 agent is 1 mg, a second dose of the DLL3 agent is about 25 mg to about 50 mg, and a third and subsequent doses of the DLL3 agent are the same and are 100 mg, and the dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered in the first cycle of administering the anti-DLL3 agent.

[0169] In some embodiments of a two-stage administration schedule, the method includes administering to a subject an anti-DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept, wherein a first dose of the DLL3 agent is 1 mg, a second dose of the DLL3 agent is about 45 mg to about 70 mg, and a third and subsequent doses of the DLL3 agent are the same and are 100 mg, and the dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered in the first cycle of administering the anti-DLL3 agent.

[0170] In certain embodiments of a two-stage administration schedule, the method includes administering to a subject an anti-DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept, wherein a first dose of the anti-DLL3 agent is 1 mg on day 1, a second dose of the anti-DLL3 agent is 25 mg or 50 mg on day 4, and a third dose of 100 mg on day 8, with subsequent doses of the anti-DLL3 agent being 100 mg starting on day 15 and every two weeks thereafter, wherein the dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered during the first cycle of administering the anti-DLL3 agent.

[0171] In some aspects, the present invention provides a method for treating SCLC or DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent and an anti-inflammatory agent (e.g., a corticosteroid such as dexamethasone, or acetaminophen), saline, an anti-IL6 antibody (e.g., tocilizumab), or an anti-TNF agent (e.g., etanercept), wherein the anti-DLL3 agent is administered according to the following three-step schedule: a) Day 1, 0.5 mg to 10 mg (e.g., about 0.5 mg to about 8 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 10 mg, or about 0.5 mg to about 10 mg) on ​​Day 2;a) a first dose (induction dose) of 5 mg to about 2 mg, or 1 mg; b) a second dose (step dose) of 3 mg to 100 mg (e.g., about 3 mg to about 10 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, or about 25 mg) on ​​the fourth day; c) a second dose (step dose) of 3 mg to 100 mg (e.g., about 3 mg to about 10 mg, about 10 mg to about a) a third dose (tiered dose) of 100 mg, about 10 mg to about 80 mg, 10 mg to about 60 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 30 mg to about 100 mg, about 30 mg to about 80 mg, about 30 mg to about 60 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, or about 50 mg; b) a fourth dose (tiered dose) of 3 mg to 200 mg on day 15; and c) a fourth dose (tiered dose) of 3 mg to 200 mg starting on day 29 and Thereafter, one or more subsequent doses (target doses) of 3 mg to 200 mg are administered once every two weeks in a 28-day cycle, where the second dose is higher than the first dose, the third dose is higher than the second dose, the fourth dose and subsequent doses are the same and higher than the third dose, and the fourth dose and subsequent doses are about 3 mg to about 100 mg, about 10 mg to about 150 mg, about 30 mg to 200 mg, about 50 mg to about 200 mg, or about 50 mg to about 1 The anti-DLL3 agent may be administered in a dose of about 80 mg, about 50 mg to about 150 mg, about 50 mg to about 120 mg, about 70 mg to about 200 mg, about 70 mg to about 180 mg, about 70 mg to about 120 mg, about 90 mg to about 200 mg, about 90 mg to about 180 mg, about 90 mg to about 150 mg, about 90 mg to about 120 mg, or about 100 mg, and an anti-inflammatory agent, saline, an anti-IL6 antibody, or an anti-TNF agent is administered during the first cycle of administration of the anti-DLL3 agent. In some embodiments of such a three-step schedule, dexamethasone is further administered by IV infusion during the first cycle of AMG757 administration.

[0172] In some embodiments of a three-stage administration schedule, the method includes administering to a subject an anti-DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept, wherein a first dose of the anti-DLL3 agent is 1 mg, a second dose of the anti-DLL3 agent is 25 mg, a third dose of the anti-DLL3 agent is 50 mg, and a fourth and subsequent doses of the anti-DLL3 agent are the same and are 100 mg, and wherein the dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered in the first cycle of administering the anti-DLL3 agent.

