Dosing regimen of anti-DLL3 agent

Abstract

The present invention provides a method for treating DLL3-positive cancer or SCLC, comprising administering an anti-DLL3 agent to a subject in need thereof at a dose of about 0.3 mg to about 100 mg or about 3 mg to about 200 mg once every two weeks. Stepwise administration of anti-DLL3 agents for the treatment of SCLC is also disclosed. 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.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of European Patent Application No. 19208214 filed on November 10, 2019 and US Provisional Patent Application No. 63 / 078,131 filed on September 14, 2020. The contents of both applications are hereby incorporated by reference in their entirety.

[0002] Submission of Sequence Listing in ASCII Text File The content of the following submission in ASCII text file is hereby incorporated by reference in its entirety: Sequence Listing in computer - readable format (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 Art

[0004] Small cell lung cancer (SCLC) is an aggressive lung cancer with a poor prognosis and limited treatment options, accounting for about 10 - 15% of lung cancers. Survival rates have remained low over the decades, with only 5% of SCLC patients surviving for 5 years, largely because there are no new treatments to combat this form of lung cancer. Approximately one - third of patients present with limited - stage disease. Most patients present with advanced - stage disease, defined as having tumors only in one side of the chest and fitting within a single radiation field. These stages affect the available treatment regimens, with limited - stage disease being treated with chemotherapy and radiation, and advanced - stage disease being treated with chemotherapy alone. Disseminated metastatic tumors with lymphoid - like characteristics are characteristic of SCLC.

[0005] Patients typically respond well to current state-of-the-art treatments that include etoposide and cisplatin, but always quickly relapse with chemoresistant disease for which no currently available treatment options exist. The prognosis in the relapsed refractory situation is very poor, with the disease progressing rapidly and the median survival being short, less than 6 months. Furthermore, SCLC patients have a high incidence of comorbidities such as hypertension, heart disease, diabetes, and tumor-associated syndromes. These, combined with the typical older age of SCLC patients, affect the ability of patients to tolerate the harsh chemotherapy regimens, further limiting treatment options. Delta-like 3 (DLL3) is a type I transmembrane protein and non-canonical Notch ligand that is differentially expressed in SCLC. Using immunohistochemistry (IHC), 85% of SCLC tumors were positively stained for DLL3 in a pattern consistent with expression in both the membrane and cytoplasm. In contrast, low levels of DLL3 protein expression were detected in normal brain, pancreas, and pituitary by cytoplasmic staining patterns (Saunders et al, Sci Transl Med. 7:302ra136 (2015)). DLL3 is a novel and promising target for the development of T cell-targeted therapies for SCLC.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] There are unmet medical needs regarding the development of treatment methods for the treatment of SCLC.

Means for Solving the Problems

[0008] Based on the present disclosure provided herein, those skilled in the art will be able to recognize or confirm many equivalents to the specific embodiments of the present invention described herein using only routine experimentation. Such equivalents are intended to be encompassed by the following embodiment (E). In an embodiment of the present invention, for example, the following items are provided. (Item 1) A method for treating DLL3-positive cancer, comprising administering an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NO: 437 and 431 to a subject in need thereof, wherein the anti-DLL3 agent is administered once every two weeks at a dose of 3 mg to 200 mg. (Item 2) 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) The method according to item 1, wherein the anti-DLL3 agent is administered once every two weeks at a dose of 3 mg, 10 mg, 30 mg, or 100 mg. (Item 4) The method according to any one of items 1 to 3, wherein the anti-DLL3 agent is administered on the 1st day and the 15th day of a 28-day cycle. (Item 5) A method for treating DLL3-positive cancer, comprising administering an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NO: 437 and 431 to a subject in need thereof, 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 the 1st day, b) a second dose (ramping dose) of 3 mg to 200 mg on the 8th day, and c) one or more subsequent doses (target doses) of 3 mg to 200 mg starting on the 15th day and then once every two weeks, wherein the second dose and the subsequent doses are the same and are higher than the first dose. (Item 6) The method according to item 5, wherein the second dose and the subsequent doses 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. (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. 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) The method according to any one of items 5 to 7, wherein the first dose is 1 mg, and the second dose and the subsequent doses are 3 mg, 10 mg, 30 mg, or 100 mg, respectively. (Item 9) A method for treating DLL3-positive cancer, comprising administering an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 437 and 431 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 (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (ramping dose) of 3 mg to 100 mg on day 4, c) a third dose (ramping 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 once every two weeks thereafter, and the second dose is higher than the first dose, the third dose and the subsequent doses are the same, and higher than the second dose; and or Schedule II: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (ramping dose) of 3 mg to 100 mg on day 8, c) a third dose (ramping dose) of 3 mg to 200 mg on day 15, and d) one or more subsequent doses (target dose) of 3 mg to 200 mg starting on day 29 and once every two weeks thereafter, and the second dose is higher than the first dose, the third dose and the subsequent doses are the same, and higher than the second dose, administered according to one of them. (Item 10) The first dose of 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 of 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 of 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. The method according to item 9. (Item 11) 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 subsequent doses are 2 to 10 times higher than the second dose. The method according to item 9. (Item 12) A method for treating DLL3-positive cancer, comprising administering an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 437 and 431 to a subject in need thereof, the anti-DLL3 agent being 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 (ramping dose) of 3 mg to 100 mg on day 4, c) a third dose (ramping dose) of 3 mg to 100 mg on day 8, d) a fourth dose (ramping 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 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 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 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. The method according to item 12. (Item 14) 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 subsequent doses are 2 to 4 times higher than the third dose, according to the method of item 12. (Item 15) The anti-DLL3 agent contains the amino acid sequence of SEQ ID NO: 438 or 520, according to the method of any one of items 1 to 14. (Item 16) The anti-DLL3 agent is administered in a 28-day cycle, and the method further includes administering physiological saline, an anti-inflammatory agent, tocilizumab, or etanercept to the subject during the first cycle of administering the anti-DLL3 agent, according to the method of any one of items 1 to 15. (Item 17) After the induction dose and the stepwise doses of the anti-DLL3 agent, 1 liter of physiological saline is administered to the subject by IV infusion, according to the method of item 16. (Item 18) The anti-inflammatory agent is a corticosteroid or acetaminophen, according to the method of item 16. (Item 19) The corticosteroid is dexamethasone, according to the method of item 18. (Item 20) Before the induction dose and the stepwise doses of the anti-DLL3 agent, the anti-inflammatory agent or tocilizumab is administered to the subject, according to the method of item 16, 18, or 19. (Item 21) 6 to 16 hours before the induction dose and the stepwise doses of the anti-DLL3 agent, the corticosteroid is administered to the subject, according to the method of item 20. (Item 22) 1 hour before the induction dose and the stepwise doses of the anti-DLL3 agent, acetaminophen or tocilizumab is administered to the subject, according to the method of item 20. (Item 23) 36 to 60 hours before the induction dose and the stepwise doses of the anti-DLL3 agent, excluding the stepwise dose on the fourth day, etanercept is administered, according to the method of item 16. (Item 24) 2 days before the induction dose and the stepwise doses of the anti-DLL3 agent, excluding the stepwise dose on the fourth day, etanercept is administered, according to the method of item 23. (Item 25) A method for treating DLL3-positive cancer, comprising administering an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 437 and 431 to a subject in need thereof, 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 (ramping 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 once 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 the same as the second dose. (Item 26) 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, as described in item 25. The method according to item 25. (Item 27) A method for treating DLL3-positive cancer, comprising administering an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 437 and 431 to a subject in need thereof, 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 (ramping dose) of 3 mg to 100 mg on day 4, c) a third dose (ramping 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 once every two weeks thereafter, wherein the second dose is higher than the first dose, the third dose is higher than the second dose, the fourth dose and the subsequent doses are the same and the same as the third dose. (Item 28) 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 each 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, the method according to item 27. (Item 29) The anti-DLL3 agent contains the amino acid sequence of SEQ ID NO: 438 or 520, the method according to any one of items 25 to 28. (Item 30) The anti-DLL3 agent is administered in a 28-day cycle, and the method further includes administering physiological saline, acetaminophen, dexamethasone, tocilizumab, or etanercept to the subject during the first cycle of administering the anti-DLL3 agent, the method according to any one of items 25 to 29. (Item 31) Physiological saline, acetaminophen, dexamethasone, or tocilizumab is administered to the subject on the 1st and 4th days, or the 1st, 4th, and 8th days of the first cycle of administering the anti-DLL3 agent, the method according to item 25 or 26. (Item 32) Etanercept is administered to the subject 2 days before the 1st day and 2 days before the 8th day of the first cycle of administering the anti-DLL3 agent, or 2 days before the 1st day, the method according to item 25 or 26. (Item 33) Physiological saline, acetaminophen, dexamethasone, or tocilizumab is administered to the subject on the 1st, 4th, and 8th days, or the 1st, 4th, 8th, and 15th days of the first cycle of administering the anti-DLL3 agent, the method according to item 27 or 28. (Item 34) Etanercept is administered to the subject 2 days before the 1st, 8th, and 15th days, or 2 days before the 1st and 8th days of the first cycle of administering the anti-DLL3 agent, the method according to item 27 or 28. (Item 35) The method further includes administering a corticosteroid before administering the anti-DLL3 agent during the first cycle, the method according to any one of items 1 to 34. (Item 36) The adrenal cortical steroid is dexamethasone administered by intravenous injection, the method according to Item 3 5. (Item 37) The cancer is small cell lung cancer (SCLC), the method according to any one of Items 1 to 36. (Item 38) The cancer is recurrent / refractory SCLC (RR SCLC) or extensive-stage SCLC (ED SCLC), the method according to any one of Items 1 to 37. (Item 39) The anti-DLL3 agent is administered by intravenous injection, the method according to any one of Items 1 to 38. (Item 40) The subject is a human, the method according to any one of Items 1 to 39.

