STUBBS MATTHEW C (US)
CHEN YING-NAN PAN (US)
PUSEY MICHELLE (US)
WO2020041466A1 | 2020-02-27 | |||
WO2018014829A1 | 2018-01-25 | |||
WO2007070514A1 | 2007-06-21 | |||
WO2018014829A1 | 2018-01-25 | |||
WO2010083283A2 | 2010-07-22 |
US20060047369W | 2006-12-12 | |||
CN2017093385W | 2017-07-18 | |||
US7598257B2 | 2009-10-06 | |||
US8722693B2 | 2014-05-13 | |||
US9249149B2 | 2016-02-02 |
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CLAIMS 1. A combination therapy comprising an ALK2 inhibitor, or pharmaceutically acceptable salt thereof, and a JAK2 inhibitor having the Formula I: or a pharmaceutically acceptable salt thereof; wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; R4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C1-4 alkyl, and C1-4 alkoxy; and Z is 3-6 membered cycloalkyl; for use in the treatment of cancer in a subject in need thereof. 2. The combination therapy of claim 1, wherein R1, R2 and R3 are all hydrogen, and R4 is cyano. 3. The combination therapy of claim 1 or 2, wherein the JAK2 inhibitor of Formula I is 3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof. 4. The combination therapy of any one of claims 1-3, wherein the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1- yl]propanenitrile, or a pharmaceutically acceptable salt thereof. 5. The combination therapy of any one of claims 1-4, wherein the ALK2 inhibitor is a compound of Formula II: or a pharmaceutically acceptable salt thereof; wherein R1 is bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C1-C3 alkoxy; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, all of which are optionally substituted with R3; and R3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO2-C1-C3 alkyl, and SO3H. 6. The combination therapy of claim 5, wherein R1 is bridged C8-cycloalkyl substituted with hydroxy. 7. The combination therapy of claim 5 or 6, wherein R2 is tetrahydropyran. 8. The combination therapy of any one of claims 1-7, wherein the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4- yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. 9. The combination therapy of claim 8, wherein the ALK2 inhibitor of Formula II is 2- amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3- azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. 10. The combination therapy of claim 8, wherein the ALK2 inhibitor of Formula II is 2- amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3- azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. 11. The combination therapy of any one of claims 1-10, wherein the ALK2 inhibitor and JAK2 inhibitor are administered in a single formulation. 12. The combination therapy of claim 11, further comprising a pharmaceutically acceptable carrier. 13. The combination therapy of any one of claims 1-10, wherein the ALK2 inhibitor and JAK2 inhibitor are administered separately. 14. The combination therapy of any one of claims 1-13, wherein the cancer is a myeloproliferative neoplasm or a myelodysplastic syndrome. 15. The combination therapy of claim 14, wherein the cancer is selected from the group consisting of chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, atypical chronic myelogenous leukemia, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). 16. The combination therapy of claim 14 or 15, wherein the cancer is myelofibrosis (MF). 17. The combination therapy of any one of claims 14-16, wherein the cancer is selected from the group consisting of primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis. 18. The combination therapy of any one of claims 1-17, wherein the subject is human. 19. The combination therapy of any one of claims 1-18, wherein the treatment comprises administering the ALK2 inhibitor and the JAK2 inhibitor at substantially the same time. 20. The combination therapy of any one of claims 1-10 and 13-18, wherein the treatment comprises administering the ALK2 inhibitor and the JAK2 inhibitor at different times. 21. The combination therapy of claim 20, wherein the ALK2 inhibitor is administered to the subject, followed by administration of the JAK2 inhibitor. 22. The combination therapy of claim 20, wherein the JAK2 inhibitor is administered to the subject, followed by administration of the ALK2 inhibitor. 23. The combination therapy of any one of claims 1-22, wherein the ALK2 inhibitor and/or the JAK2 inhibitor are administered at dosages that would not be effective when one or both of the ALK2 inhibitor and the JAK2 inhibitor are administered alone, but which amounts are effective in combination. 24. A combination therapy comprising 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5- (4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or pharmaceutically acceptable salts thereof, for use in the treatment of cancer in a subject in need thereof. 25. A pharmaceutical combination comprising (i) a JAK2 inhibitor having the Formula I: or a pharmaceutically acceptable salt thereof; wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; R4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C1-4 alkyl, and C1-4 alkoxy; Z is 3-6 membered cycloalkyl; and (ii) an ALK2 inhibitor having the Formula II: or a pharmaceutically acceptable salt thereof; wherein R1 is bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C1-C3 alkoxy; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, all of which are optionally substituted with R3; and R3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO2-C1-C3 alkyl, and SO3H. 26. The pharmaceutical combination of claim 25, wherein the JAK2 inhibitor is 3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof. 27. The pharmaceutical combination of claim 25 or 26, wherein the JAK2 inhibitor is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof. 28. The pharmaceutical combination of any one of claims 25-27, wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)- 3-aza-bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. 29. The pharmaceutical combination of any one of claims 25-28, wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H- pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. 30. The pharmaceutical combination of any one of claims 25-28, wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H- pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. 31. A pharmaceutical composition comprising an ALK2 inhibitor, a pharmaceutically acceptable carrier, and a JAK2 inhibitor having the Formula I: or a pharmaceutically acceptable salt thereof; wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; R4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C1-4 alkyl, and C1-4 alkoxy; and Z is 3-6 membered cycloalkyl. 32. The pharmaceutical composition of claim 31, wherein R1, R2 and R3 are all hydrogen, and R4 is cyano. 33. The pharmaceutical composition of claim 31 or 32, wherein the JAK2 inhibitor is 3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof. 34. The pharmaceutical composition of any one of claims 31-33, wherein the JAK2 inhibitor is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1- yl]propanenitrile, or a pharmaceutically acceptable salt thereof. 35. The pharmaceutical composition of any one of claims 31-34, wherein the ALK2 inhibitor is a compound of Formula II: or a pharmaceutically acceptable salt thereof; wherein R1 is bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C1-C3 alkoxy; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, all of which are optionally substituted with R3; and R3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO2-C1-C3 alkyl, and SO3H. 36. The pharmaceutical composition of claim 35, wherein R1 is bridged C8-cycloalkyl substituted with hydroxyl. 37. The pharmaceutical composition of claim 35 or 36, wherein R2 is tetrahydropyran. 38. The pharmaceutical composition of any one of claims 31-37, wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)- 3-aza-bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. 39. The pharmaceutical composition of any one of claims 31-38, wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H- pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. 40. The pharmaceutical composition of any one of claims 31-38, wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H- pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. 41. A method of treating myelofibrosis (MF) comprising administering to a subject in need thereof an ALK2 inhibitor that is a compound of Formula II: or a pharmaceutically acceptable salt thereof; wherein R1 is bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C1-C3 alkoxy; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, all of which are optionally substituted with R3; and R3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO2-C1-C3 alkyl, and SO3H; wherein the compound of Formula II is administered as a monotherapy. 42. The method of claim 41, wherein the compound of Formula II is 2-amino-N-(4- hydroxy-bicyclo-[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-aza-bicyclo[3.1.0]- hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II is administered as a monotherapy. 43. A method of treating myelofibrosis (MF)-induced anemia comprising administering to a subject in need thereof a JAK2 inhibitor having the Formula I: or a pharmaceutically acceptable salt thereof; wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; R4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C1-4 alkyl, and C1-4 alkoxy; and Z is 3-6 membered cycloalkyl; and an ALK2 inhibitor that is a compound of Formula II: or a pharmaceutically acceptable salt thereof; wherein R1 is bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C1-C3 alkoxy; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, all of which are optionally substituted with R3; and R3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO2-C1-C3 alkyl, and SO3H. 44. The method of claim 43, wherein the JAK2 inhibitor of Formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof; and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5- (4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt or hydrate thereof. |
