WO2025194059A1 - Combination treatment regimens - smarca2 degrader with taxane anticancer agent - Google Patents

Abstract

Disclosed are methods of treating cancer comprising administering to a subject a treatment regimen comprising a compound of Formula (I): or a pharmaceutically acceptable salt thereof, and a taxane anticancer agent.

Description

COMBINATION TREATMENT REGIMENS - SMARCA2 DEGRADER WITH TAXANE ANTICANCER AGENT

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Application No. 63/565,664, filed March 15, 2024, United States Provisional Application No. 63/570,568, filed March 27, 2024, and United States Provisional Application No. 63/658,097, filed June 10, 2024. Each aforementioned application is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0002] The disclosure pertains to methods of treating cancer comprising administering to a subject a treatment regimen comprising a SMARCA2 degrader and a taxane anti cancer agent. BACKGROUND

[0003] SMARCA2 and SMARCA4 are the core catalytic subunits of the SWUSNF complexes, which play an important role in controlling gene expression by remodeling chromatin. SMARCA4 is mutated in multiple cancers and SMARCA4 -deficient cancer cells can become highly dependent on SMARCA2 for their survival. Therefore, targeting SMARCA2 in SMARCA4 -del eted cancers using selective SMARCA2 degraders induces synthetic lethality, while sparing SMARCA4 wild-type normal cells. Cell lines with SMARCA4 damaging mutation or low expression show high SMARCA2 gene dependency scores, suggesting the synthetic lethal relationship of targeting SMARCA2 and SMARCA4- deficiency. SMARCA4 mutations occur in different types of cancer including lung adenocarcinoma, skin cancer/melanoma, uterine/endometrioid adenocarcinoma, bladder cancer, colon adenocarcinoma, among others. In addition to damaging mutation (“loss of SMARCA4 protein”), some tumors express SMARCA4 hotspot missense mutations near its ATP binding site or DNA binding site that likely alters biological function of SMARAC4.

[0004] The compound of Formula (I) is a SMARCA2 degrader:

, Formula (I).

[0005] The synthesis of Formula (I), (lS)-3-(6-(4-((6-(((6aA,SA)-6a- (difluoromethyl)-2-(3 -fluoro-2-hy droxy-phenyl)-5 , 6,6a, 7, 8, 9- hexahydropyrrolof 1 ',2' :4, 5]pyrazino[2,3 -c]pyridazin-8-yl)oxy)pyri din-3 -yl) methyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione, is set forth in Example 43 of US 20240165244. Formula (I) regulates cancer cell proliferation and growth through cell cycle arrest and DNA replication inhibition in SMARCA4 mutated cancer cells.

[0006] Docetaxel is a taxane anticancer agent that is known to regulate cell division by binding to microtubules and inhibiting their polymerization dynamics in cancer cells. See Pienta, K. J., Preclinical mechanisms of action of docetaxel and docetaxel combinations in prostate cancer. Semin Oncol, 2001. 28(4 Suppl 15): p. 3-7. Other studies also demonstrate that docetaxel induces mitochondria priming and sensitizes cancer cells to apoptosis. See Ni Chonghaile, T., el al., Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science, 2011. 334(6059): p. 1129-33.

SUMMARY

[0007] The disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a treatment regimen comprising:

(a) a compound of Formula (I): Formula (I), or a pharmaceutically acceptable salt thereof; and

(b) a taxane anticancer agent.

[0008] In some aspects, the cancer is a SMARCA4-deleted cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Fig. 1 shows that the Formula (I) combination with docetaxel resulted in deeper tumor growth inhibition (TGI) compared to each single agent alone in the SMARCA4-deficient NCI-H838 Lung Cancer Xenograft Model in Mice. NOD/SCID female mice were inoculated subcutaneously with NCI-H838-#5 cells (5xl0⁶) into the right flank in PBS 0.1 ml mixed with Matrigel. When tumor volumes reached approximately 100- 150 mm³, mice were randomized and dosed with Formula (I) at 1 mg/kg p.o. QD, docetaxel 10 mg/kg QW; or Formula (I) at 1 mg/kg p.o. QD + docetaxel 10 mg/kg i.v. QW. **P<0.05, ****p<0.001 versus vehicle (two-tailed unpaired Mann-Whitney test).