[0173] In certain embodiments of the three-phase administration schedule, the target dose is administered on day 8. In such embodiments, the method includes administering to a subject in need thereof an anti-DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept, wherein the anti-DLL3 agent is administered according to the following three-phase schedule: a) Day 1, 0.5 mg to 10 mg (e.g., about 0.5 mg to about 8 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 2 mg) g, or 1 mg) on ​​day 4; b) a second dose (step-up dose) of 3 mg to 100 mg (e.g., 3 mg to 10 mg, 10 mg to 80 mg, 10 mg to 60 mg, 20 mg to 80 mg, 20 mg to 60 mg, 20 mg to 40 mg, 25 mg, or 50 mg) on ​​day 4; c) a third dose (step-up dose) of 3 mg to 200 mg on day 8; d) a fourth dose (step-up dose) of 3 mg to 200 mg on day 15. and e) one or more subsequent doses (target doses) of 3 mg to 200 mg starting on day 29 and every two weeks thereafter, in a 28-day cycle, where the second dose is higher than the first dose, and the third, fourth, and subsequent doses are the same and higher than the second dose, and the third, fourth, and subsequent doses can be any of 3 mg to 100 mg, 10 mg to 150 mg, 30 mg to 200 mg, 30 mg to 100 mg, 50 mg to 150 mg, 70 mg to 120 mg, 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg, respectively; and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered during the first cycle of administering the anti-DLL3 agent. In certain embodiments, dexamethasone, acetaminophen, saline, or tocilizumab is administered on days 1, 4, and 8, or on days 1, 4, 8, and 15, of AMG757 administration in cycle 1. In certain embodiments, etanercept is administered two days prior to days 1, 8, and 15 of AMG757 administration in cycle 1. In certain embodiments, etanercept is administered two days prior to days 1 and 8 of AMG757 administration in cycle 1.In some embodiments of such a three-phase schedule, dexamethasone is additionally administered by IV infusion during the first cycle of AMG757 administration.

[0174] In certain embodiments of any one of the phased administration schedules, saline (e.g., about 1 liter) is administered by IV infusion after the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, 1 liter of saline is administered by IV infusion after the induction dose and phased dose of the anti-DLL3 agent in the first cycle. In some embodiments, 1 liter of saline is administered by IV infusion over about 4-5 hours after administration of the anti-DLL3 agent.

[0175] In certain embodiments of any one of the phased dosing schedules, the anti-inflammatory agent is a corticosteroid (e.g., dexamethasone) and is administered about 6 to about 16 hours before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 8 mg of dexamethasone is administered about 6 to about 16 hours after the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, 8 mg of dexamethasone is administered about 6 to about 16 hours after the induction dose and phased dose of the anti-DLL3 agent in the first cycle. In some embodiments, dexamethasone is administered orally.

[0176] In certain embodiments of any one of the phased dosing schedules, the anti-inflammatory agent is acetaminophen and is administered about 1 hour before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 650 mg of acetaminophen is administered about 1 hour before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 650 mg of acetaminophen is administered about 1 hour before the induction dose and phased dose of the anti-DLL3 agent in the first cycle. In some embodiments, acetaminophen is administered orally.

[0177] In certain embodiments of any one of the phased dosing schedules, the anti-IL6 antibody tocilizumab is administered prior to administration of the anti-DLL3 agent in cycle 1. In certain embodiments, about 8 mg / kg of tocilizumab is administered to the subject by IV infusion about 1 hour prior to administration of the anti-DLL3 agent in cycle 1. In certain embodiments, about 8 mg / kg of tocilizumab is administered to the subject by IV infusion about 1 hour prior to the induction dose and phased dose of the anti-DLL3 agent in cycle 1.

[0178] In certain embodiments of any one of the stepwise dosing schedules, the anti-TNF agent etanercept (e.g., Enbrel®) is administered prior to the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, etanercept is administered about 36 hours to about 60 hours prior to the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, etanercept is administered about 36 hours to about 60 hours prior to the induction dose and step-up dose of the anti-DLL3 agent in the first cycle, excluding the step-up dose on day 4 of a two-step or three-step dosing schedule. In certain embodiments, about 50 mg of etanercept is administered two days prior to the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 50 mg of etanercept is administered subcutaneously two days prior to the induction dose and step-up dose of the anti-DLL3 agent in the first cycle, excluding the step-up dose on day 4 of a two-step or three-step dosing schedule.

[0179] In certain embodiments of any one of the step-wise administration schedules, the subject is a human.