[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 at a dose of 0.3 mg to 100 mg, 3 mg to 200 mg, or 100 mg once every two weeks.

[0010] A method for treating DLL3-positive cancer, comprising administering an anti-DLL3 agent to a subject in need thereof, the anti-DLL3 agent being 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 administered once every two weeks thereafter, the second dose and subsequent doses being the same and higher than the first dose.

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

[0012] 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 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 (escalation dose) of 3 mg to 100 mg or 25 mg on day 4, c) a third dose (escalation dose) of 3 mg to 100 mg or 50 mg on day 8, d) a fourth dose (escalation 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 once every two weeks thereafter, wherein 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 are greater than or equal to the third dose.

[0013] 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 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 (escalation 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 once every two weeks thereafter, wherein the second dose is higher than the first dose, the third dose and subsequent doses are the same and are the same as the second dose.

[0014] 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 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 (escalation dose) of 3 mg to 100 mg on day 4, c) a third dose (escalation 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 once every two weeks thereafter, wherein 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 the same as the third dose.

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

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

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

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

[0019] E11: 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, according to the method described in E9 or E10.

[0020] E12: 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, according to any one of E9 to E11.

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

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

[0023] E15: The linker comprises (Gly4Ser)x, wherein x is an integer of 1 or more (for example, 1, 2, 3, or 4), according to the method described in E13 or E14.

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

[0025] E17: The CD3-binding domain is the method according to any one of E9 to E16, comprising a VH 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.

[0026] E18. The CD3-binding domain is the method according to any one of E9 to E17, comprising 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 VH and VL of the CD3-binding domain are linked by a linker to form a single-chain Fv (scFv), according to the method described in E17 or E18.

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

[0029] E21: The linker comprises (Gly4Ser)x, wherein x is an integer of 1 or more (for example, 1, 2, 3, or 4), according to the method described in E19 or E20.

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

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

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

[0033] E25: The linker is a peptide linker containing (Gly4Ser)x, where x is an integer of 1 or more (for example, 1, 2, 3, or 4), according to the method described in E23 or E24.

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

[0035] E27: The DLL3 binding domain includes a VH containing the amino acid sequence of SEQ ID NO: 37 and a VL containing the amino acid sequence of SEQ ID NO: 38, and the CD3 binding domain includes a VH containing the amino acid sequence of SEQ ID NO: 429 and a VL containing the amino acid sequence of SEQ ID NO: 430, according to the method described in any one of E9 to E26.

[0036] E28: The DLL3 binding domain includes a VH containing the amino acid sequence of SEQ ID NO: 435 and a VL containing the amino acid sequence of SEQ ID NO: 436, and the CD3 binding domain includes a VH containing the amino acid sequence of SEQ ID NO: 429 and a VL containing the amino acid sequence of SEQ ID NO: 430, according to the method described in any one of E9 to E26.

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

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

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

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

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

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

[0043] The method according to any one of E9 to E26E28, E30, E32, E33, or E35, wherein the anti-DLL3 agent contains the amino acid of SEQ ID NO: 520.

[0044] The method according to any one of E1 or E7 to E35, wherein an anti-DLL3 agent is administered once every two weeks at a dose of 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, about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 40 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 1 mg to about 10 mg, about 1 mg to about 3 mg, about 3 mg to about 100 mg, about 3 mg to about 90 mg, about 3 mg to about 80 mg, about 3 mg to about 70 mg, about 3 mg to about 60 mg, about 3 mg to about 50 mg, about 3 mg to about 40 mg, about 3 mg to about 30 mg, 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 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, or about 30 mg to about 40 mg.

[0045] The method according to any one of E1 or E7 - E35, wherein the anti - DLL3 agent is administered once every two weeks at a dose of 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 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, or the anti - DLL3 agent is administered once every two weeks at a dose of 3 mg, 10 mg, 30 mg, or 100 mg.

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

[0047] The method according to any one of E2 or E7 - E35, wherein the second dose and one or more subsequent doses are the same and at least 1.5 - fold, 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, at least 10 - fold, at least 20 - fold, at least 25 - fold, at least 30 - fold, at least 35 - fold, at least 40 - fold, at least 45 - fold, at least 50 - fold, at least 55 - fold, at least 60 - fold, at least 65 - fold, at least 70 - fold, at least 75 - fold, at least 80 - fold, at least 85 - fold, at least 90 - fold, at least 95 - fold, at least 100 - fold, at least 120 - fold, at least 150 - fold, at least 200 - fold higher than the first dose.

[0048] The respective first doses of the anti-DLL3 agent are 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, about 0.Any one of the following ranges: 3 mg to about 1 mg, about 1 mg to about 100 mg, about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 40 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 1 mg to about 10 mg, about 1 mg to about 3 mg, about 3 mg to about 100 mg, about 3 mg to about 90 mg, about 3 mg to about 80 mg, about 3 mg to about 70 mg, about 3 mg to about 60 mg, about 3 mg to about 50 mg, about 3 mg to about 40 mg, about 3 mg to about 30 mg, 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 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, about 30 mg to about 40 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 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; the method according to any one of E2, E7 to E35, or E39.

[0049] E41: 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, according to the method described in any one of E2, E7 to E35, E39, or E40.

[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 any one of 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, 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, according to the method described in any one of E3 or E7 to E35.

[0051] E43: 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, according to the method described in any one of E3, E7 to E35, or E42.

[0052] E44: 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 the subsequent doses of the anti-DLL3 agent start on day 15 and are 100 mg once every two weeks thereafter, according to the method described in any one of E3, E7 to E35, or E42.

[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, 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 20 mg to about 60 mg, about 20 mg to about 40 mg, or about 25 mg, 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 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, and the fourth dose and subsequent doses of the anti-DLL3 agent can be any one of about 3 mg to about 100 mg, about 10 mg to about 150 mg, about 30 mg to 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, 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, according to the method described in any one of E4 or E7 to E35.

[0054] E46: 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, by the method described in any one of E4, E7 to E35, or E45.

[0055] E47: 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, 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, by the method described in any one of E5 or E7 to E35.

[0056] E48: 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, fourth, 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, by the method described in any one of E6 or E7 to E35.

[0057] E49: The method includes administering one or more additional therapeutic agents to the subject, by the method described in any one of E1 to E48.

[0058] E50: One or more additional therapeutic agents are steroids, by the method described in E49.

[0059] E51: The additional therapeutic agent is dexamethasone, by the method described in E49 or E50.

[0060] E52: A method according to any one of E49 to E51, wherein an additional therapeutic agent is administered before treatment with an anti-DLL3 agent.

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

[0062] E54: A method according to 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 liquid (e.g., physiological saline), an anti-inflammatory agent, tocilizumab, or etanercept in the first cycle of administering the anti-DLL3 agent.

[0063] E55: A method according to E54, wherein 1 liter of physiological saline is administered to the subject by IV infusion after the induction dose and stepwise doses of the anti-DLL3 agent.

[0064] E56: A method according to E55, wherein 1 liter of physiological saline is administered over about 4 to 5 hours.

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

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

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

[0068] E60: A method according to E59, wherein the corticosteroid is administered to the subject about 6 to 16 hours before the induction dose and stepwise doses of the anti-DLL3 agent.

