COMBINATION THERAPY WITH AN ANTI-AXL ANTIBODY-DRUG CONJUGATE

• US 20200129637A1
• Filed: 04/20/2018
• Published: 04/30/2020
• Est. Priority Date: 04/20/2017
• Status: Abandoned Application

• Current Assignee: ADC Therapeutics SA, MedImmune Ltd. (Astrazeneca PLC)
• Original Assignee: ADC Therapeutics SA, MedImmune Ltd. (Astrazeneca PLC)
• Inventors: Van Berkel, Patricius Hendrikus Cornelis, Wuerthner, Jens, Hartley, John, Zammarchi, Francesca
• Application Number:
  US16/605,692
• Publication Number:
  US 20200129637A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/4523 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2863 : against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The present disclosure relates to combination therapies for the treatment of pathological conditions, such as cancer. In particular, the present disclosure relates to combination therapies comprising treatment with an Antibody Drug Conjugate (ADC) and a secondary agent.

Claims

1. A method for treating cancer in an individual, the method comprising administering to the individual an effective amount of ADCxAXL and a secondary agent.

14. The composition, method, use, or kit according to any previous claim, wherein the treatment comprises administering ADCxAXL before the secondary agent, simultaneous with the secondary agent, or after the secondary agent.

15. The composition, method, use, or kit according to any previous claim, wherein the treatment further comprises administering a chemotherapeutic agent.

16. The composition, method, use, or kit according to any previous claim, wherein the individual is human.

17. The composition, method, use, or kit according to any previous claim, wherein the individual has a disorder or has been determined to have cancer.

18. The composition, method, use, or kit according any previous claim, wherein the individual has, or has been has been determined to have, a cancer characterised by the presence of a neoplasm comprising both AXL+ve and AXL−

ve cells.

19. The composition, method, use, or kit according any previous claim, wherein the individual has, or has been has been determined to have, a cancer characterised by the presence of a neoplasm comprising, or composed of, AXL−

ve neoplastic cells.

20. The composition, method, use, or kit according to any previous claim, wherein the cancer or neoplasm is all or part of a solid tumour.

21. The composition, method, use, or kit according to any previous claim, wherein the individual has, or has been has been determined to have, a cancer which expresses AXL or AXL+ tumour-associated non-tumour cells, such as AXL+ infiltrating cells.

22. The composition, method, use, or kit according to claim 21, wherein the AXL+ infiltrating cells are dendritic cells, NK cells, or macrophages.

23. The composition, method, use, or kit according to any preceding claim, wherein the individual has, or has been has been determined to have, a cancer which expresses PD-L1.

24. The composition, method, use, or kit according to any one of the preceding claims, wherein the treatment:

a) effectively treats a broader range of disorders,

b) effectively treats resistant, refractory, or relapsed disorders,

c) has an increased response rate, and/or

d) has increased durability;

as compared to treatment with either ADCxAXL or the secondary agent alone.

25. The composition, method, use, or kit according to any one of the preceding claims, wherein the cancer is selected from the group comprising:

breast cancer, lung cancer, gastric cancer, head and neck cancer, colorectal cancer, renal cancer, pancreatic cancer, uterine cancer, hepatic cancer, bladder cancer, endometrial cancer, prostate cancer, non-Hodgkin'"'"'s lymphoma, NHL, AML), an immune disorder, cardiovascular disorder, thrombosis, diabetes, immune checkpoint disorder, and fibrotic disorder.

26. A composition, method, use, or kit according to any one of claims 1 to 25, wherein the secondary agent is Fludarabine.

27. A composition, method, use, or kit according to any one of claims 1 to 25, wherein the secondary agent is Cytarabine.

28. A composition, method, use, or kit according to any one of claims 1 to 25, wherein the secondary agent is a PD1 antagonist.

29. A composition, method, use, or kit according to claim 28, wherein the PD1 antagonist is selected from pembrolizumab, nivolumab, MEDI0680, PDR001 (spartalizumab), Camrelizumab, AUNP12, Pidilizumab Cemiplimab (REGN-2810), AMP-224, BGB-A317 (Tisleizumab), and BGB-108.

30. A composition, method, use, or kit according to any one of claims 1 to 25, wherein the secondary agent is a PD-L1 antagonist.

31. A composition, method, use, or kit according to claim 30, wherein the PD-L1 antagonist is selected from atezolizumab (Tecentriq), BMS-936559/MDX-1105, durvalumab/MEDI4736, and MSB0010718C (Avelumab).

32. A composition, method, use, or kit according to any one of claims 1 to 25, wherein the secondary agent is a GITR (Glucocorticoid-Induced TNFR-Related protein) agonist.

