Claims for Patent: 10,045,991

Summary for Patent: 10,045,991

Title:	Methods of treating pediatric cancers
Abstract:	A method of treating a pediatric cancer in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[- 1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, or a combination thereof.
Inventor(s):	Cox; Michael (Stamford, CT), Nanda; Nisha (Stamford, CT)
Assignee:	Loxo Oncology, Inc. (Stamford, CT)
Application Number:	15/622,388
Patent Claims:	1. A method of treating a Trk-associated pediatric cancer in a subject in need thereof, wherein the cancer is selected from the group consisting of: congenital mesoblastic nephroma, Ph-like acute lymphoblastic leukemia, infantile fibrosarcoma, pediatric high-grade glioma (HGG), diffuse intrinsic pontine gliomas (DIPGs), pediatric papillary thyroid carcinoma, soft tissue sarcoma, and spindle cell sarcoma, the method comprising administering to the subject a therapeutically effective amount of (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[- 1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide having the formula (I): ##STR00033## a pharmaceutically acceptable salt thereof, or combinations thereof; wherein the compound of formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof, is provided as a liquid formulation comprising: a solubilizing agent, wherein the solubilizing agent comprises a .beta.-cyclodextrin; and a base; wherein: the formulation has a pH of about 2.5 to about 5.5; and the compound of formula (I) has a concentration of about 15 mg/mL to about 35 mg/mL in the liquid formulation. 2. The method of claim 1, wherein the subject is an infant. 3. The method of claim 1, wherein the cancer is mediated by TrkA, TrkB, TrkC, or combinations thereof. 4. The method of claim 1, wherein the pediatric cancer is infantile fibrosarcoma. 5. The method of claim 4, wherein surgical resection has failed to inhibit progression of the fibrosarcoma in the subject. 6. The method of claim 1, wherein chemotherapy previously failed to inhibit tumor progression in the subject. 7. The method of claim 1, further comprising performing one or more of morphological diagnosis and molecular testing prior to administering the compound of formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof. 8. The method of claim 1, wherein the compound of formula (I) is a hydrogen sulfate salt. 9. The method of claim 1, wherein the compound of formula (I) is provided as a crystalline form. 10. The method of claim 1, wherein the formulation has a pH of about 3 to about 4. 11. The method of claim 1, wherein the .beta.-cyclodextrin is hydroxypropyl-.beta.-cyclodextrin. 12. The method of claim 1, wherein the base is a citrate. 13. The method of claim 12, wherein the base comprises sodium citrate dihydrate. 14. The method of claim 1, wherein the liquid formulation further comprises: a sweetener; a bitterness masking agent; and a flavoring agent. 15. The method of claim 1, wherein the liquid formulation is prepared from a crystalline form of the compound of formula (I) having the formula (I-HS): ##STR00034## 16. The method of claim 15, wherein the crystalline form is characterized by having XRPD diffraction peaks (2.theta. degrees) at 18.4.+-.0.2, 20.7.+-.0.2, 23.1.+-.0.2, and 24.0.+-.0.2. 17. The method of claim 15, wherein the crystalline form is characterized by having XRPD diffraction peaks (2.theta. degrees) at 10.7.+-.0.2, 18.4.+-.0.2, 20.7.+-.0.2, 23.1.+-.0.2, and 24.0.+-.0.2. 18. The method of claim 15, wherein the crystalline form is characterized by having XRPD diffraction peaks (2.theta. degrees) at 10.7.+-.0.2, 18.4.+-.0.2, 19.2.+-.0.2, 20.2.+-.0.2, 20.7.+-.0.2, 21.5.+-.0.2, 23.1.+-.0.2, and 24.0.+-.0.2. 19. The method of claim 15, wherein the crystalline form is characterized by having XRPD diffraction peaks (2.theta. degrees) at 10.7.+-.0.2, 15.3.+-.0.2, 16.5.+-.0.2, 18.4.+-.0.2, 19.2.+-.0.2, 19.9.+-.0.2, 20.2.+-.0.2, 20.7.+-.0.2, 21.5.+-.0.2, 22.1.+-.0.2, 23.1.+-.0.2, 24.0.+-.0.2, 24.4.+-.0.2, 25.6.+-.0.2, 26.5.+-.0.2, 27.6.+-.0.2, 28.2.+-.0.2, 28.7.+-.0.2, 30.8.+-.0.2, and 38.5.+-.0.2. 20. The method of claim 1, wherein the compound of formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof, is administered in 28-day cycles. 21. The method of claim 1, wherein the compound is administered in a dosage calculated to be the equal to the exposure of an adult taking the compound of formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof, at a dose of 100 mg twice a day. 22. The method of claim 1, wherein the Trk-associated pediatric cancer is associated with or having a dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same and wherein the dysregulation of a NTRK gene, a Trk protein, or expression or level of the same is a chromosome translation that results in the translation of a Trk fusion protein. 23. The method of claim 22, wherein the Trk fusion protein is selected from the group consisting of ETV6-NTRK3, RET/NTRK1, TPM3-NTRK1, BTBD1-NTRK3, VCL-NTRK2, AGBL4-NTRK2, LMNA-NTRK1, TFG-NTRK1, QKI-NTRK2, NACC2-NTRK2, TPR-NTRK1, RABGAP1L-NTRK1, MPRIP-NTRK1, SQSTM1-NTRK1, EML4-NTRK3, and AFAP1-NTRK2. 24. The method of claim 23, wherein the Trk fusion protein is ETV6-NTRK3. 25. The method of claim 1, wherein the Trk-associated pediatric cancer is associated with or having a dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same and wherein the dyregulation of a NTRK gene, a Trk protein, or expression or activity of the same is one or more point mutations in the gene. 26. The method of claim 25, wherein the one or more point mutations in the gene is one or more of (i) a TrkA point mutation selected from the group consisting of C6773T, C7232T, C7301T, R33W, A336E, A337T, R324Q, R324W, V420M, R444Q, R444W, G517R, G517V, K538A, V573M, F589L, G595R, G667C, F598L, R649W, R649L, R682S, V683G, R702C, Q627X, Q597X, and Q633X; (ii) a TrkB point mutation selected from the group consisting of A13T, E142K, R136H, V619M, F633L, G639R, G709C, G709A, and G709S; and/or (iii) a TrkC point mutation selected from the group consisting of V603M, F617L, G623R, G696C, G696A, and G696S. 27. The method of claim 1, wherein the compound of formula (I) has a concentration of about 20 mg/mL in the liquid formulation.