Dosage regimen of anti-DLL3 agents

Abstract

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

Description

[0001] This application is a divisional application of the application with the filing date of November 5, 2020, application number 202080079658.X, and invention name "Dosing Regimens of Anti-DLL3 Agents".

[0002] Cross-reference to related applications

[0003] This application claims the benefit of European Patent Application No. 19208214 filed on November 10, 2019 and U.S. Provisional Application No. 63 / 078,131 filed on September 14, 2020. The contents of both applications are incorporated herein by reference in their entireties.

[0004] Submission of the sequence listing as an ASCII text file

[0005] The following content submitted as an ASCII text file is incorporated herein by reference in its entirety: computer-readable form (CRF) of the sequence listing (filename: A-2520-WO-PCT_ST25.txt, creation date: October 28, 2020, size: 1,218,887 bytes). Technical field

[0006] This application relates to the dosage and administration of anti-DLL3 agents for the treatment of cancer. Background art

[0007] Small cell lung cancer (SCLC) is an aggressive form of lung cancer with poor prognosis and limited treatment options, and represents approximately 10%-15% of lung cancers. For decades, survival rates have remained low, with only 5% of SCLC patients surviving five years, largely due to the lack of new therapies to combat this form of lung cancer. Approximately one-third of patients present with limited-stage disease. Most patients present with extensive-stage disease, defined as tumors present only on one side of the chest and suitable for a single radiation field. These stages affect the available treatment options, where limited-stage disease is treated with chemotherapy and radiation, while extensive-stage disease is treated only with chemotherapy. Diffuse, metastatic tumors with lymphom-like features are characteristic of SCLC.

[0008] Patients typically respond well to current first-line therapies, including etoposide and cisplatin, but chemoresistant disease always recurs quickly, for which there are no available treatment options. The prognosis for recurrent refractory cases is very poor, with rapid disease progression and a short median survival of less than six months. In addition, SCLC patients have a high rate of complications, including hypertension, heart disease, diabetes, and paraneoplastic syndromes. These, combined with the typically advanced age of SCLC patients, affect the patients' ability to tolerate harsh chemotherapy regimens, further limiting treatment options.

[0009] 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 stain positive for DLL3 (pattern consistent with membranous and cytoplasmic expression). In contrast, low levels of DLL3 protein expression are detected in normal brain, islets, and pituitary with a cytoplasmic staining pattern (Saunders et al., Sci Transl Med. 7:302ra136 (2015)). DLL3 is a novel and promising target for developing targeted T cell therapies against SCLC.

[0010] There is an unmet medical need for developing therapies for treating SCLC. Summary of the Invention

[0011] Based on the disclosures provided herein, those skilled in the art will recognize, or be able to determine using only routine experimentation, many equivalent embodiments of the specific embodiments of the invention described herein. Such equivalent embodiments are intended to be covered by the following embodiments (E).

[0012] E1: A method of treating DLL3-positive cancer, the method 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, from 3 mg to 200 mg, or 100 mg once every two weeks.

[0013] E2: A method of treating DLL3-positive cancer, the method comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered according to the following regimen: a) a first dose of from 0.3 mg to 100 mg, from 0.5 mg to 10 mg, or 1 mg on day 1, b) a second dose of from 0.3 mg to 100 mg, from 3 to 200 mg, or 100 mg on day 8, and c) one or more subsequent doses of from 0.3 mg to 100 mg, from 3 mg to 200 mg, or 100 mg starting on day 15 and every two weeks thereafter, and wherein the second dose and subsequent doses are the same and higher than the first dose.

[0014] E3: A method of treating DLL3-positive cancer, the method comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered according to one of the following two regimens:

[0015] Regimen I: a) a first dose (priming dose) of from 0.5 mg to 10 mg or 1 mg on day 1, b) a second dose (ramping dose) of from 3 mg to 100 mg or from 25 mg to 50 mg on day 4, c) a third dose (ramping dose) of from 3 mg to 200 mg or 100 mg on day 8, and d) one or more subsequent doses (target dose) of from 3 mg to 200 mg or 100 mg starting on day 15 and every two weeks thereafter, and wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and are the same as or higher than the second dose; or

[0016] Regimen II: a) a first dose (priming dose) of from 0.5 mg to 10 mg or 1 mg on day 1, b) a second dose (ramping dose) of from 3 mg to 100 mg or 25 mg to 50 mg on day 8, c) a third dose (ramping dose) of from 3 mg to 200 mg or 100 mg on day 15, and c) one or more subsequent doses (target dose) of from 3 mg to 200 mg or 100 mg starting on day 29 and every two weeks thereafter, and wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and are higher than the second dose.

[0017] E4: A method of treating DLL3-positive cancer, the method comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered according to the following regimen: a) a first dose (priming dose) of from 0.5 mg to 10 mg or 1 mg on day 1, b) a second dose (ramping dose) of from 3 mg to 100 mg or 25 mg on day 4, c) a third dose (ramping dose) of from 3 mg to 100 mg or 50 mg on day 8, d) a fourth dose (ramping dose) of from 3 mg to 200 mg or 100 mg on day 15, and e) one or more subsequent doses (target dose) of from 3 mg to 200 mg or 100 mg starting on day 29 and every two weeks thereafter, and wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and the subsequent doses are the same and are the same as or higher than the third dose.

[0018] E5: A method of treating DLL3-positive cancer, the method comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered according to the following regimen: a) a first dose (ramp-up dose) from 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) from 3 mg to 200 mg on day 4, c) a third dose (target dose) from 3 mg to 200 mg on day 8, and d) one or more subsequent doses (target doses) from 3 mg to 200 mg starting on day 15 and every two weeks thereafter, and wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and the same as the second dose.

[0019] E6: A method of treating DLL3-positive cancer, the method comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered according to the following regimen: a) a first dose (ramp-up dose) from 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) from 3 mg to 100 mg on day 4, c) a third dose (step-up dose) from 3 mg to 200 mg on day 8, d) a fourth dose (target dose) from 3 mg to 200 mg on day 15, and e) one or more subsequent doses (target doses) from 3 mg to 200 mg starting on day 29 and every two weeks thereafter, and wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and the subsequent doses are the same and the same as the third dose.

[0020] E7: The method according to any one of E1-E6, wherein the anti-DLL3-positive cancer is small cell lung cancer (SCLC).

[0021] E8: The method according to any one of E1-E7, wherein the anti-DLL3-positive cancer is recurrent / refractory (RR) SCLC or extensive disease (ED) SCLC.

[0022] E9: The method according to any one of E1-E8, wherein the anti-DLL3 agent is a bispecific antibody construct comprising two binding domains: the first domain binds to human DLL3, and the second domain binds to human CD3.

[0023] E10: The method according to E9, wherein the DLL3 binding domain binds to an epitope of human DLL3 contained within the amino acid sequence of SEQ ID NO:258.

[0024] E11: The method as described in E9 or E10, wherein the DLL3 binding domain comprises (a) a heavy chain variable region (VH) which comprises: (i) VH complementarity determining region 1 (CDR-H1) which comprises the amino acid sequence of SEQ ID NO:31; (ii) CDR-H2 which comprises the amino acid sequence of SEQ ID NO:32; and (iii) CDR-H3 which comprises the amino acid sequence of SEQ ID NO:33; and (b) a light chain variable region (VL) which comprises: (i) VL complementarity determining region 1 (CDR-L1) which comprises the amino acid sequence of SEQ ID NO:34; (ii) CDR-L2 which comprises the amino acid sequence of SEQ ID NO:35; and (iii) CDR-L3 which comprises the amino acid sequence of SEQ ID NO:36.

[0025] E12: The method as described in any one of E9-E11, wherein the DLL3 binding domain comprises: (1) a VH comprising the amino acid sequence of SEQ ID NO:37 and a VL comprising the amino acid sequence of SEQ ID NO:38, or (2) a VH comprising the amino acid sequence of SEQ ID NO:435 and a VL comprising the amino acid sequence of SEQ ID NO:436.

[0026] E13: The method as described in any one of E9-E12, wherein the VH and VL of the DLL3 binding domain are linked by a linker to form a single-chain Fv (scFv).

[0027] E14: The method as described in E13, wherein the linker comprises a sequence selected from any one of SEQ ID NO:285-293.

[0028] E15: The method as described in E13 or E14, wherein the linker comprises (Gly4Ser)x, where x is an integer of 1 or greater (e.g., 1, 2, 3 or 4).

[0029] E16: The method as described in any one of E9-E15, wherein the DLL3 binding domain comprises the amino acid sequence of SEQ ID NO:39 or SEQ ID NO:437.

[0030] E17: The method according to any one of E9-E16, wherein the CD3-binding domain comprises: (a) a VH which comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:426, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:427, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:428; and a VL which comprises: 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.

[0031] E18: The method according to any one of E9-E17, wherein the CD3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO:429 and a VL comprising the amino acid sequence of SEQ ID NO:430.

[0032] E19: The method according to E17 or E18, wherein the VH and VL of the CD3-binding domain are linked by a linker to form a single-chain Fv (scFv).

[0033] E20: The method according to E19, wherein the linker comprises a sequence selected from any one of SEQ ID NO:285-293.

[0034] E21: The method according to E19 or E20, wherein the linker comprises (Gly4Ser)x, where x is an integer of 1 or greater (e.g., 1, 2, 3, or 4).

[0035] E22: The method according to any one of E17-E21, wherein the CD3-binding domain comprises the amino acid sequence of SEQ ID NO:431.

[0036] E23: The method according to any one of E9-E22, wherein the DLL3-binding domain and the CD3-binding domain are linked by a linker.

[0037] E24: The method according to E23, wherein the linker is a peptide linker comprising a sequence selected from any one of SEQ ID NO:285-293.

[0038] E25: The method according to E23 or E24, wherein the linker is a peptide linker comprising (Gly4Ser)x, where x is an integer of 1 or greater (e.g., 1, 2, 3, or 4).

[0039] E26: The method according to any one of E9 - E25, wherein the anti-DLL3 agent comprises a DLL3 binding domain and a CD3 binding domain. The DLL3 binding domain comprises (a) a heavy chain variable region (VH) which comprises: (i) VH complementarity determining region 1 (CDR-H1) which comprises the amino acid sequence of SEQ ID NO: 31; (ii) CDR-H2 which comprises the amino acid sequence of SEQ ID NO: 32; and (iii) CDR-H3 which comprises the amino acid sequence of SEQ ID NO: 33; and (b) a light chain variable region (VL) which comprises: (i) VL complementarity determining region 1 (CDR-L1) which comprises the amino acid sequence of SEQ ID NO: 34; (ii) CDR-L2 which comprises the amino acid sequence of SEQ ID NO: 35; and (iii) CDR-L3 which comprises the amino acid sequence of SEQ ID NO: 36. The CD3 binding domain comprises (a) VH which comprises: (i) CDR-H1 which comprises the amino acid sequence of SEQ ID NO: 426, (ii) CDR-H2 which comprises the amino acid sequence of SEQ ID NO: 427, and (iii) CDR-H3 which comprises the amino acid sequence of SEQ ID NO: 428; and (b) VL which comprises: (i) CDR-L1 which comprises the amino acid sequence of SEQ ID NO: 423, (ii) CDR-L2 which comprises the amino acid sequence of SEQ ID NO: 424, and (iii) CDR-L3 which comprises the amino acid sequence of SEQ ID NO: 425.

[0040] E27: The method according to any one of E9 - E26, wherein the DLL3 binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 37 and a VL having the amino acid sequence of SEQ ID NO: 38, and the CD3 binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 429 and a VL having the amino acid sequence of SEQ ID NO: 430.

[0041] E28: The method according to any one of E9 - E26, wherein the DLL3 binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 435 and a VL having the amino acid sequence of SEQ ID NO: 436, and the CD3 binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 429 and a VL having the amino acid sequence of SEQ ID NO: 430.

[0042] E29: The method according to any one of E9 - E27, wherein the DLL3 binding domain comprises the amino acids of SEQ ID NO:39 and the CD3 binding domain comprises the amino acids of SEQ ID NO:431.

[0043] E30: The method according to any one of E9 - E26 or E28, wherein the DLL3 binding domain comprises the amino acids of SEQ ID NO:437 and the CD3 binding domain comprises the amino acids of SEQ ID NO:431.

[0044] E31: The method according to E29, wherein the anti - DLL3 agent comprises the amino acid sequence of SEQ ID NO:40.

[0045] E32: The method according to E30, wherein the anti - DLL3 agent comprises the amino acid sequence of SEQ ID NO:438.

[0046] E33: The method according to any one of E9 - E32, wherein the anti - DLL3 agent further comprises a third domain that prolongs or enhances the serum half - life of the anti - DLL3 agent.

[0047] E34: The method according to E33, wherein the third domain comprises the amino acid sequence selected from any one of SEQ ID NO:541 - 548.

[0048] E35: The method according to any one of E9 - E26, E28, E30, E32, E33 or E35, wherein the anti - DLL3 agent comprises the amino acids of SEQ ID NO:520.

[0049] E36: The method according to any one of E1 or E7 - E35, wherein the anti - DLL3 agent is administered once every two weeks at the following doses: 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 0.3 mg to about 1 mg, from about 1 mg to about 100 mg, from about 1 mg to about 90 mg, from about 1 mg to about 80 mg, from about 1 mg to about 70 mg, from about 1 mg to about 60 mg, from about 1 mg to about 50 mg, from about 1 mg to about 40 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 3 mg, from about 3 mg to about 100 mg, from about 3 mg to about 90 mg, from about 3 mg to about 80 mg, from about 3 mg to about 70 mg, from about 3 mg to about 60 mg, from about 3 mg to about 50 mg, from about 3 mg to about 40 mg, from about 3 mg to about 30 mg, from about 3 mg to about 20 mg, from about 3 mg to about 10 mg, from about 3 mg to about 12 mg, from about 3 mg to about 15 mg, from about 10 mg to about 100 mg, from about 10 mg to about 90 mg, from about 10 mg to about 80 mg, from about 10 mg to about 70 mg, from about 10 mg to about 60 mg, from about 10 mg to about 50 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 10 mg to about 15 mg, from about 20 mg to about 100 mg, from about 20 mg to about 90 mg, from about 20 mg to about 80 mg, from about 20 mg to about 70 mg, from about 20 mg to about 60 mg, from about 20 mg to about 50 mg, from about 20 mg to about 40 mg, from about 20 mg to about 30 mg, from about 30 mg to about 100 mg, from about 30 mg to about 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about 70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, or from about 30 mg to about 40 mg.

[0050] E37: 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 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 mg, from about 70 mg to about 180 mg, from about 70 mg to about 150 mg, from about 70 mg to about 120 mg, from about 90 mg to about 200 mg, from about 90 mg to about 180 mg, from about 90 mg to about 150 mg, from about 90 mg to about 120 mg, from about 100 mg to about 180 mg, from about 100 mg to about 150 mg, or from about 100 mg to about 120 mg; or wherein the anti - DLL3 agent is administered once every two weeks at a dose of 3 mg, 10 mg, 30 mg or 100 mg.

[0051] E38: The method according to any one of E1 or E7 - E37, wherein the anti - DLL3 agent is administered on day 1 and day 15 of a 28 - day cycle.

[0052] E39: The method according to any one of E2 or E7 - E35, wherein the second dose and the one or more subsequent doses are the same and are at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times, at least 65 times, at least 70 times, at least 75 times, at least 80 times, at least 85 times, at least 90 times, at least 95 times, at least 100 times, at least 120 times, at least 150 times, at least 200 times higher than the first dose.