[0069] E61: A method according to E59, wherein tocilizumab or acetaminophen is administered to the subject about 1 hour before the induction dose and stepwise doses of the anti-DLL3 agent.

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

[0071] E63: The method according to E62, wherein etanercept is administered 2 days before the induction dose and the stepwise doses of the anti-DLL3 agent, excluding the stepwise dose on the fourth day.

[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 DLL3-positive cancer (e.g., 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 in the manufacture of a medicament for the treatment of SCLC, wherein the medicament is prepared to be administered 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 DLL3-positive cancer, wherein the anti-DLL3 agent is administered as described in any one of embodiments E1 to E64.

Brief Description of the Drawings

[0077]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Mode for Carrying Out the Invention

[0078] As disclosed and exemplified herein, a first-in-human clinical trial regarding the treatment of SCLC was conducted using a bispecific protein (AMG757) that targets DLL3 and CD3.

[0079] AMG757 is a half-life extended BiTE® (bispecific T cell engager) molecule developed for the treatment of SCLC. The activity of AMG757 requires simultaneous binding to both target cells (DLL3 + cells) and T cells. The pharmacological effect of AMG757 is to kill DLL3 + cells by already primed cytotoxic CD8+ 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 minimal pharmacologic effective level (MABEL) identified as the MABEL (Study 123564). Based on human PK predictions, a starting dose of 0.003 mg once every 2 weeks (Q2W) was selected that 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 of the exemplary bispecific anti-DLL3 agents disclosed herein (e.g., BiTE® molecules) are recombinant protein constructs that contain two binding domains, each domain being derived from an antigen-binding fragment of a full-length antibody. Such antigen-binding fragments retain the ability to specifically bind to an 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 a VL domain, a VH domain, a CL domain, and a CH1 domain; (ii) an F(ab’)2 fragment, which is a bivalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of a VH domain and a CH1 domain; (iv) an Fv fragment consisting of a VL domain and a VH domain of a single arm of an antibody; and (v) a dAb fragment consisting of a VH domain (Ward et al., 1989 Nature 341:544-546). Further, the two domains of an Fv fragment, VL and VH, are encoded by separate genes, but they can be joined recombinantly using a synthetic linker that allows them to be made 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, for example, 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 (VL) of an antibody light chain or the variable region (VH) of an antibody heavy chain, either alone or in combination. As is known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FRs) linked by three complementarity-determining regions (CDRs) and contribute to the formation of the antigen-binding site of the antibody.

[0082] Exemplary "complementary determining regions" (CDRs) of the DLL3 binding domain and the CD3 binding domain are set forth in the Sequence Listing. The CDRs can be determined according to Kabat, Chothia, the accumulation of both Kabat and Chothia, AbM, contact, North, and / or conformation definitions, or any method of CDR determination known in the art. See, for example, Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th ed. (hypervariable regions); Chothia et al., 1989, Nature 342:877-883 (structural loop structures). The AbM definition of CDR 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 constitute the CDR can be determined using methods known in the art.

[0083] The term "treatment" includes prophylactic treatment and / or therapeutic treatment. When administered prior to the clinical symptoms of a condition, the treatment is considered prophylactic. Therapeutic treatment includes, for example, remission or reduction of the severity of a disease, or shortening of the disease duration.

[0084] "About" or "approximately," when used in connection with a measurable numerical variable, refers to all values of the variable that are either within the experimental error of the indicated value (e.g., within the 95% confidence interval of the mean) or greater than the indicated value by up to ±10%. Numerical ranges include the numbers defining the range.

[0085] "Induction dose", when used in connection with the administration of an anti-DLL3 agent for the treatment of cancer (e.g., small cell lung cancer (SCLC)), refers to the first dose of the anti-DLL3 agent that is below the dose at which an initial 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 is observed or CRS of a certain grade (e.g., grade 2) or less is observed.

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

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

[0088] 2. Anti-DLL3 agent DLL3 is a non-canonical Notch ligand that is mainly expressed during embryonic development, functioning 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 as a promising target for T cell-based therapy by analyzing the various expression of this target in 28 SCLC tumors and a large panel of normal tissues (Study 123658).

[0089] The human DLL3 protein contains the following eight extracellular domains: a signal peptide, an N-terminus, 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 NO: 252, SEQ ID NO: 258, SEQ ID NO: 259, and SEQ ID NO: 260, respectively.

[0090] Exemplary anti-DLL3 agents are bispecific molecules that bind to DLL3 and CD3 (e.g., BiTE® (bispecific T cell engager) molecules). BiTE® molecules are recombinant protein constructs formed from two flexibly linked binding domains, each domain derived from an antibody. One binding domain of the 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. By these designs, BiTE® molecules are uniquely suited to transiently link T cells to target cells and potently activate the T cells' intrinsic cytolytic ability against the target cells. See, for example, WO 99 / 54440, WO 2005 / 040220, and WO 2008 / 119567.

[0091] Accordingly, in some embodiments, the anti-DLL3 agent described comprises the following 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, wherein x is an integer of 1 or more (e.g., 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 VH comprising CDR-H1 comprising the amino acid sequence of SEQ ID NO: 426, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 427, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 428, and a VL comprising CDR-L1 comprising the amino acid sequence of SEQ ID NO: 423, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 424, and 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 of 1 or more (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 of 1 or more (e.g., 2 or 3)).

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

[0101] In certain embodiments, the anti-DLL3 agents described herein comprise the following 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 the following 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 the following 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 of SEQ ID NO: 431. In certain embodiments, the anti-DLL3 agents described herein comprise the following 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 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 hinge-CH2-CH3-linker-hinge-CH2-CH3 in order from the N- to the C-terminus. 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 of 1 or more (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, which is linked to the 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 of 1 or more (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 the following 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 acids of SEQ ID NO: 431, and (c) a third domain that comprises an amino acid sequence selected from any one of SEQ ID NOs: 541-548. In certain embodiments, the anti-DLL3 agents described herein comprise the following 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 acids of SEQ ID NO: 431, and (c) a third domain that comprises any one of the amino acid sequences selected from SEQ ID NOs: 541-548.

[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 is a method of treating DLL3-positive cancer, comprising administering an anti-DLL3 agent to a subject in need thereof 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, this DLL3-positive cancer is small cell lung cancer (SCLC). In certain embodiments, the SCLC is recurrent / refractory SCLC (RR SCLC) or extensive-stage SCLC (ED SCLC). In certain embodiments, the subject is a human having SCLC (e.g., RR SCLC or ED SCLC).

[0109] In certain embodiments, the anti-DLL3 agent is administered once every two weeks at 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, about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 40 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 1 mg to about 10 mg, about 1 mg to about 3 mg, about 3 mg to about 100 mg, about 3 mg to about 90 mg, about 3 mg to about 80 mg, about 3 mg to about 70 mg, about 3 mg to about 60 mg, about 3 mg to about 50 mg, about 3 mg to about 40 mg, about 3 mg to about 30 mg, 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 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, or about 30 mg to about 40 mg.

[0110] In certain embodiments, the anti-DLL3 agent is administered once every two weeks at 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, 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 trial was based on the estimated minimum pharmacological effect level (MABEL) identified as the EC50 of 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 was predicted to result in a maximum serum concentration (0.61 ng / mL) equal to the MABEL. The dose of AMG757 in the Phase 1 clinical trial was 0.003 mg or more, and it was administered to patients with SCLC as an intravenous (IV) infusion once every two weeks (Q2W). This regimen is thought to achieve appropriate exposure in the target tissue (e.g., lung) throughout the dosing interval while minimizing the peak-to-trough ratio after multiple treatment cycles of AMG757.

[0114] Using the predicted human PK parameters, the concentration of AMG757 in the lung, which is designated as a representative site of action and is assumed to achieve approximately 1% of the serum exposure, was predicted (Vugmeyster et al, 2010). The initial signs of efficacy were predicted at 10 mg every two weeks based on the trough coverage of the mean EC 90 in SHP-77 cells (assuming 1% lung exposure, see Example 2).

[0115] In a clinical trial, one case of efficacy was confirmed at 0.3 mg (cohort 5) administered as an intravenous injection once every two weeks. This observed efficacy of AMG757 is surprising because it is significantly lower compared to the 10 mg Q2W dose predicted to be effective based on preclinical results. Additional confirmed efficacies were observed in higher dose cohorts. The effective dose of AMG757 can be considered to be at least 0.3 mg administered once every two weeks (e.g., from about 0.3 mg to about 100 mg or from about 3 mg to about 200 mg).