or a pharmaceutically acceptable salt thereof; wherein R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy; and Z is 3-6 membered cycloalkyl. In an embodiment of Formula I, R 1 is hydrogen. In another embodiment, R 2 is hydrogen. In yet another embodiment, R 3 is hydrogen. In still another embodiment, R 4 is cyano. In an embodiment, R 1 , R 2 and R 3 are all hydrogen, and R 4 is cyano. In another embodiment, Z is cyclopentyl. In an embodiment of the pharmaceutical composition, the ALK2 inhibitor is a compound of Formula II: or a pharmaceutically acceptable salt thereof; wherein R 1 is bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C 1 -C 3 alkoxy; R 2 is selected from the group consisting of C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 3 alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, all of which are optionally substituted with R 3 ; and R 3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO 2 -C 1 -C 3 alkyl, and SO 3 H. In an embodiment of Formula II, R 1 is bridged C 8 -cycloalkyl substituted with hydroxyl. In another embodiment, R 2 is tetrahydropyran. In yet another embodiment, R 1 is bridged C 8 - cycloalkyl substituted with hydroxyl and R 2 is tetrahydropyran. In another aspect, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier, (i) a JAK2 inhibitor having the Formula I: or a pharmaceutically acceptable salt thereof; wherein R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy; Z is 3-6 membered cycloalkyl; and (ii) an ALK2 inhibitor having the Formula IIa: or a pharmaceutically acceptable salt thereof; wherein L is a bond, (CH 2 ) n , -CH(CH 3 )-, -O-(CH 2 ) n -, -C(O)-, or -C(O)-NH-(CH 2 ) n -; n is 1, 2, or 3; R 1 is selected from 3-7 membered cycloalkyl optionally substituted one, two, or three times with a substituent independently selected from hydroxyl, halogen, C 1 -C 3 alkyl; bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C 1 -C 3 alkoxy; R 4 and R 5 are each independently selected from the group consisting of H, halogen, C 1 -C 3 alkyl; R 6 is 5-10 membered heterocycloalkyl optionally substituted one, two, or three times with R 2 ; R 2 is independently, at each occurrence, selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxy-C 1 -C 3 alkyl, C 1 -C 3 alkyl, C 2 -C 4 alkynyl, C 1 -C 3 alkyl, (CH 2 ) m - R 3 , wherein alkyl and alkoxy are optionally substituted one, two, or three times independently with halo or cyano; m is 0, 1, 2 or 3; R 3 is 4-6 membered heterocycloalkyl optionally substituted one, two, or three times with a substituent independently selected from the group consisting of oxo, SO 2 -C 1 -C 3 alkyl, C 1 -C 3 alkyl, and 3-6 membered cycloalkyl, wherein alkyl and cycloalkyl are optionally substituted one, two, or three times with halo; alternatively, two R 3 , together with the atoms to which they are attached, form a 3-6 membered cycloalkyl. In an embodiment of Formula IIa, L-R 6 is wherein y is 1, 2, or 3. In an embodiment of the pharmaceutical compositions, the ALK2 inhibitor of Formula IIa is a compound of Formula IIb: or a pharmaceutically acceptable salt thereof. In an embodiment of Formula IIa and Formula IIb, R 1 is bridged C 8 -cycloalkyl substituted with hydroxyl. In another embodiment, R 2 is tetrahydropyran. In yet another embodiment, R 1 is bridged C 8 -cycloalkyl substituted with hydroxyl and R 2 is tetrahydropyran. In yet another aspect, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier, (i) a JAK2 inhibitor having the Formula I:
or a pharmaceutically acceptable salt thereof; wherein R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy; Z is 3-6 membered cycloalkyl; and (ii) an ALK2 inhibitor having the Formula II: or a pharmaceutically acceptable salt thereof; wherein R 1 is bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C 1 -C 3 alkoxy; R 2 is selected from the group consisting of C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 3 alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, all of which are optionally substituted with R 3 ; and R 3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO 2 -C 1 -C 3 alkyl, and SO 3 H. In an embodiment of Formula I, R 1 is hydrogen. In another embodiment, R 2 is hydrogen. In yet another embodiment, R 3 is hydrogen. In still another embodiment, R 4 is cyano. In an embodiment, R 1 , R 2 and R 3 are all hydrogen, and R 4 is cyano. In another embodiment, Z is cyclopentyl. In an embodiment of Formula II, R 1 is bridged C 8 -cycloalkyl substituted with hydroxyl. In another embodiment, R 1 is In yet another embodiment of Formula II, R 2 is tetrahydropyran. In another embodiment, R 1 is bridged C 8 -cycloalkyl substituted with hydroxyl and R 2 is tetrahydropyran. In another embodiment of the pharmaceutical composition, the JAK2 inhibitor of Formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra zol-1-yl]propane- nitrile, or a pharmaceutically acceptable salt thereof. In yet another embodiment of the pharmaceutical composition, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H -pyrazol-1-yl]- propanenitrile, or a pharmaceutically acceptable salt thereof. In another embodiment of the pharmaceutical composition, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H -pyrazol-1-yl]- propanenitrile phosphoric acid salt. In still another embodiment of the pharmaceutical composition, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetr ahydro-2H-pyran-4- yl)-3-aza-bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. In an embodiment of the pharmaceutical composition, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S) -3-(tetrahydro-2H-pyran-4- yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof. In another embodiment of the pharmaceutical composition, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1S,5R) -3-(tetrahydro-2H- pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinami de, or a pharmaceutically acceptable salt thereof. In yet another embodiment of the pharmaceutical composition, the JAK2 inhibitor of Formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra zol-1-yl]propane- nitrile, or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-(3-(tetr ahydro-2H-pyran-4-yl)-3- azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. In still another embodiment of the pharmaceutical composition, the JAK2 inhibitor of Formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra zol-1-yl]propane- nitrile phosphoric acid salt, and the ALK2 inhibitor of Formula II is 2-amino-N-(4- hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyr an-4-yl)-3-azabicyclo- [3.1.0]hexan-1-yl)phenyl)-nicotinamide, or a pharmaceutically acceptable salt thereof. In an embodiment of the pharmaceutical composition, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H -pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of Formula II is 2-amino- N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetr ahydro-2H-pyran-4-yl)-3- azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof. In another embodiment of the pharmaceutical composition, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H -pyrazol-1- yl]propanenitrile phosphoric acid salt, and the ALK2 inhibitor of Formula II is 2-amino-N-(4- hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydr o-2H-pyran-4-yl)-3-azabicyclo- [3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof. In one embodiment, the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S. In another embodiment, isotopically-labeled compounds are useful in drug or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet another embodiment, the compounds described herein include a 2 H (i.e., deuterium) isotope. In still another embodiment, substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. The specific compounds described herein, and other compounds encompassed by one or more of the formulas described herein having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compounds as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the Formulas as provided herein. In some embodiments, the JAK2 inhibitor is ruxolitinib (a JAK1/2 inhibitor). Ruxolitinib ((R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) -3-cyclopentylpropanenitrile) (sometimes referred to as INCB018424), and its pharmaceutically acceptable salts have been previously been described in U.S. Patent No.7,598,257, which is incorporated herein by reference in its entirety. Ruxolitinib phosphate is described in U.S. Patent No.8,722,693, which is incorporated herein by reference in its entirety. The present disclosure describes, inter alia, combination methods using ruxolitinib, or a pharmaceutically acceptable salt thereof.In some embodiments, the JAK2 inhibitor is ruxolitinib, wherein one or more hydrogen atoms are replaced by deuterium atoms, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK2 inhibitor is any of the compounds in US Patent 9,249,149 (which is incorporated herein by reference in its entirety), or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK2 inhibitor is CTP-543, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula III: or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from H and D; each R 2 is independently selected from H and D, provided that each R 2 attached to a common carbon is the same; each R 3 is independently selected from H and D, provided that each R 3 attached to a common carbon is the same; R 4 is selected from H and D; each R 5 is the same and is selected from H and D; and R 6 , R 7 , and R 8 are each independently selected from H and D; provided that when R 1 is H, each R 2 and each R 3 are H, R 4 is H, and each of R 6 , R 7 , and R 8 is H, then each R 5 is D. In some embodiments, the JAK2 inhibitor is a compound of Formula III selected from the following compounds 100-130 in the table below (wherein R 6 , R 7 , and R 8 are each H), or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK2 inhibitor is a compound of Formula III selected from the following compounds 200-231 in the table below (wherein R 6 , R 7 , and R 8 are each D), or a pharmaceutically acceptable salt thereof.