[0053] E40: The method according to any one of E2, E7 - E35 or E39, wherein each of the first doses 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, and the second dose and subsequent doses of the anti - DLL3 agent can be any one of the following: 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.From about 3 mg to about 1 mg, from about 1 mg to about 100 mg, from about 1 mg to about 90 mg, from about 1 mg to about 80 mg, from about 1 mg to about 70 mg, from about 1 mg to about 60 mg, from about 1 mg to about 50 mg, from about 1 mg to about 40 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 3 mg, from about 3 mg to about 100 mg, from about 3 mg to about 90 mg, from about 3 mg to about 80 mg, from about 3 mg to about 70 mg, from about 3 mg to about 60 mg, from about 3 mg to about 50 mg, from about 3 mg to about 40 mg, from about 3 mg to about 30 mg, from about 3 mg to about 20 mg, from about 3 mg to about 10 mg, from about 3 mg to about 12 mg, from about 3 mg to about 15 mg, from about 10 mg to about 100 mg, from about 10 mg to about 90 mg, from about 10 mg to about 80 mg, from about 10 mg to about 70 mg, from about 10 mg to about 60 mg, from about 10 mg to about 50 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 10 mg to about 15 mg, from about 20 mg to about 100 mg, from about 20 mg to about 90 mg, from about 20 mg to about 80 mg, from about 20 mg to about 70 mg, from about 20 mg to about 60 mg, from about 20 mg to about 50 mg, from about 20 mg to about 40 mg, from about 20 mg to about 30 mg, from about 30 mg to about 100 mg, from about 30 mg to about 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about 70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, from about 30 mg to about 40 mg, from about 10 mg to about 180 mg, from about 10 mg to about 150 mg, from about 10 mg to about 120 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 mg, from about 70 mg to about 180 mg, from about 70 mg to about 150 mg, from about 70 mg to about 120 mg, from about 90 mg to about 200 mg, from about 90 mg to about 180 mg, from about 90 mg to about 150 mg, from about 90 mg to about 120 mg, from about 100 mg to about 180 mg, from about 100 mg to about 150 mg, and from about 100 mg to about 120 mg..

[0054] E41: A method as described in any one of E2, E7 - E35, E39 or E40, wherein the first dose of the anti-DLL3 agent is 1 mg, and the second dose and subsequent doses of the anti-DLL3 agent are each 3 mg, 10 mg, 30 mg or 100 mg.

[0055] E42: A method as described in any one of E3 or E7 - E35, wherein the first dose of the anti-DLL3 agent is 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 1 mg; the second dose of the anti-DLL3 agent is from about 3 mg to about 10 mg, from about 10 mg to about 100 mg, from about 10 mg to about 80 mg, from about 10 mg to about 60 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, from about 25 mg to about 50 mg, from about 30 mg to about 80 mg, from about 30 mg to about 60 mg, from about 30 mg to about 40 mg, from about 40 mg to about 80 mg, or from about 40 mg to about 60 mg; and the third dose and subsequent doses of the anti-DLL3 agent can be any one of the following: 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 10 mg to about 120 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 70 mg to about 200 mg, from about 70 mg to about 180 mg, from about 70 mg to about 150 mg, from about 70 mg to about 120 mg, from about 90 mg to about 200 mg, from about 90 mg to about 180 mg, from about 90 mg to about 150 mg, from about 90 mg to about 120 mg, from about 100 mg to about 180 mg, from about 100 mg to about 150 mg, from about 100 mg to about 120 mg, or about 100 mg.

[0056] E43: A method as described in any one of E3, E7 - E35 or E42, wherein the first dose of the anti-DLL3 agent is 1 mg, the second dose of the anti-DLL3 agent is from 25 mg to 50 mg or from 45 mg to 70 mg, and the third dose and subsequent doses of the anti-DLL3 agent are 100 mg.

[0057] E44: The method according to any one of E3, E7-E35 or E42, wherein the first dose of the anti-DLL3 agent on day 1 is 1 mg, the second dose of the anti-DLL3 agent on day 4 is 25 mg or 50 mg, the third dose of the anti-DLL3 agent on day 8 is 100 mg, and starting from day 15 and every two weeks thereafter, the subsequent doses of the anti-DLL3 agent are 100 mg.

[0058] E45: The method according to any one of E4 or E7-E35, wherein the first dose of the anti-DLL3 agent is 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 1 mg, the second dose of the anti-DLL3 agent is from about 3 mg to about 10 mg, from about 10 mg to about 100 mg, from about 10 mg to about 80 mg, from about 10 mg to about 60 mg, from about 10 mg to about 40 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, from about 20 mg to about 40 mg, or about 25 mg, the third dose of the anti-DLL3 agent is from about 3 mg to about 10 mg, from about 10 mg to about 100 mg, from about 10 mg to about 80 mg, from 10 mg to about 60 mg, from about 20 mg to about 100 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, from about 30 mg to about 100 mg, from about 30 mg to about 80 mg, from about 30 mg to about 60 mg, from about 40 mg to about 100 mg, from about 40 mg to about 80 mg, from about 40 mg to about 60 mg, or about 50 mg, and the fourth and subsequent doses of the anti-DLL3 agent can be any one of the following: from about 3 mg to about 100 mg, from about 10 mg to about 150 mg, from about 30 mg to 200 mg, from about 30 mg to about 150 mg, from about 30 mg to about 100 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 mg, from about 70 mg to about 180 mg, from about 70 mg to about 120 mg, from about 90 mg to about 200 mg, from about 90 mg to about 180 mg, from about 90 mg to about 150 mg, from about 90 mg to about 120 mg, or about 100 mg.

[0059] E46: The method according to any one of E4, E7-E35 or E45, wherein the first dose of the anti-DLL3 agent is 1 mg, the second dose of the anti-DLL3 agent is 25 mg, the third dose of the anti-DLL3 agent is 50 mg, and the fourth and subsequent doses of the anti-DLL3 agent are 100 mg.

[0060] E47: A method according to any one of E5 or E7 - E35, wherein the first dose of the anti - DLL3 agent is from 0.5 mg to 8 mg, from 0.5 mg to 6 mg, from 0.5 mg to 4 mg, from 0.5 mg to 2 mg, or 1 mg, and the second, third, and subsequent doses are each from 3 mg to 100 mg, from 10 mg to 150 mg, from 30 mg to 200 mg, from 30 mg to 100 mg, from 50 mg to 150 mg, from 70 mg to 120 mg, from 90 mg to 120 mg, from 100 mg to 200 mg, or 100 mg.

[0061] E48: A method according to any one of E6 or E7 - E35, wherein the first dose is from 0.5 mg to 8 mg, from 0.5 mg to 6 mg, from 0.5 mg to 4 mg, from 0.5 mg to 2 mg, or 1 mg, the second dose is from 3 mg to 10 mg, from 10 mg to 80 mg, from 10 mg to 60 mg, from 20 mg to 80 mg, from 20 mg to 60 mg, from 20 mg to 40 mg, 25 mg, or 50 mg, and the third, fourth, and subsequent doses are each from 3 mg to 100 mg, from 10 mg to 150 mg, from 30 mg to 200 mg, from 30 mg to 100 mg, from 50 mg to 150 mg, from 70 mg to 120 mg, from 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg.

[0062] E49: A method according to any one of E1 - E48, wherein the method comprises administering to the subject one or more additional therapeutic agents.

[0063] E50: A method according to E49, wherein the one or more additional therapeutic agents are steroids.

[0064] E51: A method according to any one of E49 or E50, wherein the additional therapeutic agent is dexamethasone.

[0065] E52: A method according to any one of E49 - E51, wherein the additional therapeutic agent is administered before treatment with the anti - DLL3 agent.

[0066] E53: A method according to any one of E48 - E51, wherein the additional therapeutic agent is administered simultaneously with the anti - DLL3 agent.

[0067] E54: A method according to any one of E2 - E53, wherein the anti - DLL3 agent is administered in a 28 - day cycle, and the method further comprises administering to the subject a fluid (e.g., saline), an anti - inflammatory agent, tocilizumab, or etanercept during the first cycle of administration of the anti - DLL3 agent.

[0068] E55: The method as described in E54, wherein after the priming dose and the escalation dose of the anti-DLL3 agent, one liter of saline is administered to the subject by intravenous infusion.

[0069] E56: The method as described in E55, wherein one liter of saline is administered over about 4 - 5 hours.

[0070] E57: The method as described in E54, wherein the anti-inflammatory agent is a corticosteroid or paracetamol.

[0071] E58: The method as described in E57, wherein the corticosteroid is dexamethasone.

[0072] E59: The method as described in any one of E54, E57 or E58, wherein an anti-inflammatory agent or tocilizumab is administered to the subject before the priming dose and the escalation dose of the anti-DLL3 agent.

[0073] E60: The method as described in E59, wherein a corticosteroid is administered to the subject about 6 - 16 hours before the priming dose and the escalation dose of the anti-DLL3 agent.

[0074] E61: The method as described in E59, wherein tocilizumab or paracetamol is administered to the subject about one hour before the priming dose and the escalation dose of the anti-DLL3 agent.

[0075] E62: The method as described in E54, wherein etanercept is administered to the subject about 36 - 60 hours (except for the escalation dose on day 4) before the priming dose and the escalation dose of the anti-DLL3 agent.

[0076] E63: The method as described in E62, wherein etanercept is administered 2 days (except for the escalation dose on day 4) before the priming dose and the escalation dose of the anti-DLL3 agent.

[0077] E64: The method as described in any one of E1 - E63, wherein the subject is a human.

[0078] E65: An anti-DLL3 agent for use in the method as described in any one of Examples E1 - E64.

[0079] 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 Examples E1 - E64.

[0080] E67: Use of an anti-DLL3 agent for the preparation of a medicament for the treatment of SCLC, wherein the medicament is prepared for administration as described in any one of Examples E1-E64.

[0081] 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 Examples E1-E64.

[0082] In addition, the present application also includes the following:

[0083] 1. A method for treating DLL3-positive cancer, the method comprising administering to a subject in need thereof an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NO: 437 and 431, wherein the anti-DLL3 agent is administered once every two weeks at a dose of from 3

[0084] mg to 200 mg.

[0085] 2. The method according to technical solution 1, wherein the anti-DLL3 agent is administered once every two weeks at a dose of from 3 mg to 100 mg, from 10 mg to 150 mg, from 30 mg to 200 mg, from 30 mg to 100 mg, from 50 mg to 150 mg, from 70 mg to 120 mg, from 90 mg to 120 mg, or from 100 mg to 200 mg.

[0086] 3. The method according to technical solution 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.

[0087] 4. The method according to any one of technical solutions 1 to 3, wherein the anti-DLL3 agent is administered on day 1 and day 15 of a 28-day cycle.

[0088] 5. A method for treating DLL3-positive cancer, the method comprising administering to a subject in need thereof an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NO: 437 and 431, wherein the anti-DLL3 agent is administered according to the following regimen: a) a first dose (ramp-up dose) of from 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) of from 3 mg to 200 mg on day 8, and c) one or more subsequent doses (target doses) of from 3 mg to 200 mg starting on day 15 and every two weeks thereafter, and wherein the second dose and the subsequent doses are the same and higher than the first dose.

[0089] 6. The method according to embodiment 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.

[0090] 7. The method according to embodiment 5 or 6, wherein the first dose is from 0.5 mg to 8 mg, from 0.5 mg to 6 mg, from 0.5 mg to 4 mg, from 0.5 mg to 2 mg, or 1 mg; and

[0091] wherein the second dose, or the subsequent doses, are from 3 mg to 100 mg, from 10 mg to 150 mg, from 30 mg to 200 mg, from 30 mg to 100 mg, from 50 mg to 150 mg, from 70 mg to 120 mg, from 90 mg to 120 mg, or from 100 mg to 200 mg.

[0092] 8. The method according to any one of embodiments 5-7, wherein the first dose is 1 mg, and the second dose and the subsequent doses are each 3 mg, 10 mg, 30 mg or 100 mg.

[0093] 9. A method of treating DLL3-positive cancer, the method comprising administering to a subject in need thereof an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NO: 437 and 431, wherein the anti-DLL3 agent is administered according to one of the following two regimens:

[0094] Regimen I: a) a first dose (priming dose) from 0.5 mg to 10 mg on day 1, b) a second dose (escalation dose) from 3 mg to 100 mg on day 4, c) a third dose (escalation dose) from 3 mg to 200 mg on day 8, and d) one or more subsequent doses (target dose) from 3 mg to 200 mg starting on day 15 and every two weeks thereafter, and wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and higher than the second dose; or

[0095] Protocol II: a) a first dose (ramp-up dose) from 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) from 3 mg to 100 mg on day 8, c) a third dose (step-up dose) from 3 mg to 200 mg on day 15, and c) one or more subsequent doses (target dose) from 3 mg to 200 mg starting on day 29 and every two weeks thereafter, and wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and higher than the second dose.

[0096] 10. The method according to aspect 9, wherein the first dose of each protocol is from 0.5 mg to 8 mg, from 0.5 mg to 6 mg, from 0.5 mg to 4 mg, from 0.5 mg to 2 mg, or 1 mg;

[0097] The second dose of each protocol is from 3 mg to 10 mg, from 10 mg to 80 mg, from 10 mg to 60 mg, from 20 mg to 80 mg, from 20 mg to 60 mg, from 25 mg to 50 mg, from 30 mg to 80 mg, from 40 mg to 60 mg, 25 mg, or 50 mg; and

[0098] The third dose and the subsequent doses of each protocol are from 3 mg to 100 mg, from 10 mg to 150 mg, from 30 mg to 200 mg, from 30 mg to 100 mg, from 50 mg to 150 mg, from 70 mg to 120 mg, from 90 mg to 120 mg, from 100 mg to 200 mg, or 100 mg.

[0099] 11. The method according to aspect 9, wherein the second dose is 20 to 90 times higher, 20 to 70 times higher, or 25 to 50 times higher than the first dose, and wherein the third dose and the subsequent doses are 2 to 10 times higher than the second dose.

[0100] 12. A method for treating DLL3-positive cancer, the method comprising administering to a subject in need thereof an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NO: 437 and 431, wherein the anti-DLL3 agent is administered according to the following regimen: a) a first dose (ramp-up dose) from 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) from 3 mg to 100 mg on day 4, c) a third dose (step-up dose) from 3 mg to 100 mg on day 8, d) a fourth dose (step-up dose) from 3 mg to 200 mg on day 15, and e) one or more subsequent doses (target doses) from 3 mg to 200 mg starting on day 29 and every two weeks thereafter, and wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and the subsequent doses are the same and higher than the third dose.

[0101] 13. The method according to claim 12, wherein the first dose is from 0.5 mg to 8 mg, from 0.5 mg to 6 mg, from 0.5 mg to 4 mg, from 0.5 mg to 2 mg, or 1 mg;

[0102] the second dose is from 3 mg to 10 mg, from 10 mg to 80 mg, from 10 mg to 60 mg, from 20 mg to 80 mg, from 20 mg to 60 mg, from 20 mg to 40 mg, or 25 mg;

[0103] the third dose is from 3 mg to 10 mg, from 10 mg to 80 mg, from 10 mg to 60 mg, from 20 mg to 80 mg, from 20 mg to 60 mg, from 30 mg to 80 mg, from 30 mg to 60 mg, from 40 mg to 80 mg, from 40 mg to 60 mg, or 50 mg; and

[0104] the fourth dose and the subsequent doses are from 3 mg to 100 mg, from 10 mg to 150 mg, from 30 mg to 200 mg, from 30 mg to 100 mg, from 50 mg to 150 mg, from 70 mg to 120 mg, from 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg.