[0116] The anti-DLL3 agent can be administered by any suitable means, for example, parenterally, subcutaneously, intraperitoneally, intratracheally, 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 dosing Due to the mechanism of action, the subject may have an increased risk of first-dose effects (e.g., cytokine release syndrome) after the first injection of AMG757. An optimal maximum tolerated dose (MTD) may be considered to require a stepwise dosing approach (e.g., an initial dose on day 1, a step dose on day 8, and subsequent doses starting on day 15 and thereafter). In certain embodiments, the following two MTDs may be estimated or established: one for the first administration (MTD1, induction dose) and one for subsequent administrations (MTD2). In certain embodiments, where applicable, the following multiple MTDs may be estimated or established: one for the initial induction dose (MTD1), as well as ones for each step dose and continuous dose.

[0118] If the 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 CRS events are observed can be determined and administered. The second dose and subsequent doses can also be determined and administered. In addition, depending on the number of steps in the stepwise dosing schedule, the second dose, third dose, 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, 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, the fourth dose and subsequent doses are the same, and higher than the third dose. These doses and dosing schedules can be derived by modeling and simulating clinical data (e.g., pharmacokinetics, safety data, etc.) so that the systemic exposure of AMG757 does not exceed what is associated with the dose at which a first-dose effect (e.g., CRS) was observed due to the high dosing frequency and potential for drug accumulation in the stepwise dosing regimen.

[0119] An exemplary dosing schedule of an anti-DLL3 agent (e.g., AMG757) on a 28-day cycle is shown in the following table (for the first cycle only), and then the anti-DLL3 agent is administered once every two weeks.

[0120] [Table 1]

[0121] Accordingly, disclosed herein is 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 a one-stage dosing schedule.

[0122] In certain embodiments, disclosed herein is 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 the following schedule: a) a first dose (induction dose) of 0.3 mg to 100 mg on day 1, b) a second dose (escalation dose) of 0.3 mg to 100 mg on day 8, and c) one or more subsequent doses (target doses) of 0.3 mg to 100 mg starting on day 15 and then once every two weeks, wherein the second dose and the subsequent doses are the same and higher than the first dose.

[0123] In certain embodiments, disclosed herein is 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 the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (escalation dose) of 3 mg to 200 mg on day 8, and c) one or more subsequent doses (target doses) of 3 mg to 200 mg starting on day 15 and then once every two weeks, wherein the second dose and the subsequent doses are the same and higher than the first dose.

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

[0125] In certain embodiments with a one-stage dosing schedule, the second and subsequent doses are the same and 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 of the anti-DLL3 agent, and each of the first, second, and subsequent doses of the anti-DLL3 agent is from about 0.3 mg to about 100 mg, from about 0.3 mg to about 90 mg, from about 0.3 mg to about 80 mg, from about 0.3 mg to about 70 mg, from about 0.3 mg to about 60 mg, from about 0.3 mg to about 50 mg, from about 0.3 mg to about 40 mg, from about 0.3 mg to about 30 mg, from about 0.3 mg to about 20 mg, from about 0.3 mg to about 10 mg, from about 0.3 mg to about 3 mg, from about 0.It can be any one of 3 mg to about 1 mg, about 1 mg to about 100 mg, about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 40 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 1 mg to about 10 mg, about 1 mg to about 3 mg, about 3 mg to about 100 mg, about 3 mg to about 90 mg, about 3 mg to about 80 mg, about 3 mg to about 70 mg, about 3 mg to about 60 mg, about 3 mg to about 50 mg, about 3 mg to about 40 mg, about 3 mg to about 30 mg, 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 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 with a one-stage dosing schedule, the first dose of the anti-DLL3 agent is from about 0.5 mg to about 10 mg, from about 0.5 mg to about 8 mg, from about 0.5 mg to about 6 mg, from about 0.5 mg to about 4 mg, from about 0.5 mg to about 2 mg, or about 1 mg; the second and subsequent doses are the same and 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, and each of the second and subsequent doses can be any one of from about 3 mg to about 200 mg, from about 3 mg to about 100 mg, from about 10 mg to about 180 mg, from about 10 mg to about 150 mg, from about 30 mg to about 200 mg, from about 30 mg to about 180 mg, from about 30 mg to about 150 mg, from about 30 mg to about 120 mg, from about 50 mg to about 200 mg, from about 50 mg to about 180 mg, from about 50 mg to about 150 mg, from about 50 mg to about 120 mg, from about 70 mg to about 200, from about 70 mg to about 180, from about 70 mg to about 150, from about 70 mg to about 120 mg, from about 90 mg to about 200, from about 90 mg to about 180, from about 90 mg to about 120 mg, or about 100 mg.

[0127] In certain embodiments with a one-stage 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 is 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 a two-stage dosing schedule.

[0129] In certain embodiments, disclosed herein is 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 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 (ramping dose) of 3 mg to 100 mg on day 4, c) a third dose (ramping 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 once every two weeks thereafter, and the second dose is higher than the first dose, the third dose and subsequent doses are the same and higher than the second dose; or Schedule II: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (ramping dose) of 3 mg to 100 mg on day 8, c) a third dose (ramping dose) of 3 mg to 200 mg on day 15, and d) one or more subsequent doses (target dose) of 3 mg to 200 mg starting on day 29 and once every two weeks thereafter, and the second dose is higher than the first dose, the third dose and subsequent doses are the same and higher than the second dose, administered according to one of the following.

[0130] In certain embodiments with a two - step 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, the third dose and subsequent doses are the same and 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 with a two-stage dosing schedule, the second dose is about 20 to about 100 times, about 20 to about 90 times, about 20 to about 70 times, about 20 to about 50 times, about 25 to about 50 times, about 30 to about 100 times, about 30 to about 90 times, about 30 to about 70 times, or about 30 to about 50 times higher than the first dose, and the third and subsequent doses are the same and about 2 to about 10 times, about 2 to about 8 times, about 2 to about 6 times, about 2 to about 4 times, about 4 to about 8 times, or about 4 to about 6 times higher than the second dose.

[0132] In certain embodiments with a two-stage dosing 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 and subsequent doses are the same and 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, 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.

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

[0134] In certain embodiments with 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 start on day 15 and are 100 mg once 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 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 dose) of 3 mg to 200 mg starting on day 15 and once every two weeks thereafter. The second dose is higher than the first dose, the third dose and subsequent doses are the same 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 dose, 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. Such a dosing schedule (administering the target dose on days 4, 8, and 15 of the first cycle) is considered advantageous in that it helps to rapidly reach the desired serum levels of the anti-DLL3 agent.

[0136] In certain embodiments, disclosed herein is 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 a three-stage dosing schedule.

[0137] In certain embodiments, disclosed herein is 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 the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1, b) a second dose (escalation dose) of 3 mg to 100 mg on day 4, c) a third dose (escalation dose) of 3 mg to 100 mg on day 8, d) a fourth dose (escalation 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, the fourth dose and subsequent doses are the same and higher than the third dose.

[0138] In certain embodiments of the 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, the fourth dose and subsequent doses are the same 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 with a three-stage dosing schedule, the second dose is about 5-fold to about 70-fold, about 20-fold to about 70-fold, about 20-fold to about 60-fold, about 25-fold to about 50-fold higher than the first dose, the third dose is about 0.5-fold to about 4-fold, about 0.5-fold to about 2.5-fold, about 1-fold to about 4-fold, or about 1-fold to about 2-fold higher than the second dose, the fourth dose and subsequent doses are the same, and are about 1-fold to about 4-fold, or about 2-fold to about 3-fold higher than the third dose.

[0140] In certain embodiments with a three-stage dosing 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 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, the third 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, 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, 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 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, 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 with a three-stage 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 with a three-stage 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 (step-up dose) of 3 mg to 100 mg on day 4, c) a third dose (step-up 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 dose) of 3 mg to 200 mg starting on day 29 and every two weeks thereafter. The second dose is higher than the first dose, the third dose is higher than the second dose, the fourth and subsequent doses are the same and are the same as 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, fourth, and subsequent doses are each 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. Such a dosing schedule is considered advantageous in that it helps to rapidly reach the desired serum levels of the anti-DLL3 agent.

[0143] The anti-DLL3 agent can be administered by any suitable means, for example, by parenteral administration, subcutaneous administration, intraperitoneal administration, intralung administration, intranasal administration, and / or intralesional administration. Parenteral administration includes intramuscular administration, intravenous administration, intraarterial administration, intraperitoneal administration, 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 having SCLC (e.g., RR SCLC or ED SCLC).