[0180] 4.Product Disclosed herein is a product comprising: (a) a container containing an anti-DLL3 agent; and (b) a package insert containing instructions for treating a DLL3-positive cancer (or for treating SLCL) in a subject, the instructions providing for administering to the subject a dose of about 0.3 mg to 100 mg, about 3 mg to about 200 mg, or 100 mg (or any of the dose ranges disclosed herein) of the anti-DLL3 agent once every two weeks (e.g., on days 1 and 15 of a 28-day cycle). The instructions may also specify that the anti-DLL3 agent is administered according to the following schedule: a) a first dose of 0.3 mg to 100 mg (or any of the dose ranges disclosed herein) on day 1, b) a second dose of 0.3 mg to 100 mg (or any of the dose ranges disclosed herein) on day 8, and c) one or more subsequent doses of 0.3 mg to 100 mg (or any of the dose ranges disclosed herein) starting on day 15 and every two weeks thereafter, wherein the second dose and the one or more subsequent doses are the same and higher than the first dose.

[0181] The instructions may also specify that the anti-DLL3 agent is administered according to the following schedule: a) a first dose of 0.5 mg to 10 mg (or any of the dose ranges disclosed herein) on day 1, b) a second dose of 3 mg to 200 mg (or any of the dose ranges disclosed herein) on day 8, and c) one or more subsequent doses of 3 mg to 200 mg (or any of the dose ranges disclosed herein) starting on day 15 and every two weeks thereafter, wherein the second dose and the one or more subsequent doses are the same and higher than the first dose.

[0182] In certain embodiments, the instructions include administering the anti-DLL3 agent according to one of two schedules: Schedule I: a) a first dose (induction dose) of 0.5 mg to 10 mg (or any of the dose ranges disclosed herein) on day 1, b) a second dose (step-up dose) of 3 mg to 100 mg (or any of the dose ranges disclosed herein) on day 4, c) a third dose (step-up dose) of 3 mg to 200 mg (or any of the dose ranges disclosed herein) on day 8, and d) one or more subsequent doses (target doses) of 3 mg to 200 mg (or any of the dose ranges disclosed herein) starting on day 15 and every two weeks thereafter, wherein the second dose is higher than the first dose, the third dose and the subsequent doses are the same, and or Schedule II: a) a first dose (induction dose) of 0.5 mg to 10 mg (or any within the dose ranges disclosed herein) on day 1, b) a second dose (step-up dose) of 3 mg to 100 mg (or any within the dose ranges disclosed herein) on day 8, c) a third dose (step-up dose) of 3 mg to 200 mg (or any within the dose ranges disclosed herein) on day 15, and d) one or more subsequent doses (target doses) of 3 mg to 200 mg (or any within the dose ranges disclosed herein) starting on day 29 and every two weeks thereafter, wherein the second dose is higher than the first dose, and the third dose and subsequent doses are the same and higher than the second dose.

[0183] In certain embodiments, the instructions specify that the anti-DLL3 agent is to be administered according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg (or any of the dose ranges disclosed herein) on day 1, b) a second dose (step-up dose) of 3 mg to 200 mg (or any of the dose ranges disclosed herein) on day 4, c) a third dose (step-up dose) of 3 mg to 200 mg (or any of the dose ranges disclosed herein) on day 8, and d) one or more subsequent doses (target doses) of 3 mg to 200 mg (or any of the dose ranges disclosed herein) starting on day 15 and every two weeks thereafter, wherein the second dose is higher than the first dose, and the third and subsequent doses are identical and are the same as the second dose.

[0184] In certain embodiments, the instructions include administering the anti-DLL3 agent according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg (or any of the dose ranges disclosed herein) on day 1, b) a second dose (step-up dose) of 3 mg to 100 mg (or any of the dose ranges disclosed herein) on day 4, c) a third dose (step-up dose) of 3 mg to 100 mg (or any of the dose ranges disclosed herein) on day 8, d) a fourth dose (step-up dose) of 3 mg to 200 mg (or any of the dose ranges disclosed herein) on day 15, and e) a fourth dose (step dose) of 0 mg (or any within a dose range disclosed herein), and e) one or more subsequent doses (target doses) of 3 mg to 200 mg (or any within a dose range disclosed herein) starting on day 29 and administered every two weeks thereafter, wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and subsequent doses are the same and higher than the third dose.

[0185] In certain embodiments, the instructions include administering the anti-DLL3 agent according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg (or any of the dose ranges disclosed herein) on day 1; b) a second dose (step-up dose) of 3 mg to 100 mg (or any of the dose ranges disclosed herein) on day 4; c) a third dose (step-up dose) of 3 mg to 200 mg (or any of the dose ranges disclosed herein) on day 8; d) a fourth dose (step-up dose) of 3 mg to 200 mg (or any of the dose ranges disclosed herein) on day 15; e) a fourth dose (step dose) of 0 mg (or any within a dose range disclosed herein), and e) one or more subsequent doses (target doses) of 3 mg to 200 mg (or any within a dose range disclosed herein) starting on day 29 and once every two weeks thereafter, wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and subsequent doses are the same and identical to the third dose.

