Bruton's tyrosine kinase inhibitor combinations and uses thereof
View Patent ↗Disclosed herein are methods, compositions, and kits for treating a B-cell malignancy comprising administering a combination of a BTK inhibitor (e.g. ibrutinib) and a PIM inhibitor. Also disclosed herein are methods, compositions, and kits for treating a BTK-resistant B-cell malignancy comprising administering a combination of a BTK inhibitor (e.g. ibrutinib) and a PIM inhibitor.
1. A method of treating a B-cell malignancy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination comprising ibrutinib and a PIM inhibitor selected from SGI-1776, AZD1208, AZD1897, LGH447, JP_11646, CX-6258, and K00135, wherein the B-cell malignancy is acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
2. The method of claim 1 , wherein the combination provides a synergistic effect compared to administration of ibrutinib or the PIM inhibitor alone.
3. The method of claim 1 , wherein the combination sensitizes the B-cell malignancy to ibrutinib.
4. The method of claim 1 , wherein the PIM inhibitor is AZD1208.
5. The method of claim 1 , wherein the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL).
6. The method of claim 5 , wherein the DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL).
7. The method claim 1 , wherein the method further comprises administering a third therapeutic agent.
8. The method of claim 7 , wherein the third therapeutic agent is a chemotherapeutic agent or a radiation therapeutic agent.
9. The method of claim 8 , wherein the third therapeutic agent is a chemotherapeutic agent; and the chemotherapeutic agent is chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.
10. The method of claim 1 , wherein the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL); and the PIM inhibitor is AZD1208.
11. The method of claim 10 , wherein the DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL).
12. The method of claim 1 , wherein the PIM inhibitor is SGI-1776.
13. The method of claim 1 , wherein the PIM inhibitor is AZD1897.
14. The method of claim 1 , wherein the PIM inhibitor is LGH447.
15. The method of claim 1 , wherein the PIM inhibitor is JP_11646.
16. The method of claim 1 , wherein the PIM inhibitor is CX-6258.
17. The method of claim 1 , wherein the PIM inhibitor is K00135.
18. The method of claim 1 , wherein, following administration of ibrutinib and the PIM inhibitor, the subject achieves a complete response (CR), exhibits a stable disease (SD), or does not exhibit progressive disease (PD).
19. The method of claim 1 , wherein, following administration of ibrutinib and the PIM inhibitor, the subject achieves a complete response (CR).
20. The method of claim 1 , wherein, following administration of ibrutinib and the PIM inhibitor, the subject does not exhibit progressive disease within 12 months.
21. The method of claim 10 , wherein, following administration of ibrutinib and the PIM inhibitor, the subject achieves a complete response (CR), exhibits a stable disease (SD), or does not exhibit progressive disease (PD).
22. The method of claim 10 , wherein, following administration of ibrutinib and the PIM inhibitor, the subject achieves a complete response (CR).
23. The method of claim 10 , wherein, following administration of ibrutinib and the PIM inhibitor, the subject does not exhibit progressive disease within 12 months.