INJECTABLE FORMULATIONS FOR TREATING CANCER
The present invention provides injectable formulations of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol and hydrates thereof and methods for treating disorders in which DOT 1-mediated protein methylation plays a part, such as cancer and neurological disorders.
1 . A formulation comprising a compound of Formula (I):
or an N-oxide, a hydrate, or salt thereof, a solubilizer, and a pH adjustment reagent, wherein the formulation comprises about 1-10% (w/v) compound of Formula (I) and about 4-40% (w/v) solubilizer.
2 . The formulation of claim 1 , comprising about 10% (w/v) compound of Formula (I).
3 . The formulation of any one of claims 1 and 2 , comprising about 40% (w/v) solubilizer.
4 . The formulation of any one of claims 1 - 3 , wherein the solubilizer is a cyclodextrin.
5 . The formulation of claim 4 , wherein the cyclodextrin is Hydroxypropyl Betadex.
6 . The formulation of any one of claims 1 - 5 , comprising about 0.1-5% (w/v) pH adjustment reagent.
7 . The formulation of claim 6 , comprising about 1-2% (w/v) pH adjustment reagent.
8 . The formulation of claim 7 , comprising about 1-1.8% (w/v) pH adjustment reagent.
9 . The formulation of claim 8 , comprising about 1.54-1.7% (w/v) pH adjustment reagent.
10 . The formulation of any one of claims 1 - 9 , wherein the pH adjustment reagent is citric acid.
11 . The formulation of claim 10 , wherein the citric acid is anhydrous citric acid or citric acid monohydrate.
12 . The formulation of any one of claims 1 - 11 , further comprising an isotonic reagent.
13 . The formulation of claim 12 , wherein the isotonic reagent is selected from sodium chloride and dextrose.
14 . The formulation of any one of claims 1 - 13 , wherein the pH of the formulation is adjusted to about 4.0-8.0.
15 . The formulation of claim 14 , wherein the pH of the formulation is adjusted to about 4.5-7.0.
16 . The formulation of claim 15 , wherein the pH of the formulation is adjusted to about 5.0-6.5.
17 . The formulation of any one of claims 1 - 16 , wherein the pH of the formulation is adjusted further with sodium hydroxide or hydrochloric acid or a combination thereof.
18 . The formulation of claim 1 , further comprising water.
19 . The formulation of claim 1 , comprising about 1.5-10% (w/v) compound of Formula (I), about 6-40% (w/v) solubilizer, and about 0.2-5% (w/v) pH adjustment reagent.
20 . The formulation of claim 1 , comprising about 10% (w/v) compound of Formula (I), about 40% (w/v) Hydroxypropyl Betadex, and about 1-2% (w/v) citric acid.
21 . The formulation of claim 1 , comprising about 1.00% (w/v) compound of Formula (I), about 4.00% (w/v) Hydroxypropyl Betadex, about 0.168% (w/v) citric acid monohydrate, and water.
22 . A method of treating leukemia comprising administering to a subject in need thereof a therapeutically effective amount of a formulation of any one of claims 1 - 21 , wherein the formulation is administered continuously for at least 20 hours, at least 1 day, or at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 35, 42, 47, 56, or 64 days.
23 . The method of claim 22 , wherein continuous administration comprises administration without a drug holiday.
24 . The method of claim 22 or 23 , wherein the formulation is diluted before administration.
25 . The method of any one of claims 22 - 24 , wherein the formulation is administered continuously for 28 days or more.
26 . The method of any one of claims 22 - 24 , wherein the formulation is in a unit dosage form and is administered continuously for at least 20 hours and up to about 14 days.
27 . The method of any one of claims 22 - 26 , wherein the formulation is administered at a dose of at least 36, 45, 54, 70, 80, or 90 mg/m 2 /day compound of Formula (I).
28 . The method of any one of claims 22 - 27 , wherein the subject is an adult and the formulation is administered at a dose of at least 90 mg/m 2 /day compound of Formula (I).
29 . The method of any one of claims 22 - 27 , wherein the subject is a pediatric patient aged 12 months or younger and the formulation is administered at a dose of at least 45 mg/m 2 /day compound of Formula (I).
30 . The method of any of claims 22 - 29 , wherein the leukemia is chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) or leukemia characterized by MLL gene rearrangement.
31 . The method of claim 30 , wherein the MLL gene rearrangement is translocation of the MLL gene 11q23.
32 . The method of claim 30 , wherein the MLL gene rearrangement is partial tandem duplication of the MLL gene.
33 . The method of claim 30 , wherein the MLL gene rearrangement results in increased or errand DOT1L methylation activity.
34 . The method of any of claims 22 - 33 , wherein the method of treatment includes resolution of fevers, resolution of cachexia or resolution of leukemia cutis.
35 . The method of any of claims 22 - 34 , wherein the method of treatment results in restoration of normal hematopoiesis.