Methods of treating cancer using a smarca2 degrader

Abstract

The present invention relates to methods for treating cancer in a subject in need thereof, comprising administering to the subject (Compound I) or a pharmaceutically acceptable salt thereof.

Description

105807.001154METHODS OF TREATING CANCER USING A SMARCA2 DEGRADERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Patent Application No. 63 / 683,784, filed August 16, 2024; United States Provisional Patent Application No. 63 / 692,234, filed September 9, 2024; United States Provisional Patent Application No. 63 / 708,988, filed October 18, 2024; United States Provisional Patent Application No. 63 / 710,811, filed October 23, 2024; and United States Provisional Patent Application No. 63 / 756,413, filed February 10, 2025. The entirety of each aforementioned application is incorporated by reference herein.TECHNICAL FIELD

[0002] The disclosure is directed to SMARCA degraders and methods of their use.BACKGROUND

[0003] Genes encoding subunits of the SWUSNF chromatin remodeling complex are among the most highly mutated in cancer, occurring in 20-24% of all human cancers; In most cases, these are loss-of-function mutations. See Shain AH, et al. PLoS One. 2013;8(l):e55119; see also Kadoch C, et al. Nat Genet. 2013;45(6):592-601.

[0004] Mammalian SWUSNF complexes have broad roles in transcriptional regulation and DNA-damage repair; however, the mechanisms by which mutations in components of the SWI / SNF complex contribute to cancer are not known. See Mittal P, et al. Nat Rev Clin Oncol. 2020;17(7):435-448.

[0005] SWI / SNF complexes use the energy generated through the hydrolysis of ATP to slide or eject nucleosomes; the complex contains either 1 of 2 ATP enzymatic subunits, SMARCA2 or SMARCA4 See Shain AH, et al. PLoS One. 2013;8(l):e55119.

[0006] In non-small cell lung cancer, mutations in SMARCA4 are observed in approximately 10% of cases, and when they do occur, they are associated with more aggressive and invasive disease, poor clinical outcomes, and shorter survival. See Schoenfeld AJ, et al. Clin Cancer Res. 2020;26:5701-5708.105807.001154

[0007] SMARCA4 encodes the protein BRG1, an ATP-dependent helicase that regulates gene transcription through chromatin remodeling. See Wang X, et al. Clin Cancer Res. 2013;20(l):21-27.

[0008] SMARCA4 is inactivated in a variety of cancers and considered a tumor suppressor. See Wang X, et al. Clin Cancer Res. 2013;20(l):21-27.

[0009] SMARCA2 and SMARCA4 work in a complementary manner. When SMARCA4 is mutated, tumors become reliant on SMARCA2 for growth and survival. See Hoffman GR, et al. Proc Natl Acad Sci USA. 2014; 111(8):3128-3133.

[0010] There are no therapies available that target SMARCA4-deficient cancers.

[0011] SMARCA4 mutation predicts poor clinical outcomes to standard first-line CIT in NSCLC. See Schoenfeld AJ, et al. Clin Cancer Res. 2020;26:5701-5708.

[0012] SMARCA4-mutated cancers become reliant on SMARCA2.

[0013] In these cancers, when SMARCA2 is depleted, the SWI / SNF (SWI / SNF, Switch / Sucrose Non-Fermentable) complex no longer functions. Cells can no longer survive and tumors regress. This concept is referred to as “Synthetic Lethality.”

[0014] Loss of SMARCA4 through mutation leads to dependency on SMARCA2.

[0015] Selectively degrading SMARCA2 offers an attractive approach to target SMARCA4 mutant tumors.

[0016] There is a need for highly potent, selective, and targeted protein degrader of SMARCA2 that provides an effective therapy in SMARCA - / -mutated cancers. The present disclosure addresses this need.SUMMARY

[0017] The disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject Compound I, or a pharmaceutically acceptable salt thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIGS. 1 and 2 show the impact of SMARCA4 mutations on survival.

[0019] FIG. 3 shows the study scheme for the study described in the Example. LOF, loss of function; NSCLC, non-small cell lung cancer.105807.001154

[0020] FIG. 4 shows the adverse events for the study described in the Example at N=69 (number of patients). (ALT, alanine aminotransferase; AST, aspartate aminotransferase).

[0021] FIG. 5 shows tumor response in patients with NSCLC, esophageal cancer, or gastric cancer in the study in the Example. [1], class 1 mutation; [2] class 2 mutation; NSCLC, non-small cell lung cancer; SLD, sum of longest diameter. *Indicates patient is still on treatment.

[0022] FIG. 6 shows the best overall response and duration of treatment in efficacy evaluable patients with NSCLC or upper gastrointestinal cancers and a loss-of-function SMARCA4 mutation by treatment group (w=30). *Indicates patient is still on treatment. NSCLC, non-small cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease, SLD, sum of longest diameters.

[0023] FIG. 7 shows the duration of treatment for patients with NSCLC and esophageal cancer in the study in the Example (at N=69). NSCLC, non-small cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease.

[0024] FIG. 8 shows patient responses in NSCLC.

[0025] FIG. 9 shows a patient response in esophageal cancer.

