Therapeutic Use of a TLR Agonist and Combination Therapy

• US 20120219615A1
• Filed: 10/03/2011
• Published: 08/30/2012
• Est. Priority Date: 10/01/2010
• Status: Abandoned Application

• Current Assignee: VentiRx Pharmaceuticals, Inc. (Bristol-Myers Squibb Company), Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: VentiRx Pharmaceuticals, Inc. (Bristol-Myers Squibb Company), Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Hershberg, Robert, Coukos, George, Dietsch, Gregory, Facciabene, Andrea, Manjarrez, Kristi, Randall, Tressa D.
• Application Number:
  US13/252,147
• Publication Number:
  US 20120219615A1
• Time in Patent Office: Days
• US Class Current: 424/450
• 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 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The present invention is directed generally to formulations of a TLR agonist preferably a TLR8 agonist, and its use in the treatment of various diseases, including combination therapies for treating cancer.

Claims

1. A method for treating cancer comprising administering to a subject in need thereof an effective amount of a formulation comprising a benzo[b]azepine TLR8 agonist and a pharmaceutically acceptable carrier, in combination with one or more additional treatment modalities.

2. The method of claim 1, wherein the TLR8 agonist is 2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b] azepine-4-carboxamide or a pharmaceutically acceptable salt thereof.

3. The method of claim 1, wherein the cancer is a solid cancer.

4. The method of claim 3, wherein the solid cancer is ovarian cancer, breast cancer, head and neck cancer, renal cancer, bladder cancer, hepatocellular cancer, colorectal cancer, lymphoma, melanoma, or any combination thereof.

5. The method of claim 1, wherein one of the one or more treatment modalities comprise administering to the subject an effective amount of an anti-cancer agent.

6. The method of claim 5, wherein the anti-cancer agent is doxorubicin, gemcitabine, cyclophosphamide, or a pharmaceutically acceptable salt thereof.

7. The method of claim 5, wherein the anti-cancer agent is administered prior to, subsequent to, or concurrently with administration of the TLR8 agonist.

8. The method of claim 1, wherein the cancer is ovarian cancer, and the anti-cancer agent is a pegylated liposomal form of doxorubicin.

9. The method of claim 1, wherein the cancer is breast cancer, and the anti-cancer agent is gemcitabine or cyclophosphamide.

10. The method of claim 1, wherein the one or more additional treatment modalities are selected from a chemotherapeutic agent, a cytokine, an antibody, a hormonal therapy, and a radiation therapy.

11. The method of claim 1, wherein the TLR8 agonist is dosed at a concentration from about 0.02 to about 10 mg/kg body weight of the subject.

12. The method of claim 11, wherein the TLR8 agonist is dosed at a concentration of about 0.02 mg/kg, about 0.05 mg/kg, about 0.075 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, or about 5 mg/kg body weight of the subject.

13. The method of claim 2, wherein the formulation has a concentration from about 0.01 to 50 mg/ml of the TLR8 agonist.

14. The method of claim 1, wherein the cancer is lymphoma and the one or more additional treatment modalities comprise a radiation therapy.

15. The method of claim 14, wherein the lymphoma is Non-Hodgkin'"'"'s lymphoma.

16. A method for treating cancer comprising administering to a subject in need there of a benzo[b]azepine TLR8 agonist at a dose between 0.002 mg/kg/week and 0.006 mg/kg/week.

17. The method of claim 16, wherein the benzo[b]azepine TLR8 agonist is 2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising anti-cancer agent and a formulation of a benzo[b]azepine TLR8 agonist.

19. The pharmaceutical composition of claim 18, wherein the TLR8 agonist is 2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition of claim 18, wherein the anti-cancer agent is doxorubicin, gemcitabine, cyclophosphamide, or a pharmaceutically acceptable salt thereof.