In some embodiments, the JAK2 inhibitor is baricitinib. In some embodiments, the JAK2 ihhibitor is fedratinib. In some embodiments, the JAK2 ihhibitor is momelotinib. In some embodiments, the JAK2 inhibitor is BMS-911543. In some embodiments, the JAK2 inhibitor is pacritinib. In some embodiments, the JAK2 inhibitor is NS-018. In some embodiments, the JAK2 inhibitor is NVP-BBT594. In some embodiments, the JAK2 inhibitor is NVP-CHZ868. Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein. Methods of Treatment Also provided herein is a combination therapy comprising administering to a subject in need thereof an ALK2 inhibitor, or pharmaceutically acceptable salt thereof, and a JAK2 inhibitor, or pharmaceutically acceptable salt thereof. In an embodiment of the combination therapy, the JAK2 inhibitor is a compound of Formula I:
or a pharmaceutically acceptable salt thereof; wherein R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy; and Z is 3-6 membered cycloalkyl. In an embodiment of Formula I, R 1 is hydrogen. In another embodiment, R 2 is hydrogen. In yet another embodiment, R 3 is hydrogen. In still another embodiment, R 4 is cyano. In an embodiment, R 1 , R 2 and R 3 are all hydrogen, and R 4 is cyano. In another embodiment, Z is cyclopentyl. In another embodiment of the combination therapy, the ALK2 inhibitor is a compound of Formula II: or a pharmaceutically acceptable salt thereof; wherein R 1 is bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C 1 -C 3 alkoxy; R 2 is selected from the group consisting of C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 3 alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, all of which are optionally substituted with R 3 ; and R 3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO 2 -C 1 -C 3 alkyl, and SO 3 H. In an embodiment of Formula II, R 1 is bridged C 8 -cycloalkyl substituted with hydroxyl. In another embodiment, R 1 is In yet another embodiment of Formula II, R 2 is tetrahydropyran. In another embodiment, R 1 is bridged C 8 -cycloalkyl substituted with hydroxyl and R 2 is tetrahydropyran. In another embodiment of the combination therapy, the JAK2 inhibitor of Formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra zol-1-yl]propane-nitrile, or a pharmaceutically acceptable salt thereof. In yet another embodiment of the combination therapy, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H -pyrazol-1-yl]-propanenitrile, or a pharmaceutically acceptable salt thereof. In another embodiment of the combination therapy, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H -pyrazol-1-yl]-propanenitrile phosphoric acid salt. In still another embodiment of the combination therapy, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetr ahydro-2H-pyran-4-yl)-3-aza- bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. In an embodiment of the combination therapy, the ALK2 inhibitor of Formula II is 2- amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3 -(tetrahydro-2H-pyran-4-yl)-3- azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof. In another embodiment of the combination therapy, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1S,5R) -3-(tetrahydro-2H-pyran-4-yl)-3- azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. In yet another embodiment of the combination therapy, the JAK2 inhibitor of Formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra zol-1-yl]propane-nitrile, or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of Formula II is 2-amino-N- (4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H- pyran-4-yl)-3-azabicyclo- [3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. In still another embodiment of the combination therapy, the JAK2 inhibitor of Formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra zol-1-yl]propane-nitrile phosphoric acid salt, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo- [2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azab icyclo-[3.1.0]hexan-1-yl)phenyl)- nicotinamide, or a pharmaceutically acceptable salt thereof. In an embodiment of the combination therapy, the JAK2 inhibitor of Formula I is (3R)- 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra zol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of Formula II is 2-amino-N- (4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrah ydro-2H-pyran-4-yl)-3-azabicyclo- [3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof. In another embodiment of the combination therapy, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H -pyrazol-1-yl]propanenitrile phosphoric acid salt, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo- [2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl )-3-azabicyclo-[3.1.0]hexan-1- yl)phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof. The combination therapy provided herein can be used in a method of treating a disease or condition in a subject, said method comprising administering to the subject in need thereof a combination or composition comprising compounds provided herein, or pharmaceutically acceptable salts thereof. In an aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an ALK2 inhibitor, or pharmaceutically acceptable salt thereof, and a JAK2 inhibitor, or pharmaceutically acceptable salt thereof. In an aspect, provided herein is a method of treating anemia in a subject in need thereof, comprising administering to the subject an ALK2 inhibitor, or pharmaceutically acceptable salt thereof, and a JAK2 inhibitor, or pharmaceutically acceptable salt thereof. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an ALK2 inhibitor, or pharmaceutically acceptable salt thereof, and a JAK2 inhibitor having the Formula I: or a pharmaceutically acceptable salt thereof; wherein R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy; and Z is 3-6 membered cycloalkyl. In an embodiment of the methods, the ALK2 inhibitor is a compound of Formula II: or a pharmaceutically acceptable salt thereof; wherein R 1 is bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C 1 -C 3 alkoxy; R 2 is selected from the group consisting of C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 3 alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, all of which are optionally substituted with R 3 ; and R 3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO 2 -C 1 -C 3 alkyl, and SO 3 H. In yet another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject: (i) a JAK2 inhibitor having the Formula I: or a pharmaceutically acceptable salt thereof; wherein R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy; Z is 3-6 membered cycloalkyl; and (ii) an ALK2 inhibitor having the Formula IIa: or a pharmaceutically acceptable salt thereof; wherein L is a bond, (CH 2 ) n , -CH(CH 3 )-, -O-(CH 2 ) n -, -C(O)-, or -C(O)-NH-(CH 2 ) n -; n is 1, 2, or 3; R 1 is selected from 3-7 membered cycloalkyl optionally substituted one, two, or three times with a substituent independently selected from hydroxyl, halogen, C 1 -C 3 alkyl; bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C 1 -C 3 alkoxy; R 4 and R 5 are each independently selected from the group consisting of H, halogen, C 1 -C 3 alkyl; R 6 is 5-10 membered heterocycloalkyl optionally substituted one, two, or three times with R 2 ; R 2 is independently, at each occurrence, selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxy-C 1 -C 3 alkyl, C 1 -C 3 alkyl, C 2 -C 4 alkynyl, C 1 -C 3 alkyl, (CH 2 ) m - R 3 , wherein alkyl and alkoxy are optionally substituted one, two, or three times independently with halo or cyano; m is 0, 1, 2 or 3; R 3 is 4-6 membered heterocycloalkyl optionally substituted one, two, or three times with a substituent independently selected from the group consisting of oxo, SO 2 -C 1 -C 3 alkyl, C 1 -C 3 alkyl, and 3-6 membered cycloalkyl, wherein alkyl and cycloalkyl are optionally substituted one, two, or three times with halo; alternatively, two R 3 , together with the atoms to which they are attached, form a 3-6 membered cycloalkyl. In an embodiment of Formula IIa, L-R 6 is wherein y is 1, 2, or 3. In an embodiment of the methods, the ALK2 inhibitor of Formula IIa is a compound of Formula IIb: or a pharmaceutically acceptable salt thereof. In an embodiment of Formula IIa and Formula IIb, R 1 is bridged C 8 -cycloalkyl substituted with hydroxyl. In another embodiment, R 2 is tetrahydropyran. In yet another embodiment, R 1 is bridged C 8 -cycloalkyl substituted with hydroxyl and R 2 is tetrahydropyran. In yet another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject (i) a JAK2 inhibitor having the Formula I: or a pharmaceutically acceptable salt thereof; wherein R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy; Z is 3-6 membered cycloalkyl; and (ii) an ALK2 inhibitor having the Formula II: or a pharmaceutically acceptable salt thereof; wherein R 1 is bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C 1 -C 3 alkoxy; R 2 is selected from the group consisting of C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 3 alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, all of which are optionally substituted with R 3 ; and R 3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO 2 -C 1 -C 3 alkyl, and SO 3 H. In an embodiment of Formula I, R 1 is hydrogen. In another embodiment, R 2 is hydrogen. In yet another embodiment, R 3 is hydrogen. In still another embodiment, R 4 is cyano. In an embodiment, R 1 , R 2 and R 3 are all hydrogen, and R 4 is cyano. In another embodiment, Z is cyclopentyl. In another embodiment of the methods, the JAK2 inhibitor of Formula I is 3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo l-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof. In yet another embodiment of the methods, the JAK2 inhibitor of Formula I is (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo l-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof. In another embodiment of the methods, the JAK2 inhibitor of Formula I is (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo l-1-yl]-propanenitrile phosphoric acid salt. In still another embodiment of the methods, the ALK2 inhibitor of Formula II is 2- amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrah ydro-2H-pyran-4-yl)-3-aza- bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. In an embodiment of the methods, the ALK2 inhibitor of Formula II is 2-amino-N-(4- hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydr o-2H-pyran-4-yl)-3-azabicyclo- [3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof. In another embodiment of the methods, the ALK2 inhibitor of Formula II is 2-amino- N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetr ahydro-2H-pyran-4-yl)-3- azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. In yet another embodiment of the methods, the JAK2 inhibitor of Formula I is 3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo l-1-yl]propane-nitrile, or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of Formula II is 2-amino-N- (4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H- pyran-4-yl)-3-azabicyclo[3.1.0]- hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. In still another embodiment of the methods, the JAK2 inhibitor of Formula I is 3-cyclo- pentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-y l]propane-nitrile phosphoric acid