Dosing regimen for the treatment of PI3K related disorders

Patent metadata

Field	Value
Publication number	US-12226418-B2
Application number	US-201916428056-A
Country	US
Kind code	B2
Filing date	May 31, 2019
Priority date	Jun 1, 2018
Publication date	Feb 18, 2025
Grant date	Feb 18, 2025

Abstract

The present application provides methods of treating PI3Kδ related disorders using pyrazolopyrimidine derivatives.

First claim

What is claimed is:

1. A method of treating a disease in a patient, wherein said disease is associated with abnormal expression or activity of PI3Kδ kinase, the method comprising:
i) administering to the patient an inhibitor of PI3Kδ, which is 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2- ethoxy-6-fluorophenyl}pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof, in a first dosage that is about 3 mg/day to about 50 mg/day for a first period of time which is about 2 weeks to about 12 weeks; and
ii) administering to the patient a second dosage of the inhibitor of PI3Kδ which is less than the first dosage administered at the end of the first period of time and which is:
(a) about 2.5 mg/day or less; or
(b) about 50 mg/week or less;

and wherein the second dosage is administered for a second period of time which occurs after the first period of time.

2. The method of claim 1 , wherein the first dosage is about 20 mg/day.

3. The method of claim 1 , wherein the first period of time is about 8 weeks to about 12 weeks.

4. The method of claim 1 , wherein the first period of time is about 8 weeks.

5. The method of claim 1 , wherein the first dosage is reduced during the first period of time.

6. The method of claim 1 , wherein the second dosage is about 2.5 mg/day or less.

7. The method of claim 1 , wherein the second dosage is about 2.5 mg/day.

8. The method of claim 1 , wherein the second dosage is about 50 mg/week or less.

9. The method of claim 1 , wherein the second dosage is about 20 mg/week.

10. The method of claim 1 , wherein the second dosage is reduced during the second period of time.

11. The method of claim 5 , wherein the patient has been identified as exhibiting one or more symptoms associated with one or more treatment-emergent adverse events (TEAEs).

12. The method of claim 11 , wherein the patient has been identified as exhibiting the one or more symptoms associated with one or more treatment-emergent adverse events (TEAEs) during the first period of time.

13. The method of claim 11 , wherein the first time period ends when the patient has been identified as exhibiting the one or more symptoms associated with one or more treatment-emergent adverse events (TEAEs).

14. The method of claim 11 , wherein the one or more treatment-emergent adverse events comprise one or more of diarrhea/colitis, nausea, fatigue, rash, neutropenia, pyrexia, hypotension, sepsis, respiratory failure, pneumonitis, pneumonia, hypertension, hyperglycemia, abdominal pain, bronchitis, dehydration, thrombocytopenia, cough, vomiting, decreased appetite, increased lacrimation, oral herpes, tachycardia, spinal cord compression, intractable pain, elevated alkaline phosphatase, elevated transaminase, hyperlipidemia, hypercalcemia, dizziness, alopecia, constipation, fluid overload, headache, hypokalemia, night sweats, encephalopathy, atrial flutter, atrial fibrillation, and dyspnea.

15. The method of claim 11 , wherein the one or more treatment-emergent adverse events comprise one or more of diarrhea/colitis, nausea, fatigue, rash, cough, vomiting, dizziness, pyrexia, hypokalemia, abdominal pain, constipation, decreased appetite, night sweats, pruritus, back pain, chills, leukopenia, neutropenia, lymphopenia, thrombocytopenia, and anemia.

16. The method of claim 11 , wherein the one or more treatment-emergent adverse events comprise one or more of diarrhea/colitis and rash.

17. The method of claim 16 , wherein the diarrhea/colitis comprises one or more of diarrhea, colitis, enterocolitis, gastrointestinal inflammation, colitis microscopic, and cytomegalovirus colitis.

18. The method of claim 16 , wherein the rash comprises one or more of dermatitis exfoliative, rash, rash erythematous, rash macular, rash maculopapular, rash pruritic, exfoliative rash, rash generalized, rash popular, and rash pustular.

19. The method of claim 14 , wherein the neutropenia comprises febrile neutropenia.

20. The method of claim 14 , wherein the elevated transaminase comprises elevated alanine transaminase (ALT), aspartate transaminase (AST), or a combination thereof.

21. The method of claim 1 , wherein the inhibitor of PI3Kδ is (S)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

22. The method of claim 1 , wherein the inhibitor of PI3Kδ is (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

23. The method of claim 1 , wherein the inhibitor of PI3Kδ is (S)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

24. The method of claim 1 , wherein the inhibitor of PI3Kδ is (R)-4-(3-(R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

25. The method of claim 1 , wherein the inhibitor of PI3Kδ is a pharmaceutically acceptable salt of 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one.

26. The method of claim 1 , wherein the inhibitor of PI3Kδ is (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one hydrochloric acid salt.

27. The method of claim 26 , wherein the salt is a 1:1 stoichiometric ratio of (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one to hydrochloric acid.

28. The method of claim 26 , wherein the salt is crystalline.

29. The method of claim 1 , wherein the disease is selected from chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia.

30. The method of claim 29 , wherein the marginal zone lymphoma is selected from extranodal marginal zone lymphoma, nodal marginal zone lymphoma, splenic marginal zone lymphoma, and unknown marginal zone lymphoma subtype.

31. The method of claim 29 , wherein the Hodgkin lymphoma is selected from classic Hodgkin lymphoma and nodular lymphocytic-predominant Hodgkin lymphoma.

32. The method of claim 29 , wherein the diffuse large B-cell lymphoma is selected from activated B-cell like diffuse large B cell lymphoma and germinal center B cell diffuse large B cell lymphoma.

33. A method of treating a disease in a patient, wherein said disease is selected from chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia, the method comprising:
i) administering to the patient (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one hydrochloric acid salt in a first dosage that is about 20 mg/day to about 50 mg/day for a first period of time which is about 8 weeks to about 9 weeks; and
ii) administering to the patient a second dosage of the (R)-4-(3-((S)-1-(4-amino-3-methyl

Assignees

• Incyte Corp

Inventors

• Yeleswaram Krishnaswamy
• Assad Albert
• Chen Xuejun

Classifications

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K45/00 Primary

  Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title