[0010] Fig. 2 show that the Formula (I) combination with nab -paclitaxel resulted in deeper tumor growth inhibition (TGI) compared to each single agent alone in the SMARCA4-deficient NCI-H838 Lung Cancer Xenograft Model in Mice. NOD/SCID female mice were inoculated subcutaneously with NCI-H838-#5 cells (5xl0⁶) into the right flank in PBS 0.1 ml mixed with Matrigel. When tumor volumes reached approximately 100- 150 mm³, mice were randomized and dosed with Formula (I) at 1 mg/kg p.o. QD, nab-paclitaxel 15 mg/kg i.v. QW, or Formula (I) at 1 mg/kg p.o. QD + nab-paclitaxel 15 mg/kg i.v. QW. **P<0.05 ***P<0.01, ****P<0.001 versus vehicle (two-tailed unpaired Mann-Whitney test). DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0011] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any sub combination.

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the disclosure. [0013] The articles “a,” “an,” and “the” as used herein and in the appended claims are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, “an element” means one element or more than one element.

[0014] Where a range of values is provided, it is to be understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0015] When a range of values is expressed, it is to be understood that the explicitly stated upper and lower limits of the range and all intervening individual values, and all intervening subranges are encompassed by the range. All ranges are inclusive and combinable.

[0016] When values are expressed herein as approximations, such as by use of the antecedent “about,” it is understood that the particular value forms another embodiment. In some ebodiments, “about” refers to a value with ±10% of the particular value.

[0017] The term “administering,” when used in the context of administering a therapeutic agent to a subject, refers to introducing the therapeutic agent into the subject’s body. For example, therapeutic agents may be introduced into a subject’s body orally, nasally, subcutaneously, intravenously, intravesically, intramuscularly, transdermally, vaginally, rectally or in any combination thereof.

[0018] “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (e.g., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.

[0019] The term “subject” is used herein to describe an animal, for example, a mammal, to whom treatment with the treatment regimen according to the disclosure is provided. In some aspects, the mammal is a human to whom treatment is provided. In other aspects, the mammal is a non-human to whom treatment is provided.

[0020] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the United States Federal government or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., in humans.

[0021] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l- carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-m ethylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.

[0022] A “pharmaceutically acceptable excipient” refers to a substance that is nontoxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. See for example, Remington, J. P. (2020). Remington, the science and practice of pharmacy, Elsevier Science.

[0023] As used herein, the term “treatment regimen” refers to coordinated dosages and administration timings of each of Formula (I) (or pharmaceutically acceptable salt thereof) and the taxane anticancer agent agent such that Formula (I) (or pharmaceutically acceptable salt thereof) and the taxane anticancer agent are administered to the subject during an overlapping period of time. Thus, the “treatment regimen” of the disclosure encompasses both concurrent administration of the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) and the taxane anticancer agent; and sequential administration of the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) and a taxane anticancer agent. Moreover, the treatment regimen encompasses administration of the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) and a taxane anticancer agent on the same day; on different days; and any permutation thereof.

[0024] In some aspects, the discosure is directed to methods of treating cancer in a subject in need thereof, comprising administering to the subject a treatment regimen comprising:

(a) a compound of Formula (I): Formula (I), or a pharmaceutically acceptable salt thereof; and

(b) a taxane anticancer agent.

[0025] Methods of making the compound of Formula (I) are known in the art, and include those set forth in US20240165244.

[0026] In some embodiments of the disclosed methods, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the taxane anticancer agent are administered concurrently or sequentially.

[0027] In some embodiments of the disclosed methods, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the taxane anticancer agent are administered concurrently.

[0028] In other embodiments of the disclosed methods, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the taxane anticancer agent are administered sequentially.