salt, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5- (4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1 -yl)phenyl)-nicotinamide, or a pharmaceutically acceptable salt thereof. In an embodiment of the methods, the JAK2 inhibitor of Formula I is (3R)-3-cyclo- pentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-y l]propanenitrile, or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of Formula II is 2-amino-N- (4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrah ydro-2H-pyran-4-yl)-3-azabicyclo- [3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof. In another embodiment of the methods, the JAK2 inhibitor of Formula I is (3R)-3- cyclo-pentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyraz ol-1-yl]propanenitrile phosphoric acid salt, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1- yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo- [3.1.0]hexan-1-yl)phenyl)- nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof. In an embodiment of the methods, the ALK2 inhibitor and JAK2 inhibitor are administered separately. In an aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an ALK2 inhibitor, or pharmaceutically acceptable salt thereof. In an embodiment of the method of treating cancer, the ALK2 inhibitor is a compound of Formula IIa: or a pharmaceutically acceptable salt thereof; wherein L is a bond, (CH 2 ) n , -CH(CH 3 )-, -O-(CH 2 ) n -, -C(O)-, or -C(O)-NH-(CH 2 ) n -; n is 1, 2, or 3; R 1 is selected from 3-7 membered cycloalkyl optionally substituted one, two, or three times with a substituent independently selected from hydroxyl, halogen, C 1 -C 3 alkyl; bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C 1 -C 3 alkoxy; R 4 and R 5 are each independently selected from the group consisting of H, halogen, C 1 -C 3 alkyl; R 6 is 5-10 membered heterocycloalkyl optionally substituted one, two, or three times with R 2 ; R 2 is independently, at each occurrence, selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxy-C 1 -C 3 alkyl, C 1 -C 3 alkyl, C 2 -C 4 alkynyl, C 1 -C 3 alkyl, (CH 2 ) m - R 3 , wherein alkyl and alkoxy are optionally substituted one, two, or three times independently with halo or cyano; m is 0, 1, 2 or 3; R 3 is 4-6 membered heterocycloalkyl optionally substituted one, two, or three times with a substituent independently selected from the group consisting of oxo, SO 2 -C 1 -C 3 alkyl, C 1 -C 3 alkyl, and 3-6 membered cycloalkyl, wherein alkyl and cycloalkyl are optionally substituted one, two, or three times with halo; alternatively, two R 3 , together with the atoms to which they are attached, form a 3-6 membered cycloalkyl. In an embodiment of the cancer treatment, Formula IIa, L-R 6 is wherein y is 1, 2, or 3. In an embodiment of the cancer treatment, the ALK2 inhibitor of Formula IIa is a compound of Formula IIb: or a pharmaceutically acceptable salt thereof. In an embodiment of Formula IIa and Formula IIb, R 1 is bridged C 8 -cycloalkyl substituted with hydroxyl. In another embodiment, R 2 is tetrahydropyran. In yet another embodiment, R 1 is bridged C 8 -cycloalkyl substituted with hydroxyl and R 2 is tetrahydropyran. In another embodiment of the method of treating cancer, the ALK2 inhibitor of Formula IIa is a compound of Formula II: or a pharmaceutically acceptable salt thereof; wherein R 1 is bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C 1 -C 3 alkoxy; R 2 is selected from the group consisting of C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 3 alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, all of which are optionally substituted with R 3 ; and R 3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO 2 -C 1 -C 3 alkyl, and SO 3 H. In still another embodiment of the method of treating cancer, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetr ahydro-2H-pyran-4- yl)-3-aza-bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. In an embodiment of the method of treating cancer, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S) -3-(tetrahydro-2H-pyran-4-yl)-3- azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof. In another embodiment of the method of treating cancer, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1S,5R) -3-(tetrahydro-2H- pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinami de, or a pharmaceutically acceptable salt thereof. In yet another embodiment of the method of treating cancer, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S) -3-(tetrahydro-2H- pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)-nicotinam ide fumarate dihydrate. In another embodiment of the method of treating cancer, the ALK2 inhibitor is administered as a monotherapy. In yet another embodiment of the method of treating cancer, the ALK2 inhibitor is administered in the absence of any other active pharmaceutical ingredient. In still another embodiment of the method of treating cancer, the ALK2 inhibitor is administered in the absence of a Janus Kinase inhibitor. In another embodiment of the methods, the cancer is a myeloproliferative neoplasm. In another embodiment of the methods, the cancer is a myelodysplastic syndrome. Myelodysplastic syndromes (MDS) can include hematopoietic stem cell disorders characterized by one or more of the following: ineffective blood cell production, progressive cytopenias, risk of progression to acute leukemia or cellular marrow with impaired morphology and maturation (dysmyelopoiesis). Myelodysplastic syndromes can also include refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation and chronic myelomonocytic leukemia. In yet another embodiment of the methods, the cancer is selected from the group consisting of chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, atypical chronic myelogenous leukemia, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). In still another embodiment, the cancer is myelofibrosis (MF). In an embodiment of the methods, the cancer is selected from the group consisting of primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis. In an aspect, provided herein is a method of treating anemia in a subject in need thereof, comprising administering to the subject a JAK2 inhibitor of Formula I and an ALK2 inhibitor of Formula II. In another embodiment of the methods, the anemia is cancer-induced anemia. In another embodiment of the methods, the anemia is due to myeloproliferative or myelodysplastic hematological malignancies. In another embodiment of the methods, the anemia is a myelofibrosis-induced anemia. In an embodiment of the methods of treating anemia, the JAK2 inhibitor of Formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra zol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof; and the ALK2 inhibitor of Formula II is 2-amino-N- (4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-p yran-4-yl)-3-azabicyclo[3.1.0]- hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt or hydrate thereof. In another embodiment of the methods, the subject is human. In yet another embodiment of the methods, the treatment comprises administering the ALK2 inhibitor and the JAK2 inhibitor at substantially the same time. In still another embodiment of the methods, the treatment comprises administering the ALK2 inhibitor and the JAK2 inhibitor at different times. In an embodiment of the methods, the ALK2 inhibitor is administered to the subject, followed by administration of the JAK2 inhibitor. In another embodiment, the JAK2 inhibitor is administered to the subject, followed by administration of the ALK2 inhibitor. In another embodiment of the methods, the ALK2 inhibitor and/or JAK2 inhibitor are administered at dosages that would not be effective when one or both of the ALK2 inhibitor and the JAK2 inhibitor are administered alone, but which amounts are effective in combination. In yet another aspect, provided herein is a method of treating a cancer comprising administering to a subject in need thereof 2-amino-N-(4-hydroxy-bicyclo-[2.2.2]octan-1-yl)-5- (4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0] -hexan-1-yl)phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof, and (3R)-3-cyclopentyl-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenit rile, or pharmaceutically acceptable salts thereof. In still another aspect, provided herein is a method of treating a cancer comprising administering to a subject in need thereof 2-amino-N-(4-hydroxy-bicyclo-[2.2.2]octan-1-yl)-5- (4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0] -hexan-1-yl)phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof, and (3R)-3-cyclopentyl-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenit rile phosphoric acid salt. In an aspect, provided herein is a method of treating myelofibrosis (MF) comprising administering to a subject in need thereof 2-amino-N-(4-hydroxy-bicyclo-[2.2.2]octan-1-yl)-5- (4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0] -hexan-1-yl)phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof, and (3R)-3-cyclopentyl-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenit rile, or pharmaceutically acceptable salts thereof. In another aspect, provided herein is a method of treating myelofibrosis comprising administering to a subject in need thereof 2-amino-N-(4-hydroxy-bicyclo-[2.2.2]octan-1-yl)-5- (4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0] -hexan-1-yl)phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof, and (3R)-3-cyclopentyl-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenit rile phosphoric acid salt. In yet another aspect, provided herein is a method of treating polycythemia vera (PV) comprising administering to a subject in need thereof 2-amino-N-(4-hydroxy-bicyclo-[2.2.2]- octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-aza bicyclo[3.1.0]-hexan-1-yl)- phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof, and (3R)- 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra zol-1-yl]propanenitrile, or pharmaceutically acceptable salts thereof. In another aspect, provided herein is a method of treating polycythemia vera (PV) comprising administering to a subject in need thereof 2-amino-N-(4-hydroxy-bicyclo-[2.2.2]- octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-aza bicyclo[3.1.0]-hexan-1-yl)- phenyl)nicotinamide (Compound A), or a pharmaceutically acceptable salt thereof, and (3R)- 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra zol-1-yl]propanenitrile phosphoric acid salt. In yet another aspect, provided herein is a method of treating myelofibrosis (MF) comprising administering to a subject in need thereof an ALK2 inhibitor that is a compound of Formula II: or a pharmaceutically acceptable salt thereof; wherein R 1 is bridged 5-10 membered cycloalkyl optionally substituted one, two, or three times with hydroxyl or C 1 -C 3 alkoxy; R 2 is selected from the group consisting of C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 3 alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, all of which are optionally substituted with R 3 ; and R 3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO 2 -C 1 -C 3 ; wherein the compound of Formula II is administered as a monotherapy. In an embodiment of the method of treating myelofibrosis (MF), the compound of Formula II is 2-amino-N-(4-hydroxy-bicyclo-[2.2.2]octan-1-yl)-5-(4-(3-(tet rahydro-2H-pyran-4- yl)-3-aza-bicyclo[3.1.0]-hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. In