Polymorphic forms of RAD1901-2HCl
Various polymorphic forms of RAD1901-2HCl, including three crystalline and amorphous forms, are prepared and characterized. Uses of the various polymorphic forms of RAD1901-2HCl for cancer treatment are also disclosed.
1. A method of treating breast cancer, comprising administering to a subject in need thereof a solid form of RAD1901-2HCl, having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at 7.1 degrees 2θ±0.2 degree 2θ at about relative humidity 0%.
2. The method of claim 1 , wherein the solid form has an X-ray powder diffraction pattern comprising peaks, in terms of 2-theta, at 7.1 degrees 2θ±0.2 degree 2θ and 14.3 degrees 2θ±0.2 degree 2θ at about relative humidity 0%.
3. The method of claim 1 , wherein the solid form has an X-ray powder diffraction pattern further comprising at least one peak, in terms of 2-theta, selected from the group consisting of 14.3 degrees 2θ±0.2 degree 2θ and 18.3 degrees 2θ±0.2 degree 2θ at about relative humidity 0%.
4. The method of claim 1 , wherein the solid form has an X-ray powder diffraction pattern further comprising at least two peaks, in terms of 2-theta, selected from the group consisting of 14.3 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ and 12.0 degrees 2θ±0.2 degree 2θ, at about relative humidity 0%.
5. The method of claim 1 , wherein the solid form has an X-ray powder diffraction pattern further comprising at least three peaks, in terms of 2-theta, selected from the group consisting of 14.3 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ and 18.9 degrees 2θ±0.2 degree 2θ, at about relative humidity 0%.
6. The method of claim 1 , wherein the solid form has an X-ray powder diffraction pattern further comprising at least four peaks, in terms of 2-theta, selected from the group consisting of 14.3 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9 degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ and 11.0 degrees 2θ±0.2 degree 2θ, at about relative humidity 0%.
7. The method of claim 1 , wherein the solid form has an X-ray powder diffraction pattern further comprising at least four peaks, in terms of 2-theta, selected from the group consisting of 14.3 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9 degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees 2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree 2θ, at about relative humidity 0%.
8. The method of claim 1 , wherein the solid form has an X-ray powder diffraction pattern further comprising at least six peaks, in terms of 2-theta, selected from the group consisting of 14.3 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9 degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees 2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree 2θ, at about relative humidity 0%.
9. The method of claim 1 , wherein the solid form has an X-ray powder diffraction pattern further comprising at least seven peaks, in terms of 2-theta, selected from the group consisting of 14.3 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9 degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees 2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree 2θ, at about relative humidity 0%.
10. The method of claim 1 , wherein the solid form has an X-ray powder diffraction pattern further comprising at least eight peaks, in terms of 2-theta, selected from the group consisting of 14.3 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9 degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees 2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree 2θ, at about relative humidity 0%.
11. The method of claim 1 , wherein the solid form has an X-ray powder diffraction pattern comprising the peaks, in terms of 2-theta, of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9 degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees 2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree 2θ, at about relative humidity 0%.
12. The method of claim 1 , wherein the solid form has an X-ray powder diffraction pattern as shown in FIG. 4G at about relative humidity 0%.
13. The method of claim 1 , wherein the solid form has a differential scanning calorimetry (DSC) thermogram comprising a melting onset at 218.2° C. and an endothermic peak at 232.1° C.
14. The method of claim 13 , wherein the solid form has a differential scanning calorimetry (DSC) thermogram as shown in the bottom figure of FIG. 8 .
15. The method of claim 1 , wherein the solid form has a thermogravimetric analysis (TGA) as shown in the top graph of FIG. 8 .
16. The method of claim 1 , wherein said breast cancer is ER+.
17. The method of claim 16 , wherein the breast cancer is a resistant ER-driven cancer that progressed after endocrinological treatment, wherein the endocrinological treatment comprises administration of a drug selected from a Selective Estrogen Receptor Degrader (SERD), an aromatase inhibitor, a selective estrogen receptor modulator (SERM), a Human Epidermal Growth Factor Receptor 2 (Her2) inhibitor, a chemo therapeutic agent, a cdk4/6 inhibitor, an m-TOR inhibitor, or rituximab.
18. The method of claim 17 , wherein
the SERD is selected from fulvestrant, 17β-[2-[4-[(diethylamino)methyl]-2-methoxyphenoxy]ethyl]-7α-methylestra-1,3,5(10)-trien-3-ol (TAS-108BU or SR16234), 11β-Fluoro-7a-(14,14,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra-1,3,5(10)-triene-3,17β-diol (ZK191703), (11β,17β)-11-[4-[[5-[(4,4,5,5,5-Pentafluoropentyl)sulfonyl]-pentyl]oxy]phenylestra-1,3,5,(10)-triene-3,17-diol (RU58668), Brilanestrant (GDC-0810 or ARN-810), Etacstil (GW5638 or -DPC974), (S)-2-(4-(2-(3-(fluoromethyl)-azetidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol (SRN-927), and (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (AZD9496);
the aromatase inhibitor is selected from anastrozole, exemestane, and letrozole;
the selective estrogen receptor modulator is selected from tamoxifen, raloxifene, lasofoxifene, and toremifene;
the Her2 inhibitor is selected from trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab;
the chemo therapeutic agent is selected from abraxane, adriamycin, carboplatin, cytoxan, daunorubicin, doxil, ellence, fluorouracil, gemzar, helaven, Ixempra, methotrexate, mitomycin, micoxantrone, navelbine, taxol, taxotere, thiotepa, vincristine, and xeloda; and
the angiogenesis inhibitor is bevacizumab.
19. The method of claim 17 , wherein the subject is further administered a cdk4/6 inhibitor and/or an m-TOR inhibitor.
20. The method of claim 19 , wherein the cdk4/6 inhibitor and/or m-TOR inhibitor is selected from palbociclib, ribociclib, abemaciclib, or everolimus, or a combination thereof.
21. The method of claim 16 , wherein the breast cancer is a resistant ER-driven cancer that progress after endocrinological treatment, wherein the breast cancer has one or more mutant ER binding domains comprising one or more mutations selected from the group consisting of Y537X 1 wherein X 1 is S, N, or C, D538G, L536X 2 wherein X 2 is R or Q, P535H, V534E, S463P, V392I, and E380Q, or a combination thereof.