[0026] FIG. 10 shows the pharmacokinetics from the study in the Example (Mean Concentration on Cycle 1, Day 1). AUC, area under the curve; Cmax, maximum concentration; DCso, half-maximal degradation concentration; PK, pharmacokinetics.

[0027] FIG. 11 shows the AUC of baseline normalized SMARCA2 / BRM degradation DI predose to D8 predose for the study in the Example. AUC, area under the curve.

[0028] FIG. 12 shows the maximal observed SMARCA2 / BRM degradation during cycle 1 for the study in the Example.

[0029] FIG. 13 (A) shows that pre- and on-treatment biopsies demonstrate complete SMARCA2 / BRM degradation in tumor tissue in a patient with a partial response receiving Compound 1283 mg. (B) shows that pre- and on-treatment biopsies demonstrate selective SMARCA2 / BRM degradation relative to SMARCA4 / BRG1 in tumor tissue in a patient with a missense SMARCA4 mutation receiving Compound I 665 mg.

[0030] FIG. 14 shows results from a 41 -year-old female with ovarian cancer with missense SMARCA4 mutation receiving 500mg Compound I monotherapy. Fresh baseline105807.001154 and on-treatment lung biopsies taken 23 days apart; On-treatment biopsy taken on C2D2, 1 day post dose. Shows Selective degradation of SMARCA2 in tumor tissue; 99% decrease in SMARCA2 expression (H-score) with treatment.

[0031] FIG. 15 shows confirmation of target engagement. A biopsy of 42-y ear-old Caucasian male with large cell neuroendocrine cancer in the Compound 1 120 mg + docetaxel cohort; and a shift in cells from high intensity SMARCA2 staining to weak or absent staining.

[0032] FIG. 16 shows confirmation of target engagement. SMARCA2 levels in PBMCs show 65% degradation on C2D1 pre-dose relative to baseline, suggesting sustained SMARCA2 decrease over time.

[0033] FIG. 17 shows the study design for the Compound I + docetaxel combination. LOF, loss of function; NSCLC, non-small cell lung cancer.

[0034] FIG. 18 shows the adverse event profile for the Compound I + docetaxel combination.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0035] The present disclosure may be understood more readily by reference to the following detailed description of desired embodiments and the examples included therein.

[0036] 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. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0037] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. The term “comprising” should be understood as having its open-ended meaning of “including,” but the term also includes closed embodiments. For example, a composition that comprises components A and B can be a composition that includes A, B, and other components, but it can also be a composition made of A and B only.

[0038] Any documents cited herein are incorporated by reference in their entireties for any and all purposes.105807.001154

[0039] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or implied. The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” For example, “about 10%” can indicate a range of 9% to 11%, and “about 1” can mean from 0.9- 1.1.

[0040] Unless indicated to the contrary, the numerical values should be understood to include numerical values which are the same when reduced to the same number of significant figures and numerical values which differ from the stated value by less than the experimental error of conventional measurement technique of the type described in the present application to determine the value.

[0041] All ranges disclosed herein are inclusive of the recited endpoint and independently of the endpoints. The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0042] 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.

[0043] “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.105807.001154

[0044] 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 (i.e., a patient) to whom treatment is provided. In other aspects, the mammal is a non-human to whom treatment is provided.

[0045] “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.

[0046] “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 and 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, oxalic 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- hydroxyethane-sulfonic 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- methylglucamine 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, fumarate, oxalate, hippurate, and the like.105807.001154

[0047] As used herein, the term “effective amount” or “therapeutically effective amount” in the context of the administration of a substance to a subject refers to the amount of the substance that achieves a desired therapeutic effect.

[0048] The present invention provides compositions and methods for treating cancer in a subject in need thereof. In particular, the methods provided herein relate to methods of treating transcription-dependent tumors in a subject using a specific degrader of SMARCA2. The cancer can include transcription-dependent tumors including, for example, non-small cell lung cancer, pancreatic cancer, breast cancer, esophageal cancer, gastric cancer, and the like. The cancer can include one or more tumors with mutated SMARCA4. The cancer can include one or more advanced or metastatic solid tumors.

[0049] Compound I is SMARCA2 degrader that demonstrates selective pre-clinical activity in SMARCA4 -altered tumor cells. Compound I demonstrates >1000-fold selectively for SMARCA4 mutated cancer cells compared to wild-type cells. Compound I is highly potent (plasma DCso = 21 nM); highly selective for SMARCA2 over SMARCA4 (cellular assays >1000X; HiBiT 40X selective; selectivity confirmed in vivo); efficacious in various CDX and PDX models at well-tolerated doses; clean on hERG; and a Moderate CYP3 A4 inhibitor, (abbreviations: CDX, cell line-derived xenograft; DCso, half-maximal degradation concentration; hERG, human Ether-a-go-go-Related Gene; PDX, patient-derived xenografts; VBC, VHL, elongin B, and elongin C complex; VHL, von Hippel-Lindau.)

[0050] The structure of Compound I is shown below:Compound I.105807.001154

[0051] Compound I, and methods of making Compound I, are set forth in WO202 1 / 252666. The methods of the disclosure comprise administering to the subject Compound I, or a pharmaceutically acceptable salt thereof.