[0029] In some aspects, the subject is administered the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), in an amount of about 5 mg - about 1600 mg per dose, such as, for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, about 600 mg, about 605 mg, about 610 mg, about 615 mg, about 620 mg, about 625 mg, about 630 mg, about 635 mg, about 640 mg, about 645 mg, about 650 mg, about 655 mg, about 660 mg, about 665 mg, about 670 mg, about 675 mg, about 680 mg, about 685 mg, about 690 mg, about 695 mg, about 700 mg, about 705 mg, about 710 mg, about 715 mg, about 720 mg, about 725 mg, about 730 mg, about 735 mg, about 740 mg, about 745 mg, about 750 mg, about 755 mg, about 760 mg, about 765 mg, about 770 mg, about 775 mg, about 780 mg, about 785 mg, about 790 mg, about 795 mg, about 800 mg, about 805 mg, about 810 mg, about 815 mg, about 820 mg, about 825 mg, about 830 mg, about 835 mg, about 840 mg, about 845 mg, about 850 mg, about 855 mg, about 860 mg, about 865 mg, about 870 mg, about 875 mg, about 880 mg, about 885 mg, about 890 mg, about 895 mg, about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg, about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg, about 1000 mg, about 1005 mg, about 1010 mg, about 1015 mg, about 1020 mg, about 1025 mg, about 1030 mg, about 1035 mg, about 1040 mg, about 1045 mg, about 1050 mg, about 1055 mg, about 1060 mg, about 1065 mg, about 1070 mg, about 1075 mg, about 1080 mg, about 1085 mg, about 1090 mg, about 1095 mg, about 1100 mg, about 1105 mg, about 1110 mg, about 1115 mg, about 1120 mg, about 1125 mg, about 1130 mg, about 1135 mg, about 1140 mg, about 1145 mg, about 1150 mg, about 1155 mg, about 1160 mg, about 1165 mg, about 1170 mg, about 1175 mg, about 1180 mg, about 1185 mg, about 1190 mg, about 1195 mg, about 1200 mg, about 1205 mg, about 1210 mg, about 1215 mg, about 1220 mg, about 1225 mg, about 1230 mg, about 1235 mg, about 1240 mg, about 1245 mg, about 1250 mg, about 1255 mg, about 1260 mg, about 1265 mg, about 1270 mg, about 1275 mg, about 1280 mg, about 1285 mg, about 1290 mg, about 1295 mg, about 1300 mg, about 1305 mg, about 1310 mg, about 1315 mg, about 1320 mg, about 1325 mg, about 1330 mg, about 1335 mg, about 1340 mg, about 1345 mg, about 1350 mg, about 1355 mg, about 1360 mg, about 1365 mg, about 1370 mg, about 1375 mg, about 1380 mg, about 1385 mg, about 1390 mg, about 1395 mg, about 1400 mg, about 1405 mg, about 1410 mg, about 1415 mg, about 1420 mg, about 1425 mg, about 1430 mg, about 1435 mg, about 1440 mg, about 1445 mg, about 1450 mg, about 1455 mg, about 1460 mg, about 1465 mg, about 1470 mg, about 1475 mg, about 1480 mg, about 1485 mg, about 1490 mg, about 1495 mg, about 1500 mg, about 1505 mg, about 1510 mg, about 1515 mg, about 1520 mg, about 1525 mg, about 1530 mg, about 1535 mg, about 1540 mg, about 1545 mg, about 1550 mg, about 1555 mg, about 1560 mg, about 1565 mg, about 1570 mg, about 1575 mg, about 1580 mg, about 1585 mg, about 1590 mg, about 1595 mg, or about 1600 mg per dose.

[0030] In some aspects, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered intravenously.

[0031] In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered intravenously once per week for 3 weeks.

[0032] In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered intravenously in cycles, wherein each cycle comprises administering the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), once per week for 3 weeks.

[0033] In some aspects of the disclosed methods, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered orally.

[0034] In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered orally once per week for 3 weeks.

[0035] In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered orally in cycles, wherein each cycle comprises administering the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), once per week for 3 weeks.

[0036] In some aspects of the disclosed methods, the subject is administered a compound of Formula (I).

[0037] In other aspects of the disclosed methods, the subject is administered a pharmaceutically acceptable salt of a compound of Formula (I).

[0038] In some aspects of the disclosed methods, the subject is administered a taxane anti cancer agent. Taxane anticancer agents are a class of anticancer drugs that bind to tubulin/microtubules and stabilize microtubules, thereby blocking mitosis and resulting in apoptosis. See, e.g., Ojima I, et al. Taxane anticancer agents: a patent perspective. Expert Opin Ther Pat. 2016;26(1): 1-20. doi: 10, 1517/13543776.2016.11 1 1872. Exemplary taxane anticancer agents include paclitaxel, docetaxel, cabazitaxel, and nab-paclitaxel. Other taxane anticancer agents include larotaxel, milataxel, or tataxel, and tesetaxel, BMS- 184476, docosahexaenoic acid (DHA)-paclitaxel (“Taxoprexin”), and poiy(L-giutamic acid) PG- paclitaxel (“Opaxio”).