[0105] 14. The method according to claim 12, wherein the second dose is 5 to 30 times higher, 20 to 70 times higher, or 25 to 50 times higher than the first dose, the third dose is 0.5 to 3 times higher than the second dose, and the fourth dose and the subsequent doses are 2 to 4 times higher than the third dose.

[0106] 15. The method according to any one of technical solutions 1-14, wherein the anti-DLL3 agent comprises the amino acid sequence of SEQ ID NO: 438 or 520.

[0107] 16. The method according to any one of technical solutions 1-15, wherein the anti-DLL3 agent is administered in a 28-day cycle, and the method further comprises administering saline, an anti-inflammatory agent, tocilizumab or etanercept to the subject in the first cycle of administering the anti-DLL3 agent.

[0108] 17. The method according to technical solution 16, wherein after the priming dose and escalation dose of the anti-DLL3 agent, one liter of saline is administered to the subject by intravenous infusion.

[0109] 18. The method according to technical solution 16, wherein the anti-inflammatory agent is a corticosteroid or paracetamol.

[0110] 19. The method according to technical solution 18, wherein the corticosteroid is dexamethasone.

[0111] 20. The method according to technical solutions 16, 18 or 19, wherein the anti-inflammatory agent or tocilizumab is administered to the subject before the priming dose and escalation dose of the anti-DLL3 agent.

[0112] 21. The method according to technical solution 20, wherein the corticosteroid is administered to the subject 6-16 hours before the priming dose and escalation dose of the anti-DLL3 agent.

[0113] 22. The method according to technical solution 20, wherein paracetamol or tocilizumab is administered to the subject one hour before the priming dose and escalation dose of the anti-DLL3 agent.

[0114] 23. The method according to technical solution 16, wherein etanercept is administered 36-60 hours before the priming dose and escalation dose of the anti-DLL3 agent except for the escalation dose on the 4th day.

[0115] 24. The method according to technical solution 23, wherein etanercept is administered 2 days before the priming dose and escalation dose of the anti-DLL3 agent except for the escalation dose on the 4th day.

[0116] 25. A method of treating DLL3-positive cancer, the method comprising administering to a subject in need thereof an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NO: 437 and 431, wherein the anti-DLL3 agent is administered according to the following regimen: a) a first dose (ramp-up dose) from 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) from 3 mg to 200 mg on day 4, c) a third dose (target dose) from 3 mg to 200 mg on day 8, and d) one or more subsequent doses (target doses) from 3 mg to 200 mg starting on day 15 and every two weeks thereafter, and wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and the same as the second dose.

[0117] 26. The method according to claim 25, wherein the first dose is from 0.5 mg to 8 mg, from 0.5 mg to 6 mg, from 0.5 mg to 4 mg, from 0.5 mg to 2 mg, or 1 mg, and the second dose, the third dose, and the subsequent doses are each from 3 mg to 100 mg, from 10 mg to 150 mg, from 30 mg to 200 mg, from 30 mg to 100 mg, from 50 mg to 150 mg, from 70 mg to 120 mg, from 90 mg to 120 mg, from 100 mg to 200 mg, or 100 mg.

[0118] 27. A method of treating DLL3-positive cancer, the method comprising administering to a subject in need thereof an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NO: 437 and 431, wherein the anti-DLL3 agent is administered according to the following regimen: a) a first dose (ramp-up dose) from 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) from 3 mg to 100 mg on day 4, c) a third dose (step-up dose) from 3 mg to 200 mg on day 8, d) a fourth dose (target dose) from 3 mg to 200 mg on day 15, and e) one or more subsequent doses (target doses) from 3 mg to 200 mg starting on day 29 and every two weeks thereafter, and wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and the subsequent doses are the same and the same as the third dose.

[0119] 28. The method according to embodiment 27, wherein the first dose is from 0.5 mg to 8 mg, from 0.5 mg to 6 mg, from 0.5 mg to 4 mg, from 0.5 mg to 2 mg, or 1 mg, the second dose is from 3 mg to 10 mg, from 10 mg to 80 mg, from 10 mg to 60 mg, from 20 mg to 80 mg, from 20 mg to 60 mg, from 20 mg to 40 mg, 25 mg, or 50 mg, and the third dose, the fourth dose, and the subsequent doses are each from 3 mg to 100 mg, from 10 mg to 150 mg, from 30 mg to 200 mg, from 30 mg to 100 mg, from 50 mg to 150 mg, from 70 mg to 120 mg, from 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg.

[0120] 29. The method according to any one of embodiments 25 - 28, wherein the anti-DLL3 agent comprises the amino acid sequence of SEQ ID NO: 438 or 520.

[0121] 30. The method according to any one of embodiments 25 - 29, wherein the anti-DLL3 agent is administered in a 28-day cycle, and the method further comprises administering saline, acetaminophen, dexamethasone, tocilizumab, or etanercept to the subject in the first cycle of administering the anti-DLL3 agent.

[0122] 31. The method according to embodiment 25 or 26, wherein saline, acetaminophen, dexamethasone, or tocilizumab is administered to the subject on day 1 and day 4, or day 1, day 4, and day 8 of the first cycle of administering the anti-DLL3 agent.

[0123] 32. The method according to embodiment 25 or 26, wherein etanercept is administered to the subject two days before day 1 and two days before day 8, or two days before day 1 of the first cycle of administering the anti-DLL3 agent.

[0124] 33. The method according to embodiment 27 or 28, wherein saline, acetaminophen, dexamethasone, or tocilizumab is administered to the subject on day 1, day 4, and day 8, or day 1, day 4, day 8, and day 15 of the first cycle of administering the anti-DLL3 agent.

[0125] 34. The method according to embodiment 27 or 28, wherein etanercept is administered to the subject two days before day 1, two days before day 8, and two days before day 15, or two days before day 1 and two days before day 8 of the first cycle of administering the anti-DLL3 agent.

[0126] 35. The method according to any one of technical solutions 1-34, wherein the method further comprises administering a corticosteroid before administering the anti-DLL3 agent in the first cycle.

[0127] 36. The method according to technical solution 35, wherein the corticosteroid is dexamethasone administered by intravenous infusion.

[0128] 37. The method according to any one of technical solutions 1-36, wherein the cancer is small cell lung cancer (SCLC).

[0129] 38. The method according to any one of technical solutions 1-37, wherein the cancer is recurrent / refractory SCLC (RR SCLC) or extensive disease SCLC (ED SCLC).

[0130] 39. The method according to any one of technical solutions 1-38, wherein the anti-DLL3 agent is administered by intravenous infusion.

[0131] 40. The method according to any one of technical solutions 1-39, wherein the subject is a human. Description of the Drawings

[0132] Figure 1 Shows the predicted serum concentration-time curve of AMG 757 in humans after administration of a short intravenous infusion every two weeks. The dashed lines represent the concentrations required for 50% and 90% maximum effects of AMG 757-mediated CD69 upregulation (EC50 and EC90 values are 0.61 ng / mL and 4.6 ng / mL, respectively), which were identified as the most sensitive markers of AMG 757 activity (Study 123564).

[0133] Figure 2 Shows the predicted lung concentration-time curve of AMG 757 in humans after administration of a short intravenous infusion every two weeks. The dashed lines represent the concentrations required for 50% and 90% maximum effects of AMG 757-mediated cell killing in SHP-77 cells (EC50 and EC90 values are 2.8 ng / mL and 5.7 ng / mL, respectively).

[0134] Figure 3 Shows an example of escalated dosing, assuming that an adverse event associated with the first dose effect occurs at 0.03 mg.

[0135] Figure 4Demonstrated partial response (PR) in SCLC patients treated with AMG 757. The safety analysis set included all subjects who received at least one dose of AMG 757. N = the number of subjects with evaluable post-baseline assessments. PR* indicates that the PR is unconfirmed. PD** classifies subjects with PD on post-baseline scans and withdraws them from the study without further confirmatory scans.

[0136] Figure 5 Shows the mean steady-state serum AMG 757 concentration-time curve in SCLC patients treated with the molecule. In Figure 5 , * indicates stepwise dosing, and data are shown during the 2-week dosing interval after the dose on Day 15 of Cycle 2. Data from the only patient enrolled in the 0.1 mg group were not available because the patient withdrew during Cycle 1.

[0137] Figure 6 Shows a summary of the objective responses in SCLC patients treated with AMG 757. Detailed Description

[0138] As disclosed and exemplified herein, a Phase 1 clinical study was conducted using a bispecific protein (AMG 757) targeting DLL3 and CD3 for the treatment of SCLC.

[0139] AMG 757 is a half-life extended (bispecific T cell engager) molecule developed for the treatment of SCLC. The activity of AMG 757 requires simultaneous binding to both the target cell (DLL3 + cells) and T cells. The pharmacological action of AMG 757 is mediated by the specific redirection of previously primed cytotoxic CD8 + or CD4 + T lymphocytes to kill DLL3 + cells. The starting dose for the first-in-human (FIH) study was selected based on the minimum expected biological effect level (MABEL), which was identified as the EC of AMG 757-mediated CD69 upregulation in SHP-77 cells 50 (Study 123564). Based on human PK predictions, a starting dose of 0.003 mg once every two weeks (Q2W) was selected, which was expected to produce a maximum serum concentration equivalent to the MABEL (0.61 ng / mL). This regimen was expected to achieve sufficient exposure in target tissues (such as the lung) throughout the dosing interval while minimizing the peak-to-trough ratio after multiple treatment cycles of AMG 757. Based on the clinical experience of the FIH study, a dose of at least 0.3 mg Q2W was desired.

[0140] 1. Definitions

[0141] Some exemplary bispecific anti-DLL3 agents disclosed herein (e.g., molecules) are recombinant protein constructs that contain two binding domains, each domain derived from an antigen-binding fragment of a full-length antibody. Such antigen-binding fragments retain the ability to specifically bind an antigen (preferably with substantially the same binding affinity). Examples of antigen-binding fragments include (i) Fab fragments, monovalent fragments consisting of the VL, VH, CL, and CH1 domains; (ii) F(ab') 2 fragments, bivalent fragments that contain two Fab fragments linked by a disulfide bridge in the hinge region; (iii) Fd fragments consisting of the VH and CH1 domains; (iv) Fv fragments consisting of the VL and VH domains of a single arm of an antibody, and (v) dAb fragments (Ward et al., 1989 Nature 341:544-546), which consist of the VH domain. In addition, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, the two domains can be joined using recombinant methods by a synthetic linker that enables them to form a single protein chain, where the VL and VH regions pair to form a monovalent molecule (referred to as a single-chain Fv (scFv); see, e.g., Bird et al. Science 242:423-426 (1988) and Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883).

[0142] "Variable domain" refers to the variable region of an antibody light chain (VL) or the variable region of an antibody heavy chain (VH), either alone or in combination. As is known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FRs) connected by three complementarity-determining regions (CDRs) and contribute to the formation of the antigen-binding site of the antibody.

[0143] Exemplary “complementary determining regions” (CDRs) of DLL3 binding domains and CD3 binding domains are provided in the Sequence Listing. CDRs can be defined according to the Kabat, Chothia, cumulative Kabat and Chothia, AbM, contact, North, and / or conformational definitions or any CDR determination method well known in the art. See, e.g., 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 CDRs is a compromise between Kabat and Chothia and uses the AbM antibody modeling software of Oxford Molecular Methods well known in the art can be used to determine the properties of the amino acid residues in a particular antibody that constitute the CDRs.

[0144] The term “treatment” includes prophylactic and / or therapeutic treatment. If administered prior to the clinical manifestation of a disorder, the treatment is considered prophylactic. Therapeutic treatment includes, for example, improving or reducing the severity of a disease, or shortening the length of a disease.

[0145] “About” or “approximately” when used in conjunction with a measurable numerical variable refers to the indicated value of the variable and all values of the variable that are within the experimental error of the indicated value (e.g., within the 95% confidence interval of the mean) or ±10% of the indicated value, whichever is greater. Numerical ranges include the numbers defining the range.

[0146] “Priming dose,” when referring to the administration of an anti - DLL3 agent for treating cancer (e.g., small cell lung cancer (SCLC)), refers to the initial dose of the anti - DLL3 agent that is equal to or lower than the dose at which a first dose effect (e.g., cytokine release syndrome (CRS)) is observed. As is known in the art, the priming dose can be determined by modeling and simulation of safety and pharmacokinetic data. For example, the priming dose can be the maximum tolerated dose (MTD) of the anti - DLL3 agent at which no CRS or CRS of a certain grade or lower (e.g., grade 2) is observed.

[0147] “Target dose,” when referring to the administration of an anti - DLL3 agent for treating cancer (e.g., SCLC), is the dose at which the target effect of the anti - DLL3 agent (e.g., improving or reducing the severity of SCLC, or shortening the length of SCLC) is achieved.

[0148] "Step dose", when referring to the administration of an anti-DLL3 agent for treating cancer (e.g., SCLC), means a dose that is higher than the dose of the anti-DLL3 agent administered previously. A step dose includes one or more doses that increase from a priming dose up to a target dose.

[0149] 2. Anti-DLL3 agent

[0150] DLL3 is an atypical Notch ligand that is mainly expressed during embryonic development (playing a role during somitogenesis). Compared to other Notch ligands expressed on the cell surface, DLL3 accumulates in the Golgi apparatus in normal tissues (Geffers et al., J Cell Biol. [Journal of Cell Biology] 178:465-476 (2007)). By analyzing the differential expression of DLL3 in 28 SCLC tumors and a large number of normal tissues, DLL3 was identified as a tumor-associated antigen and a compelling target for T cell-based therapy (Study 123658).

[0151] The human DLL3 protein contains eight extracellular domains: signal peptide, 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 as SEQ ID NO:252, 258, 259, and 260, respectively, in the sequence listing.

[0152] Exemplary anti-DLL3 agents are bispecific molecules that bind DLL3 and CD3, such as (bispecific T cell engager) molecules. The molecule is a recombinant protein construct made up of two flexibly linked binding domains, each domain derived from an antibody. One binding domain of the molecule is specific for a tumor-associated surface antigen (e.g., DLL3); the second binding domain is specific for CD3 (a subunit of the T cell receptor complex on T cells). By its specific design, the antibody construct is uniquely suited to transiently link T cells to target cells and, at the same time, potently activate the innate cytolytic potential of T cells against the target cells. See, for example, WO 99 / 54440, WO 2005 / 040220, and WO 2008 / 119567.

[0153] Thus, in some embodiments, the anti-DLL3 agent comprises 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 within the amino acid sequence of SEQ ID NO:260. More preferably, the first domain binds to an epitope of DLL3 contained within the amino acid sequence of SEQ ID NO:258.

[0154] In certain embodiments, the DLL3 binding domain comprises (a) a heavy chain variable region (VH) that comprises: (i) VH complementarity determining region 1 (CDR-H1) that comprises the amino acid sequence of SEQ ID NO:31; (ii) CDR-H2 that comprises the amino acid sequence of SEQ ID NO:32; and (iii) CDR-H3 that comprises the amino acid sequence of SEQ ID NO:33; and (b) a light chain variable region (VL) that comprises: (i) VL complementarity determining region 1 (CDR-L1) that comprises the amino acid sequence of SEQ ID NO:34; (ii) CDR-L2 that comprises the amino acid sequence of SEQ ID NO:35; and (iii) CDR-L3 that comprises the amino acid sequence of SEQ ID NO:36.

[0155] In certain embodiments, the DLL3 binding domain comprises a VH that comprises the amino acid sequence of SEQ ID NO:37 and a VL that comprises the amino acid sequence of SEQ ID NO:38. In certain preferred embodiments, the DLL3 binding domain comprises a VH that comprises the amino acid sequence of SEQ ID NO:435 and a VL that comprises the amino acid sequence of SEQ ID NO:436.