[0186] In certain embodiments, the instructions specify that during the first cycle of administering the anti-DLL3 agent, an anti-inflammatory agent (e.g., a corticosteroid such as dexamethasone, or acetaminophen), saline, an anti-IL6 antibody (e.g., tocilizumab), or an anti-TNF agent (e.g., etanercept) is also administered. In certain embodiments, the instructions specify that during the first cycle of administering the anti-DLL3 agent, dexamethasone is further administered (e.g., by IV administration prior to the cycle dose of the anti-DLL3 agent). [Example]

[0187] Example 1 Prediction of Human AMG757 Pharmacokinetics and First-in-Human Dose Selection Allometric scaling of PK parameters obtained from studies in cynomolgus monkeys at doses ranging from 12 to 4500 μg / kg was used to predict human PK parameters for AMG757. A two-compartment model with linear elimination was used to characterize the pharmacokinetics of AMG757 from pooled cynomolgus monkey data, excluding data from animals that tested positive for anti-drug antibodies after the first dose. This model included linear clearance (CL), central compartment volume of distribution (V), and C ), distribution clearance (CL D ), and peripheral volume of distribution (V T ) were used to parameterize the AMG757 PK parameters. Allometry was used to predict human AMG757 PK using exponents of 0.75 and 1 for the clearance and volume parameters, respectively. Body weights of human and cynomolgus monkeys were assumed to be 60 kg and 3 kg, respectively. The resulting monkey AMG757 PK parameters and predicted human AMG757 PK parameters are shown in Table 1.

[0188] [Table 6]

[0189] In combination with these PK predictions, the FIH starting dose was selected based on the estimated minimum effective level (MABEL) identified in vitro. This concentration was determined by evaluating the most sensitive marker of AMG757 activity in the most sensitive DLL3-expressing cell line (Study 123564). Using predicted human exposures in conjunction with animal exposures from the GLP toxicity study, the AUC for the proposed dose in the FIH study was calculated. tau (168 hours for cynomolgus monkeys and 336 hours for humans in GLP toxicity studies), and C max Based on this, a standard ratio calculation was used to calculate the exposure margin.

[0190] The FIH study will evaluate the safety, tolerability, and pharmacokinetics of AMG757 in patients with small cell lung cancer. The predicted human PK parameters described above were used to simulate expected exposure at the proposed FIH doses (Figure 1). The doses of AMG757 in the FIH study are: 0.003 mg, 0.01 mg, 0.03 mg, 0.1 mg, 0.3 mg, 1 mg, 3 mg, 10 mg, 30 mg, 100 mg, and higher (Study 20160323), administered as a short-term IV infusion (approximately 1 hour) once every two weeks in patients with small cell lung cancer (SLCL). This regimen will maximize the in vitro EC2000 of AMG757-mediated cell killing in the lung while minimizing the peak-to-trough ratio during multiple treatment cycles of AMG757. 90 Adequate exposure levels above (5.2 ng / mL) are reliably achieved.

[0191] The starting dose selection in the FIH study was based on the in vitro MABEL. Briefly, the EC of AMG757-mediated cell killing of SHP-77 tumor cells was 50 values ​​and EC for induction of T cell activation (de novo expression of CD69 and CD25) from human peripheral blood mononuclear cells (PBMCs). 50 AMG757-induced de novo expression of CD69 on T cells was identified as the most sensitive parameter of AMG757 activity, based on evaluation of individual dose-response curves from 12 different PBMC donors. MABEL (mean EC 50 ) was calculated to be 0.61 ng / mL (5.8 pM) (Test 123564).

[0192] In vitro EC as a basis for MABEL and FIH starting doses 50 The use of this strategy is supported by the safe implementation to date of this strategy to identify the maximum recommended starting dose of BiTE® molecules to date in clinical development.

[0193] Example 2: Prediction of the minimum effective exposure of AMG757 in humans The effective exposure of AMG757 was predicted based on in vitro data obtained in Study 122717, which evaluated the in vitro pharmacology of AMG757. The half-maximal dose (EC) of AMG757-mediated cell killing in SHP-77 cells (a human DLL3-expressing cell line) was used to predict the effective dose. 50 ) and 90% of maximum efficacy (EC 90 ) was used to estimate the concentration range in which efficacy could be expected.