[0039] In some embodiments, the taxane anticancer agent is docetaxel.

[0040] In some embodiments, the taxane anticancer agent is paclitaxel.

[0041] In some embodiments, the taxane anticancer agent is cabazitaxel.

[0042] In some embodiments, the taxane anticancer agent is nab-paclitaxel.

[0043] In some aspects of the disclosed methods, the taxane anticancer agent is administered intravenously.

[0044] In some aspects of the disclosed methods, the taxane anticancer agent is administered in an amount of about 10 mg/m² to about 300 mg/m², such as, for example about 10 mg/m², about 11 mg/m², about 12 mg/m², about 13 mg/m², about 14 mg/m², about 15 mg/m², about 16 mg/m², about 17 mg/m², about 18 mg/m², about 19 mg/m², about 20 mg/m², about 21 mg/m², about 22 mg/m², about 23 mg/m², about 24 mg/m², about 25 mg/m², about 26 mg/m², about 27 mg/m², about 28 mg/m², about 29 mg/m², about 30 mg/m², about 31 mg/m², about 32 mg/m², about 33 mg/m², about 34 mg/m², about 35 mg/m², about 36 mg/m², about 37 mg/m², about 38 mg/m², about 39 mg/m², about 40 mg/m², about 41 mg/m², about 42 mg/m², about 43 mg/m², about 44 mg/m², about 45 mg/m², about 46 mg/m², about 47 mg/m², about 48 mg/m², about 49 mg/m², about 50 mg/m², about 51 mg/m², about 52 mg/m², about 53 mg/m², about 54 mg/m², about 55 mg/m², about 56 mg/m², about 57 mg/m², about 58 mg/m², about 59 mg/m², about 60 mg/m², about 61 mg/m², about 62 mg/m², about 63 mg/m², about 64 mg/m², about 65 mg/m², about 66 mg/m², about 67 mg/m², about 68 mg/m², about 69 mg/m², about 70 mg/m², about 71 mg/m², about 72 mg/m², about 73 mg/m², about 74 mg/m², about 75 mg/m², about 76 mg/m², about 77 mg/m², about 78 mg/m², about 79 mg/m², about 80 mg/m², about 81 mg/m², about 82 mg/m², about 83 mg/m², about 84 mg/m², about 85 mg/m², about 86 mg/m², about 87 mg/m², about 88 mg/m², about 89 mg/m², about 90 mg/m², about 91 mg/m², about 92 mg/m², about 93 mg/m², about 94 mg/m², about 95 mg/m², about 96 mg/m², about 97 mg/m², about 98 mg/m², about 99 mg/m², about 100 mg/m², about 101 mg/m², about 102 mg/m², about 103 mg/m², about 104 mg/m², about 105 mg/m², about 106 mg/m², about 107 mg/m², about 108 mg/m², about 109 mg/m², about 110 mg/m², about 111 mg/m², about 112 mg/m², about 113 mg/m², about 114 mg/m², about 115 mg/m², about 116 mg/m², about 117 mg/m², about 118 mg/m², about 119 mg/m², about 120 mg/m², about 121 mg/m², about 122 mg/m², about 123 mg/m², about 124 mg/m², about 125 mg/m², about 126 mg/m², about 127 mg/m², about 128 mg/m², about 129 mg/m², about 130 mg/m², about 131 mg/m², about 132 mg/m², about 133 mg/m², about 134 mg/m², about 135 mg/m², about 136 mg/m², about 137 mg/m², about 138 mg/m², about 139 mg/m², about 140 mg/m², about 141 mg/m², about 142 mg/m², about 143 mg/m², about 144 mg/m², about 145 