[0052] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject Compound I,(Compound I), or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the subject is administered Compound I.

[0054] In some embodiments, the subject is administered a pharmaceutically acceptable salt of Compound I.

[0055] In some embodiments, the pharmaceutically acceptable salt of Compound I is a hydrochloride salt, a fumarate salt, an oxalate salt, or a hippurate salt.

[0056] In some embodiments, the pharmaceutically acceptable salt of Compound I is a trihydrochloride salt.

[0057] In some embodiments, the subject is a human.

[0058] In some embodiments, the cancer is a transcription-dependent cancer.

[0059] 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.

[0060] In some embodiments, the cancer has a mutated SMARCA4 gene.

[0061] In some embodiments, the mutated SMARCA4 gene has a Class 1 mutation (loss of function).105807.001154

[0062] In some embodiments, the mutated SMARCA4 gene has a Class 2 mutation (missense).

[0063] In some embodiments, the cancer is non-small cell lung cancer, ovarian cancer, pancreatic cancer, breast cancer, esophageal cancer, or gastric cancer.

[0064] In some embodiments, the cancer is non-small cell lung cancer, pancreatic cancer, breast cancer, or esophageal cancer.

[0065] In some embodiments, the cancer is non-small cell lung cancer.

[0066] In some embodiments, the cancer is esophageal cancer.

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

[0068] In some embodiments, the cancer is pancreatic cancer.

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

[0070] In some embodiments, the cancer is gastric cancer.

[0071] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof, is administered intravenously.

[0072] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof, is administered once per week.

[0073] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof, is administered intravenously once per week.

[0074] In some embodiments, Compound I or pharmaceutically acceptable salt thereof, is administered intravenously once per week for 3 weeks.

[0075] In some embodiments, Compound I or pharmaceutically acceptable salt thereof, is administered intravenously in cycles, wherein each cycle comprises administering Compound I, or pharmaceutically acceptable salt thereof, once per week for 3 weeks.

[0076] In some embodiments, Compound I or pharmaceutically acceptable salt thereof, is administered intravenously over 1-2 hours.

[0077] In some embodiments, Compound I or pharmaceutically acceptable salt thereof, is administered intravenously over 1 hour.

[0078] In some embodiments, Compound I or pharmaceutically acceptable salt thereof, is administered intravenously over 1.5 hours.

[0079] In some embodiments, Compound I or pharmaceutically acceptable salt thereof, is administered intravenously over 2 hours.105807.001154