[0156] 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 that comprises a sequence selected from any one of SEQ ID NO:285-293. In some embodiments, the linker is a GS linker, such as 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 greater (e.g., 2 or 3) (e.g., SEQ ID NO:292, 293).

[0157] 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.

[0158] In certain embodiments, the CD3 binding domain comprises: (a) a VH that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:426, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:427, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:428; and a VL that comprises 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.

[0159] 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, such as 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 greater (e.g., 2 or 3).

[0160] In certain embodiments, the CD3 binding domain comprises the amino acid sequence of SEQ ID NO:431.

[0161] 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, such as 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 greater (e.g., 2 or 3).

[0162] In certain embodiments, the anti-DLL3 agents disclosed herein comprise two domains. The first domain binds to DLL3 (preferably human DLL3) and comprises (a) a heavy chain variable region (VH) that comprises: (i) VH complementarity determining region 1 (CDR-H1) that comprises the amino acid sequence of SEQ ID NO:31; (ii) CDR-H2 that comprises the amino acid sequence of SEQ ID NO:32; and (iii) CDR-H3 that comprises the amino acid sequence of SEQ ID NO:33; and (b) a light chain variable region (VL) that comprises: (i) VL complementarity determining region 1 (CDR-L1) that comprises the amino acid sequence of SEQ ID NO:34; (ii) CDR-L2 that comprises the amino acid sequence of SEQ ID NO:35; and (iii) CDR-L3 that comprises the amino acid sequence of SEQ ID NO:36. The second domain binds to CD3 (preferably human CD3) and comprises (a) a VH that comprises: (i) CDR-H1 that comprises the amino acid sequence of SEQ ID NO:426, (ii) CDR-H2 that comprises the amino acid sequence of SEQ ID NO:427, and (iii) CDR-H3 that comprises the amino acid sequence of SEQ ID NO:428; and (b) a VL that comprises: (i) CDR-L1 that comprises the amino acid sequence of SEQ ID NO:423, (ii) CDR-L2 that comprises the amino acid sequence of SEQ ID NO:424, and (iii) CDR-L3 that comprises the amino acid sequence of SEQ ID NO:425.

[0163] In certain embodiments, the anti-DLL3 agents described herein comprise two domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises a VH that comprises the amino acid sequence of SEQ ID NO:37 and a VL that comprises 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 that comprises the amino acid sequence of SEQ ID NO:429 and a VL that comprises the amino acid sequence of SEQ ID NO:430. In certain preferred embodiments, the anti-DLL3 agents described herein comprise two domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises a VH that comprises the amino acid sequence of SEQ ID NO:435 and a VL that comprises 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 that comprises the amino acid sequence of SEQ ID NO:429 and a VL that comprises the amino acid sequence of SEQ ID NO:430.

[0164] In certain embodiments, the anti-DLL3 agents described herein comprise two domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises the amino acid sequence of SEQ ID NO:39, and (b) a second domain that binds to CD3 (preferably human CD3) and comprises the amino acid sequence of SEQ ID NO:431. In certain embodiments, the anti-DLL3 agents described herein comprise two domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises the amino acid sequence of SEQ ID NO:437, and (b) a second domain that binds to CD3 (preferably human CD3) and comprises the amino acid sequence of SEQ ID NO:431.

[0165] 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.

[0166] 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, in N-terminal to C-terminal order: hinge-CH2-CH3-linker-hinge-CH2-CH3. In some embodiments, the linker is a GS linker, such as 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 greater (e.g., 6). In certain embodiments, the third domain comprises an amino acid sequence selected from any one of SEQ ID NOs:541-548.

[0167] 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 a third domain by a second linker. In certain embodiments, the first linker is a peptide linker comprising a sequence selected from any of SEQ ID NOs: 285-293, and the second linker comprises a sequence selected from any of SEQ ID NOs: 285, 286, 288, 289, 290, 292, and 293. In some embodiments, the first linker is a GS linker, such as 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 greater (e.g., 2 or 3) and the second linker comprises a sequence selected from any of SEQ ID NOs: 285, 286, 288, 289, 290, 292, and 293.

[0168] In certain embodiments, the anti-DLL3 agent described herein comprises three domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises the amino acid sequence of SEQ ID NO: 39, (b) a second domain that binds to CD3 (preferably human CD3) and comprises the amino acid sequence of SEQ ID NO: 431, and (c) a third domain that comprises an amino acid sequence selected from any of SEQ ID NOs: 541-548. In certain embodiments, the anti-DLL3 agent described herein comprises three domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises the amino acid sequence of SEQ ID NO: 437, (b) a second domain that binds to CD3 (preferably human CD3) and comprises the amino acid sequence of SEQ ID NO: 431, and (c) a third domain that comprises an amino acid sequence selected from any of SEQ ID NOs: 541-548.

[0169] In certain embodiments, the anti-DLL3 agent described herein comprises the amino acid sequence of SEQ ID NO: 520.

[0170] 3. Administration of the anti-DLL3 agent

[0171] The present disclosure provides methods of treating DLL3-positive cancers, the methods comprising administering an anti-DLL3 agent to a subject in need thereof once every two weeks at a dose of from about 0.3 mg to about 100 mg, from about 3 mg to about 200 mg, or about 100 mg. In certain embodiments, the DLL3-positive cancer is small cell lung cancer (SCLC). In certain embodiments, the SCLC is recurrent / refractory SCLC (RR SCLC) or extensive disease SCLC (ED SCLC). In certain embodiments, the subject is a human having SCLC (e.g., RR SCLC or ED SCLC).

[0172] In certain embodiments, the anti-DLL3 agent is administered once every two weeks at a dose of 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 0.3 mg to about 1 mg, from about 1 mg to about 100 mg, from about 1 mg to about 90 mg, from about 1 mg to about 80 mg, from about 1 mg to about 70 mg, from about 1 mg to about 60 mg, from about 1 mg to about 50 mg, from about 1 mg to about 40 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 3 mg, from about 3 mg to about 100 mg, from about 3 mg to about 90 mg, from about 3 mg to about 80 mg, from about 3 mg to about 70 mg, from about 3 mg to about 60 mg, from about 3 mg to about 50 mg, from about 3 mg to about 40 mg, from about 3 mg to about 30 mg, from about 3 mg to about 20 mg, from about 3 mg to about 10 mg, from about 3 mg to about 12 mg, from about 3 mg to about 15 mg, from about 10 mg to about 100 mg, from about 10 mg to about 90 mg, from about 10 mg to about 80 mg, from about 10 mg to about 70 mg, from about 10 mg to about 60 mg, from about 10 mg to about 50 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 10 mg to about 15 mg, from about 20 mg to about 100 mg, from about 20 mg to about 90 mg, from about 20 mg to about 80 mg, from about 20 mg to about 70 mg, from about 20 mg to about 60 mg, from about 20 mg to about 50 mg, from about 20 mg to about 40 mg, from about 20 mg to about 30 mg, from about 30 mg to about 100 mg, from about 30 mg to about 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about 70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, or from about 30 mg to about 40 mg.

[0173] In certain embodiments, the anti-DLL3 agent is administered once every two weeks at a dose of from about 3 mg to about 100 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 150 mg, from about 10 mg to about 120 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 mg, from about 70 mg to about 180 mg, from about 70 mg to about 150 mg, from about 70 mg to about 120 mg, from about 90 mg to about 200 mg, from about 90 mg to about 180 mg, from about 90 mg to about 150 mg, from about 90 mg to about 120 mg, from about 100 mg to about 180 mg, from about 100 mg to about 150 mg, or from about 100 mg to about 120 mg.

[0174] 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.

[0175] In certain embodiments, the anti-DLL3 agent is administered on Day 1 and Day 15 of a 28-day cycle.

[0176] As described in Example 2, the starting dose for the First in Human (FIH) study was based on the Minimum Anticipated Biological Effect Level (MABEL), which was identified as the EC50 for AMG 757-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 expected to produce a maximum serum concentration equivalent to the MABEL (0.61 ng / mL). In the Phase 1 clinical study, the doses of AMG 757 were 0.003 mg and higher, and were administered once every two weeks (Q2W) as an intravenous (IV) infusion in patients with SCLC. This regimen is believed to achieve sufficient exposure of the target tissue (such as the lung) throughout the dosing interval while minimizing the peak-to-trough ratio after multiple treatment cycles of AMG 757.

[0177] Predicted human PK parameters were used to predict the concentration of AMG 757 in the lung, which was designated as the representative site of action and was assumed to achieve approximately 1% of serum exposure (Vugmeyster et al., 2010). Based on the mean EC 90 of the trough coverage of cell killing in SHP-77 cells (assuming 1% lung exposure), early signs of predicted efficacy at 10 mg every 2 weeks are shown in Example 2.

[0178] In clinical studies, intravenous infusions of 0.3 mg every two weeks (cohort 5) resulted in a confirmed response. This observed efficacy of AMG 757 was surprising because it was significantly lower than the 10 mg Q2W dose predicted to be effective based on preclinical results. Additional confirmed responses were observed in the high-dose cohorts. It is believed that the effective dose of AMG 757 can be administered at least 0.3 mg every two weeks (e.g., from about 0.3 mg to about 100 mg or from about 3 mg to about 200 mg).

[0179] The anti-DLL3 agent can be administered by any suitable means, including parenteral, subcutaneous, intraperitoneal, intralung, intranasal, and / or intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the anti-DLL3 agent is administered by intravenous (IV) infusion (e.g., a short intravenous infusion (about 60 minutes)) every two weeks.

[0180] 3.1 Escalating dosing

[0181] Due to its mechanism of action, the risk of the subject's first-dose effects (such as cytokine release syndrome) may increase after the initial infusion of AMG 757. It is believed that an escalating dosing method (e.g., an initial dose on day 1, an escalated dose on day 8, and subsequent doses starting on day 15 and thereafter) may be required for the optimal maximum tolerated dose (MTD). In some aspects, two MTDs can be estimated or established, one for the initial dosing (MTD1, the priming dose) and one for subsequent dosing (MTD2). In some aspects, multiple MTDs can be estimated or established, one for the initial priming dose (MTD1) and one for each or multiple escalated doses and subsequent doses (if applicable).

[0182] If a subject experiences a first dose effect (e.g., cytokine release syndrome (CRS)), an appropriate first dose (MTD1) not exceeding the dose at which the CRS event was observed can be determined and implemented. A second dose and subsequent doses can also be determined and implemented. Additionally, depending on the number of steps in the escalation dosing scheme, a second dose, third dose, fourth dose, and subsequent doses can be determined and implemented. In some embodiments, the second dose and subsequent doses are the same and higher than the first dose. In some embodiments, the second dose is higher than the first dose and the third dose and subsequent doses are the same and higher than the second dose. In some embodiments, the second dose is higher than the first dose, the third dose is higher than the second dose and the fourth and subsequent doses are the same and higher than the third dose. Due to the increasing dosing frequency and potential drug accumulation in the escalation dosing scheme, these doses and dosing regimens can be guided by modeling and simulation of clinical data (such as pharmacokinetics, safety data, etc.) to ensure that the systemic exposure of AMG757 does not exceed the dose associated with the first dose effect (such as CRS) that was observed.

[0183] The following table shows an exemplary escalation dosing scheme (cycle 1 only) of an anti-DLL3 agent (e.g., AMG 757) over a 28-day cycle, after which the anti-DLL3 agent is administered every two weeks.

[0184] Exemplary single and multi-escalation dosing schemes (cycle 1 only)

[0185]

[0186] Accordingly, methods of treating DLL3-positive cancers are disclosed herein, the methods comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered according to an escalation dosing scheme.

[0187] In some embodiments, a method of treating a DLL3-positive cancer is disclosed herein, the method comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered according to the following scheme: a) a first dose (ramp-up dose) from 0.3 mg to 100 mg on day 1, b) a second dose (escalation dose) from 0.3 mg to 100 mg on day 8, and c) one or more subsequent doses (target doses) from 0.3 mg to 100 mg starting on day 15 and every two weeks thereafter, and wherein the second dose and subsequent doses are the same and higher than the first dose.

[0188] In certain embodiments, a method of treating DLL3-positive cancer is disclosed herein, the method 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 (ramp-up dose) from 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) from 3 mg to 200 mg on day 8, and c) one or more subsequent doses (target doses) from 3 mg to 200 mg starting on day 15 and every two weeks thereafter, and wherein the second dose and the subsequent doses are the same and higher than the first dose.

[0189] In certain embodiments of a step-up dosing regimen, the second dose and the 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, or at least 200-fold higher than the first dose.

[0190] In certain embodiments of a stepwise dosing regimen, the second dose and subsequent doses are the same and are at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times, at least 65 times, at least 70 times, at least 75 times, at least 80 times, at least 85 times, at least 90 times, at least 95 times, or at least 100 times higher than the first dose, and each of the first, second, and subsequent doses of the anti-DLL3 agent can be any of the following: 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.from about 3 mg to about 1 mg, from about 1 mg to about 100 mg, from about 1 mg to about 90 mg, from about 1 mg to about 80 mg, from about 1 mg to about 70 mg, from about 1 mg to about 60 mg, from about 1 mg to about 50 mg, from about 1 mg to about 40 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 3 mg, from about 3 mg to about 100 mg, from about 3 mg to about 90 mg, from about 3 mg to about 80 mg, from about 3 mg to about 70 mg, from about 3 mg to about 60 mg, from about 3 mg to about 50 mg, from about 3 mg to about 40 mg, from about 3 mg to about 30 mg, from about 3 mg to about 20 mg, from about 3 mg to about 10 mg, from about 3 mg to about 12 mg, from about 3 mg to about 15 mg, from about 10 mg to about 100 mg, from about 10 mg to about 90 mg, from about 10 mg to about 80 mg, from about 10 mg to about 70 mg, from about 10 mg to about 60 mg, from about 10 mg to about 50 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 10 mg to about 15 mg, from about 20 mg to about 100 mg, from about 20 mg to about 90 mg, from about 20 mg to about 80 mg, from about 20 mg to about 70 mg, from about 20 mg to about 60 mg, from about 20 mg to about 50 mg, from about 20 mg to about 40 mg, from about 20 mg to about 30 mg, from about 30 mg to about 100 mg, from about 30 mg to about 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about 70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, and from about 30 mg to about 40 mg.

[0191] In certain embodiments of a step - up dosing regimen, 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 dose and subsequent doses are the same and are at least 3 - fold, at least 5 - fold, at least 10 - fold, at least 20 - fold, at least 30 - fold, at least 40 - fold, at least 50 - fold, at least 60 - fold, at least 70 - fold, at least 80 - fold, at least 90 - fold, at least 100 - fold, at least 120 - fold, at least 150 - fold, or at least 200 - fold higher than the first dose, and each of the second dose and subsequent doses can be any of the following: 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.

[0192] In certain embodiments of a step - up dosing regimen, the first dose of the anti - DLL3 agent is 1 mg, and the second dose and subsequent doses are the same and are 3 mg, 10 mg, 30 mg, or 100 mg.

[0193] In certain embodiments, methods of treating DLL3 - positive cancers are disclosed herein, the methods comprising administering an anti - DLL3 agent to a subject in need thereof, wherein the anti - DLL3 agent is administered according to a two - step dosing regimen.