mg/m², about 146 mg/m², about 147 mg/m², about 148 mg/m², about 149 mg/m², about 150 mg/m², about 151 mg/m², about 152 mg/m², about 153 mg/m², about 154 mg/m², about 155 mg/m², about 156 mg/m², about 157 mg/m², about 158 mg/m², about 159 mg/m², about 160 mg/m², about 161 mg/m², about 162 mg/m², about 163 mg/m², about 164 mg/m², about 165 mg/m², about 166 mg/m², about 167 mg/m², about 168 mg/m², about 169 mg/m², about 170 mg/m², about 171 mg/m², about 172 mg/m², about 173 mg/m², about 174 mg/m², about 175 mg/m², about 176 mg/m², about 177 mg/m², about 178 mg/m², about 179 mg/m², about 180 mg/m², about 181 mg/m², about 182 mg/m², about 183 mg/m², about 184 mg/m², about 185 mg/m², about 186 mg/m², about 187 mg/m², about 188 mg/m², about 189 mg/m², about 190 mg/m², about 191 mg/m², about 192 mg/m², about 193 mg/m², about 194 mg/m², about 195 mg/m², about 196 mg/m², about 197 mg/m², about 198 mg/m², about 199 mg/m², about 200 mg/m², about 201 mg/m², about 202 mg/m², about 203 mg/m², about 204 mg/m², about 205 mg/m², about 206 mg/m², about 207 mg/m², about 208 mg/m², about 209 mg/m², about 210 mg/m², about 211 mg/m², about 212 mg/m², about 213 mg/m², about 214 mg/m², about 215 mg/m², about 216 mg/m², about 217 mg/m², about 218 mg/m², about 219 mg/m², about 220 mg/m², about 221 mg/m², about 222 mg/m², about 223 mg/m², about 224 mg/m², about 225 mg/m², about 226 mg/m², about 227 mg/m², about 228 mg/m², about 229 mg/m², about 230 mg/m², about 231 mg/m², about 232 mg/m², about 233 mg/m², about 234 mg/m², about 235 mg/m², about 236 mg/m², about 237 mg/m², about 238 mg/m², about 239 mg/m², about 240 mg/m², about 241 mg/m², about 242 mg/m², about 243 mg/m², about 244 mg/m², about 245 mg/m², about 246 mg/m², about 247 mg/m², about 248 mg/m², about 249 mg/m², about 250 mg/m², about 251 mg/m², about 252 mg/m², about 253 mg/m², about 254 mg/m², about 255 mg/m², about 256 mg/m², about 257 mg/m², about 258 mg/m², about 259 mg/m², about 260 mg/m², about 261 mg/m², about 262 mg/m², about 263 mg/m², about 264 mg/m², about 265 mg/m², about 266 mg/m², about 267 mg/m², about 268 mg/m², about 269 mg/m², about 270 mg/m², about 271 mg/m², about 272 mg/m², about 273 mg/m², about 274 mg/m², about 275 mg/m², about 276 mg/m², about 277 mg/m², about 278 mg/m², about 279 mg/m², about 280 mg/m², about 281 mg/m², about 282 mg/m², about 283 mg/m², about 284 mg/m², about 285 mg/m², about 286 mg/m², about 287 mg/m², about 288 mg/m², about 289 mg/m², about 290 mg/m², about 291 mg/m², about 292 mg/m², about 293 mg/m², about 294 mg/m², about 295 mg/m², about 296 mg/m², about 297 mg/m², about 298 mg/m², about 299 mg/m², or about 300 mg/m². When the anticancer agent is nab-paclitaxel, the administered taxane anticancer agent is in an amount defined on a paclitaxel basis.