[0080] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount between 20-1000 mg per dose such as, for example, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg,112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 211 mg, 212 mg, 213 mg, 214 mg, 215 mg, 216 mg, 217 mg, 218 mg, 219 mg, 220 mg, 221 mg, 222 mg, 223 mg, 224 mg, 225 mg, 226 mg, 227 mg, 228 mg, 229 mg, 230 mg, 231 mg, 232 mg, 233 mg, 234 mg, 235 mg, 236 mg, 237 mg, 238 mg, 239 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 251 mg, 252 mg, 253 mg, 254 mg, 255 mg, 256 mg, 257 mg, 258 mg, 259 mg, 260 mg, 261 mg, 262 mg, 263 mg, 264 mg, 265 mg, 266 mg, 267 mg, 268 mg, 269 mg, 270 mg, 271 mg, 272 mg, 273 mg, 274 mg, 275 mg, 276 mg, 277 mg, 278 mg, 279 mg, 280 mg, 281 mg, 282 mg, 283 mg, 284 mg, 285 mg, 286 mg, 287 mg, 288 mg, 289 mg, 290 mg, 291 mg, 292 mg, 293 mg, 294 mg, 295 mg, 296 mg, 297 mg, 298 mg, 299 mg, 300 mg, 301 mg, 302 mg, 303 mg, 304 mg, 305 mg, 306 mg, 307 mg, 308 mg, 309 mg, 310 mg, 311 mg, 312 mg, 313 mg, 314 mg, 315 mg, 316 mg, 317 mg, 318 mg, 319 mg, 320 mg, 321 mg, 322 mg, 323 mg, 324 mg, 325 mg, 326 mg, 327 mg, 328 mg, 329 mg, 330 mg, 331 mg, 332 mg, 333 mg, 334 mg, 335 mg, 336 mg, 337 mg, 338 mg, 339 mg, 340 mg, 341 mg, 342 mg,105807.001154343 mg, 344 mg, 345 mg, 346 mg, 347 mg, 348 mg, 349 mg, or 350 mg, 351 mg, 352 mg, 353 mg, 354 mg, 355 mg, 356 mg, 357 mg, 358 mg, 359 mg, 360 mg, 361 mg, 362 mg, 363 mg, 364 mg, 365 mg, 366 mg, 367 mg, 368 mg, 369 mg, 370 mg, 371 mg, 372 mg, 373 mg, 374 mg, 375 mg, 376 mg, 377 mg, 378 mg, 379 mg, 380 mg, 381 mg, 382 mg, 383 mg, 384 mg, 385 mg, 386 mg, 387 mg, 388 mg, 389 mg, 390 mg, 391 mg, 392 mg, 393 mg, 394 mg, 395 mg, 396 mg, 397 mg, 398 mg, 399 mg, 400 mg per dose, 401 mg, 402 mg, 403 mg, 404 mg, 405 mg, 406 mg, 407 mg, 408 mg, 409 mg, 410 mg, 411 mg, 412 mg, 413 mg, 414 mg, 415 mg, 416 mg, 417 mg, 418 mg, 419 mg, 420 mg, 421 mg, 422 mg, 423 mg, 424 mg, 425 mg, 426 mg, 427 mg, 428 mg, 429 mg, 430 mg, 431 mg, 432 mg, 433 mg, 434 mg, 435 mg, 436 mg, 437 mg, 438 mg, 439 mg, 440 mg, 441 mg, 442 mg, 443 mg, 444 mg, 445 mg, 446 mg, 447 mg, 448 mg, 449 mg, 450 mg, 451 mg, 452 mg, 453 mg, 454 mg, 455 mg, 456 mg, 457 mg, 458 mg, 459 mg, 460 mg, 461 mg, 462 mg, 463 mg, 464 mg, 465 mg, 466 mg, 467 mg, 468 mg, 469 mg, 470 mg, 471 mg, 472 mg, 473 mg, 474 mg, 475 mg, 476 mg, 477 mg, 478 mg, 479 mg, 480 mg, 481 mg, 482 mg, 483 mg, 484 mg, 485 mg, 486 mg, 487 mg, 488 mg, 489 mg, 490 mg, 491 mg, 492 mg, 493 mg, 494 mg, 495 mg, 496 mg, 497 mg, 498 mg, 499 mg, 500 mg, 501 mg, 502 mg, 503 mg, 504 mg, 505 mg, 506 mg, 507 mg, 508 mg, 509 mg, 510 mg, 511 mg, 512 mg, 513 mg, 514 mg, 515 mg, 516 mg, 517 mg, 518 mg, 519 mg, 520 mg, 521 mg, 522 mg, 523 mg, 524 mg, 525 mg, 526 mg, 527 mg, 528 mg, 529 mg, 530 mg, 531 mg, 532 mg, 533 mg, 534 mg, 535 mg, 536 mg, 537 mg, 538 mg, 539 mg, 540 mg, 541 mg, 542 mg, 543 mg, 544 mg, 545 mg, 546 mg, 547 mg, 548 mg, 549 mg, 550 mg, 551 mg, 552 mg, 553 mg, 554 mg, 555 mg, 556 mg, 557 mg, 558 mg, 559 mg, 560 mg, 561 mg, 562 mg, 563 mg, 564 mg, 565 mg, 566 mg, 567 mg, 568 mg, 569 mg, 570 mg, 571 mg, 572 mg, 573 mg, 574 mg, 575 mg, 576 mg, 577 mg, 578 mg, 579 mg, 580 mg, 581 mg, 582 mg, 583 mg, 584 mg, 585 mg, 586 mg, 587 mg, 588 mg, 589 mg, 590 mg, 591 mg, 592 mg, 593 mg, 594 mg, 595 mg, 596 mg, 597 mg, 598 mg, 599 mg, 600 mg, 601 mg, 602 mg, 603 mg, 604 mg, 605 mg, 606 mg, 607 mg, 608 mg, 609 mg, 610 mg, 611 mg, 612 mg, 613 mg, 614 mg, 615 mg, 616 mg, 617 mg, 618 mg, 619 mg, 620 mg, 621 mg, 622 mg, 623 mg, 624 mg, 625 mg, 626 mg, 627 mg, 628 mg, 629 mg, 630 mg, 631 mg, 632 mg, 633 mg, 634 mg, 635 mg, 636 mg, 637 mg, 638 mg, 639 mg, 640 mg, 641 mg, 642 mg, 643 mg, 644 mg, 645 mg, 646 mg, 647 mg, 648 mg, 649 mg, 650 mg, 651 mg, 652 mg, 653 mg, 654 mg, 655 mg, 656 mg, 657 mg, 658 mg, 659 mg, 660 mg, 661 mg, 662 mg, 663 mg, 664 mg, 665 mg, 666 mg, 667 mg, 668 mg, 669 mg, 670 mg, 671 mg, 672 mg, 673 mg, 674 mg, 675 mg, 676 mg, 677105807.001154 mg, 678 mg, 679 mg, 680 mg, 681 mg, 682 mg, 683 mg, 684 mg, 685 mg, 686 mg, 687 mg, 688 mg, 689 mg, 690 mg, 691 mg, 692 mg, 693 mg, 694 mg, 695 mg, 696 mg, 697 mg, 698 mg, 699 mg, 700 mg, 701 mg, 702 mg, 703 mg, 704 mg, 705 mg, 706 mg, 707 mg, 708 mg, 709 mg, 710 mg, 711 mg, 712 mg, 713 mg, 714 mg, 715 mg, 716 mg, 717 mg, 718 mg, 719 mg, 720 mg, 721 mg, 722 mg, 723 mg, 724 mg, 725 mg, 726 mg, 727 mg, 728 mg, 729 mg, 730 mg, 731 mg, 732 mg, 733 mg, 734 mg, 735 mg, 736 mg, 737 mg, 738 mg, 739 mg, 740 mg, 741 mg, 742 mg, 743 mg, 744 mg, 745 mg, 746 mg, 747 mg, 748 mg, 749 mg, 750 mg, 751 mg, 752 mg, 753 mg, 754 mg, 755 mg, 756 mg, 757 mg, 758 mg, 759 mg, 760 mg, 761 mg, 762 mg, 763 mg, 764 mg, 765 mg, 766 mg, 767 mg, 768 mg, 769 mg, 770 mg, 771 mg, 772 mg, 773 mg, 774 mg, 775 mg, 776 mg, 777 mg, 778 mg, 779 mg, 780 mg, 781 mg, 782 mg, 783 mg, 784 mg, 785 mg, 786 mg, 787 mg, 788 mg, 789 mg, 790 mg, 791 mg, 792 mg, 793 mg, 794 mg, 795 mg, 796 mg, 797 mg, 798 mg, 799 mg, 800 mg, 801 mg, 802 mg, 803 mg, 804 mg, 805 mg, 806 mg, 807 mg, 808 mg, 809 mg, 810 mg, 811 mg, 812 mg, 813 mg, 814 mg, 815 mg, 816 mg, 817 mg, 818 mg, 819 mg, 820 mg, 821 mg, 822 mg, 823 mg, 824 mg, 825 mg, 826 mg, 827 mg, 828 mg, 829 mg, 830 mg, 831 mg, 832 mg, 833 mg, 834 mg, 835 mg, 836 mg, 837 mg, 838 mg, 839 mg, 840 mg, 841 mg, 842 mg, 843 mg, 844 mg, 845 mg, 846 mg, 847 mg, 848 mg, 849 mg, 850 mg, 851 mg, 852 mg, 853 mg, 854 mg, 855 mg, 856 mg, 857 mg, 858 mg, 859 mg, 860 mg, 861 mg, 862 mg, 863 mg, 864 mg, 865 mg, 866 mg, 867 mg, 868 mg, 869 mg, 870 mg, 871 mg, 872 mg, 873 mg, 874 mg, 875 mg, 876 mg, 877 mg, 878 mg, 879 mg, 880 mg, 881 mg, 882 mg, 883 mg, 884 mg, 885 mg, 886 mg, 887 mg, 888 mg, 889 mg, 890 mg, 891 mg, 892 mg, 893 mg, 894 mg, 895 mg, 896 mg, 897 mg, 898 mg, 899 mg, 900 mg, 901 mg, 902 mg, 903 mg, 904 mg, 905 mg, 906 mg, 907 mg, 908 mg, 909 mg, 910 mg, 911 mg, 912 mg, 913 mg, 914 mg, 915 mg, 919 mg, 917 mg, 918 mg, 919 mg, 920 mg, 921 mg, 922 mg, 923 mg, 924 mg, 925 mg, 926 mg, 927 mg, 928 mg, 929 mg, 930 mg, 931 mg, 932 mg, 933 mg, 934 mg, 935 mg, 936 mg, 937 mg, 938 mg, 939 mg, 940 mg, 941 mg, 942 mg, 943 mg, 944 mg, 945 mg, 946 mg, 947 mg, 948 mg, 949 mg, 950 mg, 951 mg, 952 mg, 953 mg, 954 mg, 955 mg, 956 mg, 957 mg, 958 mg, 959 mg, 960 mg, 961 mg, 962 mg, 963 mg, 964 mg, 965 mg, 966 mg, 967 mg, 968 mg, 969 mg, 970 mg, 971 mg, 972 mg, 973 mg, 974 mg, 975 mg, 976 mg, 977 mg, 978 mg, 979 mg, 980 mg, 981 mg, 982 mg, 983 mg, 984 mg, 985 mg, 986 mg, 987 mg, 988 mg, 989 mg, 990 mg, 991 mg, 992 mg, 993 mg, 994 mg, 995 mg, 996 mg, 997 mg, 998 mg, 999 mg, or 1000 mg per dose.105807.001154