[0194] The lung was used as a representative site of action for AMG757, and was assumed to achieve approximately 1% of the free serum exposure (Vugmeyser et al., J Pharm Sci. 99:1028-1045 (2010)). Based on this assumption, the EC of AMG757-mediated cell killing in SHP-77 cells was calculated. 50 The dose of AMG757 resulting in trough coverage of 0.05 was considered to be minimally effective. Mean EC of cell killing in SHP-77 cells for the entire treatment cycle 90 Based on trough coverage (assuming 1% lung exposure), early signs of efficacy were predicted at 10 mg IV once every 2 weeks (Figure 2).

[0195] Example 3 Phase 1 Study Evaluating the Safety, Tolerability, and Pharmacokinetics of AMG757 in Subjects with SLCL background Small cell lung cancer (SCLC) accounts for 10-15% of lung cancers (Rudin et al., J Clin Oncol. 33: 4106-4111 (2015)), and is an aggressive subtype of lung cancer that exhibits neuroendocrine differentiation and is strongly associated with smoking (Koinis et al. al, Transl Lung Cancer Res. 5:39-50 (2016)). SCLC exhibits a unique natural history characterized by a high proliferation rate, rapid doubling time, and early establishment of widespread metastatic disease (Gustafsson et al, Cancer. 113:5-21 (2008)). Thirty percent of patients present with disease limited to one hemithorax (limited disease (LD)), whereas the majority of cases present with disease beyond a single radiation treatment field (extensive disease (ED)). SCLC is highly sensitive to first-line chemotherapy (with a response rate of approximately 60%-70%) and radiation, in stark contrast to subsequent resistance to second-line and subsequent treatments after disease recurrence (Byers et al, Cancer. 121:664-672 (2015)). Patients with ED develop drug resistance and die as a result of their disease within a median time of 10-12 months from diagnosis (Rudin et al, 2015). For patients with ED-SLCL, first-line treatment is platinum-based chemotherapy. Most patients in the United States receive platinum-etoposide (EP) chemotherapy (with either carboplatin or cisplatin), with some patients, especially outside the United States, receiving platinum-irinotecan as an alternative. In March 2019, atezolizumab was approved by the United States Food and Drug Administration (US FDA) in combination with carboplatin and etoposide for the first-line treatment of adult patients with ED-SCLC (Tecentriq® United States Prescribing Information [USPI], 2019). After recurrence, topotecan is the only second-line agent approved by the US FDA. However, despite its indication in this setting, topotecan has disappointing response rates (Byers et al., Cancer. 121:664-672 (2015)).

[0196] AMG757 is a half-life extended (HLE) BiTE® molecule that targets DLL3 as a tumor-specific antigen and T-cell receptor-related cluster of differentiation 3 (CD3) on T cells. AMG757 is being developed for the treatment of SCLC and is a potent molecule that acts by forming an immunological synapse between CD3-positive T cells and cancer cells expressing the DLL3 protein. The resulting proximity leads to directed lysis of DLL3-positive target cells by the T cells. AMG757 monotherapy significantly inhibited the growth of subcutaneously implanted DLL3-expressing human melanoma WM266-4 cells and induced regression of orthotopic SHP-77-Luc lung tumors.

[0197] Study design Study 20160323 is an open-label, ascending, multiple-dose Phase 1 study evaluating AMG757 administered as a short-term intravenous (IV) infusion every 2 weeks (e.g., with or without a step-up dose on day 8) in subjects with small cell lung cancer. There are two indications for this study: A: relapsed / refractory small cell lung cancer (RR SLCL), and B: extensive-stage SCLC (ED SCLC).

[0198] Due to its known mechanism of action, subjects are at increased risk of CRS during the initiation of AMG757 treatment.

[0199] The exam consists of three parts: (1) Part A: Evaluating AMG757 in subjects with relapsed / refractory small cell lung cancer (RR SCLC). Part A includes two phases: (A1) a dose-finding phase to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of AMG757, and (A2) a dose-expansion phase to confirm the safety and tolerability of the selected doses. (2) Part B: Evaluate AMG757 in subjects with extensive-stage SCLC (ED SCLC). Part B will begin once the MTD or RP2D is identified in Part A. (3) Part C (Evaluation of Additional CRS Mitigation Strategies): AMG757 monotherapy for subjects with RR SCLC that has progressed after at least one platinum-based regimen. To reduce the risk of CRS, one or more of the following prophylactic measures may be administered (during 1 cycle only): IV hydration, additional corticosteroid prophylaxis with oral dexamethasone, tocilizumab prophylaxis, etanercept prophylaxis, or acetaminophen prophylaxis.