[0045] In some embodiments, the taxane anticancer agent is administered in an amount of about 60 mg/m² to about 100 mg/m².

[0046] In some embodiments, the taxane anticancer agent is administered in an amount of about 25 mg/m².

[0047] In some embodiments, the taxane anticancer agent is administered in an amount of about 135 mg/m² to about 175 mg/m².

[0048] In some embodiments, the taxane anticancer agent is administered in an amount of about 125 mg/m² to about 260 mg/m².

[0049] In some embodiments in which the taxane anticancer agent is docetaxel, the docetaxel is administered in accordance with the December 2013 Revision (Sanofi-aventis) of the TAXOTERE (docetaxel) Injection Concentrate, Intravenous Infusion (IV) prescribing information.

[0050] In some embodiments in which the taxane anticancer agent is paclitaxel, the paclitaxel is administered in accordance with the April 2011 Revision (Bristol-Myers Squibb) of the TAXOL® (paclitaxel) INJECTION prescribing information.

[0051] In some embodiments in which the taxane anticancer agent is carbitaxel, the carbitaxel is administered in accordance with the June 2010 Revision (Sanofi-aventis) of the JEVTANA (cabazitaxel) Injection prescribing information.

[0052] In some embodiments in which the taxane anticancer agent is nab-paclitaxel, the nab-paclitaxel is administered in accordance with the October 2022 Revision (Bristol- Myers Squibb) of the ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound), for intravenous use prescribing information. [0053] In some aspects of the disclosed methods, the taxane anticancer agent is administered by intravenous infusion over a period of about 0.5 - about 24 hours, such as, for example, about 0.5 hr, about 1 hr, about 2 hr, about 3 hr, about 4 hr, about 5 hr, about 6 hr, about 7 hr, about 8 hr, about 9 hr, about 10 hr, about 11 hr, about 12 hr, about 13 hr, about 14 hr, about 15 hr, about 16 hr, about 17 hr, about 18 hr, about 19 hr, about 20 hr, about 21 hr, about 22 hr, about 23 hr, or about 24 hr.

[0054] In some embodiments, the taxane anticancer agent is administered by intravenous infusion over about 1 hour.

[0055] In some embodiments, the taxane anticancer agent is administered by intravenous infusion over about 3 hours.

[0056] In some embodiments, the taxane anticancer agent is administered by intravenous infusion over about 6 hours.

[0057] In some aspects of the disclosed methods, the taxane anticancer agent is administered by intravenous infusion over a period of about 0.5 hr - about 24 hours once every three weeks, such as, for example, about 0.5 hr, about 1 hr, about 2 hr, about 3 hr, about 4 hr, about 5 hr, about 6 hr, about 7 hr, about 8 hr, about 9 hr, about 10 hr, about 11 hr, about 12 hr, about 13 hr, about 14 hr, about 15 hr, about 16 hr, about 17 hr, about 18 hr, about 19 hr, about 20 hr, about 21 hr, about 22 hr, about 23 hr, or about 24 hronce every three weeks.

[0058] In some embodiments, the taxane anticancer agent is administered by intravenous infusion over about 1 hour once every three weeks.

[0059] In some embodiments, the taxane anticancer agent is administered by intravenous infusion over about 3 hours once every three weeks.

[0060] In some embodiments, the taxane anticancer agent is administered by intravenous infusion over about 6 hours once every three weeks.

[0061] In some aspects of the disclosed methods, the taxane anticancer agent is administered by intravenous infusion over a period of 0.5 - 24 hours on days 1, 8, and 15 of each 28 day cycle, such as, for example, about 0.5 hr, about 1 hr, about 2 hr, about 3 hr, about 4 hr, about 5 hr, about 6 hr, about 7 hr, about 8 hr, about 9 hr, about 10 hr, about 11 hr, about 12 hr, about 13 hr, about 14 hr, about 15 hr, about 16 hr, about 17 hr, about 18 hr, about 19 hr, about 20 hr, about 21 hr, about 22 hr, about 23 hr, or about 24 hr on days 1, 8, and 15 of each 28 day cycle. [0062] In some embodiments, the taxane anticancer agent is administered by intravenous infusion over about 0.5 hour on days 1, 8, and 15 of each 28 day cycle.

[0063] In some aspects, the treatment regimen of the disclosure further comprise an additional therapeutic agent. Exemplary additional therapeutic agents include, for example, other anticancer agents (e.g., gemcitabine, doxorubicin, cyclophosphamide, cisplatin, carbop latin, fluorouracil), corticosteroids (e.g., prednisone or dexamethasone), antihistamines (e.g., dexchloropheniramine or diphenylhydramine), H2 antagonist (e.g., ranitidine), and antiemetics.

[0064] In some aspects, the methods of the disclosre are directed to treating cancer in a subject. In some embodiments, the cancer is one or more of include squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be treated using compounds according to the present disclosure include, for example, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.

[0065] In other embodiments, the cancer is one or more of breast cancer, non-small cell lung cancer, lung squamous cell carcinoma, uterine/endometrio adenocarcinoma, ovarian cancer, lung adenocarcinoma, bladder cancer, skin cancer, hormone refractory prostate cancer, colon adenocarcinoma, gastric adenocarcinoma, pancreatic cancer, AIDS-related Kaposi’s sarcoma, or squamous cell carcinoma of the head and neck cancer.

[0066] In some embodiments, the cancer is breast cancer or prostate cancer.

[0067] In some embodiments, the cancer is breast cancer.