[0081] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount between 20-350 mg per dose, such as, for example, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg,112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg,133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg,154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg,175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg,196 mg, 197 mg, 198 mg, 199 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 211 mg, 212 mg, 213 mg, 214 mg, 215 mg, 216 mg,217 mg, 218 mg, 219 mg, 220 mg, 221 mg, 222 mg, 223 mg, 224 mg, 225 mg, 226 mg, 227 mg, 228 mg, 229 mg, 230 mg, 231 mg, 232 mg, 233 mg, 234 mg, 235 mg, 236 mg, 237 mg,238 mg, 239 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 251 mg, 252 mg, 253 mg, 254 mg, 255 mg, 256 mg, 257 mg, 258 mg,259 mg, 260 mg, 261 mg, 262 mg, 263 mg, 264 mg, 265 mg, 266 mg, 267 mg, 268 mg, 269 mg, 270 mg, 271 mg, 272 mg, 273 mg, 274 mg, 275 mg, 276 mg, 277 mg, 278 mg, 279 mg,280 mg, 281 mg, 282 mg, 283 mg, 284 mg, 285 mg, 286 mg, 287 mg, 288 mg, 289 mg, 290 mg, 291 mg, 292 mg, 293 mg, 294 mg, 295 mg, 296 mg, 297 mg, 298 mg, 299 mg, 300 mg,301 mg, 302 mg, 303 mg, 304 mg, 305 mg, 306 mg, 307 mg, 308 mg, 309 mg, 310 mg, 311 mg, 312 mg, 313 mg, 314 mg, 315 mg, 316 mg, 317 mg, 318 mg, 319 mg, 320 mg, 321 mg,322 mg, 323 mg, 324 mg, 325 mg, 326 mg, 327 mg, 328 mg, 329 mg, 330 mg, 331 mg, 332105807.001154 mg, 333 mg, 334 mg, 335 mg, 336 mg, 337 mg, 338 mg, 339 mg, 340 mg, 341 mg, 342 mg, 343 mg, 344 mg, 345 mg, 346 mg, 347 mg, 348 mg, 349 mg, or 350 mg per dose.

