Claims for Patent: 12,144,809

Summary for Patent: 12,144,809

Title:	Treatment of prostate cancer
Abstract:	Methods for treating prostate cancer, including advanced prostate cancer, in a subject in need thereof, include administering once-daily to the subject, at least 80 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof. Another method includes: administering once-daily to the subject in need thereof, an oral load dose formulation having from 240 mg to 480 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, and thereafter administering once-daily to the subject, an oral maintenance dose formulation having 80 mg to 160 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof.
Inventor(s):	Vijaykumar Reddy RAJASEKHAR, Brendan Mark JOHNSON, David B. MacLean, Lynn Seely, Paul N. MUDD, Jr., Hélène M. Faessel
Assignee:	Sumitomo Pharma Switzerland GmbH , Takeda Pharmaceutical Co Ltd
Application Number:	US18/758,904
Patent Claims:	1. A method of treating prostate cancer in a subject in need thereof, the method comprising: (i) orally administering a loading dose of 360 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea to the subject; (ii) beginning about one day after administration of the 360 mg loading dose, orally administering a single 120 mg solid preparation of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea to the subject once a day; and (iii) co-administering a P-glycoprotein (P-gp) inhibitor to the subject at least six hours after the oral administration of the single 120 mg solid preparation of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea; wherein the subject is in need of co-administration of the P-gp inhibitor. 2. The method of claim 1, wherein the P-gp inhibitor is amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, dronedarone, eliglustat, erythromycin, felodipine, itraconazole, ketoconazole, lapatinib, lopinavir/ritonavir, propafenone, quercetin, quinidine, reserpine, ranolazine, saquinavir, telaprevir, tipranavir, ticagrelor, tacrolimus, or verapamil. 3. The method of claim 1, wherein the subject's serum testosterone concentration is below 50 ng/dL within 4 days of administering the loading dose. 4. The method of claim 1, wherein the subject's serum testosterone concentration is below 50 ng/dL within 24 to 48 hours of commencing treatment with administration of the loading dose. 5. The method of claim 1, wherein the subject's serum testosterone concentration is below 20 ng/dL within three weeks of commencing treatment with administration of the loading dose. 6. The method of claim 1, wherein the subject's serum testosterone concentration is below 20 ng/dL within two weeks of commencing treatment with administration of the loading dose. 7. The method of claim 1, wherein the subject's serum testosterone concentration is below 20 ng/dL within one week of commencing treatment with administration of the loading dose. 8. The method of claim 1, wherein the subject's serum testosterone concentration is below 20 ng/dL within 4 days of commencing treatment with administration of the loading dose. 9. The method of claim 3, wherein the subject's serum testosterone concentration is below 20 ng/dL within three weeks of commencing treatment with administration of the loading dose. 10. The method of claim 3, wherein the subject's serum testosterone concentration is below 20 ng/dL within two weeks of commencing treatment with administration of the loading dose. 11. The method of claim 3, wherein the subject's serum testosterone concentration is below 20 ng/dL within one week of commencing treatment with administration of the loading dose. 12. The method of claim 1, wherein the 120 mg solid preparation is administered to the subject for 48 weeks or greater from administration of the loading dose. 13. The method of claim 1, wherein the subject's serum testosterone concentration is below 50 ng/dL within 8 days of administering the loading dose. 14. The method of claim 1, further comprising: temporarily discontinuing administering the 120 mg solid preparation of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea to the subject to allow the subject's serum testosterone concentration to increase. 15. The method of claim 14, wherein the subject's serum testosterone concentration is at least about 280 ng/dL within about 8 weeks after discontinuing. 16. The method of claim 14, wherein the subject's serum testosterone concentration is at least about 280 ng/dL within about 4 weeks after discontinuing. 17. The method of claim 1, wherein the subject has previously been administered enzalutamide. 18. The method of claim 1, further comprising administering enzalutamide. 19. The method of claim 1, wherein the 120 mg solid preparation is a capsule or tablet. 20. The method of claim 1, wherein the 120 mg solid preparation is administered with food. 21. The method of claim 14, wherein the subject's serum testosterone concentration is at least about 280 ng/dL within about 90 days after discontinuing. 22. The method of claim 19, wherein the subject's serum testosterone concentration is below 50 ng/dL within 4 days of administering the loading dose. 23. A method of treating prostate cancer in a subject in need thereof, the method comprising: (i) orally administering a loading dose of 360 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, to the subject; (ii) beginning about one day after administration of the 360 mg loading dose, orally administering a maintenance dose of 120 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, to the subject once a day; and (iii) co-administering a P-glycoprotein (P-gp) inhibitor to the subject, separating administrations of the P-gp inhibitor and the 120 mg maintenance dose of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, to the subject by at least 6 hours, wherein the subject is in need of co-administration of the P-gp inhibitor. 24. The method of claim 23, wherein the P-gp inhibitor is administered at least 6 hours after administration of the 120 mg maintenance dose of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, to the subject. 25. A method of treating prostate cancer, the method comprising: (i) identifying a subject having prostate cancer in need of administration of a P-glycoprotein (P-gp) inhibitor; (ii) orally administering a loading dose of 360 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, to the subject; (iii) beginning about one day after administration of the 360 mg loading dose, orally administering a maintenance dose of 120 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, once a day to the subject to treat the prostate cancer; and (iv) administering the P-gp inhibitor to the subject, wherein the administration of the P-gp is separated by at least six hours from the administration of the 120 mg maintenance dose of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof. 26. The method of claim 25 wherein the prostate cancer is advanced prostate cancer. 27. The method of claim 25 wherein the method results in testosterone concentrations of below 50 ng/dL in the subject. 28. A method of treating a subject having advanced prostate cancer and who is in need of administration of a P-glycoprotein (P-gp) inhibitor comprising: (i) orally administering a loading dose of 360 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, to the subject; (ii) beginning about one day after administration of the 360 mg loading dose, orally administering a maintenance dose of 120 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, to the subject once a day; and (iii) administering the P-gp inhibitor to the subject, wherein the administration of the P-gp inhibitor is separated from the administration of the 120 mg maintenance dose of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof by at least 6 hours. 29. The method of claim 28, wherein the method results in testosterone concentrations of below 50 ng/dL in the subject.