[0068] In some embodiments, the cancer is metastatic breast cancer.

[0069] In some embodiments, the cancer is prostate cancer.

[0070] In some embodiments, the cancer is hormone-refractory metastatic prostate cancer.

[0071] In some embodiments, the cancer is non-small cell lung cancer.

[0072] In some embodiments, the cancer is adenocarcinoma of the pancreas.

[0073] In some embodiments of the disclosed methods, the cancer is a SMARCA4 deficient cancer. As used herein, the term “SMARCA4 deficient” means that the cancer either lacks a SMARCA4 gene, or has a mutated SMARCA4 gene that encodes a fully- or partially- non-functional SMARCA4 protein.

[0074] In some embodiments of the disclosed methods, the cancer is not a SMARCA4 deficient cancer.

[0075] In some aspects, the methods of the disclosure comprise administering to the subject, in addition to the disclosed treatment regimen, an additional therapeutic agent. Examplary additional therapeutic agents that may be administered with the disclosed treatment regimen include cyclophosphamide, cisplatin, doxorubicin, prednisone, and fluorouracil.

[0076] In some aspects of the methods of the disclosure, administration of the disclosed treatment regimen results in greater tumor growth inhibition than results from administration of either Formula (I) alone or the taxane anticancer agent alone. As used herein, tumor growth inhibition is calculated as follows: Mean % Inhibition = (mean(C)- mean(T))/mean(C) * 100%, wherein C is the tumor volume in the control arm, and T is the tumor volume in the treatment arm.

[0077] In some aspects of the methods of the disclosure, administration of the disclosed treatment regimen results in at least 40% tumor growth inhibition, such as, for example, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% tumor growth inhibition, relative to no treatment. [0078] In some aspects of the methods of the disclosure, the cancer exhibits a complete response (CR) or a partial response (PR) to the administration of the treatment regimen, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.

[0079] In some embodiments, the cancer exhibits a complete response (CR) to the administration of the treatment regimen, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.

[0080] In other embodiments, the cancer exhibits a partial response (PR) to the administration of the treatment regimen, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.

EXAMPLES

Example 1

[0081] A study is conducted to evaluate the anti-tumor efficacy of the Formula (I) + taxane combination in SMARCA4 deficient human lung cancer xenogtaft models in mice. Specific objectives include:

1. To determine whether the Formula (I) + docetaxel combination in SMARCA4 deficient lung cancer models in mice results in deeper tumor growth inhibition (TGI) compared to each single agent alone.

2. To determine whether the Formula (I) + nab -paclitaxel combination in SMARCA4 deficient lung cancer models in mice results in deeper tumor growth inhibition (TGI) compared to each single agent alone.

[0082] Materials

• Formula (I)

• Docetaxel (Jiangsu Hengrui Medicine CO., LTD)

Docetaxel is stored in solution form at 2-8 °C.

• Nab-paclitaxel (CSPC Pharmaceutical Group Co., Ltd) o Nab-paclitaxel is stored in solution form at 2-8 °C.

[0083] Experimental Procedures

[0084] NCI-H838 tumor bearing mouse model [0085] The NCI-H838-#5 tumor cells are maintained in vitro with RPMI1640 medium supplemented with 10% fetal bovine serum at 37°C in an atmosphere of 5% CO2 in air. The cells in exponential growth phase are harvested and quantitated by cell counter before tumor inoculation. NOD-SCID female mice are inoculated subcutaneously in the right front flank region with NCI-H838-#5 tumor cells (5 x 10⁶) in 0.1 ml of PBS mixed with Matrigel (1:1) for tumor development. The randomization is performed when the mean tumor size reaches approximately 100-150 mm³. Tumor volumes are measured every other day after randomization in two dimensions using a caliper, and the volume are expressed in mm³ using the formula: “V = (L x W x W)/2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L).

[0086] Data Analysis

[0087] Tumor volumes at the end of studies are evaluated by the Mann- Whitney test (unpaired, nonparametric test). **P<0.05 ***P<0.01, ****P<0.001 versus vehicle are shown in graphs.