[0194] In certain embodiments, a method of treating DLL3 - positive cancers is disclosed herein, the method comprising administering an anti - DLL3 agent to a subject in need thereof, wherein the anti - DLL3 agent is administered according to one of the following two regimens:

[0195] Regimen I: a) a first dose (ramp-up dose) from 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) from 3 mg to 100 mg on day 4, c) a third dose (step-up dose) from 3 mg to 200 mg on day 8, and d) one or more subsequent doses (target doses) from 3 mg to 200 mg starting on day 15 and every two weeks thereafter, and wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and higher than the second dose; or

[0196] Regimen II: a) a first dose (ramp-up dose) from 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) from 3 mg to 100 mg on day 8, c) a third dose (step-up dose) from 3 mg to 200 mg on day 15, and c) one or more subsequent doses (target doses) from 3 mg to 200 mg starting on day 29 and every two weeks thereafter, and wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and higher than the second dose.

[0197] In certain embodiments of the two-step dosing regimen, the second dose is at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, or at least 90-fold higher than the first dose, and the third dose and the 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.

[0198] In certain embodiments of the two-step dosing regimen, the second dose is from about 20-fold to about 100-fold, from about 20-fold to about 90-fold, from about 20-fold to about 70-fold, from about 20-fold to about 50-fold, from about 25-fold to about 50-fold, from about 30-fold to about 100-fold, from about 30-fold to about 90-fold, from about 30-fold to about 70-fold, or from about 30-fold to about 50-fold higher than the first dose, and the third dose and the subsequent doses are the same and from about 2-fold to about 10-fold, from about 2-fold to about 8-fold, from about 2-fold to about 6-fold, from about 2-fold to about 4-fold, from about 4-fold to about 8-fold, or from about 4-fold to about 6-fold higher than the second dose.

[0199] In certain embodiments of the two-step dosing regimen, the first dose 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 1 mg, the second dose is from about 3 mg to about 10 mg, from about 10 mg to about 100 mg, from about 10 mg to about 80 mg, from about 10 mg to about 60 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, from about 25 mg to about 50 mg, from about 30 mg to about 80 mg, from about 30 mg to about 60 mg, from about 30 mg to about 40 mg, from about 40 mg to about 80 mg, or from about 40 mg to about 60 mg, and the third dose and the subsequent doses are the same and are from about 3 mg to about 100 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 150 mg, from about 10 mg to about 120 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 70 mg to about 200 mg, from about 70 mg to about 180 mg, from about 70 mg to about 150 mg, from about 70 mg to about 120 mg, from about 90 mg to about 200 mg, from about 90 mg to about 180 mg, from about 90 mg to about 150 mg, from about 90 mg to about 120 mg, from about 100 mg to about 180 mg, from about 100 mg to about 150 mg, from about 100 mg to about 120 mg, or about 100 mg.

[0200] In certain embodiments of the two-step dosing regimen, the first dose is 1 mg, the second dose is from about 25 mg to about 50 mg, and the third dose and the subsequent doses are the same and are 100 mg. In certain embodiments of the two-step dosing regimen, the first dose is 1 mg, the second dose is from about 45 mg to about 70 mg, and the third dose and the subsequent doses are the same and are 100 mg.

[0201] In certain embodiments of the two-step dosing regimen, the first dose on day 1 is 1 mg, the second dose on day 4 is 25 mg or 50 mg, the third dose on day 8 is 100 mg, and starting on day 15 and every two weeks thereafter, one or more subsequent doses are 100 mg.

[0202] In certain embodiments of Regimen I, the target dose is administered on Day 4. In such embodiments, the anti-DLL3 agent is administered according to the following regimen: a) a first dose (ramp-up dose) from 0.5 mg to 10 mg on Day 1, b) a second dose (step-up dose, equal to the target dose) from 3 mg to 200 mg on Day 4, c) a third dose (target dose) from 3 mg to 200 mg on Day 8, and d) one or more subsequent doses (target doses) from 3 mg to 200 mg starting on Day 15 and every two weeks thereafter, wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and the same as the second dose. In certain embodiments, the first dose is from 0.5 mg to 8 mg, from 0.5 mg to 6 mg, from 0.5 mg to 4 mg, from 0.5 mg to 2 mg, or 1 mg, and the second, third, and subsequent doses are each from 3 mg to 100 mg, from 10 mg to 150 mg, from 30 mg to 200 mg, from 30 mg to 100 mg, from 50 mg to 150 mg, from 70 mg to 120 mg, from 90 mg to 120 mg, from 100 mg to 200 mg, or 100 mg. It is believed that such a dosing regimen (where the target dose is administered on Days 4, 8, and 15 of the first cycle) is beneficial because it helps to rapidly achieve the desired serum level of the anti-DLL3 agent.

[0203] In certain embodiments, methods of treating DLL3-positive cancer are disclosed herein, the methods comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered according to a three-step dosing regimen.

[0204] In certain embodiments, methods of treating DLL3-positive cancer are disclosed herein, the methods comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered according to the following regimen: a) a first dose (ramp-up dose) from 0.5 mg to 10 mg on Day 1, b) a second dose (step-up dose) from 3 mg to 100 mg on Day 4, c) a third dose (step-up dose) from 3 mg to 100 mg on Day 8, d) a fourth dose (step-up dose) from 3 mg to 200 mg on Day 15, and e) one or more subsequent doses (target doses) from 3 mg to 200 mg starting on Day 29 and every two weeks thereafter, and wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and the subsequent doses are the same and higher than the third dose.

[0205] In certain embodiments of the three-step dosing regimen, the second dose is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 40 times, or at least 50 times higher than the first dose, the third dose is at least 0.5 times, at least 1 time, at least 2 times, at least 3 times, or at least 5 times higher than the second dose, and the fourth and subsequent doses are the same and at least 1 time, at least 2 times, at least 3 times, or at least 5 times higher than the third dose.

[0206] In certain embodiments of the three-step dosing regimen, the second dose is from about 5 times to about 70 times, from about 20 times to about 70 times, from about 20 times to about 60 times, from about 25 times to about 50 times higher than the first dose, the third dose is from about 0.5 times to about 4 times, from about 0.5 times to about 2.5 times, from about 1 times to about 4 times, or from about 1 times to about 2 times higher than the second dose, and the fourth and subsequent doses are the same and from about 1 times to about 4 times or from about 2 times to about 3 times higher than the third dose.

[0207] In certain embodiments of the three-step dosing regimen, the first dose 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 1 mg, the second dose is from about 3 mg to about 10 mg, from about 10 mg to about 100 mg, from about 10 mg to about 80 mg, from about 10 mg to about 60 mg, from about 10 mg to about 40 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, from about 20 mg to about 40 mg, or about 25 mg, the third dose is from about 3 mg to about 10 mg, from about 10 mg to about 100 mg, from about 10 mg to about 80 mg, from 10 mg to about 60 mg, from about 20 mg to about 100 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, from about 30 mg to about 100 mg, from about 30 mg to about 80 mg, from about 30 mg to about 60 mg, from about 40 mg to about 100 mg, from about 40 mg to about 80 mg, from about 40 mg to about 60 mg, or about 50 mg, and the fourth and subsequent doses are the same and from about 3 mg to about 10 mg, from about 10 mg to about 200 mg, from about 10 mg to about 150 mg, from about 30 mg to 200 mg, from about 30 mg to about 150 mg, from about 30 mg to about 100 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 mg, from about 70 mg to about 180 mg, from about 70 mg to about 120 mg, from about 90 mg to about 200 mg, from about 90 mg to about 180 mg, from about 90 mg to about 150 mg, from about 90 mg to about 120 mg, or about 100 mg.

[0208] In certain embodiments of the three-step dosing regimen, 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.

[0209] In certain embodiments of the three-step dosing regimen, the target dose is administered on day 8. In such embodiments, the anti-DLL3 agent is administered according to the following regimen: a) a first dose (ramp-up dose) from 0.5 mg to 10 mg on day 1, b) a second dose (step-up dose) from 3 mg to 100 mg on day 4, c) a third dose (step-up dose, equal to the target dose) from 3 mg to 200 mg on day 8, d) a fourth dose (target dose) from 3 mg to 200 mg on day 15, and e) one or more subsequent doses (target doses) from 3 mg to 200 mg starting on day 29 and every two weeks thereafter, and wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and the subsequent doses are the same and are the same as the third dose. In certain embodiments, the first dose is from 0.5 mg to 8 mg, from 0.5 mg to 6 mg, from 0.5 mg to 4 mg, from 0.5 mg to 2 mg, or 1 mg, the second dose is from 3 mg to 10 mg, from 10 mg to 80 mg, from 10 mg to 60 mg, from 20 mg to 80 mg, from 20 mg to 60 mg, from 20 mg to 40 mg, 25 mg, or 50 mg, and the third, fourth, and subsequent doses are each from 3 mg to 100 mg, from 10 mg to 150 mg, from 30 mg to 200 mg, from 30 mg to 100 mg, from 50 mg to 150 mg, from 70 mg to 120 mg, from 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg. It is believed that such a dosing regimen is beneficial because it helps to rapidly achieve the desired serum level of the anti-DLL3 agent.

[0210] The anti-DLL3 agent can be administered by any suitable means, including parenteral, subcutaneous, intraperitoneal, intralung, intranasal, and / or intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In certain embodiments, the anti-DLL3 agent is administered by intravenous (IV) infusion.

[0211] In certain embodiments, the DLL3-positive cancer is small cell lung cancer (SCLC). In certain embodiments, the SCLC is recurrent / refractory SCLC (RR SCLC) or extensive disease SCLC (ED SCLC). In certain embodiments, the subject is a human having SCLC (e.g., RR SCLC or ED SCLC).

[0212] 3.2 Co - administration

[0213] In some embodiments, the compositions and methods of the present invention provide for the use of an anti - DLL3 agent in combination with one or more additional therapeutic agents. In certain embodiments, one or more additional therapeutic agents are agents that mitigate the CRS of the anti - DLL3 agent (e.g., AMG 757). In certain embodiments, 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 co - administering an anti - DLL3 agent (e.g., AMG 757) with one or more anti - inflammatory agents, liquids (e.g., saline), anti - IL6 antibodies (e.g., tocilizumab), and anti - TNF agents (e.g., etanercept).

[0214] In some embodiments, one or more additional therapeutic agents may be anti - inflammatory agents (e.g., for prophylactic treatment of CRS). The anti - inflammatory agent may be administered before, concurrently with, or after the administration of the anti - DLL3 agent. Exemplary anti - inflammatory agents include acetaminophen, sodium naproxen, ibuprofen, tramadol, aspirin, celecoxib, valdecoxib, indomethacin, or other non - steroidal anti - inflammatory drugs (NSAIDs). Other anti - inflammatory agents include, for example, beclomethasone, hydrocortisone hydroxy, betamethasone, methylprednisolone, budesonide, prednisone, cortisone, prednisolone, dexamethasone, and triamcinolone, or other glucocorticoids. In certain embodiments, the anti - inflammatory agent is a corticosteroid. In certain embodiments, the corticosteroid is dexamethasone. In certain embodiments, the anti - inflammatory agent is acetaminophen. In certain embodiments, 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 of dosing of AMG 757. In certain embodiments, dexamethasone is administered orally.

[0215] In some embodiments, one or more additional therapeutic agents for mitigating CRS are fluids (e.g., saline), anti - IL6 antibodies (e.g., tocilizumab), or anti - TNF agents (e.g., etanercept). Each of these agents may be administered before, concurrently with, or after the administration of the anti - DLL3 agent. In certain embodiments, saline is administered (e.g., by intravenous administration) after the administration of the anti - DLL3 agent. In certain embodiments, an anti - IL6 antibody (e.g., tocilizumab) or an anti - TNF agent (e.g., etanercept) is administered before the administration of the anti - DLL3 agent.

[0216] When using steroids (such as dexamethasone), higher doses of anti-DLL3 agents may be required. Thus, in some aspects, the present invention provides a method for treating SCLC or DLL3-positive cancer, the method comprising administering to a subject in need thereof a steroid (such as a corticosteroid (such as, dexamethasone)) and an anti-DLL3 agent, wherein the anti-DLL3 agent is administered once every two weeks at a dose from about 0.3 mg to 100 mg (such as 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 0.3 mg to about 1 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 3 mg to about 15 mg, or from about 3 mg to about 12 mg, once every two weeks).

[0217] In some aspects, the present invention provides a method for treating SCLC or DLL3-positive cancer, the method comprising administering to a subject in need thereof a steroid (such as, a corticosteroid (such as, dexamethasone)) and an anti-DLL3 agent, wherein the anti-DLL3 agent is administered once every two weeks at a dose from about 0.3 mg to 100 mg or from about 3 mg to about 200 mg (such as 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 10 mg to about 120 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 180 mg, from about 70 mg to about 150 mg, from about 70 mg to about 120 mg, from about 90 mg to about 180 mg, from about 90 mg to about 150 mg, from about 90 mg to about 120 mg, or about 3 mg, 10 mg, 30 mg, or 100 mg, once every two weeks). In certain embodiments, the anti-DLL3 agent is administered in a 28-day cycle. In certain embodiments, the steroid is administered in the first cycle of administering the anti-DLL3 agent.

[0218] In some aspects, the present invention provides methods of treating SCLC or DLL3-positive cancers, the methods comprising administering to a subject in need thereof a steroid (e.g., a corticosteroid (e.g., dexamethasone)) and an anti-DLL3 agent, wherein the anti-DLL3 agent is administered according to the following schedule: (a) a first dose from 0.3 mg to 100 mg on day 1 (e.g., 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 0.3 mg to about 1 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 3 mg to about 15 mg, or from about 3 mg to about 12 mg, on day 1), (b) a second dose from 0.3 mg to 100 mg on day 8 (e.g., 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 0.3 mg to about 1 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 3 mg to about 15 mg, or from about 3 mg to about 12 mg, on day 8), and (c) one or more subsequent doses from 0.3 mg to 100 mg starting on day 15 and every two weeks thereafter (e.g., 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 0.3 mg to about 1 mg, or from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 3 mg to about 15 mg, or from about 3 mg to about 12 mg), and 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 the one or more subsequent doses are at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times, at least 65 times, at least 70 times, at least 75 times, at least 80 times, at least 85 times, at least 90 times, at least 95 times, or at least 100 times higher than the first dose.

[0219] In certain embodiments, an anti-DLL3 agent (e.g., AMG 757) is administered to a subject with DLL3-positive cancer (e.g., SCLC) over a 28-day cycle, wherein the anti-DLL3 agent is administered in the first cycle in combination with an anti-inflammatory agent, a fluid (e.g., saline), an anti-IL6 antibody (e.g., tocilizumab), an anti-TNF agent (e.g., etanercept), or a combination thereof. In certain embodiments, a corticosteroid (e.g., dexamethasone) is further administered in the first cycle in combination with the anti-DLL3 agent and an anti-inflammatory agent, a fluid (e.g., saline), an anti-IL6 antibody (e.g., tocilizumab), an anti-TNF agent (e.g., etanercept), or a combination thereof. In certain embodiments, the corticosteroid (e.g., dexamethasone) is administered by intravenous infusion in Cycle 1 of the AMG 757 administration.

[0220] In certain embodiments, a fluid (e.g., saline) is administered by intravenous infusion after administration of the anti-DLL3 agent in the first cycle. In certain embodiments, one liter of saline is administered by intravenous infusion after administration of the anti-DLL3 agent in the first cycle. In certain embodiments, one liter of saline is administered by intravenous infusion in the first cycle after the priming dose and one or more escalated doses of the anti-DLL3 agent. In some embodiments, one liter of saline is administered by intravenous infusion approximately 4 - 5 hours after administration of the anti-DLL3 agent.

[0221] 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 in the first cycle, it is administered from about 6 to about 16 hours prior to administration of the anti-DLL3 agent. In certain embodiments, about 8 mg of dexamethasone is administered from 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 from about 6 to about 16 hours prior to the priming dose and one or more escalated 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.