an embodiment of the method of treating myelofibrosis (MF), the compound of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S) -3-(tetrahydro-2H- pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinami de, or a pharmaceutically acceptable salt thereof. In another embodiment of the method of treating myelofibrosis (MF), the compound of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1S,5R) -3-(tetrahydro- 2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotin amide, or a pharmaceutically acceptable salt thereof. In an embodiment of the method of treating myelofibrosis (MF), the compound of Formula II is 2-amino-N-(4-hydroxy-bicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S )-3-(tetrahydro-2H- pyran-4-yl)-3-azabicyclo[3.1.0]-hexan-1-yl)phenyl)nicotinami de fumarate dihydrate. In still another aspect, provided herein is a method of treating a JAK2-associated disorder comprising administering to a subject in need thereof a JAK2 inhibitor and an ALK2 inhibitor. In an embodiment of the methods, the JAK2-associated disorder is selected from the group consisting of polycythemia vera, graft versus host disease, allograft rejection, atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis, allergic contact sensitization, pemphigus vulgaris (PV), and bullous pemphigoid (BP). In an embodiment of the methods, the method involves the administration of a therapeutically effective amount of a combination or composition comprising compounds provided herein, or pharmaceutically acceptable salts thereof, to a subject (including, but not limited to a human or animal) in need of treatment (including a subject identified as in need). In another embodiment of the methods, the treatment includes co-administering the amount of the ALK2 inhibitor and the amount of the JAK2 inhibitor. In an embodiment, the amount of the ALK2 inhibitor and the amount of the JAK2 inhibitor are in a single formulation or unit dosage form. In still other embodiments, the amount of the ALK2 inhibitor and the amount of the JAK2 inhibitor are in a separate formulations or unit dosage forms. In the foregoing methods, the treatment can include administering the amount of ALK2 inhibitor and the amount of JAK2 inhibitor at substantially the same time or administering the amount of ALK2 inhibitor and the amount of JAK2 inhibitor at different times. In some embodiments of the foregoing methods, the amount of ALK2 inhibitor and/or the amount of JAK2 inhibitor is administered at dosages that would not be effective when one or both of ALK2 inhibitor and JAK2 inhibitor is administered alone, but which amounts are effective in combination. In some embodiments, the method or treatment reduces hepcidin serum levels in patients relative to baseline, compared to normal levels in patients, or compared to levels in patients treated with the JAK2 inhibitor alone. The hepcidin serum levels can be reduced by more than about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 100%. In some embodiments, the hepcidin serum levels are reduced by about 50% or more relative to baseline. In some embodiments, the hepcidin serum levels are reduced to less than about 150 ng/mL, 140, 130, 120, 110, 100, 90, 80, 70, 60 or about 50 ng/mL. Hepcidin levels can be tested by standard techniques, including radioimmunoassays, ELISA, ligand binding assay or mass spectrometry. In some embodiments, the method or treatment increases serum iron concentration in patients relative to baseline, compared to normal levels in patients or compared to levels in patients treated with the JAK2 inhibitor alone. The serum iron concentration can be increased by more than about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 100%. Serum iron concentration can be tested by standard techniques. In some embodiments, the method or treatment increases hemoglobin serum levels in patients relative to baseline, compared to normal levels in patients or compared to levels in patients treated with the JAK2 inhibitor alone. The hemoglobin serum levels can be increased by more than about 5%, 10%, 15%, 20%, 25% or about 30%. Hemoglobin levels can be tested by standard techniques. In some embodiments, the method or treatment increases transferrin saturation (TSAT) in patients relative to baseline, compared to normal levels in patients or compared to levels in patients treated with the JAK2 inhibitor alone. The TSAT can be increased by more than about 5%, 10%, 15%, 20%, 25% or about 30%. TSAT can be tested by standard techniques. In some embodiments, the method or treatment reduces ferritin blood levels in patients relative to baseline, compared to normal levels in patients, or compared to levels in patients treated with the JAK2 inhibitor alone. The ferritin blood levels can be reduced by more than about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 100%. Ferritin blood levels can be tested by standard techniques. Package Formulations Packaged pharmaceutical formulations or pharmaceutical products are included herein. Such packaged formulations include one or more pharmaceutical formulations comprising a combination of an ALK2 inhibitor and a JAK2 inhibitor. The combination of compounds in formulated form is contained in a container. The package typically contains instructions for using the formulation to treat an animal (typically a human patient) suffering from cancer or a JAK2-associated disorder. In certain embodiments the packaged pharmaceutical formulation or pharmaceutical product contains the combination of compounds described herein in a container with instructions for administering the dosage forms on a fixed schedule. In some of these embodiments, the combination of compounds is provided in separate unit dosage forms. In a particular embodiment, the compounds of the combination can be dosed on the same schedule, whether by administering a single formulation or unit dosage form containing all of the compounds of the combination, or by administering separate formulations or unit dosage forms of the compounds of the combination. However, some of the compounds used in the combination may be administered more frequently than once per day, or with different frequencies that other compounds in the combination. Therefore, in one embodiment the packaged pharmaceutical formation contains a formulation or unit dosage form containing all of the compounds in the combination of compounds, and an additional formulation or unit dosage form that includes one of the compounds in the combination of agents, with no additional active compound, in a container, with instructions for administering the dosage forms on a fixed schedule. The package formulations provided herein include comprise prescribing information, for example, to a patient or health care provider, or as a label in a packaged pharmaceutical formulation. Prescribing information may include for example efficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical formulation. In all of the foregoing the combination of compounds of the invention can be administered alone, as mixtures, or with additional active agents. Administration / Dosage / Formulations In another aspect, provided herein is a pharmaceutical composition or pharmaceutical combination comprising the compounds disclosed herein, together with a pharmaceutically acceptable carrier. Administration of the combination includes administration of the combination in a single formulation or unit dosage form, administration of the individual agents of the combination concurrently but separately, or administration of the individual agents of the combination sequentially by any suitable route. The dosage of the individual agents of the combination may require more frequent administration of one of the agent(s) as compared to the other agent(s) in the combination. Therefore, to permit appropriate dosing, packaged pharmaceutical products may contain one or more dosage forms that contain the combination of agents, and one or more dosage forms that contain one of the combination of agents, but not the other agent(s) of the combination. Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In particular, the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a disclosed compound for the treatment of pain, a depressive disorder, or drug addiction in a patient. In one embodiment, the compounds provided herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions provided herein comprise a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier. The drug compounds provided herein (for example, an ALK2 inhibitor and a JAK2 inhibitor) are present in the combinations, dosage forms, pharmaceutical compositions and pharmaceutical formulations disclosed herein in a ratio in the range of 100:1 to 1:100. For example, the ratio of a JAK2 inhibitor: an ALK2 inhibitor can be in the range of 1:100 to 1:1, for example, 1:100, 1:90, 1:80, 1:70, 1:60, 1:50, 1:40, 1:30, 1:20, 1:10, 1:5, 1:2, or 1:1 of JAK2 inhibitor : ALK2 inhibitor. In another example, the ratio of an ALK2 inhibitor : a JAK2 inhibitor can be in the range of 1:100 to 1:1, for example, 1:100, 1:90, 1:80, 1:70, 1:60, 1:50, 1:40, 1:30, 1:20, 1:10, 1:5, 1:2, or 1:1 of an ALK2 inhibitor : a JAK2 inhibitor. The optimum ratios, individual and combined dosages, and concentrations of the drug compounds that yield efficacy without toxicity are based on the kinetics of the active ingredients’ availability to target sites, and are determined using methods known to those of skill in the art. Routes of administration of any of the compositions discussed herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, the preferred route of administration is oral. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions are not limited to the particular formulations and compositions that are described herein. For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gel caps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. For parenteral administration, the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application. It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings of the present disclosure as set forth. EXAMPLES The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the skill of the art. Processes for preparing the compounds disclosed herein can be found, at least, in WO 2018/014829 and WO 2010/083283, the contents of which are incorporated in their entirety. Example 1: Turpentine-Induced Anemia C57Bl/6 mice (7-8-week-old, female) were purchased from Charles River Laboratories, Wilmington, MA, and placed on low iron chow (Test Diet #AIN-76A 5TJK) two weeks prior to beginning study. Mice were continued on this diet through the course of the study. Mice were injected subcutaneously in the intrascapular region of the back of the recipient mouse with sterile filtered turpentine (Aldrich, cat# 24245), or sterile saline in a 100 ul volume every week for three weeks. Therapeutic agents were orally administered at a total volume of 10mL/kg body weight. Mice were administered vehicle (0.5% DMAC: 95% methylcellulose) or compound (n = 10 per dose group) starting shortly after the first turpentine injection (day 0), and continuing every day until the study termination. Blood was collected via by orbital sinus once weekly, and complete blood counts (CBCs) were determined by hematology instrumentation (Abaxis, model HM5). Statistical analyses were performed using Graphpad Prism software. Mice were handled according to Incyte IACUC protocols. In each of the experiments performed, the ALK2 inhibitor (Compound A, 2-amino-N- (4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-p yran-4-yl)-3-azabicyclo[3.1.0]- hexan-1-yl)phenyl)nicotinamide) (100 mg/kg QD) corrected the anemia brought on by turpentine. In Figure 1, Compound A improved the red blood cell count, hemoglobin, and hematocrit to levels similar to saline (non-turpentine induced anemia) control at 28 days post first turpentine injection. In Figure 2, with Compound A dosed at 30 mg/kg BID, the same trend was demonstrated by day 21 post first turpentine injection, and the change was statistically significant (* p < 0.05; ** p < 0.01; *** p < 0.001; ****p < 0.0001 as determined by unpaired t-test). Also, the JAK2 inhibitor (ruxolitinib, 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile) (90 mg/kg BID) exacerbated the anemias brought on by turpentine injection in each experiment, most likely due to the pan-cytopenic effects of JAK2 inhibition in mice. Compound A improved the blood parameters of mice that were also dosed with ruxolitinib, with significant increases in RBC, hemoglobin, and hematocrit levels in Figure 2. Together these experiments indicate that ALK2 inhibition can reverse the decreases in RBC counts, hemoglobin, and hematocrit brought on by turpentine generated, inflammation induced anemia, and this anti-anemia efficacy from ALK2 inhibition is possible in the presence of ruxolitinib. Example 2: Clinical Protocol A study of the ALK2 inhibitor administered as a monotherapy or in combination with the JAK2 inhibitor is performed in adult participants with anemia due to myeloproliferative or myelodysplastic hematological malignancies. Overall study design. Phase I / II study open-label, multicenter, dose-escalation and expansion, safety and preliminary efficacy study of Compound A administered as a monotherapy or in combination with ruxolitinib in subjects with anemia (defined as Hgb < 10 g/dL) due to myeloproliferative or myelodysplastic hematological malignancies. For both the monotherapy and the combination portions, each participant will be observed for at least one treatment cycle (28 days). Part 1: Monotherapy portion including both the dose-escalation and the expansion stages where Compound A is administered alone in subjects with anemia due to lower-risk myelodysplastic syndromes (MDS). Combination portion including the dose-escalation stage where Compound A is administered in combination with ruxolitinib in subjects with primary myelofibrosis (PMF), post polycythaemia vera (PV) or post essential thrombocythaemia (ET) myelofibrosis and presenting anemia; collectively called “MF” subjects. Part 2: Combination portion including only the expansion stage where Compound A is administered in combination with ruxolitinib in MF subjects. Both the monotherapy and the combination portions are divided in 2 stages. The dose-escalation stage will determine the maximum tolerated doses (MTDs), the recommended expansion phase doses (REPDs) that will be taken forward in the corresponding expansion portions and the biologically active dose (BAD) defined as the tolerated dose(s) that produce evidence of biological effect of the explored dose(s) / regimen(s). The expansion stage will evaluate the safety, efficacy, PK, and PD of the REPD selected in the dose-escalation stages (monotherapy and combination portions) from the corresponding treatment groups. Three (3) different treatment groups are provided. For the monotherapy portion, only 1 treatment group is provided: Treatment Group A (TGA) including subjects with anemia due to lower-risk myelodysplastic syndromes (MDS). For the combination portion, two different treatment groups are defined among subjects with anemia due to MF: Treatment Group B (TGB) including MF subjects with anemia on a stable dose of ruxolitinib for at least 8 weeks of treatment (acceptable starting doses are 10 mg twice daily [BID], 15 mg BID, 20 mg BID and 25 mg BID); and Treatment Group C (TGC) including JAK-treatment naïve MF subjects with anemia. Treatment may continue as long as subjects are receiving benefit from the study treatment(s) and have not met any criteria for permanent treatment discontinuation. The primary objectives of each part of study include, for Part 1 (Dose-escalation stages of the monotherapy and the combination portions (all treatment groups) and Expansion stage of the monotherapy portion) evaluation of the safety and tolerability of Compound A administered alone or in combination with ruxolitinib. For Part 2 (Expansion stages of the combination portion - TGB and TGC only) evaluation of the efficacy of Compound A administered in combination with ruxolitinib. Secondary objectives applicable to all treatment groups include evaluation of PD parameters (including the hepcidin blood levels), PK parameters of Compound A and of ruxolitinib where applicable, for the expansion stage of the monotherapy and the combination portions the efficacy based on response criteria applicable to MDS patients. The overall design of the study includes a screening part for up to 28 days to confirm the subjects’ eligibility, a treatment part as long as the subjects benefit from study drug(s) therapy and do not present any study drug(s) treatment discontinuation criterion, and a follow-up part for survival / long-term outcomes after permanent discontinuation of study drug(s) up to study closure. Compound A is administered orally as a tablet / capsule. Starting doses may vary from about a daily amount of about 10 to about 50 mg, including a starting dose of about 25 mg QD or about 30 mg QD. Dose escalation is based on type and severity of toxicity and the PK/PD results observed. Administration may range from a daily amount of about 10 to about 150 mg, including about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125 and about 150 mg. For TGB and TGC groups, ruxolitinib is administered continuously per oral route as a tablet twice daily (BID). For TGC, the starting dose is about 15 mg BID if the subject’s platelet value is between 100 and 200 x 10 9 /L. The starting dose is about 20 mg BID if the subject’s platelet value is greater than 200 x 10 9 /L. During treatment by ruxolitinib and according to the disease response and hematology toxicity experienced by the subjects, additional doses include 5 mg, 10 mg, 15 mg, 20 mg and 25 mg BID. Dose escalation is based on type and severity of toxicity and the PK/PD results observed. The following laboratory testing is performed on subject samples. Iron metabolism (measurements to be performed centrally) is tested in the chemistry panel, including serum hepcidin, serum iron, serum ferritin & ferritin index [FTI], ferritin saturation, serum transferrin, transferrin saturation, total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC), serum non-transferrin-bound iron (NTBI), soluble serum transferrin receptor (sTFR), and growth differentiation factor 15 (GDF-15) = Bone morphogenetic protein (BMP) receptor. Hematological parameters are tested as part of the hematology panel,including reticulocytes, nucleotide red blood cell, erythrocyte hemoglobin, erythropoietin (EPO), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and myeloblasts in peripheral blood. Additional markers of inflammation are tested as part of the biochemistry panel, including C- reactive protein (CRP), and cytokine panel including Interleukin (IL)-1, IL-2 & IL-2 receptor (IL-2R), IL-6, IL-8 & IL-22. Inclusion Criteria: Inclusion criteria for the treatment groups A, B and C include the following: Ability to comprehend and willingness to sign a written informed consent form (ICF) for the study, Aged of 18 years or older at the time of signing the informed consent, Histologically-confirmed disease, Participant with anemia due to MDS or MF defined as: a. a hemoglobin [Hgb] value < 10 g/dL out of the influence of red blood cell (RBC) transfusions; considering a 2-week washout period must be demonstrated during screening recorded on three (3) separate occasions with at least seven (7) days between measurements, or b. Participant who has received at least four (4) units of RBC transfusions during the 28 days immediately preceding Cycle 1 Day 1 OR has received an average of at least four (4) units of RBC transfusions in the eight (8) weeks immediately preceding Cycle 1 Day 1, for a hemoglobin level of < 8.5 g/dL, in the absence of bleeding or treatment-induced anemia. In addition, the most recent transfusion episode must have occurred in the 28 days prior to Cycle 1 Day 1. Note: the latter option corresponds to the definition of a transfusion-dependent participant at baseline. Eastern Cooperative Oncology Group (ECOG) performance status score of: a.0 or 1 for the dose-escalation portions (monotherapy and combination portions), b.0, 1 or 2 for the expansion portions (monotherapy and combination portions), Life expectancy greater than 6 months, Willingness to undergo a pretreatment and regular on-study bone marrow biopsies and/or aspirates (as appropriate to disease). If a biopsy and aspirate are not possible or contraindicated, or the tissue requirement cannot be satisfied, this requirement may be waived with approval from the Sponsor’s medical monitor. Willingness to avoid pregnancy or fathering children based on the following criteria: (i) Postmenopausal woman (i.e., surgically sterile with a hysterectomy and/or bilateral oophorectomy OR > 12 months of amenorrhea and at least 50 years of age.) (ii) Woman of childbearing potential who has a negative serum pregnancy test at screening and prior to the first dose on Day 1 who agrees to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow-up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the subject and their understanding confirmed. (iii) Man who agrees to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through safety follow-up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the subject and their understanding confirmed. Inclusion criteria defining the disease characteristics: Subject with peripheral blood myeloblast count < 10%. Subject not requiring cytoreductive therapy or a therapeutic intervention. For Treatment Group A (TGA) Additional inclusion criteria for the treatment groups A include a confirmed diagnosis of myelodysplastic syndrome (MDS) according to the 2016 World Health Organization (WHO) criteria (Swerdlow et al, 2017 and Arber et al, Blood, 2016). For the myelodysplastic syndrome (MDS) subjects: very-low, low or intermediate MDS as defined by the IPSS-R criteria (Greenberg et al, Blood, 2012), except subjects presenting with myelodysplastic syndrome with ring sideroblasts (MDS-RS), OR For the MDS/MPN overlap syndrome subjects: i. Low or intermediate chronic myelomonocytic leukemia (CMML) according to Patnaik et al, 2013, or ii. Favorable or intermediate unclassifiable MDS/MPN overlap syndromes (MDS/MPN, unclassifiable) as per Liu et al, 2012 criteria, iii. Except participants presenting with atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML) or MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). For Treatment Groups B and C (TGB and TGC): Additional inclusion criteria for the treatment Groups B and C (TGB and TGC) include a histologically-confirmed diagnosis of primary myelofibrosis (PMF), post polycythaemia vera (PV) or post essential thrombocythaemia (ET) myelofibrosis according to the 2016 World Health Organization criteria (Swerdlow et al, 2017 and Passamonti et al, ASH publications, 2016 for PMF and Barosi et al, Leukemia, 2008 for post-ET and post-PV myelofibrosis) and prior treatment. For TGB, each subject must have been on a therapeutic and stable regimen of ruxolitinib (10 mg, 15 mg, 20 mg or 25 mg BID) for at least eight (8) consecutive weeks immediately preceding the first treatment dose in the study, and each subject for whom the dose and dose-regimen of ruxolitinib to treat MF has not been modified at any time during the 8 weeks immediately preceding the 1st treatment dose in the study. For TGC, each subject must be naïve of any treatment by any JAK inhibitor. Exclusion Criteria: Exclusion criteria for the treatment groups A, B and C include the following: Subjects with laboratory values at screening as defined in Table 1. Table 1: Exclusionary Laboratory Values