[0200] The primary objectives of both Part A and Part B of this study are to evaluate the safety and tolerability of AMG757 and to determine the MTD or RP2D of AMG757. Secondary objectives of both Part A and Part B of this study are to characterize the pharmacokinetics (PK) of AMG757 and to evaluate the preliminary antitumor activity of AMG757.

[0201] Part A1: Dose-finding phase AMG757 will be administered via a short IV infusion (approximately 60 minutes). The pre-specified doses (dose levels planned for the study) used in dose escalation will be 0.003 mg (Cohort 1), 0.01 mg (Cohort 2), 0.03 mg (Cohort 3), 0.1 mg (Cohort 4), 0.3 mg (Cohort 5), 1 mg (Cohort 6), 3 mg (Cohort 7), 10 mg (Cohort 8), 30 mg (Cohort 9), and 100 mg (Cohort 10), administered biweekly. The dosing schedule during the first cycle may be adjusted to include one or more step doses as described below. If a compelling clinical response is observed during the escalation period, further dose escalation may be halted. Alternative dose levels or administration schedules of AMG757 may be considered based on emerging pharmacokinetic (PK), pharmacodynamic (PD), and safety data. If the MTD is not reached at the planned dose cohort levels (Cohorts 1-10) and is supported by safety and PK / PD data, higher doses may be considered.

[0202] Step-dosing: Subjects may experience first-dose effects (e.g., cytokine release syndrome with associated symptoms, and any other potentially emerging and unknown first-dose effects) after the first infusion of AMG757. It is believed that the optimal MTD may require a step-dosing approach (e.g., first dose on day 1, and step-dose on day 8). Two MTDs can be estimated: one for the first dose (MTD1), and one for subsequent doses (MTD2).

[0203] If, at any time during this study, a subject experiences a first-dose effect (e.g., a CRS event of any grade) for the first time, safety data should be reviewed to determine an appropriate starting dose (MTD1) that does not exceed the dose at which Grade 2 or higher CRS is observed. These doses and dosing schedules will be derived through modeling and simulation of emerging clinical data (e.g., pharmacokinetics, safety data, etc.) to ensure that systemic exposure to AMG757 does not exceed that associated with the initial effective dose. The increased dosing frequency of the step-dose regimen and the potential for drug accumulation should be considered.

[0204] For all subjects enrolled in subsequent cohorts throughout the study, dose escalation will continue at a constant dose relative to the first dose of the first cycle of AMG757 (MTD1), with only the step-up dose increasing according to the pre-specified doses in the dose escalation to determine MTD2. An example of step-up dosing is shown in Figure 3.

[0205] A phased dosing schedule is outlined below, which may be adapted to include one or more of the following treatments according to DLRT recommendations based on emerging safety data: Single step administration with: induction dose on day 1, followed by step-up dose (equal to target dose) on day 8, and target dose on day 15, and Q2W. · Two-phase dosing (option 1) with: induction dose on day 1, followed by a step-up dose on day 4, a step-up dose (equal to the target dose) on day 8, and a target dose on day 15, then Q2W. Two-phase dosing (option 2) with: induction dose on day 1, followed by a step-up dose on day 8, a step-up dose on day 15 (equal to the target dose), and the target dose on day 1 of cycle 2, then Q2W. 3-phase dosing with: induction dose on day 1, followed by a step-up dose on day 4, a step-up dose on day 8, a step-up dose on day 15 (equal to the target dose), and the target dose on day 1 of cycle 2, then Q2W.

[0206] Part A2: Dose Expansion Phase. Part A2 will begin once the MTD or RP2D is selected based on the dose exploration phase (Part A1).

[0207] Part B: Part B will begin once the preliminary MTD or RP2D in Indication A (Part A1) has been established.

[0208] Part C: Following DLRT recommendations based on emerging safety data, one or more additional CRS mitigation strategies outlined below may be evaluated. Part C will begin while Part A1 is ongoing. Prophylaxis with IV hydration of 1 L of normal saline over 4-5 hours immediately after the induction and step-up doses in cycle 1 Additional corticosteroid prophylaxis with dexamethasone 8 mg PO 6 to 16 hours prior to the induction and step-up doses in cycle 1 Tocilizumab 8 mg / kg IV 1 hour before the induction and step-up doses in cycle 1 Etanercept 50 mg SQ on day -2, then 2 days before the induction dose and step-up dose in cycle 1 (excluding the step-up dose on day 4 in a two- or three-step regimen) Acetaminophen 650 mg po 1 hour before the induction and step-up doses in cycle 1

[0209] The CRS mitigation strategies are initially administered with IV dexamethasone. Based on the emerging safety profile, IV dexamethasone may be discontinued while continuing one of the CRS strategies alone to assess the safety profile without steroid premedication.