[0222] In certain embodiments, the anti-inflammatory agent is acetaminophen and is administered approximately 1 hour before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, approximately 650 mg of acetaminophen is administered approximately 1 hour before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, approximately 650 mg of acetaminophen is administered approximately 1 hour before the priming dose and one or more step doses of the anti-DLL3 agent in the first cycle. In some embodiments, acetaminophen is administered orally.

[0223] In certain embodiments, the anti-IL6 antibody is tocilizumab and is administered before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, approximately 8 mg / kg of tocilizumab is administered to the subject by intravenous infusion approximately 1 hour before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, approximately 8 mg / kg of tocilizumab is administered to the subject by intravenous infusion approximately 1 hour before the priming dose and one or more step doses of the anti-DLL3 agent in the first cycle.

[0224] In certain embodiments, the anti-TNF agent is etanercept (e.g., ) and is administered before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, etanercept is administered from approximately 36 hours to approximately 60 hours before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, etanercept is administered 2 days before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, approximately 50 mg of etanercept is administered subcutaneously 2 days before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, approximately 50 mg of etanercept is administered subcutaneously 2 days before the priming dose and one or more step doses of the anti-DLL3 agent in the first cycle, except for the step dose on day 4 in a two-step or three-step dosing regimen.

[0225] Exemplary CRS mitigation strategies for an anti-DLL3 agent (e.g., AMG 757) 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 intravenous infusion) in the first cycle of AMG 757 administration (e.g., before dosing in cycle 1 of AMG 757).

[0226] Exemplary CRS mitigation strategies (one-step dosing, cycle 1 only)

[0227]

[0228] * : Etanercept can be administered within ±12 hours of the scheduled dose in the table above.

[0229] Exemplary CRS mitigation strategy (two-step dosing, option 1, cycle 1 only)

[0230]

[0231]

[0232] * : Etanercept can be administered within ±12 hours of the scheduled dose in the table above. Exemplary CRS mitigation strategy (two-step dosing, option 2, cycle 1 only)

[0233]

[0234] * : Etanercept can be administered within ±12 hours of the scheduled dose in the table above. Exemplary CRS mitigation strategy (three-step dosing, cycle 1 only)

[0235]

[0236] * : Etanercept can be administered within ±12 hours of the scheduled dose in the table above.

[0237] In some aspects, the present invention provides methods of treating SCLC, or DLL3-positive cancers, the methods comprising administering to a subject in need thereof an anti-DLL3 agent and an anti-inflammatory agent (e.g., a corticosteroid (e.g., dexamethasone), or acetaminophen), saline, an anti-IL6 antibody (e.g., tocilizumab), or an anti-TNF agent (e.g., etanercept), and wherein the anti-DLL3 agent is administered according to the following one-step protocol over a 28-day cycle: a) a first dose (ramp-up dose) on day 1 from 0.5 mg to 10 mg (e.g., 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), b) a second dose (step-up dose) on day 8 from 3 mg to 200 mg (e.g., 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 150 mg, from about 90 mg to about 120 mg, or about 100 mg), and c) one or more subsequent doses (target doses) starting on day 15 and every two weeks thereafter from 3 mg to 200 mg (e.g., 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 150 mg, from about 90 mg to about 120 mg, or about 100 mg), wherein the second dose and the subsequent doses are the same and higher than the first dose, and wherein the anti-inflammatory agent, saline, anti-IL6 antibody, or anti-TNF agent is administered during the first cycle of administering the anti-DLL3 agent.In certain embodiments, the second dose 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.

[0238] In some embodiments of a step-up regimen, 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, and the second dose and subsequent doses of the anti-DLL3 agent are the same and are 3 mg, 10 mg, 30 mg, or 100 mg, and wherein dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered during the first cycle of administration of the anti-DLL3 agent. In some embodiments of such a step-up regimen, corticosteroids are further administered by intravenous infusion during Cycle 1 of AMG 757 administration.

[0239] In some aspects, the present invention provides methods of treating SCLC, or DLL3-positive cancers, the methods comprising administering to a subject in need thereof an anti-DLL3 agent and an anti-inflammatory agent (e.g., a corticosteroid (e.g., dexamethasone), or acetaminophen), saline, an anti-IL6 antibody (e.g., tocilizumab), or an anti-TNF agent (e.g., etanercept), wherein the anti-DLL3 agent is administered according to the following two-step regimen over a 28-day cycle: Regimen I: a) a first dose (ramp-up dose) on day 1 from 0.5 mg to 10 mg (e.g., 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 1 mg), b) a second dose (step-up dose) on day 4 from 3 mg to 100 mg (e.g., from about 3 mg to about 10 mg, from about 10 mg to about 80 mg, from about 10 mg to about 60 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, from about 25 mg to about 50 mg, from about 30 mg to about 80 mg, from about 30 mg to about 60 mg, from about 30 mg to about 40 mg, from about 40 mg to about 80 mg, or from about 40 mg to about 60 mg), c) a third dose (step-up dose) on day 8 from 3 mg to 200 mg, and d) one or more subsequent doses (target dose) starting on day 15 and every two weeks thereafter from 3 mg to 200 mg, and wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and higher than the second dose, and the third dose and the subsequent doses can be any of the following: 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 10 mg to about 120 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 70 mg to about 200 mg, from about 70 mg to about 180 mg, from about 70 mg to about 150 mg, from about 70 mg to about 120 mg, from about 90 mg to about 200 mg, from about 90 mg to about 180 mg, from about 90 mg to about 150 mg, from about 90 mg to about 120 mg, from about 100 mg to about 180 mg, from about 100 mg to about 150 mg, from about 100 mg to about 120 mg, or about 100 mg, and wherein the anti-inflammatory agent, saline, anti-IL6 antibody, or anti-TNF agent is administered during the first cycle of administering the anti-DLL3 agent. In some embodiments of such a two-step regimen, the corticosteroid is further administered by intravenous infusion during the first cycle of AMG 757 administration.

[0240] In certain embodiments, the method comprises administering to a subject in need thereof an anti-DLL3 agent (e.g., AMG 757) and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept, wherein the anti-DLL3 agent is administered according to the following two-step regimen in a 28-day cycle: a first dose of 1 mg on day 1, a second dose of 25 mg or 50 mg on day 4, a third dose of 100 mg on day 8, and starting on day 15 and every two weeks thereafter, one or more subsequent doses of 100 mg, and wherein dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered during the first cycle of administering the anti-DLL3 agent. In certain embodiments, dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered on the same day as or prior to one or more priming doses and one or more step doses of AMG 757 in cycle 1. In certain embodiments, dexamethasone is further administered by intravenous infusion during cycle 1 of the administration of AMG 757.

[0241] In certain embodiments of Regimen I, the target dose is administered on Day 4. In such embodiments, the method comprises administering an anti-DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept to a subject in need thereof, wherein the anti-DLL3 agent is administered according to the following two-step regimen over a 28-day cycle: Regimen I: a) a first dose (priming dose) from 0.5 mg to 10 mg (such as 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 1 mg) on Day 1, b) a second dose (escalation dose) from 3 mg to 200 mg on Day 4, c) a third dose (target dose) from 3 mg to 200 mg on Day 8, and d) one or more subsequent doses (target doses) from 3 mg to 200 mg starting on Day 15 and every two weeks thereafter, wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and the same as the second dose, and the second dose, the third dose, and the subsequent doses can be any of the following: 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 10 mg to about 120 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 70 mg to about 200 mg, from about 70 mg to about 180 mg, from about 70 mg to about 150 mg, from about 70 mg to about 120 mg, from about 90 mg to about 200 mg, from about 90 mg to about 180 mg, from about 90 mg to about 150 mg, from about 90 mg to about 120 mg, from about 100 mg to about 180 mg, from about 100 mg to about 150 mg, from about 100 mg to about 120 mg, or about 100 mg, and wherein dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered during the first cycle of administering the anti-DLL3 agent. In certain embodiments, dexamethasone, acetaminophen, saline, or tocilizumab is administered on Day 1 and Day 4, or Day 1, Day 4, and Day 8 of the administration of AMG 757 in Cycle 1. In certain embodiments, etanercept is administered two days prior to Day 1 and Day 8 of the administration of AMG 757 in Cycle 1. In certain embodiments, etanercept is administered two days prior to Day 1 of the administration of AMG 757 in Cycle 1. In certain embodiments, the method further comprises administering dexamethasone by intravenous infusion during the first cycle of administering AMG 757.

[0242] In some aspects, the present invention provides methods of treating SCLC, or DLL3-positive cancers, the methods comprising administering to a subject in need thereof an anti-DLL3 agent and an anti-inflammatory agent (e.g., a corticosteroid (e.g., dexamethasone), or acetaminophen), saline, an anti-IL6 antibody (e.g., tocilizumab), or an anti-TNF agent (e.g., etanercept), wherein the anti-DLL3 agent is administered according to the following two-step regimen over a 28-day cycle: Regimen II: a) a first dose (ramp-up dose) of from 0.5 mg to 10 mg (e.g., 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 1 mg) on Day 1, b) a second dose (step-up dose) of from 3 mg to 100 mg (e.g., from about 3 mg to about 10 mg, from about 10 mg to about 80 mg, from about 10 mg to about 60 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, from about 25 mg to about 50 mg, from about 30 mg to about 80 mg, from about 30 mg to about 60 mg, from about 30 mg to about 40 mg, from about 40 mg to about 80 mg, or from about 40 mg to about 60 mg) on Day 8, c) a third dose (step-up dose) of from 3 mg to 200 mg on Day 15, and c) one or more subsequent doses (target dose) of from 3 mg to 200 mg starting on Day 29 and every two weeks thereafter, and wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and higher than the second dose, and the third dose and the subsequent doses can be any of the following: 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 10 mg to about 120 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 70 mg to about 200 mg, from about 70 mg to about 180 mg, from about 70 mg to about 150 mg, from about 70 mg to about 120 mg, from about 90 mg to about 200 mg, from about 90 mg to about 180 mg, from about 90 mg to about 150 mg, from about 90 mg to about 120 mg, from about 100 mg to about 180 mg, from about 100 mg to about 150 mg, from about 100 mg to about 120 mg, or about 100 mg, and wherein the anti-inflammatory agent, saline, anti-IL6 antibody, or anti-TNF agent is administered during the first cycle of administering the anti-DLL3 agent. In some embodiments of such a two-step regimen, the corticosteroid is further administered by intravenous infusion during the first cycle of AMG 757 administration.

[0243] In some embodiments of the two-step dosing regimen, the method comprises administering to a subject 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 dose of the anti-DLL3 agent is from about 25 mg to about 50 mg, and the third dose and subsequent doses of the anti-DLL3 agent are the same and are 100 mg, and wherein dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered during the first cycle of administering the anti-DLL3 agent.

[0244] In some embodiments of the two-step dosing regimen, the method comprises administering to a subject 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 dose of the anti-DLL3 agent is from about 45 mg to about 70 mg, and the third dose and subsequent doses of the anti-DLL3 agent are the same and are 100 mg, and wherein dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered during the first cycle of administering the anti-DLL3 agent.

[0245] In certain embodiments of the two-step dosing regimen, the method comprises administering to a subject an anti-DLL3 agent and dexamethasone, acetaminophen, saline, tocilizumab, or etanercept, wherein the first dose of the anti-DLL3 agent on day 1 is 1 mg, the second dose of the anti-DLL3 agent on day 4 is 25 mg or 50 mg, the third dose on day 8 is 100 mg, and starting on day 15 and every two weeks thereafter, the subsequent doses of the anti-DLL3 agent are 100 mg, and wherein dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered during the first cycle of administering the anti-DLL3 agent.

[0246] In some aspects, the present invention provides methods for treating SCLC, or DLL3-positive cancers, the methods comprising administering to a subject in need thereof an anti-DLL3 agent and an anti-inflammatory agent (e.g., a corticosteroid (e.g., dexamethasone), or acetaminophen), saline, an anti-IL6 antibody (e.g., tocilizumab), or an anti-TNF agent (e.g., etanercept), and wherein the anti-DLL3 agent is administered according to the following three-step regimen over a 28-day cycle: a) a first dose (ramp-up dose) on day 1 from 0.5 mg to 10 mg (e.g., 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 1 mg), b) a second dose (step-up dose) on day 4 from 3 mg to 100 mg (e.g., from about 3 mg to about 10 mg, from about 10 mg to about 100 mg, from about 10 mg to about 80 mg, from about 10 mg to about 60 mg, from about 10 mg to about 40 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, from about 20 mg to about 40 mg, or about 25 mg), c) a third dose (step-up dose) on day 8 from 3 mg to 100 mg (e.g., from about 3 mg to about 10 mg, from about 10 mg to about 100 mg, from about 10 mg to about 80 mg, from 10 mg to about 60 mg, from about 20 mg to about 100 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, from about 30 mg to about 100 mg, from about 30 mg to about 80 mg, from about 30 mg to about 60 mg, from about 40 mg to about 100 mg, from about 40 mg to about 80 mg, from about 40 mg to about 60 mg, or about 50 mg), d) a fourth dose (step-up dose) on day 15 from 3 mg to 200 mg, and e) one or more subsequent doses (target dose) from 3 mg to 200 mg starting on day 29 and every two weeks thereafter, and wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and the subsequent doses are the same and higher than the third dose, and the fourth and the subsequent doses can be any of the following: from about 3 mg to about 100 mg, from about 10 mg to about 150 mg, from about 30 mg to 200 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 mg, from about 70 mg to about 180 mg, from about 70 mg to about 120 mg, from about 90 mg to about 200 mg, from about 90 mg to about 180 mg, from about 90 mg to about 150 mg, from about 90 mg to about 120 mg, or about 100 mg, and wherein the anti-inflammatory agent, saline, anti-IL6 antibody, or anti-TNF agent is administered during the first cycle of administering the anti-DLL3 agent.In some embodiments of such a three-step regimen, corticosteroids are further administered by intravenous infusion during Cycle 1 of AMG 757 administration.

[0247] In some embodiments of the three-step dosing regimen, the method comprises administering to a subject 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 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 the same and are 100 mg, and wherein dexamethasone, acetaminophen, saline, tocilizumab, or etanercept are administered during Cycle 1 of the administration of the anti-DLL3 agent.

[0248] In certain embodiments of the three-step dosing regimen, 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, wherein the anti-DLL3 agent is administered according to the following three-step regimen over a 28-day cycle: a) a first dose (ramp-up dose) on day 1 from 0.5 mg to 10 mg (e.g., 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 1 mg), b) a second dose (step-up dose) on day 4 from 3 mg to 100 mg (e.g., from 3 mg to 10 mg, from 10 mg to 80 mg, from 10 mg to 60 mg, from 20 mg to 80 mg, from 20 mg to 60 mg, from 20 mg to 40 mg, 25 mg, or 50 mg), c) a third dose (step-up dose) on day 8 from 3 mg to 200 mg, d) a fourth dose (target dose) on day 15 from 3 mg to 200 mg, and e) one or more subsequent doses (target doses) from day 29 onwards and every two weeks thereafter from 3 mg to 200 mg, and wherein the second dose is higher than the first dose, the third dose, the fourth dose, and the subsequent doses are the same and higher than the second dose, and the third dose, the fourth dose, and the subsequent doses can be any of the following: from 3 mg to 100 mg, from 10 mg to 150 mg, from 30 mg to 200 mg, from 30 mg to 100 mg, from 50 mg to 150 mg, from 70 mg to 120 mg, from 90 mg to 120 mg, 100 mg to 200 mg, or 100 mg, and wherein dexamethasone, acetaminophen, saline, tocilizumab, or etanercept is administered during the first cycle of administering the anti-DLL3 agent. In certain embodiments, dexamethasone, acetaminophen, saline, or tocilizumab is administered on days 1, 4, and 8, or days 1, 4, 8, and 15 of the administration of AMG 757 in the first cycle. In certain embodiments, etanercept is administered two days prior to days 1, 8, and 15 of the administration of AMG 757 in the first cycle. In certain embodiments, etanercept is administered two days prior to days 1 and 8 of the administration of AMG 757 in the first cycle. In some embodiments of such a three-step regimen, corticosteroids are further administered by intravenous infusion during the first cycle of the administration of AMG 757.

