BTK Inhibitors to Treat Solid Tumors Through Modulation of the Tumor Microenvironment
In certain embodiments, the invention includes therapeutic methods of using a BTK inhibitor to treat solid tumor cancers by modulation of the tumor microenvironment, including macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts.
1 - 37 . (canceled)
38 . A method of treating a chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), the method comprising administering to a human subject in need thereof, a therapeutically effective amount of: (i) a BTK inhibitor compound of the formula:
or a pharmaceutically-acceptable salt thereof, by oral administration, and (ii) obinutuzumab by intravenous administration.
39 . The method of claim 38 , wherein 100 mg of the BTK inhibitor, or a pharmaceutically-acceptable salt thereof, is administered to the subject twice daily.
40 . The method of claim 38 , wherein 100 mg of the BTK inhibitor, or a pharmaceutically-acceptable salt thereof, is administered to the subject twice daily starting on treatment cycle 1 day 1.
41 . The method of claim 38 , wherein 100 mg of the BTK inhibitor, or a pharmaceutically-acceptable salt thereof, is administered to the subject twice daily starting on treatment cycle 1 day 1 until disease progression.
42 . The method of claim 38 , wherein the BTK inhibitor, or a pharmaceutically-acceptable salt thereof, is administered to the subject before the obinutuzumab.
43 . The method of claim 42 , wherein the obinutuzumab is administered to the subject starting with treatment cycle 2.
44 . The method of claim 43 , wherein 100 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 1.
45 . The method of claim 43 , wherein 900 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 2.
46 . The method of claim 43 , wherein 1000 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 8.
47 . The method of claim 43 , wherein 1000 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 15.
48 . The method of claim 43 , wherein 1000 mg of the obinutuzumab is administered to the subject on day 1 of one or more treatment cycles selected from the group consisting of treatment cycle 3, treatment cycle 4, treatment cycle 5, treatment cycle 6, and treatment cycle 7.
49 . The method of claim 43 , wherein:
100 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 1;
900 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 2;
1000 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 8; and
1000 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 15.
50 . The method of claim 49 , wherein 1000 mg of the obinutuzumab is administered to the subject on day 1 of one or more treatment cycles selected from the group consisting of treatment cycle 3, treatment cycle 4, treatment cycle 5, treatment cycle 6, and treatment cycle 7.
51 . The method of claim 39 , wherein the BTK inhibitor, or a pharmaceutically-acceptable salt thereof, is administered to the subject before obinutuzumab.
52 . The method of claim 51 , wherein the obinutuzumab is administered to the subject starting with treatment cycle 2.
53 . The method of claim 52 , wherein 100 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 1.
54 . The method of claim 52 , wherein 900 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 2.
55 . The method of claim 52 , wherein 1000 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 8.
56 . The method of claim 52 , wherein 1000 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 15.
57 . The method of claim 52 , wherein 1000 mg of the obinutuzumab is administered to the subject on day 1 of one or more treatment cycles selected from the group consisting of treatment cycle 3, treatment cycle 4, treatment cycle 5, treatment cycle 6, and treatment cycle 7.
58 . The method of claim 52 , wherein:
100 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 1;
900 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 2;
1000 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 8; and
1000 mg of the obinutuzumab is administered to the subject on treatment cycle 2 day 15.
59 . The method of claim 58 , wherein 1000 mg of the obinutuzumab is administered to the subject on day 1 of one or more treatment cycles selected from the group consisting of treatment cycle 3, treatment cycle 4, treatment cycle 5, treatment cycle 6, and treatment cycle 7.
60 . The method of claim 38 , wherein the method comprises treating chronic lymphocytic leukemia (CLL).
61 . The method of claim 60 , wherein the chronic lymphocytic leukemia is relapsed or refractory chronic lymphocytic leukemia.
62 . The method of claim 61 , wherein the human subject is a human subject with a 17p chromosomal deletion.
63 . The method of claim 61 , wherein the human subject is a human subject with an 11q chromosomal deletion.
64 . The method of claim 38 , wherein the method comprises treating small lymphocytic lymphoma (SLL).
65 . The method of claim 38 , wherein the human subject in need thereof is suffering from chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
66 . The method of claim 38 , wherein the free form of the BTK inhibitor is administered.
67 . The method of claim 38 , wherein the pharmaceutically acceptable salt of the BTK inhibitor is administered.