[0145] 3.2 Co-administration In some embodiments, the compositions and methods of the 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 mitigate the CRS of the anti-DLL3 agent (e.g., AMG757). In certain embodiments, examples of the one or more additional therapeutic agents include anti-inflammatory agents, fluids (e.g., saline), anti-IL6 antibodies (e.g., tocilizumab), or anti-TNF agents (e.g., etanercept). In certain embodiments, the methods disclosed herein include the administration of 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 anti-inflammatory agents (e.g., anti-inflammatory agents for prophylactically treating CRS). This anti-inflammatory agent may be administered before, simultaneously with, or after the administration of the anti-DLL3 agent. Exemplary anti-inflammatory agents include acetaminophen, sodium naproxen, ibuprofen, tramadol, aspirin, celecoxib, baldecoxib, indomethacin, or other non-steroidal anti-inflammatory drugs (NSAIDs). Other anti-inflammatory agents include, for example, beclomethasone, hydrocortisone, 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, this corticosteroid is dexamethasone. In certain embodiments, the anti-inflammatory agent is acetaminophen. In certain embodiments, the anti-inflammatory agent (e.g., a corticosteroid such as dexamethasone, or acetaminophen) is administered before the administration of the anti-DLL3 agent. In certain embodiments, dexamethasone is administered intravenously, for example, before the first cycle dose of AMG757. In certain embodiments, dexamethasone is administered orally.

[0147] In some embodiments, the one or more additional therapeutic agents for alleviating CRS are a liquid (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 the anti-TNF agent (e.g., etanercept) is administered before the administration of the anti-DLL3 agent.

[0148] When using a steroid (e.g., dexamethasone), higher doses of the anti-DLL3 agent may be required. Thus, in some embodiments, 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 at a dose of 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 embodiments, 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 or about 3 mg to about 200 mg (e.g., once every two weeks at a dose of 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 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 in which the anti-DLL3 agent is administered.

[0150] In one aspect, the present invention is a method for 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 according to the following schedule: (a) a first dose of 0.3 mg to 100 mg on day 1 (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, 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), (b) a second dose of 0.3 mg to 100 mg on day 8 (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, 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), and (c) one or more subsequent doses of 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, 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) starting on day 15 and then once every two weeks, 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-fold, 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, at least 10-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 55-fold, at least 60-fold, at least 65-fold, at least 70-fold, at least 75-fold, at least 80-fold, at least 85-fold, at least 90-fold, at least 95-fold, or at least 100-fold higher than the first dose.

[0151] In certain embodiments, an anti-DLL3 agent (e.g., AMG 757) is administered to a subject having DLL3-positive cancer (e.g., SCLC) in a 28-day cycle, and the anti-DLL3 agent is administered in the first cycle together with an anti-inflammatory agent, a liquid (e.g., saline), an anti-IL6 antibody (e.g., tocilizumab), an anti-TNF agent (e.g., etanercept), or a combination thereof. In certain embodiments, in the first cycle, an anti-DLL3 agent, and an anti-inflammatory agent, a liquid (e.g., saline), an anti-IL6 antibody (e.g., tocilizumab), an anti-TNF agent (e.g., etanercept), or a combination thereof are further administered together with a corticosteroid (e.g., dexamethasone). In certain embodiments, in the first cycle of AMG 757 administration, a corticosteroid (e.g., dexamethasone) is administered by IV infusion.

[0152] In certain embodiments, after administration of anti-DLL3 in the first cycle, a liquid such as saline is administered by IV infusion. In certain embodiments, after administration of the anti-DLL3 agent in the first cycle, 1 liter of saline is administered by IV infusion. In certain embodiments, after the induction dose and the step dose of the anti-DLL3 agent in the first cycle, 1 liter of saline is administered by IV infusion. In some embodiments, after administration of the anti-DLL3 agent, 1 liter of saline is administered by IV infusion over about 4 to 5 hours.

[0153] In certain embodiments, an anti-inflammatory agent is administered prior to 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 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 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 the stepwise 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 prior to administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 650 mg of acetaminophen is administered about 1 hour prior to administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 650 mg of acetaminophen is administered about 1 hour prior to the induction dose and the stepwise 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 the first cycle. 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 the first cycle. 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 the stepwise doses of the anti-DLL3 agent in the first cycle.

[0156] In certain embodiments, the anti-TNF agent is etanercept (e.g., Enbrel®) and is administered prior to administration of the anti-DLL3 agent in the first cycle. In certain embodiments, etanercept is administered about 36 to about 60 hours prior to administration of the anti-DLL3 agent in the first cycle. In certain embodiments, etanercept is administered about 36 to about 60 hours prior to the induction and step doses of the anti-DLL3 agent in the first cycle. In certain embodiments, etanercept is administered 2 days prior to administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 50 mg of etanercept is administered subcutaneously 2 days prior to administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 50 mg of etanercept is administered subcutaneously 2 days prior to the induction and step doses of the anti-DLL3 agent, excluding the step dose on day 4 according to a two-step or three-step schedule, in the first cycle.

[0157] Exemplary CRS mitigation strategies for anti-DLL3 agents (e.g., AMG757) using an anti-inflammatory agent (e.g., dexamethasone or acetaminophen), saline, an anti-IL6 antibody (e.g., tocilizumab), or an anti-TNF agent (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., prior to the dose of AMG757 in the first cycle).

[0158] [Table 2]

[0159] [Table 3]

[0160] [Table 4]

[0161]

Table 5

[0162] In one aspect, the present invention is 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), physiological 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-step schedule: a) a first dose (induction 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 about 1 mg) on day 1; b) a second 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 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 150 mg, about 90 mg to about 120 mg, or about 100 mg) on day 8; and c) one or more subsequent doses (target doses) 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 200, about 90 mg to about 180, about 90 mg to about 150 mg, about 90 mg to about 120 mg, or about 100 mg) starting on day 15 and then once every two weeks, and the second dose and subsequent doses are the same and higher than the first dose, and the anti-inflammatory agent, physiological saline, anti-IL6 antibody, or anti-TNF agent is administered in the first cycle in which the anti-DLL3 agent is administered.In certain embodiments, the second and subsequent doses are the same and 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 the one-step schedule, the method comprises administering an anti-DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept, wherein the first dose of the anti-DLL3 agent is 1 mg, the second and subsequent doses of the anti-DLL3 agent are the same and are 3 mg, 10 mg, 30 mg, or 100 mg, and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered in the first cycle in which the anti-DLL3 agent is administered. In some such embodiments of the one-step schedule, in the first cycle of AMG757 administration, dexamethasone is further administered by IV infusion.

[0164] In one aspect, the present invention is a method for treating SLCL or DLL3-positive cancer, comprising administering to a subject in need an anti-DLL3 agent and an anti-inflammatory agent (e.g., a corticosteroid such as dexamethasone, or acetaminophen), physiological 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-step schedule: Schedule I: a) a first dose (induction 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) on day 1, b) a second dose (step-up 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) 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 doses) of 3 mg to 200 mg once every two weeks starting on day 15 and administered in a 28-day cycle, wherein the second dose is higher than the first dose, the third dose and subsequent doses are the same, and the third dose and subsequent doses are higher than the second dose, and the third dose and subsequent doses can be any one of 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, 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 the anti-inflammatory agent, physiological saline, anti-IL6 antibody, or anti-TNF agent is administered in the first cycle in which the anti-DLL3 agent is administered.In some embodiments of such a two - step schedule, in the first cycle of AMG757 administration, dexamethasone is further administered by IV infusion.

[0165] In certain embodiments, the method comprises administering to a subject in need an anti - DLL3 agent (e.g., AMG757) and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept, wherein the anti - DLL3 agent is administered according to the following two - step 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 are 100 mg once every two weeks starting on day 15, in a 28 - day cycle, and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered in 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 step doses of AMG757 in the first cycle. In some embodiments of such a two - step schedule, in the first cycle of AMG757 administration, dexamethasone is further administered by IV infusion.

[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 an anti-DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept, the anti-DLL3 agent being administered according to the following two-step schedule: Schedule I: a) a first dose (induction 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) on Day 1, b) a second dose (ramping 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 dose) of 3 mg to 200 mg starting on Day 15 and once every two weeks thereafter, in a 28-day cycle, the second dose being higher than the first dose, the third dose and subsequent doses being the same and the same as the second dose, the second dose, third dose, and subsequent doses being any one of 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, 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 dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered in the first cycle in which the anti-DLL3 agent is administered. In certain embodiments, dexamethasone, acetaminophen, saline, or tocilizumab is administered on Days 1 and 4 or Days 1, 4, and 8 of AMG757 administration in Cycle 1. In certain embodiments, etanercept is administered 2 days prior to Days 1 and 8 of AMG757 administration in Cycle 1.In certain embodiments, etanercept is administered 2 days prior to the first day of AMG757 administration in the first cycle. In certain embodiments, the method further comprises administering dexamethasone by IV infusion in the first cycle of AMG757 administration.