[0249] In certain embodiments of any stepwise dosing regimen, saline (e.g., about 1 liter) is administered by intravenous infusion after administration of the anti-DLL3 agent in the first cycle. In certain embodiments, in the first cycle, one liter of saline is administered by intravenous infusion after the priming dose and one or more step doses of the anti-DLL3 agent. In some embodiments, one liter of saline is administered by intravenous infusion about 4 - 5 hours after administration of the anti-DLL3 agent.

[0250] In certain embodiments of any stepwise dosing regimen, 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, in the first cycle, about 8 mg of dexamethasone is administered from about 6 to about 16 hours before administration of the anti-DLL3 agent. In certain embodiments, 8 mg of dexamethasone is administered about 6 to about 16 hours before the priming dose and one or more step doses of the anti-DLL3 agent in the first cycle. In some embodiments, dexamethasone is administered orally.

[0251] In certain embodiments of any stepwise dosing regimen, 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, in the first cycle, about 650 mg of acetaminophen is administered about 1 hour before administration of the anti-DLL3 agent. In certain embodiments, in the first cycle, about 650 mg of acetaminophen is administered about 1 hour before the priming dose and one or more step doses of the anti-DLL3 agent. In some embodiments, acetaminophen is administered orally.

[0252] In certain embodiments of any stepwise dosing regimen, the anti-IL6 antibody tocilizumab is administered before administration of the anti-DLL3 agent in the first cycle. In certain embodiments, in the first cycle, about 8 mg / kg of tocilizumab is administered to the subject by intravenous infusion about one hour before administration of the anti-DLL3 agent. In certain embodiments, in the first cycle, about 8 mg / kg of tocilizumab is administered to the subject by intravenous infusion about one hour before the priming dose and one or more step doses of the anti-DLL3 agent.

[0253] In certain embodiments of any stepwise dosing regimen, the anti-TNF agent etanercept is administered before administration of the anti-DLL3 agent in the first cycle (e.g., )。In certain embodiments, in the first cycle, etanercept is administered from about 36 hours to about 60 hours before the administration of the anti-DLL3 agent. In certain embodiments, etanercept is administered from about 36 hours to about 60 hours before the priming dose and one or more escalation doses of the anti-DLL3 agent in the first cycle, except for the escalation dose on day 4 in a two-step or three-step dosing regimen. In certain embodiments, about 50 mg of etanercept is administered 2 days before the administration of the anti-DLL3 agent in the first cycle. In certain embodiments, about 50 mg of etanercept is administered subcutaneously 2 days before the priming dose and one or more escalation doses of the anti-DLL3 agent in the first cycle, except for the escalation dose on day 4 in a two-step or three-step dosing regimen.

[0254] In certain embodiments of any of the stepwise dosing regimens, the subject is a human.

[0255] 4. Articles

[0256] Articles are disclosed herein that comprise: (a) a container containing an anti-DLL3 agent; and (b) a package insert with instructions for treating DLL3-positive cancer (or treating SCLC) in a subject, wherein the instructions specify a dose of the anti-DLL3 agent from about 0.3 mg to about 100 mg, from about 3 mg to about 200 mg, or 100 mg (or any dose range disclosed herein) to be administered to the subject every two weeks (e.g., on days 1 and 15 of a 28-day cycle). The instructions may also specify the administration of the anti-DLL3 agent according to the following regimen: a) a first dose from 0.3 mg to 100 mg (or any dose range disclosed herein) on day 1, b) a second dose from 0.3 mg to 100 mg on day 8 (or any dose range disclosed herein), and c) one or more subsequent doses from 0.3 mg to 100 mg (or any dose range disclosed herein) starting on day 15 and every two weeks thereafter, and wherein the second dose and the one or more subsequent doses are the same and higher than the first dose.

[0257] The instructions may also specify the administration of the anti-DLL3 agent according to the following regimen: a) a first dose from 0.5 mg to 10 mg (or any dose range disclosed herein) on day 1, b) a second dose from 3 mg to 200 mg on day 8 (or any dose range disclosed herein), and c) one or more subsequent doses from 3 mg to 200 mg (or any dose range disclosed herein) starting on day 15 and every two weeks thereafter, and wherein the second dose and the one or more subsequent doses are the same and higher than the first dose.

[0258] In certain embodiments, the specification specifies administering an anti-DLL3 agent according to one of the following two regimens: Regimen I: a) a first dose (priming dose) from 0.5 mg to 10 mg (or any dose range disclosed herein) on Day 1, b) a second dose (ramping dose) from 3 mg to 100 mg (or any dose range disclosed herein) on Day 4, c) a third dose (ramping dose) from 3 mg to 200 mg (or any dose range disclosed herein) on Day 8, and d) one or more subsequent doses (target doses) from 3 mg to 200 mg (or any dose range disclosed herein) starting on Day 15 and every two weeks thereafter, and wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and higher than the second dose; or Regimen II: a) a first dose (priming dose) from 0.5 mg to 10 mg (or any dose range disclosed herein) on Day 1, b) a second dose (ramping dose) from 3 mg to 100 mg (or any dose range disclosed herein) on Day 8, c) a third dose (ramping dose) from 3 mg to 200 mg (or any dose range disclosed herein) on Day 15, and c) one or more subsequent doses (target doses) from 3 mg to 200 mg (or any dose range disclosed herein) starting on Day 29 and every two weeks thereafter, and wherein 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.

[0259] In certain embodiments, the specification specifies administering an anti-DLL3 agent according to the following regimen: a) a first dose (priming dose) from 0.5 mg to 10 mg (or any dose range disclosed herein) on Day 1, b) a second dose (ramping dose) from 3 mg to 200 mg (or any dose range disclosed herein) on Day 4, c) a third dose (ramping dose) from 3 mg to 200 mg (or any dose range disclosed herein) on Day 8, and d) one or more subsequent doses (target doses) from 3 mg to 200 mg (or any dose range disclosed herein) starting on Day 15 and every two weeks thereafter, and wherein the second dose is higher than the first dose, and the third dose and the subsequent doses are the same and the same as the second dose.

[0260] In certain embodiments, the specification specifies administering an anti-DLL3 agent according to the following regimen: a) a first dose (priming dose) from 0.5 mg to 10 mg (or any dose range disclosed herein) on day 1, b) a second dose (ramping dose) from 3 mg to 100 mg (or any dose range disclosed herein) on day 4, c) a third dose (ramping dose) from 3 mg to 100 mg (or any dose range disclosed herein) on day 8, d) a fourth dose (ramping dose) from 3 mg to 200 mg (or any dose range disclosed herein) on day 15, and e) one or more subsequent doses (target doses) from 3 mg to 200 mg (or any dose range disclosed herein) starting on day 29 and every two weeks thereafter, wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and the subsequent doses are the same and higher than the third dose.

[0261] In certain embodiments, the specification specifies administering an anti-DLL3 agent according to the following regimen: a) a first dose (priming dose) from 0.5 mg to 10 mg (or any dose range disclosed herein) on day 1, b) a second dose (ramping dose) from 3 mg to 100 mg (or any dose range disclosed herein) on day 4, c) a third dose (ramping dose) from 3 mg to 200 mg (or any dose range disclosed herein) on day 8, d) a fourth dose (ramping dose) from 3 mg to 200 mg (or any dose range disclosed herein) on day 15, and e) one or more subsequent doses (target doses) from 3 mg to 200 mg (or any dose range disclosed herein) starting on day 29 and every two weeks thereafter, wherein the second dose is higher than the first dose, the third dose is higher than the second dose, and the fourth dose and the subsequent doses are the same and the same as the third dose.

[0262] In certain embodiments, the specification specifies that an anti-inflammatory agent (e.g., a corticosteroid (e.g., dexamethasone), or acetaminophen), saline, an anti-IL6 antibody (e.g., tocilizumab), or an anti-TNF agent (e.g., etanercept) is also administered during the first cycle of administering the anti-DLL3 agent. In certain embodiments, the specification specifies that dexamethasone is further administered during the first cycle of administering the anti-DLL3 agent (e.g., by intravenous administration prior to the cyclical dosing of the anti-DLL3 agent).

[0263] Examples

[0264] Example 1 Prediction of Human AMG 757 Pharmacokinetics and First-in-Human Dose Selection

[0265] Using allometric scaling of PK parameters obtained from studies in cynomolgus monkeys in the dose range of 12 to 4500 μg / kg, the human PK parameters of AMG 757 were predicted. A two-compartment model with linear elimination was used to characterize the pharmacokinetics of AMG757 from the pooled cynomolgus monkey data, excluding data from animals identified as positive for antidrug antibodies following the administration of the first dose. The model was parameterized with linear clearance (CL), volume of distribution in the central compartment (V C ), clearance of distribution (CL D ), and peripheral volume of distribution (V T ). Allometry was used to predict human AMG 757 PK (exponents of 0.75 and 1 were used for clearance and volume parameters, respectively). The body weights of humans and cynomolgus monkeys were assumed to be 60 kg and 3 kg, respectively. The derived monkey and predicted human AMG 757 PK parameters are provided in Table 1.

[0266] Table 1 Pharmacokinetic parameters of cynomolgus monkeys and predicted humans for human AMG 757 exposure

[0267]

[0268] CL = systemic clearance; CL D = clearance of distribution; t 1 / 2 = terminal half-life; Vc = central volume of distribution; V T = peripheral volume of distribution

[0269] a Assume monkey body weight is 3 kg

[0270] b Assume human body weight is 60 kg

[0271] Combining these PK predictions, the FIH starting dose was selected based on the minimum expected biological effect level (MABEL) identified in vitro. This concentration was determined by evaluating the most sensitive biomarker of AMG 757 activity in the most sensitive DLL3-expressing cell line (Study 123564). Combining animal exposures in GLP toxicology studies, an exposure margin was calculated using a standard ratio based on AUC tau (168 hours for cynomolgus monkeys and 336 hours for humans in GLP toxicology studies) and C max of the proposed dose in the FIH study.

[0272] The FIH study evaluated the safety, tolerability, and pharmacokinetics of AMG 757 in patients with small cell lung cancer. The predicted human PK parameters described above were used to simulate the predicted exposure at the proposed FIH dose ( Figure 1)。The doses of AMG 757 studied in the FIH were 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 doses, administered as short intravenous infusions (about 1 hour) every two weeks in patients with small cell lung cancer (SCLC) (Study 20160323). This regimen ensured sufficient exposure in the lung above the in vitro EC for AMG757-mediated cell killing (5.2 ng / mL) during multiple treatment cycles of AMG 757 while minimizing the peak-to-trough ratio. 90 while minimizing the peak-to-trough ratio.

[0273] The selection of the FIH starting dose was based on in vitro MABEL. Briefly, the EC values for AMG 757-mediated cell killing of SHP-77 tumor cells and induction of human peripheral blood mononuclear cell (PBMC) T cell activation (de novo expression of CD69 and CD25) were compared, and de novo expression of CD69 induced by AMG 757 on T cells was identified as the most sensitive parameter for AMG 757 activity. Based on the evaluation of individual dose-response curves from 12 different PBMC donors, the MABEL (mean EC 50 ) was calculated to be 0.61 ng / mL (5.8 pM; Study 123564). 50 ) was calculated to be 0.61 ng / mL (5.8 pM; Study 123564).

[0274] The prior safe implementation of this strategy supports the use of in vitro EC 50 as the basis for MABEL and FIH starting doses to identify the maximum recommended starting dose of a prior molecule in clinical development.

[0275] Example 2 Prediction of the minimum effective exposure of AMG 757 in humans

[0276] The effective exposure of AMG 757 was predicted based on in vitro data generated in Study 122717, which evaluated the in vitro pharmacology of AMG757. The concentration range for expected efficacy was evaluated using the concentrations for AMG 757-mediated half-maximal effect (EC 50 ) and 90% maximal effect (EC 90 ) in SHP-77 cells (a human DLL3-expressing cell line).

[0277] The lung was used as the representative site of action of AMG 757 and was assumed to achieve an exposure of approximately 1% free serum exposure (Vugmeyser et al., J Pharm Sci. [Journal of Pharmaceutical Sciences] 99:1028-1045 (2010)). Based on this assumption, the EC that provides AMG 757-mediated cell killing in SHP-77 cells 50The dose of AMG 757 with trough coverage was considered the lowest effective. Throughout the treatment cycle, based on the mean EC of cell kill in SHP-77 cells (assuming 1% pulmonary exposure) 90 with trough coverage, early signs of efficacy were predicted every two weeks at 10 mg IV( Figure 2 ).

[0278] Example 3 Phase 1 study to evaluate the safety, tolerability, and pharmacokinetics of AMG 757 in subjects with SCLC

[0279] Background

[0280] Small cell lung cancer (SCLC), which accounts for 10% - 15% of lung cancers (Rudin et al., J Clin Oncol. [Journal of Clinical Oncology] 33:4106 - 4111 (2015)), is an aggressive subtype of lung cancer with neuroendocrine differentiation and is strongly associated with smoking (Koinis et al., Transl Lung Cancer Res. [Translational Lung Cancer Research] 5:39 - 50 (2016)). It shows a distinct natural history, characterized by a high growth fraction, rapid doubling time, and early establishment of widespread metastatic lesions (Gustafsson et al., Cancer. 113:5 - 21 (2008)). Although 30% of patients present with disease confined to one hemithorax [limited disease (LD)], most cases have disease not covered by a single radiotherapy field [extensive disease (ED)]. SCLC is extremely sensitive to first-line chemotherapy (response rates of approximately 60% - 70%) and radiation therapy, in stark contrast to the subsequent resistance to second-line and subsequent therapies after disease recurrence (Byers et al., Cancer. 121:664 - 672 (2015)). Patients with ED develop resistance and die from the disease at a median time of 10 to 12 months from diagnosis (Rudin et al., 2015). For patients with ED SCLC, first-line treatment is platinum-based chemotherapy. In the United States, most patients receive platinum-etoposide (EP) chemotherapy (carboplatin or cisplatin), and some patients receive platinum-irinotecan as an alternative, especially outside the United States. In March 2019, the US Food and Drug Administration (US FDA) approved atezolizumab in combination with carboplatin and etoposide for first-line treatment of adult patients with ED-SCLC( US Prescribing Information [USPI], 2019). After recurrence, topotecan is the only second-line drug approved by the US FDA. However, despite this, topotecan has produced disappointing response rates (Byers et al., Cancer. 121:664 - 672 (2015)).

[0281] AMG 757 is a molecule with a half-life extension (HLE) that targets DLL3, a tumor-specific antigen, and cluster of differentiation 3 (CD3), a T-cell receptor-associated complex on T cells. AMG 757 is being developed for the treatment of SCLC and is an effective molecule that acts by forming an immune synapse between CD3-positive T cells and cancer cells expressing the DLL3 protein. The resulting proximity triggers the redirected lysis of DLL3-positive target cells by T cells. AMG 757 monotherapy significantly inhibited the growth of subcutaneous implanted DLL3-expressing human melanoma WM266-4 cells and induced the regression of orthotopic SHP-77-Luc lung cancer.