33. A composition, method, use, or kit according to claim 32, wherein the GITR (Glucocorticoid-Induced TNFR-Related protein) agonist is selected from MEDI1873, TRX518, GWN323, MK-1248, MK 4166, BMS-986156 and INCAGN1876.

34. A composition, method, use, or kit according to any one of claims 1 to 25, wherein the secondary agent is a OX40 agonist.

35. A composition, method, use, or kit according to claim 34, wherein the OX40 agonist is selected from MEDI0562, MEDI6383, MOXR0916, RG7888, OX40mAb24, INCAGN1949, GSK3174998, and PF-04518600.

36. A composition, method, use, or kit according to any one of claims 1 to 25, wherein the secondary agent is a CTLA-4 antagonist.

37. A composition, method, use, or kit according to claim 36, wherein the CTLA-4 antagonist is selected from ipilimumab and Tremelimumab.

38. A composition, method, use, or kit according to any one of claims 1 to 25, wherein the secondary agent is a hypomethylating agent.

39. A composition, method, use, or kit according to claim 38, wherein the hypomethylating agent is azacitidine.

40. A composition, method, use, or kit according to claim 38, wherein the hypomethylating agent is decitabine.

41. A composition, method, use, or kit according to any one of claims 1 to 25, wherein the secondary agent is a PARP inhibitor (PARPi).

42. A composition, method, use, or kit according to claim 41, wherein the PARPi is selected from Olaparib, CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib/SAR24-550/BSI-201, Veliparib (ABT-888), Niraparib/MK-4827, BGB-290, 3-aminobenzamide, and E7016.

43. A composition, method, use, or kit according to any one of claims 1 to 25, wherein the secondary agent is an agent that upregulates HER2 expression.

44. A composition, method, use, or kit according to claim 41, wherein the agent that upregulates HER2 expression is selected from gemcitabine and tamoxifen.

45. A composition, method, use, or kit according to any one of claims 1 to 25, wherein the secondary agent is an AXL-kinase inhibitor (AXLi).

46. A composition, method, use, or kit according to claim 45, wherein the AXLi is selected from BGB324 (bemcentinib), TP0903, Gilteritinib (ASP2215), Cabozantinib (XL184), SG17079, Merestinib, amuvatinib (MP-470), bosutinib (SKI-606), MGCD265, and foretinib (GSK1363089/XL880).

47. A composition, method, use, or kit according to any one of claims 1 to 25, wherein the secondary agent is a BRAF inhibitor (BRAFi).

48. A composition, method, use, or kit according to claim 47, wherein the BRAFi is selected from vemurafenib, PLX4720, dabrafenib, Sorafenib, Encorafenib, and GDC0879.

49. A composition, method, use, or kit according to any one of claims 1 to 25, wherein the secondary agent is a MEK inhibitor (MEKi).

50. A composition, method, use, or kit according to claim 49, wherein the AXLi is selected from Trametinib, Cobimetinib, Binimetinib, Selumetinib, PD-325901, CI-1040, PD035901, U0126, and TAK-733.

2. A first composition comprising ADCxAXL for use in a method of treating cancer in an individual, wherein the treatment comprises administration of the first composition in combination with a second composition comprising a secondary agent.

3. A first composition comprising a secondary agent for use in a method of treating a disorder in an individual, wherein the treatment comprises administration of the first composition in combination with a second composition comprising ADCxAXL.

4. Use of ADCxAXL in the manufacture of a medicament for treating cancer in an individual, wherein the medicament comprises ADCxAXL, and wherein the treatment comprises administration of the medicament in combination with a composition comprising a secondary agent.

5. Use of a secondary agent in the manufacture of a medicament for treating cancer in an individual, wherein the medicament comprises a secondary agent, and wherein the treatment comprises administration of the medicament in combination with a composition comprising ADCxAXL.

6. A kit comprising:

a first medicament comprising ADCxAXL;

a second medicament comprising a secondary agent; and

, optionally,

a package insert comprising instructions for administration of the first medicament to an individual in combination with the second medicament for the treatment of cancer.

7. A kit comprising a medicament comprising ADCxAXL and a package insert comprising instructions for administration of the medicament to an individual in combination with a composition comprising a secondary agent for the treatment of cancer.

8. A kit comprising a medicament comprising a secondary agent and a package insert comprising instructions for administration of the medicament to an individual in combination with a composition comprising ADCxAXL for the treatment of cancer.

9. A pharmaceutical composition comprising ADCxAXL and a secondary agent.

10. A method of treating cancer in an individual, the method comprising administering to the individual an effective amount of the composition of claim 9.

11. The composition of claim 9 for use in a method of treating cancer in an individual.

12. The use of the composition of claim 9 in the manufacture of a medicament for treating cancer in an individual.

13. A kit comprising the composition of claim 9 and a set of instructions for administration of the medicament to an individual for the treatment of cancer.