[0167] In one aspect, the present invention is a method of 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), physiological 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 II: a) a first dose (induction 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) on day 1, b) a second dose (step-up 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) on day 8, c) a third dose (step-up dose) of 3 mg to about 200 mg on day 15, and d) one or more subsequent doses (target doses) of 3 mg to 200 mg once every two weeks starting on day 29 and administered in a 28-day cycle, wherein the second dose is higher than the first dose, the third dose and subsequent doses are the same and higher than the second dose, and the third dose and subsequent doses can be any one of 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, 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 the anti-inflammatory agent, physiological saline, anti-IL6 antibody, or anti-TNF agent is administered in the first cycle in which the anti-DLL3 agent is administered.In some embodiments of such a two-stage schedule, in the first cycle of AMG757 administration, dexamethasone is further administered by IV infusion.

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

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

[0170] In certain embodiments of the two-stage dosing schedule, the method comprises administering an anti-DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept to a subject, 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 is 100 mg on day 8, the subsequent doses of the anti-DLL3 agent begin on day 15 and are 100 mg once every two weeks thereafter, and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered in the first cycle in which the anti-DLL3 agent is administered.

[0171] In one aspect, the present invention is 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), physiological 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) 0.5 mg to 10 mg on day 1 (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.a) a first dose (induction dose) of 5 mg to about 2 mg, or 1 mg; b) a second dose (ramping dose) of 3 mg to 100 mg on day 4 (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); c) a third dose (ramping dose) of 3 mg to 100 mg on day 8 (e.g., 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 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); d) a fourth dose (ramping dose) of 3 mg to 200 mg on day 15; and e) administered in a 28-day cycle according to one or more subsequent doses (target doses) of 3 mg to 200 mg 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, the fourth dose and subsequent doses are the same and higher than the third dose, and the fourth dose and subsequent doses can be any one of 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, 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, and an anti-inflammatory agent, physiological saline, an anti-IL6 antibody, or an anti-TNF agent is administered in the first cycle in which this anti-DLL3 agent is administered. In some embodiments of such a three-step schedule, in the first cycle of AMG757 administration, dexamethasone is further administered by IV infusion.

[0172] In some embodiments of the three-stage dosing schedule, the method comprises administering an anti-DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept to a subject, 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, the fourth and subsequent doses of the anti-DLL3 agent are the same and are 100 mg, and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered in the first cycle in which the anti-DLL3 agent is administered.

[0173] In certain embodiments with a three - stage dosing schedule, the target dose is administered on day 8. In such embodiments, the method comprises administering an anti - DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept to a subject in need thereof, the anti - DLL3 agent being administered according to the following three - stage schedule: a) a first dose (induction 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) on day 1; 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 (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 once every two weeks starting on day 29 and administered in a 28 - day cycle, the second dose being higher than the first dose, the third dose, the fourth dose, and the subsequent doses being the same and higher than the second dose, and the third dose, the fourth dose, and the subsequent doses can each 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, and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered in the first cycle in which the anti - DLL3 agent is administered. 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 the first cycle. In certain embodiments, etanercept is administered 2 days prior to days 1, 8, and 15 of AMG757 administration in the first cycle. In certain embodiments, etanercept is administered 2 days prior to days 1 and 8 of AMG757 administration in the first cycle.In some embodiments of such a three - stage schedule, in the first cycle of AMG757 administration, dexamethasone is further administered by IV infusion.

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

[0175] In certain embodiments of any one of the step - wise dosing schedules, the anti - inflammatory agent is a corticosteroid (e.g., dexamethasone) and is administered about 6 to about 16 hours before 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 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 loading dose and step - wise doses 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 step - wise dosing schedules, the anti - inflammatory agent is acetaminophen and is administered about 1 hour before administration of the anti - DLL3 agent in the first cycle. In certain embodiments, about 650 mg of acetaminophen is administered about 1 hour before 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 loading dose and step - wise doses 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 dosing schedules, tocilizumab, an anti-IL6 antibody, is administered prior to administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 8 mg / kg of tocilizumab is administered to the subject by IV infusion approximately 1 hour prior to administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 8 mg / kg of tocilizumab is administered to the subject by IV infusion approximately 1 hour prior to the induction dose and stepwise doses of the anti-DLL3 agent in the first cycle.

[0178] In certain embodiments of any one of the dosing schedules, etanercept (e.g., Enbrel®), an anti-TNF agent, is administered prior to administration of the anti-DLL3 agent in the first cycle. In certain embodiments, etanercept is administered approximately 36 to approximately 60 hours prior to administration of the anti-DLL3 agent in the first cycle. In certain embodiments, etanercept is administered approximately 36 to approximately 60 hours prior to the induction dose and stepwise doses of the anti-DLL3 agent, excluding the stepwise dose on day 4 according to a two-step or three-step dosing schedule, in the first cycle. In certain embodiments, about 50 mg of etanercept is administered 2 days prior to administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 50 mg of etanercept is administered subcutaneously 2 days prior to the induction dose and stepwise doses of the anti-DLL3 agent, excluding the stepwise dose on day 4 according to a two-step or three-step dosing schedule, in the first cycle.

[0179] In certain embodiments of any one of the dosing schedules, the subject is human.

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

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

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

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

[0184] In certain embodiments, the instructions are to administer the anti-DLL3 agent according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg (or any within the dosage ranges disclosed herein) on day 1, b) a second dose (ramping dose) of 3 mg to 100 mg (or any within the dosage ranges disclosed herein) on day 4, c) a third dose (ramping dose) of 3 mg to 100 mg (or any within the dosage ranges disclosed herein) on day 8, d) a fourth dose (ramping dose) of 3 mg to 200 mg (or any within the dosage ranges disclosed herein) on day 15, and e) one or more subsequent doses (target doses) of 3 mg to 200 mg (or any within the dosage ranges 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, the fourth dose and subsequent doses are the same and higher than the third dose.

[0185] In certain embodiments, the instructions are to administer the anti-DLL3 agent according to the following schedule: a) a first dose (induction dose) of 0.5 mg to 10 mg on day 1 (or any within the dosage ranges disclosed herein), b) a second dose (ramping dose) of 3 mg to 100 mg on day 4 (or any within the dosage ranges disclosed herein), c) a third dose (ramping dose) of 3 mg to 200 mg on day 8 (or any within the dosage ranges disclosed herein), d) a fourth dose (ramping dose) of 3 mg to 200 mg on day 15 (or any within the dosage ranges disclosed herein), and e) one or more subsequent doses (target doses) of 3 mg to 200 mg (or any within the dosage ranges 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, the fourth dose and subsequent doses are the same and are the same as the third dose.

[0186] In certain embodiments, the instructions provide that in 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 provide that in 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 Using allometric scaling of PK parameters obtained from studies in cynomolgus monkeys at doses in the range of 12–4500 μg / kg, human PK parameters of AMG757 were predicted. The pharmacokinetics of AMG757 were characterized from pooled cynomolgus monkey data using a two-compartment model with linear elimination, excluding data from animals identified as positive for anti-drug antibodies after the first dose administration. This model was parameterized using linear clearance (CL), volume of distribution of the central compartment (V C ), distribution clearance (CL D ), and peripheral volume of distribution (V T ). Allometry was used to predict human AMG757 PK using exponents of 0.75 and 1 for the clearance and volume parameters, respectively. The body weights of humans and cynomolgus monkeys were assumed to be 60 kg and 3 kg, respectively. The resulting AMG757 PK parameters in monkeys and the 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 pharmacological effect 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 the predicted human exposure in combination with the animal exposure levels from GLP toxicity studies, exposure margins were calculated using standard ratio calculations based on AUC tau (168 hours for cynomolgus monkeys and 336 hours for humans in the GLP toxicity study), and C max .

[0190] The FIH study evaluated the safety, tolerability, and pharmacokinetics of AMG757 in patients with small cell lung cancer. Using the predicted human PK parameters described above, the predicted exposures at the proposed FIH doses were simulated (Figure 1). The doses of AMG757 in the FIH study were as follows: 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 short-term IV infusions (≈1 hour) once every two weeks in patients with small cell lung cancer (SLCL). This regimen minimized the peak-to-trough ratio during multiple treatment cycles of AMG757 while ensuring appropriate exposure in the lung to exceed the in vitro EC 90 (5.2 ng / mL) of AMG757-mediated cell death.