[0210] Each subject enrolled in Part C will receive only one of the additional CRS mitigation strategies listed above in addition to the AMG757 treatment described above. Subjects will start on a dose of AMG757 that is deemed safe and tolerable. If the incidence of CRS is decreasing based on new safety data, one or more of the strategies listed above may be implemented in Parts A or B.

[0211] Table 2 outlines the eligibility criteria for study 20160323.

[0212] [Table 7]

[0213] Example 4 Study Endpoints for Study 20160323 The hypothesis of Study 20160323 is that AMG757 is safe and tolerable in subjects with indications A and B.

[0214] Primary endpoints: dose-limiting toxicities (DLTs), treatment-emergent adverse events (AEs), treatment-related AEs, and clinically significant changes in vital signs, ECG, physical examination, and laboratory tests.

[0215] Secondary Endpoints: For Indications A and B: (1) PK parameters of AMG757 after intravenous administration, including but not limited to, maximum observed concentration (C max ), minimum observed concentration (C min ), area under the concentration-time curve (AUC) over a 2-week dosing interval, accumulation after multiple doses, and, where possible, half-life (t 1 / 2), (2) objective response (OR) per modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in solid tumors, (3) duration of response (DOR), and (4) 1-year progression-free survival (PFS), and (5) 1-year overall survival (OS). For Indication B only: recurrence-free survival (RFS).

[0216] Exploratory Endpoints: For Indications A and B: (1) Incidence of anti-AMG757 antibody formation, (2) Changes in blood protein, nucleic acid, and cellular biomarkers (e.g., cytokines, lymphocyte status, CTCs, sDLL3), (3) Cell surface protein expression (e.g., DLL3) and tumor-infiltrating lymphocyte status in tumor tissue at baseline. For Indication B only: Effect of prior chemotherapy on T-cell cytokine production before AMG757 treatment. For Part C only: Incidence of CRS.

[0217] Example 5: Effect in humans Human Pharmacokinetics: A preliminary AMG757 PK analysis using a non-compartmental approach was performed on subjects in cohorts 1-5. Preliminary PK results indicate increased AMG757 exposure at doses between 0.003 mg and 0.3 mg. The estimated terminal half-life (t 1 / 2 ) is approximately 1 week across doses after multiple Q2W administration. No significant accumulation was observed (<2-fold).

[0218] One response was confirmed with 0.3 mg IV Q2W (Cohort 5).

[0219] Below is a summary of the doses and administration schedules of AMG757 used in the various cohorts in this study.

[0220] [Table 8]

[0221] Antitumor activity was assessed using a modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, with assessments performed at screening and every 8±1 weeks after AMG757 treatment until disease progression, withdrawal of consent, or initiation of new anticancer therapy.

[0222] Forty patients (median age [range] 64 years [44-80]; EOCG PS 0-1, n=39 [97.5%]; median prior lines: 2.0 [1-6]; n=17 [42.5%] enrolled at eight dose levels (DL) before PD-1 / PD-L1 treatment) received ≥1 dose of AMG757. The median duration of treatment was 6.1 weeks (0.1-59.4). Adverse events (AEs) occurred in 39 patients (97.5%), resulting in discontinuation in 4 patients (10.0%); 32 (80.0%) were treatment-related, including 7 (17.5%) grade ≥3 and 1 (2.5%) grade 5 (pneumonitis; DL5 [0.3 mg]). Cytokine release syndrome (CRS) was reported in 18 patients (45.0%), with grade 2 CRS in 5 patients (12.5%) and grade ≥3 CRS in none. CRS manifested primarily as fever ± hypotension, was reversible, did not lead to treatment interruption or discontinuation, occurred primarily within 24 hours of the first two doses of AMG757, and was managed with supportive care, corticosteroids, and / or anti-IL-6 treatment. Six patients (17.6%) developed treatment-emergent anti-AMG757-binding antibodies. Anti-AMG757 antibodies were not associated with AEs and had no clear effect on drug exposure. The mean (±SD) steady-state serum concentration-time profile of AMG757 is shown in Figure 5. ANG757 demonstrated a dose-proportional increase in exposure (Figure 5).

