Therapeutic combinations of acalabrutinib and capivasertib to treat B-cell malignancies
The present disclosure relates to therapeutic combinations of acalabrutinib and capivasertib, or pharmaceutically acceptable salts thereof, for treating, preventing, partially alleviating, or ameliorating a B-cell malignancy, such as non-Hodgkin's lymphoma, in a subject in need thereof. The present disclosure also relates to pharmaceutical compositions comprising acalabrutinib and capivasertib. The present disclosure also relates to kits comprising acalabrutinib and capivasertib.
1 . A method of treating a B-cell malignancy in a human subject in need thereof, comprising administering to the human subject a first amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, and a second amount of a compound of Formula II:
or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount.
2 . The method of claim 1 , wherein the B-cell malignancy is non-Hodgkin lymphoma.
3 . The method of claim 1 , wherein the B-cell malignancy is selected from the group consisting of mantle cell lymphoma; follicular lymphoma; de novo diffuse large B-cell lymphoma; transformed diffuse large B-cell lymphoma; T-cell/histiocyte-rich large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma; leg-type primary cutaneous diffuse large B-cell lymphoma; Epstein-Barr virus-positive diffuse large B-cell lymphoma; diffuse large B-cell lymphoma associated with chronic inflammation; primary mediastinal large B-cell lymphoma; intravascular large B-cell lymphoma; anaplastic lymphoma kinase-positive (ALK+) large B-cell lymphoma; and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or of BCL6 and MYC.
4 . The method of claim 1 , wherein the B-cell malignancy is selected from the group consisting of de novo diffuse large B-cell lymphoma; transformed diffuse large B-cell lymphoma; T-cell/histiocyte-rich large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma; leg-type primary cutaneous diffuse large B-cell lymphoma; Epstein-Barr virus-positive diffuse large B-cell lymphoma; diffuse large B-cell lymphoma associated with chronic inflammation; primary mediastinal large B-cell lymphoma; intravascular large B-cell lymphoma; anaplastic lymphoma kinase-positive (ALK+) large B-cell lymphoma; and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or of BCL6 and MYC.
5 . The method of claim 1 , wherein the B-cell malignancy is diffuse large B-cell lymphoma.
6 . The method of claim 5 , wherein the diffuse large B-cell lymphoma is selected from the group consisting of de novo diffuse large B-cell lymphoma, relapsed/refractory diffuse large B-cell lymphoma, and transformed diffuse large B-cell lymphoma.
7 . The method of claim 5 , wherein the diffuse large B-cell lymphoma is selected from the group consisting of germinal center B-cell (GCB) diffuse large B-cell lymphoma and activated B-cell (ABC) diffuse large B-cell lymphoma.
8 . The method of claim 5 , wherein the diffuse large B-cell lymphoma is activated B-cell (ABC) diffuse large B-cell lymphoma.
9 . The method of claim 5 , wherein the human subject has previously received at least one prior chemo-immunotherapy for the diffuse large B-cell lymphoma.
10 . The method of claim 1 wherein the method comprises orally administering to the human subject the compound of Formula I, or a pharmaceutically acceptable salt thereof, and the compound of Formula II, or a pharmaceutically acceptable salt thereof.
11 . The method of claim 10 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is orally co-administered to the human subject with the compound of Formula II, or a pharmaceutically acceptable salt thereof.
12 . The method of claim 10 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is orally administered to the human subject before or after the compound of Formula II, or a pharmaceutically acceptable salt thereof.
13 . The method of claim 1 , wherein the first amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, administered to the human subject is from about 75 mg to about 225 mg daily.
14 . The method of claim 1 , wherein the first amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, administered to the human subject is about 100 mg once daily.
15 . The method of claim 1 , wherein the first amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, administered to the human subject is about 100 mg twice daily.
16 . The method of claim 1 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is orally administered to the human subject under a continuous dosing schedule.
17 . The method of claim 1 , wherein the compound of Formula II, or a pharmaceutically acceptable salt thereof, is orally administered to the human subject under an intermittent dosing schedule.
18 . The method of claim 1 , wherein:
the compound of Formula I, or a pharmaceutically acceptable salt thereof, is orally administered to the human subject under a continuous dosing schedule; and
the compound of Formula II, or a pharmaceutically acceptable salt thereof, is orally administered to the human subject under an intermittent dosing schedule.
19 . The method of claim 1 , wherein the second amount of the compound of Formula II, or a pharmaceutically acceptable salt thereof, administered to the human subject is from about 50 mg twice daily to about 900 mg twice daily.
20 . A pharmaceutical composition comprising:
a compound of Formula I:
or a pharmaceutically acceptable salt thereof;
a compound of Formula II:
or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier.
21 . A kit comprising:
a first pharmaceutical composition comprising a compound of Formula I:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;
a second pharmaceutical composition comprising a compound of Formula II:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
22 . The method of claim 8 , wherein the activated B-cell (ABC) diffuse large B-cell lymphoma is relapsed/refractory activated B-cell (ABC) diffuse large B-cell lymphoma.