[0282] Study Design

[0283] Study 20160323 was an open-label, escalating, multi-dose Phase 1 study that evaluated the administration of AMG 757 as a short-term intravenous (IV) infusion every 2 weeks (e.g., with or without a Day 8 step-up dose) in subjects with small cell lung cancer. This study had two indications: A: recurrent / refractory small cell lung cancer (RR-SCLC) and B: extensive disease SCLC (ED-SCLC).

[0284] Due to its known mechanism of action, the risk of CRS in subjects increased during the initiation of AMG 757 treatment.

[0285] This study consisted of three parts:

[0286] (1) Part A: Evaluate AMG 757 in subjects with recurrent / refractory small cell lung cancer (RR SCLC). Part A consisted of two phases: (A1) Dose exploration phase to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of AMG 757, and (A2) Dose expansion phase to confirm the safety and tolerability of the selected dose.

[0287] (2) Part B: Evaluate AMG 757 in patients with extensive disease SCLC (ED SCLC). Part B started once the MTD or RP2D was identified in Part A.

[0288] (3) Part C (evaluate additional CRS mitigation strategies): AMG 757 monotherapy was used in subjects with RR SCLC who had progressed after at least 1 platinum-based regimen. To mitigate the risk of CRS, one or more of the following prophylactic measures (during Cycle 1 only) could be implemented: intravenous fluid hydration, additional corticosteroid prophylaxis with oral dexamethasone, administration of tocilizumab prophylaxis, etanercept prophylaxis, or acetaminophen prophylaxis.

[0289] ​The primary objectives of both Part A and Part B of this study were to evaluate the safety and tolerability of AMG 757 and to determine the MTD or RP2D of AMG 757. The secondary objectives of Part A and Part B of this study were to characterize the pharmacokinetics (PK) of AMG 757 and to preliminarily evaluate the anti-tumor activity of AMG 757.

[0290] Part A1: Dose Escalation Phase

[0291] AMG 757 was administered as a short intravenous infusion (approximately 60 minutes). The pre-specified doses (for the planned dose levels of the study) to be used in dose escalation were: 0.003 mg (cohort 1), 0.01 mg (cohort 2), 0.03 mg (cohort 3), 0.1 mg (cohort 4), 0.3 mg (cohort 5), 1 mg (cohort 6), 3 mg (cohort 7), 10 mg (cohort 8), 30 mg (cohort 9), and 100 mg (cohort 10), administered once every two weeks. The dosing schedule in the first cycle could be adjusted to include one or more step doses as described below. If a convincing clinical response was observed during the escalation period, further dose escalation could be stopped. Alternative dose levels of AMG 757 or one or more dosing schedules could be explored based on emerging pharmacokinetic (PK), pharmacodynamic (PD), and safety data. If the MTD was not reached at the planned dose cohort levels (cohorts 1 - 10) and safety and PK / PD data supported it, higher doses could be explored.

[0292] Step Dosing: After the initial infusion of AMG 757, subjects may experience a first-dose effect (e.g., cytokine release syndrome with associated manifestations and any other potential evolving and unknown first-dose effects). It is believed that the optimal MTD may require a step-dosing approach (e.g., an initial dose on day 1 and a step dose on day 8). Two MTDs could be estimated, one for the initial dosing (MTD1) and one for subsequent dosing (MTD2).

[0293] At any time during the study, when a subject first experiences a first-dose effect (such as a CRS event of any grade), safety data need to be examined to determine the appropriate dose to be implemented as the initial dose (MTD1), which does not exceed the dose at which grade 2 or higher CRS was observed. These doses and dosing schedules are guided by the modeling and simulation of emerging clinical data (such as pharmacokinetic, safety data, etc.) to ensure that the systemic exposure of AMG 757 does not exceed the dose associated with the observed first-dose effect. The increased dosing frequency and possible drug accumulation of the step-dosing schedule need to be considered.

[0294] For all subjects enrolled in subsequent cohorts throughout the study, for the first dose of the first cycle of AMG 757 (MTD1), dose escalation continued at a constant dose, and only the step dose was escalated according to the pre-specified dose in the dose escalation to determine MTD2. Figure 3 An example of stepwise dosing is shown.

[0295] The stepwise dosing regimens are summarized below. In accordance with the DLRT recommendations based on emerging safety data, the dosing regimens can be adapted to include one or more of the following measures.

[0296] · Single-step dosing involves a priming 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 then Q2W.

[0297] · Two-step dosing (Option 1) involves a priming 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.

[0298] · Two-step dosing (Option 2) involves a priming dose on Day 1, followed by a step dose on Day 8, a step dose on Day 15 (equal to the target dose) and the target dose on Day 1 of Cycle 2, then Q2W.

[0299] · Three-step dosing involves a priming dose on Day 1, followed by a step dose on Day 4, a step dose on Day 8, a step dose on Day 15 (equal to the target dose) and the target dose on Day 1 of Cycle 2, then Q2W.

[0300] Part A2: Dose expansion phase. Once the MTD or RP2D has been selected based on the dose exploration phase (Part A1), Part A2 begins.

[0301] Part B: Once the preliminary MTD or RP2D in Indication A (Part A1) has been established, Part B will begin.

[0302] Part C: In accordance with the DLRT recommendations based on emerging safety data, one or more additional CRS mitigation strategies as outlined below can be evaluated. Part C will begin when Part A1 is ongoing.

[0303] · Prophylaxis with 1 L of normal saline intravenously over 4 - 5 hours immediately after the priming dose and one or more step doses in Cycle 1

[0304] · Additional corticosteroid prophylaxis with 8 mg of dexamethasone orally 6 - 16 hours before the priming dose and one or more step doses in the first cycle

[0305] · Administer 8 mg / kg tocilizumab intravenously 1 hour before the priming dose and one or more step doses in the 1st cycle.

[0306] · Administer 50 mg etanercept subcutaneously on Day - 2 and then 2 days before the priming dose and one or more step doses in Cycle 1 (except for the step dose on Day 4 in the case of two - step or three - step dosing).

[0307] · Administer 650 mg acetaminophen orally 1 hour before the priming dose and one or more step doses in the 1st cycle.

[0308] The above CRS mitigation strategy will first be administered using intravenous dexamethasone. Based on the emerging safety profile, intravenous dexamethasone can be discontinued while only continuing one of the above CRS strategies to evaluate the safety profile without steroid pre - medication.

[0309] Each subject enrolled in Part C will receive only one of the above additional CRS mitigation strategies in addition to their AMG 757 therapy as described above. Subjects will start taking a dose of AMG 757 that is considered safe and tolerable. If, based on emerging safety data, the incidence of CRS decreases, one or more of the above strategies can be implemented into Part A or B.

[0310] Table 2 summarizes the eligibility criteria for Study 20160323

[0311] Table 2 Key eligibility criteria

[0312]

[0313]

[0314] Example 4 Study endpoints for Trial 20160323

[0315] The hypothesis for Study 20160323 is that AMG 757 is safe and tolerable in subjects with Indications A and B.

[0316] Primary endpoints: Dose - limiting toxicity (DLT), adverse events (AE) occurring during treatment, treatment - related AE, and clinically significant changes in vital signs, ECG, physical examination, and clinical laboratory tests.

[0317] Secondary endpoints: For Indications A and B: (1) PK parameters of AMG 757 after intravenous administration, including but not limited to the maximum observed concentration (C max ), the minimum observed concentration (C min ), the area under the concentration - time curve (AUC) over a 2 - week dosing interval, accumulation after multiple dosing, and, if feasible, the half - life (t1 / 2 ), (2) objective response (OR) according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, (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).

[0318] Exploratory endpoints: For indications A and B: (1) incidence of anti-AMG 757 antibody formation, (2) changes in protein, nucleic acid, and cellular biomarkers (e.g., cytokines, lymphocyte status, CTC, sDLL3) in the blood; (3) cell surface protein expression (e.g., DLL3) and tumor-infiltrating lymphocyte status in tumor tissue at baseline. For indication B only: effect of prior chemotherapy on T cell cytokine production prior to AMG 757 treatment. For part C only: incidence of CRS.

[0319] Role in 5 human subjects

[0320] Pharmacokinetics in humans: A preliminary AMG 757 PK analysis was performed on subjects in groups 1 - 5 using a non-compartmental model approach. The preliminary PK results showed that AMG 757 exposure increased with dose from 0.003 mg to 0.3 mg. After multiple Q2W administrations, the estimated terminal half-life (t 1 / 2 ) was approximately one week. No significant accumulation (<2-fold) was observed.

[0321] There was one confirmed response (group 5) at 0.3 mg IV Q2W.

[0322] The following is a summary of the AMG 757 doses and dosing regimens used in the different groups in the study.

[0323]

[0324] Antitumor activity was evaluated using the modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; 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 therapy.

[0325] Forty patients (median age [range], 64 years [44 - 80]; ECOG PS: 0 - 1, n = 39 [97.5%], median prior lines: 2.0 [1 - 6]; prior PD-1 / PD-L1 treatment: n = 17 [42.5%]) enrolled at eight dose levels (DL) received ≥1 dose of AMG 757. Median treatment duration was 6.1 weeks (0.1 - 59.4). Adverse events (AE) occurred in 39 (97.5%) patients, resulting in discontinuation in 4 (10.0%); 32 (80.0%) were treatment-related, including 7 (17.5%) ≥ grade 3 and 1 (2.5%) grade 5 (pneumonia; DL5 [0.3 mg]). Cytokine release syndrome (CRS) was reported in 18 (45.0%) patients; 5 (12.5%) had grade 2 CRS; no ≥ grade 3 CRS. CRS presented mainly as fever ± hypotension, was reversible, did not lead to treatment interruption or discontinuation, occurred mainly within 24 hours of the first two doses of AMG 757, and was managed with supportive care, corticosteroids, and / or anti-IL-6 treatment. Six (17.6%) patients developed treatment-emergent anti-AMG 757 binding antibodies. Anti-AMG 757 antibodies were not associated with AE and had no clear effect on drug exposure. Figure 5 The mean (+SD) steady-state serum concentration-time curve of AMG 757 is shown. AMG 757 showed dose-proportional increases in exposure ( Figure 5 ).

[0326] Six (15.8%) patients reported confirmed partial responses (PR) (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 ). Eleven (28.9%) reported stable disease, which included 1 patient with a proceeding unconfirmed PR at DL8. Patients with confirmed PR had a median of 2 (1 - 4) prior therapy lines, and response durations were 1.9+ to 9.4+ months. DLL3 was observed to be expressed at any level in tumor samples from 31 / 32 (96.9%) patients, with an overall H score of 40 - 300. Across a wide range of DLL3 expression, tumor shrinkage occurred (H score, 55 - 300). The results suggest that AMG 757 has acceptable safety at doses up to 10 mg and shows antitumor activity in patients with SCLC.

[0327] Fifty-nine patients enrolled at ten dose levels (DL) received ≥1 dose of AMG 757. Figure 6Shows the objective response summary of patients who met the overall response rate (ORR) analysis criteria as of the relevant data cutoff date. Seven (14.6%) patients reported confirmed partial responses (PR) (1 / 12 [8.3%] at DL5, 1 / 8 [12.5%] at DL6, 3 / 7 [42.9%] at DL7, 2 / 10 [20%] at DL8, and 0 / 7 [0%] at DL9 Figure 6 )). Twelve (25%) (including two (2 / 7 [28.6%]) in cohort 9) reported stable disease. In cohort 9, one patient observed grade 3 CRS and was managed with supportive care, corticosteroids, and vasopressor treatment. The results suggest that AMG 757 has acceptable safety at doses up to 30 mg and shows antitumor activity in patients with SCLC.

[0328] Seven patients enrolled in cohort 10 received ≥1 dose of AMG 757, and 4 subjects received 100 mg (day 8) at least once. No new safety signals were observed in these patients compared to the earlier cohorts.

[0329] This specification will be most thoroughly understood in light of the teachings of the references cited within the specification. The examples within the specification provide an illustration of embodiments of the invention and should not be construed as limiting the scope of the invention. Those skilled in the art will readily recognize that the invention encompasses many other embodiments. All publications, patents, and sequences cited in this disclosure are incorporated by reference in their entirety. To the extent that the material incorporated by reference conflicts or is inconsistent with this specification, this specification will supersede any such material. The citation of any reference herein is not an admission that such reference is prior art to the present invention.

[0330] Those skilled in the art will recognize or be able to ascertain many equivalent forms of the specific embodiments of the invention described herein using only routine experimentation. Such equivalent embodiments are intended to be covered by the following claims.

[0331] Table 3 Sequence Listing

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

Claims

1. Use of an anti-DLL3 agent in the preparation of a kit for treating DLL3-positive small cell lung cancer (SCLC) in a human subject in need thereof, wherein the anti-DLL3 agent is a bispecific antibody construct that binds to human DLL3 and human CD3, and the anti-DLL3 agent comprises a DLL3-binding domain, the DLL3-binding domain comprising (a) a heavy chain variable region (VH), the VH comprising (i) a VH complementarity determining region 1 (CDR-H1) consisting of the amino acid sequence of SEQ ID NO:31, (ii) a CDR-H2 consisting of the amino acid sequence of SEQ ID NO:32, and (iii) a CDR-H3 consisting of the amino acid sequence of SEQ ID NO:33; and (b) a light chain variable region (VL), the VH comprising (i) a VL complementarity determining region 1 (CDR-L1) consisting of the amino acid sequence of SEQ ID NO:34, (ii) a CDR-L2 consisting of the amino acid sequence of SEQ ID NO:35, and (iii) a CDR-L3 consisting of the amino acid sequence of SEQ ID NO:36; wherein the kit comprises a medicament formulated to administer the anti-DLL3 agent by a one-hour intravenous (IV) infusion according to the following regimen: a) A first dose of 1 mg on Day 1, b) A second dose of 10 mg on Day 8, c) A third dose of 10 mg on Day 15, and one or more subsequent 10 mg doses every two weeks thereafter, wherein the kit further comprises an anti-inflammatory agent formulated to be administered before the first dose of the anti-DLL3 agent on Day 1 and before the second dose of the anti-DLL3 agent on Day 8; and wherein the kit further comprises saline, and wherein one liter of saline is administered to the subject by IV infusion over a period of 4 to 5 hours.

2. The use according to claim 1, wherein the cancer is recurrent / refractory SCLC (RR SCLC).

3. The use according to claim 1 or claim 2, wherein the anti-DLL3 agent comprises the amino acid sequence of SEQ ID NO:

520.

4. The use according to claim 1 or claim 2, wherein the anti-inflammatory agent is dexamethasone.

5. The use according to claim 3, wherein the anti-inflammatory agent is dexamethasone.

6. The use according to claim 1 or claim 2, wherein the saline is administered to the subject after the first and second doses of the anti-DLL3 agent.

7. The use according to claim 3, wherein the saline is administered to the subject after the first and second doses of the anti-DLL3 agent.

8. The use according to claim 4, wherein the saline is administered to the subject after the first and second doses of the anti-DLL3 agent.

9. The use according to claim 5, wherein the saline is administered to the subject after the first and second doses of the anti-DLL3 agent.

10. The use according to claim 1 or claim 2, wherein one liter of saline is administered by IV infusion on the 15th day.

11. The use according to claim 3, wherein one liter of saline is administered by IV infusion on the 15th day.

12. The use according to claim 4, wherein one liter of saline is administered by IV infusion on the 15th day.

13. The use according to claim 5, wherein one liter of saline is administered by IV infusion on the 15th day.

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