TGA, TGB, and TGC = treatment group A, B, and C, ULN = upper limit of normal. Subject with any major surgery within 28 days prior to the first study treatment, Any prior chemotherapy, immunomodulatory drug therapy, immunosuppressive therapy, biological therapy, endocrine therapy, targeted therapy, antibody, erythropoietin- stimulating agent (ESA), hypomethylating agent, or granulocyte colony stimulating factor [G- CSF], granulocyte/macrophage colony stimulating factor [GM-CSF], romiplostin, eltrombopag, folic acid (folate), or vitamin B12 (cobalamin) to treat the subject’s disease with the exception of ruxolitinib for TGB only within 5 half-lives or 28 days (whichever is shorter) prior to the first study treatment.Subject undergoing treatment with another investigational medication or having been treated with an investigational medication within 28 days prior to screening, Subject undergoing treatment within 28 days or 5 half-lives (whichever is longer) of the first study treatment with a potent/strong inhibitor or inducer of CYP3A4/5, or expected to receive such treatment during the study. Any prior radiation therapy within 28 days or 5 half-lives (whichever is longer) of the first study treatment. Palliative radiation therapy to single sites or small fields allowed with at least one (1) week washout prior to the first study treatment. Any prior allogenic or autologous transplantation, or the subject is a candidate for an allogenic or autologous transplantation, History of leukocytosis (history of WBC > 25 x 10 9 /L), Presence of any hematological malignancy other than MDS or MF, Active invasive malignancy over the previous 5 years except subjects with early- stage basal cell or squamous cell skin cancer, or completely resected intraepithelial carcinoma of the cervix, or completely resected papillary thyroid and follicular thyroid cancers who may be eligible participate at the Investigator's discretion. Subjects with malignancies with indolent behavior such as prostate cancer treated with radiation or surgery may be enrolled as long as they have a reasonable expectation to have been cured with the treatment modality received, Known active disease involving the central nervous system (CNS), for example, brain metastasis or spinal cord compression, except primary CNS lymphoma, History of clinically significant or uncontrolled cardiac disease, including recent (within the last 12 months) unstable angina or acute myocardial infarction, or New York Heart Association Class III or IV congestive heart failure, or clinically significant arrhythmias not controlled by medication. Subjects with a pacemaker and well controlled rhythm for at least 1 month before the first dose of study medication will be allowed, History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful. Screening QTc interval > 450 milliseconds is excluded. For subjects with an intraventricular conduction delay (QRS interval 120 ms), the JTc interval may be used in place of the QTc with sponsor approval. Subjects with left bundle branch block are excluded. Subjects with QTc prolongation due to a pacemaker may enroll with prior approval from the sponsor’s medical monitor, Presence of chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment. Subjects with acute bacterial infection requiring antibiotic use should delay screening / enrollment until the course of antibiotic therapy has been completed and the infection is not active anymore, Subject with diagnosis of chronic liver disease (e.g., chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis), Subject with known active hepatitis A, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection or who are HIV-positive, Unwillingness to be transfused with blood components including red blood cell packs and platelet transfusions, Subjects who, in the opinion of the investigator, are unable or unlikely to comply with the dose schedule and study evaluations, Any condition in the investigator's judgment that would interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data, Active alcohol or drug addiction that would interfere with their ability to comply with the study requirements, Gastroesophageal reflux disease not controlled by medication (i.e., currently symptomatic or endoscopic evidence of esophagitis) within 28 days prior to first study drug(s) dose,
Has any unresolved toxicity > Grade 2 from previous therapy except for stable chronic toxicities (< Grade 2) not expected to resolve, such as stable Grade 2 peripheral neuropathy, Subject has known hypersensitivity or severe reaction, or any known contraindications to the use to any of the active substances or excipients in Compound A or ruxolitinib or similar compounds as appropriate to the relevant treatment group, Females who are pregnant or currently breastfeeding, Unable to swallow and retain oral medication, and Unable to comprehend or unwilling to sign the informed consent form (ICF). Additional exclusion criteria for Treatment Groups B and C (TGB and TGC) include a subject with any history of platelet counts < 50 x 10 9 /L or ANC < 0.5 x 10 9 /L except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason, and any subject undergoing treatment with hematopoietic growth factor receptor agonist (i.e., erythropoietin [EPO]), granulocyte colony stimulating factor (G-CSF), romiplostin, eltrombopag at any time within 4 weeks prior to screening, and subject undergoing treatment within 14 days or 5 half-lives (whichever is longer) of 1st study drug(s) dose with a potent/strong inhibitor or inducer of CYP3A4 or expected to receive such treatment during the course of the study, and any subject unwilling or unable to undergo MRIs or CT Scans par study protocol requirements. Primary Analyses: Part 1: Safety analyses for TGA – Dose escalation and expansion, TGB – Dose escalation, TGC – Dose escalation: The safety of Compound A administered alone or in combination with ruxolitinib will be analyzed using the following parameters descriptively by part, treatment group, and dose level in safety population: - Frequency, duration, and severity of adverse events (AEs), severe adverse events (SAEs) and dose-limiting toxicity (DLTs), - Changes in vital signs and clinical evaluations including electrocardiograms (ECGs), - Clinical laboratory blood and urine sample evaluations, - The rate of DLTs will be summarized for each cohort of the dose-escalation portions. Part 2: Efficacy analyses for TGB – Dose expansion, TGC – Dose expansion: The proportion of participants with an anemia response defined as an Hgb increase ≥ 1.5 g/dL for ≥ 12 weeks during treatment, if transfusion independent OR achieving transfusion independence for ≥ 12 weeks if transfusion dependent at baseline if applicable, will be estimated with its 95% confidence intervals (CI). The proportion will be tested against 20% using a one-sample proportion test in full analysis set (FAS) population at a one-sided alpha of 5%. Participants with missing assessments that prevent the evaluation of the primary endpoint will be considered as nonresponders on that treatment arm. No data imputation will be applied. Secondary Analyses: Analyses of Dose-escalation stages of the monotherapy and the combination portions (all treatment groups) and Expansion stage of the monotherapy portion include efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of Compound A administered alone or in combination with ruxolitinib in the defined patient populations. Expansion stage of the combination portion (TGB and TGC only) include safety of Compound A administered in combination with ruxolitinib in anemic MF subjects. The safety assessments will include: PK for plasma Compound A: C max , t max , AUC 0-t , AUC 0-^ . t ½ , Cl^)^^9]^)^^DQG^^]^ PK for urine Compound A: Ae96h and CLr, PK for saliva Compound A: C max , t max , AUC 0-t , AUC 0-^^DQG^ CLs, and PK for metabolites of Compound A In plasma (C max , t max , AUC 0-t , AUC 0-^ ), and In urine (Ae, CLr, Fe (%excreted)), The following PD parameters will be summarized descriptively by part, stage, treatment group, and dose level in PD evaluable population at each visit. - Plasma hepcidin levels, - PD parameters to assess the iron homeostasis: total serum iron (TSI), ferritin, transferrin, transferrin saturation (TSAT), total iron-binding capacity (TIBC), unsaturated iron- binding capacity (UIBC), non-transferrin-bound serum iron (NTBI), - PD parameters to assess the erythropoiesis: reticulocyte count (RC), nucleated red blood cell (NRBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), hemoglobin, hematocrit, red blood cell (RBC) count, mean corpuscular hemoglobin concentration (MCHC), red blood cell distribution width (RDW), - Other PD parameters: erythropoietin (EPO), Part 1 efficacy analyses for TGA dose expansion: - Percentage of participants with hematological improvement for erythroid line (HI-E), for platelets (HI-P), and for neutrophils (HI-N) as per Cheson et al, 2006, definitions will be estimated with 95% CI. - Mean change from baseline in the Hgb value over 4-week treatment periods will be summarized descriptively. - Percentage of participants with > 50% reduction in transfusion burden as compared to baseline in any 8-week window during treatment period will be estimated. - Percentage of participants with complete response (CR) or partial response (PR) as per Cheson et al, 2006 definitions for myelodysplastic syndromes, or as per the Savona et al, 2015 definitions for the MDS/MPN overlap syndromes as applicable will be estimated with 95% CI. - Progression-free survival (PFS) defined as the interval from the first dose of Compound A until the first documentation of definitive disease progression (as per Cheson et al, 2006 definitions for myelodysplastic syndromes or Savona et al, 2015 definitions for MDS/MPN overlap syndromes) or death due to any cause will be estimated using Kaplan-Meier method. - Leukemia-free survival (LFS), defined as the interval from the first dose of Compound A until the first documented leukemia transformation (a blast percentage of > 20% in the bone marrow or the peripheral blood at any time during the study) or death from any cause will be estimated using Kaplan-Meier method.