[0223] Confirmed partial responses (PRs) were reported in six patients (15.8%) (1 / 12 [8.3%] in DL5, 1 / 8 [12.5%] in DL6, 3 / 7 [42.9%] in DL7, and 1 / 7 [14.3%] in DL8 [Figure 4]). Stable disease was reported in 11 patients (28.9%), and one patient had an unconfirmed PR in DL8. Patients with confirmed PRs had a median response time of 2 (1-4) months before the introduction of treatment and a response duration of 1.9+ to 9.4+ months. DLL3 expression at any level was observed in 31 / 32 (96.9%) patient tumor samples, with an overall H-score ranging from 40 to 300. Tumor shrinkage occurred across a wide range of DLL3 expression (H-score, 55-300). The results indicate that AMG757 has acceptable safety and antitumor activity in patients with SCLC at doses up to 10 mg.

[0224] Fifty-nine patients enrolled across 10 dose levels (DL) received ≥1 dose of AMG757. A summary of the objective responses for patients who met the overall response rate (ORR) analysis criteria at the relevant data cutoff date is shown in Figure 6. Seven (14.6%) patients reported a confirmed partial response (PR) (1 / 12 [8.3%] at DL5, 1 / 8 [12.5%] at DL6, 3 / 7 [42.9%] at DL7, 2 / 10 [20%] at DL8, and 0 / 7 [0%] at DL9 [Figure 6]). Stable disease was reported in 12 (25%) patients, including two in cohort 9 (2 / 7 [28.6%]). One case of grade 3 CRS was observed in one patient in cohort 9 and was managed with supportive care, corticosteroids, and vasopressor therapy. The results indicate that AMG757 has acceptable safety and antitumor activity in patients with SLCL at doses up to 30 mg.

[0225] Seven patients enrolled in Cohort 10 received ≥ 1 dose of AMG757, with 4 subjects receiving at least one 100 mg dose (on Day 8). No new safety signals were observed in these patients compared to previous cohorts.

[0226] The specification is most thoroughly understood in light of the teachings of the references cited within. The embodiments within the specification provide illustrations of embodiments of the invention and should not be construed as limiting the scope of the invention. One of ordinary skill in the art will readily recognize that many other embodiments are encompassed by the present invention. All publications, patents, and sequences cited in this disclosure are incorporated by reference in their entirety. To the extent that the material incorporated by reference contradicts or is inconsistent with the present specification, the present specification takes precedence over any such material. The citation of any reference herein does not constitute an admission that such reference is prior art to the present invention.

[0227] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein, and such equivalents are intended to be encompassed by the embodiments described above.

[0228] [Table 9]

[0229] [Table 10]

[0230] [Table 11]

[0231] [Table 12]

[0232] [Table 13]

[0233] [Table 14]

[0234]

Table 15

[0235] Table 16

[0236] Table 17

[0237] Table 18

[0238] Table 19

[0239] Table 20

[0240] Table 21

[0241] Table 22

[0242] Table 23

[0243] Table 24

[0244] Table 25

[0245] Table 26

[0246] Table 27

[0247] Table 28

[0248] Table 29

[0249]

Table 30

[0250] Table 31

[0251] Table 32

[0252] Table 33

[0253] Table 34

[0254] Table 35

[0255] Table 36

[0256] Table 37

[0257] Table 38

[0258] Table 39

[0259] Table 40

[0260] Table 41

[0261] Table 42

[0262] Table 43

[0263] Table 44

[0264] Table 45

[0265] Table 46

[0266] Table 47

[0267] Table 48

[0268] Table 49

[0269]

Table 50

[0270] Table 51

[0271] Table 52

[0272] Table 53

[0273] Table 54

[0274] Table 55

[0275] Table 56

[0276] Table 57

[0277] Table 58

[0278] Table 59

[0279] Table 60

[0280] Table 61

[0281] Table 62

[0282] Table 63

[0283] Table 64

[0284] Table 65

[0285] Table 66

[0286] Table 67

[0287] Table 68

[0288] Table 69

[0289] Table 70

[0290] Table 71

[0291] Table 72

[0292] Table 73

[0293] Table 74

[0294] Table 75

[0295] Table 76

[0296] Table 77

[0297] Table 78

[0298] Table 79

[0299] Table 80

Claims

[Claim 1] The invention described in this specification.

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