JPWO2020159822A5

JPWO2020159822A5 -

Info

Publication number: JPWO2020159822A5
Application number: JP2021543165A
Authority: JP
Publication date: 2023-02-02

Claims

A composition comprising a therapeutically effective amount of tucatinib, or a salt or solvate thereof, for treating breast cancer in a subject, the subject being treated comprising:
(a) not undergoing concurrent treatment with a therapeutically effective amount of a compound that modulates the activity of a cytochrome p450 protein;
(b) has not been concurrently treated with a therapeutically effective amount of a substrate of cytochrome p450 protein, or
(c) not undergoing concurrent treatment with a therapeutically effective amount of a substrate of P-glycoprotein (P-gp);
said composition.

(a) the subject to be treated, who has not received treatment with the compound or substrate of the substrate within the past 7 days;
(b) the subject to be treated, who has not received treatment with the compound or substrate of the substrate within the past 3 months;
(c) the subject being treated, has not received treatment with the compound or substrate of the substrate within the past 12 months, or
(d) the subject being treated has not previously undergone treatment with the compound or substrate of the substrate;
A composition according to claim 1 .

3. The composition of claim 1 or 2, wherein the compound that modulates cytochrome p450 protein activity is an inhibitor of cytochrome p450 protein activity.

(a) the cytochrome p450 protein is CYP3A4 and optionally the compound that inhibits the activity of CYP3A4 is itraconazole, or
(b) the cytochrome p450 protein is CYP2C8 and optionally the compound that inhibits the activity of CYP2C8 is gemfibrozil;
4. The composition of claim 3.

3. The composition of claim 1 or 2, wherein the compound that modulates cytochrome p450 protein activity is an inducer of cytochrome p450 protein activity.

6. The composition of claim 5, wherein the cytochrome p450 protein is CYP3A4.

6. The composition of claim 5, wherein the cytochrome p450 protein is CYP2C8.

The composition according to any one of claims 5 to 7, wherein the compound that induces activity of cytochrome p450 protein is rifampin.

3. The composition of claim 1 or 2, wherein the cytochrome p450 protein is CYP3A4 or CYP2C8.

10. The composition of claim 9, wherein the cytochrome p450 protein substrate is selected from the group consisting of budesonide, buspirone, eplerenone, eletriptan, felodipine, fluticasone, lovastatin, midazolam, saquinavir, sildenafil, simvastatin, triazolam, and vardenafil. .

The group in which the substrate of P-gp consists of amitriptyline, carbamazepine, clonidine, cyclosporine, digitoxin, digoxin, imipramine, phenobarbital, phenytoin, quinidine, rifampicin, sirolimus, tacrolimus, temsirolimus, trimipramine, vincristine, paclitaxel, and dabigatran etexilate 3. The composition of claim 1 or 2, selected from

(a) the therapeutically effective amount of tucatinib administered to the subject is in a dose of about 150 mg to about 650 mg; or
(b) The composition of any one of claims 1-11, wherein the therapeutically effective amount of tucatinib administered to the subject is at a dose of about 300 mg.

13. The composition of claim 12, wherein tucatinib or a salt or solvate thereof is for administration once or twice daily.

14. The composition of claim 13, wherein tucatinib or a salt or solvate thereof is for administration at a dose of about 300 mg twice daily.

15. The composition of any one of claims 1-14, wherein tucatinib or a salt or solvate thereof is for oral administration to a subject.

The composition according to any one of claims 1 to 15, wherein the breast cancer is HER2-positive breast cancer.

17. The composition of claim 16, wherein the cancer is determined to be HER2 positive using in situ hybridization, fluorescent in situ hybridization, or immunohistochemistry.

The composition of any one of claims 1-17, wherein the breast cancer is metastatic.

19. The composition of Claim 18, wherein the breast cancer has metastasized to the brain.

A composition according to any preceding claim, wherein the breast cancer is locally advanced and/or unresectable.

21. The composition of any one of claims 1-20, wherein treating further comprises administering to the subject one or more additional therapeutic agents to treat breast cancer.