[0088] Results

[0089] Formula (I) combination with docetaxel results in deeper tumor growth inhibition (TGI) compared to each single agent alone in NCI-H838 SMARCA4 deficient tumors at well tolerated doses

[0090] The efficacy of Formula (I) and docetaxel on tumor growth inhibition is evaluated in SMARCA4 deficient lung cancer models in mice. For the NCI-H838 CDX model, mice are inoculated subcutaneously with the NCI-H838 tumor cells (5 x 10⁶). Formula (I) administered orally (p.o.) every day (QD) at 1 mg/kg significantly inhibits the growth of NCI-H838 tumors. Once weekly (QW) intravenous (i.v.) administration of docetaxel at 10 mg/kg also shows significant tumor growth inhibition in this model. The combination of Formula (I) (1 mg/kg p.o. QD) and docetaxel (10 mg/kg i.v. QW) results in a significantly higher TGI compared to each single agent alone. See Fig. 1.

[0091] The efficacy of Formula (I) and nab-paclitaxel on tumor growth inhibition is evaluated in SMARCA4 deficient lung cancer models in mice. For the NCI-H838 CDX model, mice are inoculated subcutaneously with the NCI-H838 tumor cells (5 x 10⁶). Formula (I) QD p.o. dosing at 1 mg/kg significantly inhibits the tumor growth of NCI-H838 in combination with nab-paclitaxel 15 mg/kg i.v. administrated every three weeks (see Fig. 2).

Claims

What is claimed:

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a treatment regimen comprising:

(a) a compound of Formula (I): Formula (I), or a pharmaceutically acceptable salt thereof; and

(b) a taxane anticancer agent.

2. The method of claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the taxane anticancer agent are administered concurrently or sequentially.

3. The method of claim 1 or claim 2, wherein the taxane anticancer agent is docetaxel, paclitaxel, nab-paclitaxel, or cabazitaxel.

4. The method of claim 3, wherein the taxane anticancer agent is docetaxel.

5. The method of any one of the preceding claims, wherein the subject is administered the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), in an amount of about 5 mg to about 1600 mg per dose.

6. The method of any one of the preceding claims, wherein the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered intravenously.

7. The method of any one of the preceding claims, wherein the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered orally.

8. The method of any one of the preceding claims, wherein the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered once per week for 3 weeks.

9. The method of any one of the preceding claims, wherein the subject is administered a compound of Formula (I).

10. The method of any one of claims 1 to 8, wherein the subject is administered a pharmaceutically acceptable salt of a compound of Formula (I).

11. The method of any one of the preceding claims, wherein the taxane anticancer agent is administered intravenously.

12. The method of any one of the preceding claims, wherein the taxane anticancer agent is administered in an amount of about 10 mg/m² to about 300 mg/m².

13. The method of claim 11 or claim 12, wherein the taxane anticancer agent is administered by intravenous infusion over about 0.5 hr - about 3 hours, once every three weeks.

14. The method of any one of the preceding claims, wherein the treatment regimen further comprises an additional therapeutic agent.

15. The method of claim 14, wherein the additional therapeutic agent is gemcitabine, doxorubicin, cyclophosphamide, cisplatin, carboplatin, fluorouracil, prednisone, dexamethasone, dexchloropheniramine, diphenylhydramine, ranitidine, or an antiemetic.

16. The method of any one of claims 1 to 15, wherein the cancer is breast cancer, nonsmall cell lung cancer, lung squamous cell carcinoma, uterine/endometrio adenocarcinoma, ovarian cancer, lung adenocarcinoma, bladder cancer, skin cancer, hormone refractory prostate cancer, colon adenocarcinoma, gastric adenocarcinoma, pancreatic cancer, AIDS- related Kaposi’s sarcoma, or squamous cell carcinoma of the head and neck cancer.

17. The method of any one of the preceding claims, wherein the cancer is a SMARCA4 deficient cancer.

18. The method of any one of the preceding claims, wherein administration of the treatment regimen results in greater tumor growth inhibition than results from administration of either Formula (I) alone or the taxane anticancer agent alone.

19. The method of any one of the preceding claims, wherein administration of the treatment regimen results in at least 40% tumor growth inhibition relative to no treatment.

20. The method of any one of claims 1 to 19, wherein the cancer exhibits a complete response (CR) or a partial response (PR) to the administration of the treatment regimen, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.

21. The method of claim 20, wherein the cancer exhibits a complete response (CR) to the administration of the treatment regimen, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.

22. The method of claim 20, wherein the cancer exhibits a partial response (PR) to the administration of the treatment regimen, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.