[0082] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount between 20-400 mg per dose, such as, for example, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 r ng, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 r ng, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 r ng, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 r ng, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 r ng, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 r ng, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 211 mg, 212 mg, 213 mg, 214 mg, 215 mg, 216 mg, 217 mg, 218 mg, 219 mg, 220 mg, 221 mg, 222 mg, 223 mg, 224 mg, 225 mg, 226 mg, 227 mg, 228 mg, 229 mg, 230 mg, 231 mg, 232 mg, 233 mg, 234 mg, 235 mg, 236 mg, 237 mg, 238 mg, 239 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 251 mg, 252 mg, 253 mg, 254 mg, 255 mg, 256 mg, 257 mg, 258 mg, 259 mg, 260 mg, 261 mg, 262 mg, 263 mg, 264 mg, 265 mg, 266 mg, 267 mg, 268 mg, 269 mg, 270 mg, 271 mg, 272 mg, 273 mg, 274 mg, 275 mg, 276 mg, 277 mg, 278 mg, 279 mg, 280 mg, 281 mg, 282 mg, 283 mg, 284 mg, 285 mg, 286 mg, 287 mg, 288 mg, 289 mg, 290 mg, 291 mg, 292 mg, 293 mg, 294 mg, 295 mg, 296 mg, 297 mg, 298 mg, 299 mg, 300 mg, 301 mg, 302 mg, 303 mg, 304 mg, 305 mg, 306 mg, 307 mg, 308 mg, 309 mg, 310 mg, 311 mg, 312 mg, 313 mg, 314 mg, 315 mg, 316 mg, 317 mg, 318 mg, 319 mg, 320 mg, 321 mg,105807.001154322 mg, 323 mg, 324 mg, 325 mg, 326 mg, 327 mg, 328 mg, 329 mg, 330 mg, 331 mg, 332 mg, 333 mg, 334 mg, 335 mg, 336 mg, 337 mg, 338 mg, 339 mg, 340 mg, 341 mg, 342 mg,343 mg, 344 mg, 345 mg, 346 mg, 347 mg, 348 mg, 349 mg, or 350 mg, 351 mg, 352 mg, 353 mg, 354 mg, 355 mg, 356 mg, 357 mg, 358 mg, 359 mg, 360 mg, 361 mg, 362 mg, 363 mg, 364 mg, 365 mg, 366 mg, 367 mg, 368 mg, 369 mg, 370 mg, 371 mg, 372 mg, 373 mg,374 mg, 375 mg, 376 mg, 377 mg, 378 mg, 379 mg, 380 mg, 381 mg, 382 mg, 383 mg, 384 mg, 385 mg, 386 mg, 387 mg, 388 mg, 389 mg, 390 mg, 391 mg, 392 mg, 393 mg, 394 mg,395 mg, 396 mg, 397 mg, 398 mg, 399 mg, or 400 mg per dose.

[0083] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount between 24-283 mg per dose.

[0084] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount of 283 mg per dose.

[0085] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount between 24-376 mg per dose.

[0086] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount between 24-500 mg per dose.

[0087] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount between 24-900 mg per dose.

[0088] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount between 120-500 mg per dose.

[0089] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount between 160-500 mg per dose.

[0090] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount or 24 mg per dose.

[0091] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount of 48 mg per dose.

[0092] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount of 80 mg per dose.

[0093] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount of 120 mg per dose.

[0094] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount of 160 mg per dose.105807.001154

[0095] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount of 212 mg per dose.

[0096] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount of 283 mg per dose.

[0097] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount of 376 mg per dose.

[0098] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount of 500 mg per dose.

[0099] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount of 665 mg per dose.

[0100] In some embodiments, Compound I, or pharmaceutically acceptable salt thereof (on a Compound I basis), is administered in an amount of 900 mg per dose.

[0101] In some aspects of the disclosure, the disclosed methods further comprise administering docetaxel to the subject in combination with Compound I, or pharmaceutically acceptable salt thereof.