For transfusion-dependent (TD) participants at screening: o Percentage of participants with reduction of units of RBC transfusions by an absolute number of ≥ 4 RBC transfusions/8 week compared with the pretreatment transfusion number in the previous eight (8) weeks if applicable as per Cheson et al, 2006, will be estimated. o Percentage of participants with red blood cell-transfusion independency (RBC-TI) defined as the absence of any RBC-transfusion for at least eight consecutive weeks during the treatment period will be estimated.
Part 2 safety analyses for TGB and TGC dose expansion:
The safety of Compound A administered in combination with ruxolitinib will be analyzed using the following parameters descriptively by treatment group, and dose level in safety population:
Frequency, duration, and severity of AEs and SAEs, Changes in vital signs, ECGs, and physical examinations, Changes in clinical blood and urine laboratory parameters. Part 2 efficacy analyses for TGB and TGC dose expansion:
- Anemia response o Duration of anemia response, defined as
■ The interval from the first onset of Hgb increase ≥ 1.5 g/dL for≥ 12 weeks to the earliest date of loss of anemia response that persists for at least four (4) weeks, or death from any cause for the Tl participants at baseline, or
■ Duration of transfusion-independence is defined as the interval from the first onset date of transfusion independence to the earliest onset date of transfusion dependence or death from any cause for the TD participants at baseline, will be estimated separately for transfusion dependent (TD) and transfusion- independent (Tl) participants at baseline using Kaplan-Meier method with 95%
Cl.
Mean change from baseline in the Hgb value over 12-week treatment periods will summarized descriptively.
Rate of RBC-transfusion through Weeks 24 and 48 defined as the average number of RBC units per participant-month during treatment. The proportion of participants receiving RBC transfusions over each month post baseline period will be estimated, and the total number of RBC units received per participant over each month post baseline period will be calculated.
- The splenic response rate at Week 24 (SSR24) defined as the proportion of participants achieving a ≥ 35% reduction in spleen volume at Week 24 relative to baseline as measured by MRI or CT scan, will be estimated with 95% Cl.
- Spleen length response defined as the proportion of participants achieving a ≥ 50% reduction in spleen length at any visit relative to baseline as measured by palpation will be estimated.
- Symptom response rate at Week 24 defined as the proportion of participants who achieve a ≥ 50% reduction in total symptom score (TSS) at Week 24 relative to baseline as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 form (Gwaltney et al, 2017), will be estimated.
- Percentage of participants with CR or PR according to the Tefferi et al, 2013 definitions will be estimated with 95% Cl.
- The morphologic effects of the combination of Compound A with ruxolitinib on bone marrow will be summarized descriptively.
- Progression-free survival (PFS) defined as the interval from the first dose of study treatment until the first documentation of definitive disease progression or death due to any cause as per the Tefferi et al, 2013 definitions, will be estimated with the Kaplan Meier method.
- Leukemia-free survival (LFS) defined as the interval from the first dose of Compound A until the first documented leukemia transformation or death from any cause, will be estimated with the Kaplan Meier method.
For PFS, the earliest time when any event is observed as follows:
- For spleen volume increase, the progression date will be the date of the first MRI showing a 25% or greater increase in spleen volume as compared to the on-study nadir (the on study period includes the Baseline evaluation),
- For splenic irradiation, splenectomy, or death, the date of progression will be the actual date of the event,
- For leukemic transformation: o Determined by bone marrow blast count of 20% or greater, the progression date will be the date of the bone marrow aspirate or biopsy as applicable, o Determined by peripheral blast count, the date of progression will be the date of the first peripheral blast count of 20% or greater that is subsequently confirmed by EITHER eight (8) weeks of sustained high blast counts [i.e., no intervening counts of < 20%) OR by bone marrow aspirate/biopsy. Part 2 safety analyses for TGB and TGC dose expansion:
The safety assessments will be identical to those in the dose-escalation portions.
Example 3: Additional Clinical Protocol for MF-lnduced Anemia This study is a phase 1/2, open-label, multicenter, dose-escalation and -expansion study assessing Compound A alone (treatment group A [TGA]) or in combination with ruxolitinib (treatment group B [TGB]), in patients with MF who are transfusion-dependent or present with symptomatic anemia. For TGA, patients must have been intolerant, resistant, refractory, or lost response to prior therapy (≥12 weeks) with Janus kinase inhibitors and have a risk category of intermediate-2 or high according to the Dynamic International
Prognostic Scoring System (DIPSS); for TGB, patients must have been on a therapeutic and stable regimen of ruxolitinib for ≥12 consecutive weeks prior to first dose of study treatment and have a DIPSS risk category of intermediate- 1 or -2, or high. To be eligible patients must be ≥18 years of age, have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 for the dose-escalation stages or 0-2 for the dose-expansion stage, have life expectancy > 6 months, and have histologically confirmed primary or secondary (postpolycythemia vera, post-essential thrombocythemia) MF.
Patients are ineligible if they have any other hematologic malignancy; have undergone any prior allogeneic or autologous stem cell transplantation; have undergone major surgery within 28 days of first dose of study drug; or received prior chemotherapy, immunomodulatory drug, immunosuppressive, biological, endocrine, or targeted therapy, or an antibody/hypomethylating agent within 5 half-lives or 28 days before first dose of study drug.
In Part 1 (dose escalation) of the study, patients will be enrolled into TGA or TGB. Compound A monotherapy will be administered orally at a starting dose of 50 mg/day in TGA (28-day cycles). Dose-escalation stages will use a Bayesian optimal interval design to determine the maximum tolerated dose (MTD), with dose increases not exceeding 100% (2- fold) until a treatment-related toxicity Grade ≥2 is observed. Dose escalation in TGB will start 2 dose levels below the maximum evaluated dose determined to be safe and tolerable in TGA (recommended dose expansion [RDE]); patients in TGB will receive Compound A in combination with ruxolitinib. In each treatment group in Part 1, ≤24 patients will be treated in the dose-escalation stage. In Part 2 (dose expansion), the RDE in TGB will be evaluated in combination with ruxolitinib in approximately 25 patients. Patients will receive treatment for up to 12 months, and treatment may continue if patients are deriving clinical benefit and have no evidence of progressive disease.
The primary study objective is to determine the safety and tolerability of Compound A monotherapy or in combination with ruxolitinib (assessed by the frequency and severity of adverse events [AEs], physical examinations, and monitoring vital signs and laboratory values, and identification of dose-limiting toxicities, MTD, and RDE for TGB). Secondary objectives are to determine the efficacy of Compound A monotherapy or in combination with ruxolitinib (assessed by anemia response, duration of anemia response, mean change from baseline in hemoglobin, and rate of RBC transfusion through week 24 and 48), evaluate pharmacokinetics of Compound A, and evaluate the effect of Compound A as monotherapy or in combination with ruxolitinib on hepcidin level, iron homeostasis, and erythropoiesis. The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims. All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.