22. The composition of claim 21, wherein the one or more additional therapeutic agents are selected from the group consisting of capecitabine and anti-HER2 antibodies.

22. The composition of claim 21, wherein the one or more additional therapeutic agents are capecitabine and trastuzumab.

the one or more additional therapeutic agents comprises capecitabine, wherein the capecitabine is for administration to the subject at a dose of about 500 mg/m ² to about 1500 mg/m ² ;
Optionally, capecitabine is for administration to the subject at a dose of about 1000 mg/m ² ,
Optionally, the capecitabine is for oral administration to the subject and
Optionally, capecitabine is for administration to the subject twice daily
24. A composition according to claim 21 or 23.

the one or more additional therapeutic agents comprises trastuzumab;
(a) trastuzumab is for administration to the subject at a dose of about 400 mg to about 800 mg, optionally trastuzumab is for administration to the subject at a dose of about 600 mg;
(b) trastuzumab is for administration to the subject at a dose of about 4 mg/kg to about 10 mg/kg, optionally about 8 mg/kg;
(c) trastuzumab is to be administered to the subject at an initial dose of about 8 mg/kg and then at subsequent doses of about 6 mg/kg;
(d) the trastuzumab is for subcutaneous administration to the subject;
(e) the trastuzumab is for intravenous administration to a subject; or
(f) trastuzumab is to be administered about once every week, about once every two weeks, about once every three weeks, or about once every four weeks;
24. A composition according to claim 21 or 23.

24. The composition of claim 23, wherein tucatinib, capecitabine and trastuzumab are for administration to the subject in a 21 day treatment cycle.

27. The composition of claim 26, wherein tucatinib is to be administered to the subject twice daily on each day of a 21-day treatment cycle.

28. The composition of claim 26 or 27, wherein capecitabine is for administration to the subject twice daily on each of days 1-14 of a 21-day treatment cycle.

29. The composition of any one of claims 26-28, wherein trastuzumab is administered to the subject once per 21-day treatment cycle.

30. The composition of claim 29, wherein the dose of trastuzumab during the first 21-day treatment cycle is 8 mg/kg and the dose of trastuzumab during subsequent 21-day treatment cycles is 6 mg/kg.

31. The composition of any one of claims 1-30, wherein the subject to be treated has been previously treated with one or more additional therapeutic agents for breast cancer.

32. The composition of claim 31, wherein the one or more additional therapeutic agents are anti-HER2 antibodies or anti-HER2 antibody-drug conjugates.

33. The composition of claim 32, wherein the one or more additional therapeutic agents is trastuzumab, pertuzumab and/or T-DM1.

34. The composition of any one of claims 1-33, wherein the subject to be treated has not been treated with another therapeutic agent for breast cancer within the past 12 months.

35. The composition of any one of claims 1-34, wherein the subject to be treated has not been previously treated with another therapeutic agent for breast cancer.

36. The composition of any one of claims 1-35, wherein the subject to be treated has not been previously treated with lapatinib, neratinib, afatinib, or capecitabine.

37. Any one of claims 1-36, wherein treatment of the subject results in a tumor growth inhibition (TGI) index of at least about 85%, optionally treatment of the subject results in a TGI index of about 100%. Composition.

One or more therapeutic effects in the subject are improved after administration of tucatinib to the subject compared to baseline, and optionally, the one or more therapeutic effects are measured by the size of the tumor originating from the breast cancer, objective response 38. The composition of any one of claims 1-37, selected from the group consisting of response rate, duration of response, time to response, progression-free survival and overall survival.

39. The composition of any one of claims 1-38, wherein the subject is a human.

Use of a composition comprising a therapeutically effective amount of tucatinib, or a salt or solvate thereof, in the manufacture of a medicament for treating breast cancer in a subject, the subject being treated comprising:
(a) not undergoing concurrent treatment with a therapeutically effective amount of a compound that modulates the activity of a cytochrome p450 protein;
(b) has not been concurrently treated with a therapeutically effective amount of a substrate of cytochrome p450 protein, or
(c) not undergoing concurrent treatment with a therapeutically effective amount of a substrate of P-glycoprotein (P-gp);
said use.