[0191] The selection of the starting dose in the FIH study was based on in vitro MABEL. Briefly, the EC 50 value of AMG757-mediated cell death in SHP-77 tumor cells and the EC 50 value of induction of T cell activation (de novo expression of CD69 and CD25) from human peripheral blood mononuclear cells (PBMCs) were compared, and de novo expression of CD69 on T cells induced by AMG757 was identified as the most sensitive parameter of AMG757 activity. Based on the 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) (Study 123564).

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

[0193] Example 2 Prediction of the Minimum Effective Exposure of AMG757 in Humans Based on in vitro data obtained from study 122717 evaluating the in vitro pharmacology of AMG757, the effective exposure of AMG757 was predicted. Using the concentration for the maximum half-maximal effect (EC 50 ) and 90% of the maximum effect (EC 90 ) of AMG757-mediated cell death in SHP-77 cells (human DLL3-expressing cell line), the concentration range where efficacy could be expected was estimated.

[0194] The lung was used as a representative site of action of AMG757, assuming that an exposure of approximately 1% of the free serum exposure was achieved (Vugmeyser et al., J Pharm Sci. 99:1028-1045 (2010)). Based on this assumption, the dose of AMG757 that provided trough coverage of the EC 50 of AMG757-mediated cell death in SHP-77 cells was considered the minimum efficacy. Based on the trough coverage of the mean EC 90 of cell death in SHP-77 cells over the entire treatment cycle (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 lung cancer subtype that shows neuroendocrine differentiation and is strongly associated with smoking (Koinis et al, Transl Lung Cancer Res. 5:39-50 (2016)). SCLC exhibits a unique natural history characterized by a high growth rate, rapid doubling time, and early establishment of widespread metastatic lesions (Gustafsson et al, Cancer. 113:5-21 (2008)). Thirty percent of patients have disease limited to one hemithorax [limited disease (LD)], but the majority of cases have disease that does not fit within one radiation treatment field [extensive disease (ED)]. SCLC is highly sensitive to first-line chemotherapy (response rates of approximately 60%-70%) and radiation, in stark contrast to resistance to second-line treatment and subsequent therapies after disease recurrence (Byers et al, Cancer. 121:664 672 (2015)). Patients with ED develop drug resistance and die as a result of the disease at a median time of 10-12 months from diagnosis (Rudin et al, 2015). In the case of patients with ED SLCL, the first-line treatment is platinum-based chemotherapy. Most patients in the United States receive platinum-etoposide (EP) chemotherapy (with either carboplatin or cisplatin), and some patients, particularly outside the United States, receive platinum-irinotecan as an alternative. In March 2019, atezolizumab was approved by the United States Food and Drug Administration (US FDA) for first-line treatment of adult patients with ED-SCLC in combination with carboplatin and etoposide (Tecentriq (registered trademark) United States Prescribing Information [USPI], 2019). After recurrence, topotecan is the only second-line drug approved by the US FDA. However, despite its indication in this setting, topotecan has an unexpectedly low response rate (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 cluster of differentiation 3 (CD3) on T cells. AMG757 is 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 DLL3 protein. As a result of the resulting proximity, redirected lysis of DLL3-positive target cells by T cells is induced. Treatment with AMG757 alone 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 two weeks (with or without stepwise dosing on Day 8) in subjects with small cell lung cancer. This study has the following two indications: A: Relapsed / Refractory Small Cell Lung Cancer (RR SLCL), and B: Extensive Disease SCLC (ED SCLC).

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

[0199] This study consists of the following three parts: (1) Part A: Evaluate AMG757 in subjects with relapsed / refractory small cell lung cancer (RR SCLC). Part A consists of the following two phases: (A1) A dose-escalation 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 dose. (2) Part B: Evaluate AMG757 in subjects with extensive disease SCLC (ED SCLC). Part B is initiated when the MTD or RP2D is identified in Part A. (3) Part C (Evaluation of Additional CRS Mitigation Strategies): Monotherapy with AMG757 for subjects with RR SCLC who progressed after at least one platinum-based regimen. To reduce the risk of CRS, one or more of the following prophylactic measures may be implemented (only within one cycle): IV hydration, additional corticosteroid prophylaxis by oral administration of dexamethasone, tocilizumab prophylaxis, etanercept prophylaxis, or acetaminophen prophylaxis.

[0200] The primary objectives of both Part A and Part B of this trial are to evaluate the safety and tolerability of AMG757 and to determine the MTD or RP2D of AMG757. The secondary objectives of both Part A and Part B of this trial are to clarify the pharmacokinetic (PK) characteristics of AMG757 and to evaluate the preliminary antitumor activity of AMG757.

[0201] Part A1: Dose Escalation Phase AMG757 is administered by short IV infusion (about 60 minutes). The pre-specified doses (dose levels planned for the investigation) used in dose escalation are 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), and are administered once every two weeks. The dosing schedule in 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 stopped. Alternative dose levels or dosing schedules of AMG757 may be considered based on new 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] Stepwise dosing: Subjects may experience first-dose effects (e.g., cytokine release syndrome with associated symptoms, and any other potential and unknown first-dose effects) after the first infusion of AMG757. An optimal MTD may require a stepwise dosing approach (e.g., an initial dose on day 1 and a step dose on day 8). Two MTDs can be estimated: one for the first administration (MTD1) and one for subsequent administrations (MTD2).

[0203] At any point during this study, if a subject experiences a first-dose effect (e.g., a CRS event of any grade) for the first time, it is necessary to review the safety data and determine the appropriate dose to implement as the first dose (MTD1) that does not exceed the dose at which grade 2 or higher CRS is observed. These doses and dosing schedules are derived by modeling and simulating new clinical data (e.g., pharmacokinetics, safety data, etc.) to ensure that the systemic exposure of AMG757 does not exceed that associated with the dose at which an effect was seen with the first dose. It is necessary to consider the increased frequency of administration in the stepwise dosing regimen and the potential for drug accumulation.

[0204] For all subjects enrolled in subsequent cohorts throughout this study, dose escalation is continued at a fixed dose relative to the first dose of the first cycle of AMG757 (MTD1), and only the step dose is increased according to the pre-specified dose for dose escalation to determine MTD2. An example of stepwise dosing is shown in Figure 3.

[0205] The outline of the stepwise dosing schedule is summarized below. This dosing schedule can be adapted to include one or more of the following treatments according to the DLRT recommendations based on new safety data. · Single-step dosing with the following: an introductory dose on day 1, followed by a step dose on day 8 (equal to the target dose), and the target dose on day 15, and Q2W. · Two-step dosing (option 1) with the following: an introductory dose on day 1, followed by a step dose on day 4, a step dose on day 8 (equal to the target dose), and the target dose on day 15, then Q2W. ·Two - stage administration (Option 2) with the following: an introductory 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. ·Three - stage administration with the following: an introductory 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 - escalation phase. Start Part A2 when the MTD or RP2D is selected based on the dose - finding phase (Part A1).

[0207] Part B: Start Part B when the preliminary MTD or RP2D in Indication A (Part A1) is established.

[0208] Part C: One or more additional CRS mitigation strategies outlined below may be evaluated according to the DLRT recommendations based on new safety data. Start Part C during the progress of Part A1. ·Prophylaxis by IV hydration with 1 L of normal saline over 4 - 5 hours immediately after the introductory dose and step - up doses in Cycle 1 ·Additional corticosteroid prophylaxis with 8 mg of dexamethasone PO 6 - 16 hours before the introductory dose and step - up doses in Cycle 1 ·8 mg / kg of tocilizumab IV 1 hour before the introductory dose and step - up doses in Cycle 1 ·On Day - 2, then etanercept 50 mg SQ 2 days before the introductory dose and step - up doses in Cycle 1 (except for the step - up dose on Day 4 in two - stage or three - stage administration) ·650 mg of acetaminophen po 1 hour before the introductory dose and step - up doses in Cycle 1

[0209] The above CRS mitigation strategy is initially administered with IV dexamethasone. Based on the new safety profile, IV dexamethasone can be discontinued while continuing one of the above CRS strategies alone to evaluate the safety profile without pre-steroid dosing.

[0210] Each subject enrolled in Part C receives only one of the above additional CRS mitigation strategies in addition to the AMG757 treatment described above. Subjects start at a dose of AMG757 that is safe and considered acceptable. Based on new safety data, if the incidence of CRS is decreasing, one or more of the above strategies can be implemented in Part A or B.