[0102] As used herein, the phrase “in combination with” refers to coordinated dosages and administration timings of each of Compound I (or pharmaceutically acceptable salt thereof) and docetaxel such that Compound I (or pharmaceutically acceptable salt thereof) and docetaxel are administered to the subject during an overlapping period of time. Thus, “in combination with” encompasses both concurrent administration of the compound of Compound I (or a pharmaceutically acceptable salt thereof) and docetaxel; and sequential administration of the compound of Compound I (or a pharmaceutically acceptable salt thereof) and docetaxel. Moreover, “in combination with” encompasses administration of Compound I (or a pharmaceutically acceptable salt thereof) and docetaxel on the same day; on different days; and any permutation thereof.

[0103] In some aspects of the disclosed methods, the docetaxel is administered intravenously.

[0104] In some aspects of the disclosed methods, the docetaxel is administered in an amount of about 10 mg / m2to about 100 mg / m2.

[0105] In some aspects of the disclosed methods, the docetaxel is administered in an amount of about 10 mg / m2to about 100 mg / m2per dose 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 / m2,105807.001154 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, or about 100 mg / m2.

[0106] In some embodiments, the docetaxel is administered in an amount of about 60 mg / m2to about 100 mg / m2per dose.

[0107] In some embodiments, the docetaxel is administered in an amount of about 75 mg / m2per dose.

[0108] In some embodiments, the docetaxel is administered in an amount of about 100 mg / m2per dose.

[0109] In some embodiments, the docetaxel is administered in accordance with the December 2013 Revision (Sanofi-aventis) of the TAXOTERE (docetaxel) Injection Concentrate, Intravenous Infusion (IV) prescribing information.

[0110] In some aspects of the disclosed methods, the docetaxel 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.105807.001154

[0111] In some embodiments, the docetaxel is administered by intravenous infusion over about 1 hour.

[0112] In some embodiments, the docetaxel is administered by intravenous infusion over about 3 hours.

[0113] In some embodiments, the docetaxel is administered by intravenous infusion over about 6 hours.

[0114] In some aspects of the disclosed methods, the docetaxel 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 hr once every three weeks.

[0115] In some embodiments, the docetaxel is administered by intravenous infusion over about 1 hour once every three weeks.

[0116] In some embodiments, the docetaxel is administered by intravenous infusion over about 3 hours once every three weeks.

[0117] In some embodiments, the docetaxel is administered by intravenous infusion over about 6 hours once every three weeks.

[0118] In some aspects of the disclosed methods, the docetaxel 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.

[0119] In some embodiments, the docetaxel is administered by intravenous infusion over about 0.5 hour on days 1, 8, and 15 of each 28 day cycle.

[0120] In some aspects, the disclosure provides methods of treating non-small cell lung cancer, esophageal cancer, or gastric cancer in a subject in need thereof, comprising intravenously administering to the subject 160-500 mg of Compound I,105807.001154(Compound I), or a pharmaceutically acceptable salt thereof (on a Compound I basis).

[0121] In some embodiments, the cancer is non-small cell lung cancer or esophageal cancer.

[0122] In some embodiments, the cancer is non-small cell lung cancer.

[0123] In other embodiments, the cancer is esophageal cancer.

[0124] In some embodiments, the subject is administered 160 mg of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).

[0125] In some embodiments, the subject is administered 212 mg of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).

[0126] In some embodiments, the subject is administered 283 mg of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).

[0127] In some embodiments, the subject is administered 376 mg of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).

[0128] In some embodiments, the subject is administered 500 mg of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).

[0129] In some embodiments, the methods further comprise intravenously administering docetaxel to the subject in combination with Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).

[0130] In some aspects of the methods of the disclosure, the cancer exhibits significant tumor shrinkage (relative to baseline) in response to the administration. In some embodiments, the tumor shrinks by greater than 10%, such as, for example, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%,105807.001154 greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, or greater than 95%.

[0131] In other embodiments, the tumor shrinks (relative to baseline) by at least 30%, such as for example, at least 30%, at least 35%, 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%.

[0132] In some aspects of the methods of the disclosure, the cancer exhibits a complete response (CR), a partial response (PR), or a stable disease (SD) as a result of the administration of Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl. l criteria.

[0133] In some aspects of the methods of the disclosure, the cancer exhibits a complete response (CR) or a partial response (PR) as a result of the administration of Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl .l criteria.

[0134] In some aspects of the methods of the disclosure, the cancer exhibits a partial response (PR) or a stable disease (SD) as a result of the administration of Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl. l criteria.

[0135] In some aspects of the methods of the disclosure, the cancer exhibits a complete response (CR) as a result of the administration of Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.

[0136] In some aspects of the methods of the disclosure, the cancer exhibits a partial response (PR) as a result of the administration of Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.

[0137] In some aspects of the methods of the disclosure, the cancer exhibits a stable disease (SD) as a result of the administration of Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.

[0138] In some embodiments, a prolonged stable disease is maintained for at least 4 weeks, at least 8 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks, such as,105807.001154 for example, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, and the like.