[0211] Table 2 summarizes the eligibility criteria for Study 20160323.

[0212]

Table 7

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

[0214] Primary endpoints: Dose-limiting toxicity (DLT), treatment-emergent adverse events (AE), treatment-related AE, and clinically significant changes in vital signs, ECG, physical examination, and clinical laboratory tests.

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

[0216] Exploratory endpoints: For indications A and B: (1) occurrence of anti-AMG757 antibody formation, (2) changes in proteins, nucleic acids, and cellular biomarkers (e.g., cytokines, lymphocyte status, CTC, sDLL3) in blood, (3) cell surface protein expression (e.g., DLL3) and lymphocyte infiltration 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: Occurrence of CRS.

[0217] Example 5 Effects in Humans Pharmacokinetics in humans: For subjects in cohorts 1 - 5, a preliminary AMG757 PK analysis using a non-compartmental approach was performed. The preliminary PK results indicate an increase in AMG757 exposure at doses from 0.003 mg to 0.3 mg. The estimated terminal half-life (t 1 / 2 ) is approximately 1 week across the entire dose range after multiple Q2W administrations. No significant accumulation was observed (<2-fold).

[0218] One case of response was confirmed at 0.3 mg IV Q2W (cohort 5).

[0219] The following is an overview of the AMG757 doses and administration schedules used in various cohorts in this study.

[0220]

Table 8

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

[0222] Forty patients (median age [range] 64 years [44 - 80]; ECOG PS: 0 - 1, n = 39 [97.5%]; median prior lines: 2.0 [1 - 6]; pre-PD-1 / PD-L1 treatment: n = 17 [42.5%] enrolled at 8 dose levels (DL)) 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 patients (80.0%) were treatment-related, including 7 patients (17.5%) of grade ≥ 3 and 1 patient (2.5%) of grade 5 (pneumonia; DL5 [0.3 mg]). Cytokine release syndrome (CRS) was reported in 18 patients (45.0%), 5 patients (12.5%) had grade 2 CRS, and no grade ≥ 3 CRS occurred. CRS mainly presented as fever ± hypotension, was reversible, did not lead to treatment interruption or discontinuation, mainly occurred within 24 hours of the first 2 doses of AMG757, and was managed with supportive therapy, corticosteroids, and / or anti-IL-6 treatment. Six patients (17.6%) developed anti-AMG757 binding antibodies that occurred with treatment. Anti-AMG757 antibodies were not associated with AEs and did not have a clear impact on drug exposure. The mean (± SD) steady-state serum concentration-time profile of AMG757 is shown in Figure 5. ANG757 showed a dose-proportional increase in exposure (Figure 5).

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

[0224] Fifty-nine patients enrolled at 10 dose levels (DL) received ≥1 dose of AMG757. The summary of objective responses of patients who met the overall response rate (ORR) analysis criteria as of the relevant data cut-off date is shown in Figure 6. Seven (14.6%) patients had a confirmed partial response (PR) reported (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 2 in cohort 9 (2 / 7 [28.6%]). One grade 3 CRS was observed in one patient in cohort 9 and was managed with supportive therapy, corticosteroids, and pressor treatment. The results indicate that AMG757 has acceptable safety at doses up to 30 mg and exhibits antitumor activity in patients with SLCL.

[0225] Seven patients enrolled in cohort 10 received ≥1 dose of AMG757, and 4 subjects received 100 mg at least once (on day 8). No new safety signals were observed in these patients compared to the previous cohorts.

[0226] This specification is most fully understood in light of the teachings of the references cited herein. The embodiments within this specification provide examples of embodiments of the present invention and should not be construed as limiting the scope of the present invention. Those skilled 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 hereby incorporated by reference in their entirety. To the extent that the incorporated materials conflict with or are inconsistent with this specification, this specification shall control over any such materials. The citation of any reference in this specification does not admit 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. Such equivalents are intended to be encompassed by the above embodiments.

[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

1. A composition for use in a method of treating DLL3-positive small cell lung cancer (SCLC), comprising an anti-DLL3 agent comprising the amino acid sequence of SEQ ID NO: 438, said method comprising administering said anti-DLL3 agent to a human subject in need thereof, wherein said anti-DLL3 agent is administered at a dose of 10 mg to 100 mg once every two weeks.

2. The composition according to claim 1, wherein said anti-DLL3 agent is administered at a dose of 10 mg, 30 mg, or 100 mg once every two weeks.

3. The composition according to claim 1 or claim 2, wherein said anti-DLL3 agent is administered on days 1 and 15 of a 28-day cycle.

4. The composition according to any one of claims 1 to 3, wherein said anti-DLL3 agent is administered in a 28-day cycle, and said method further comprises administering saline, an anti-inflammatory agent, tocilizumab, or etanercept to said subject in the first cycle in which said anti-DLL3 agent is administered.

5. The composition according to claim 4, wherein 1 liter of saline is administered to said subject by IV infusion.

6. The composition according to claim 5, wherein 1 liter of saline is administered by IV infusion over 4 to 5 hours.

7. The composition according to any one of claims 4 to 6, wherein an anti-inflammatory agent is administered to said subject, and said anti-inflammatory agent is a corticosteroid or acetaminophen.

8. The composition according to claim 7, wherein said corticosteroid is dexamethasone.

9. The composition according to claim 8, wherein said corticosteroid is dexamethasone administered by IV infusion.

10. Said anti-DLL3 agent is administered according to the following schedule: a) a first dose of 0.3 mg to 3 mg on day 1, b) a second dose of 10 mg to 100 mg on day 8, and c) one or more subsequent doses of 10 mg to 100 mg starting on day 15 and then once every two weeks, wherein said second dose and subsequent doses are the same. The composition according to any one of claims 1 to 9.

11. The composition according to claim 10, wherein said first dose is about 1 mg to about 3 mg, and said second dose and subsequent doses are about 10 mg to about 15 mg.

12. A composition for use in a method of treating DLL3-positive small cell lung cancer (SCLC) comprising an anti-DLL3 agent comprising the amino acid sequence of SEQ ID NO: 438, said method comprising administering said anti-DLL3 agent to a human subject in need thereof, said anti-DLL3 agent being administered according to the following schedule: a) A first dose (induction dose) of 0.5 mg to 2 mg on day 1, b) A second dose (escalation dose) of 3 mg to 100 mg on day 8, and c) One or more subsequent doses (target doses) of 3 mg to 100 mg starting on day 15 and once every two weeks thereafter wherein said second dose and subsequent doses are the same, and an anti-inflammatory agent is administered to said subject on day 1 before said induction dose of said anti-DLL3 agent and on day 8 before said escalation dose. Composition.

13. Said first dose is 1 mg, Said second dose and subsequent doses are 3 mg, 10 mg, 30 mg, or 100 mg, respectively, of the composition according to claim 12.

14. The composition according to claim 12 or claim 13, wherein said second dose and subsequent doses are each 10 mg.

15. Said anti-DLL3 agent is administered in a 28-day cycle, and said method further comprises administering to said subject physiological saline, an anti-inflammatory agent, tocilizumab, or etanercept during the first cycle of administering said anti-DLL3 agent. Composition according to any one of claims 12 to 14.

16. After said induction dose and said escalation dose of said anti-DLL3 agent, 1 liter of physiological saline is administered to said subject by IV infusion, characterized in that the composition according to claim 15.

17. The composition according to claim 16, wherein 1 liter of physiological saline is administered by IV infusion over 4 to 5 hours.

18. The composition according to claim 16 or claim 17, wherein 1 liter of physiological saline is administered by IV infusion on day 15.

19. Said anti-inflammatory agent is a corticosteroid or acetaminophen, of the composition according to any one of claims 12 to 18.

20. Said corticosteroid is dexamethasone, of the composition according to claim 19.

21. The composition according to claim 20, wherein said dexamethasone is administered by IV infusion.

22. The composition according to any one of claims 14 to 21, wherein tocilizumab is administered to the subject before the induction dose and the stepwise dose of the anti-DLL3 agent.

23. The composition according to any one of claims 1 to 22, wherein the anti-DLL3 agent comprises the amino acid sequence of SEQ ID NO:

520.

24. The composition according to any one of claims 1 to 23, wherein the cancer is relapsed / refractory SCLC (RR SCLC) or extensive-stage SCLC (ED SCLC).

25. The composition according to any one of claims 1 to 24, wherein the anti-DLL3 agent is administered by IV infusion.

26. The composition according to claim 25, wherein the anti-DLL3 agent is administered by intravenous (IV) infusion over 1 hour.

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