[0139] Aspects

[0140] In some embodiments, the disclosure is directed to the following aspects.1. A method of treating non-small cell lung cancer in a human subject in need thereof, comprising administering to the human subject 24 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).2. A method of treating non-small cell lung cancer in a human subject in need thereof, comprising administering to the human subject 48 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).3. A method of treating non-small cell lung cancer in a human subject in need thereof, comprising administering to the human subject 80 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).4. A method of treating non-small cell lung cancer in a human subject in need thereof, comprising administering to the human subject 120 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).5. A method of treating non-small cell lung cancer in a human subject in need thereof, comprising administering to the human subject 160 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).6. A method of treating non-small cell lung cancer in a human subject in need thereof, comprising administering to the human subject 212 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).105807.0011547. A method of treating non-small cell lung cancer in a human subject in need thereof, comprising administering to the human subject 283 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).8. A method of treating non-small cell lung cancer in a human subject in need thereof, comprising administering to the human subject 376 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).9. A method of treating non-small cell lung cancer in a human subject in need thereof, comprising administering to the human subject 500 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).10. A method of treating non-small cell lung cancer in a human subject in need thereof, comprising administering to the human subject 665 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).11. A method of treating non-small cell lung cancer in a human subject in need thereof, comprising administering to the human subject 900 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).12. A method of treating esophageal cancer in a human subject in need thereof, comprising administering to the human subject 24 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).13. A method of treating esophageal cancer in a human subject in need thereof, comprising administering to the human subject 48 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).14. A method of treating esophageal cancer in a human subject in need thereof, comprising administering to the human subject 80 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).15. A method of treating esophageal cancer in a human subject in need thereof, comprising administering to the human subject 120 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).16. A method of treating esophageal cancer in a human subject in need thereof, comprising administering to the human subject 160 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).105807.00115417. A method of treating esophageal cancer in a human subject in need thereof, comprising administering to the human subject 212 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).18. A method of treating esophageal cancer in a human subject in need thereof, comprising administering to the human subject 283 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).19. A method of treating esophageal cancer in a human subject in need thereof, comprising administering to the human subject 376 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis). 0. A method of treating esophageal cancer in a human subject in need thereof, comprising administering to the human subject 500 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis). 1. A method of treating esophageal cancer in a human subject in need thereof, comprising administering to the human subject 665 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis). 2. A method of treating esophageal cancer in a human subject in need thereof, comprising administering to the human subject 900 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis). 3. A method of treating gastric cancer in a human subject in need thereof, comprising administering to the human subject 24 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis). 4. A method of treating gastric cancer in a human subject in need thereof, comprising administering to the human subject 48 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis). 5. A method of treating gastric cancer in a human subject in need thereof, comprising administering to the human subject 80 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis). 6. A method of treating gastric cancer in a human subject in need thereof, comprising administering to the human subject 120 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).105807.001154 7. A method of treating gastric cancer in a human subject in need thereof, comprising administering to the human subject 160 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis). 8. A method of treating gastric cancer in a human subject in need thereof, comprising administering to the human subject 212 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis). 9. A method of treating gastric cancer in a human subject in need thereof, comprising administering to the human subject 283 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).30. A method of treating gastric cancer in a human subject in need thereof, comprising administering to the human subject 376 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).31. A method of treating gastric cancer in a human subject in need thereof, comprising administering to the human subject 500 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).32. A method of treating gastric cancer in a human subject in need thereof, comprising administering to the human subject 665 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).33. A method of treating gastric cancer in a human subject in need thereof, comprising administering to the human subject 900 mg per dose of Compound I, or a pharmaceutically acceptable salt thereof (on a Compound I basis).34. The method of any preceding aspect, wherein the dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered intravenously.35. The method of any preceding aspect, wherein the dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered once per week.36. The method of any preceding aspect, wherein the cancer exhibits a complete response (CR) as a result of the administration of Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.37. The method of any preceding aspect, wherein the cancer exhibits a partial response (PR) as a result of the administration of Compound I, or pharmaceutically acceptable105807.001154 salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.38. The method of any preceding aspect, wherein the cancer exhibits stable disease (SD) as a result of the administration of Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl. l criteria.39. The method of any preceding aspect, wherein each dose of Compound I, or pharmaceutically acceptable salt thereof, is administered intravenously. 0. The method of any preceding aspect, wherein each dose Compound I, or pharmaceutically acceptable salt thereof, is administered once per week. 1. The method of any preceding aspect, wherein the method further comprises administering to the human subject docetaxel in combination with Compound I, or pharmaceutically acceptable salt thereof. 2. The method of aspect 41, wherein the docetaxel is administered intravenously. 3. The method of aspect 41 or aspect 42, wherein the docetaxel is administered once per week. 4. The method of aspect 41 or aspect 42, wherein the docetaxel is administered once every three weeks. 5. The method of any one of aspects 41-44, wherein the cancer exhibits a complete response (CR) as a result of the administration of docetaxel in combination with Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl. l criteria. 6. The method of any one of aspects 41-44, wherein the cancer exhibits a partial response (PR) as a result of the administration of docetaxel in combination with Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl. l criteria. 7. The method of any one of aspects 41-44, wherein the cancer exhibits stable disease (SD) as a result of the administration of docetaxel in combination with Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl. l criteria.105807.00115448. The method aspect 38 or 47, wherein the cancer exhibits stable disease (SD), as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria, for at least 4 weeks.49. The method aspect 38 or 47, wherein the cancer exhibits stable disease (SD), as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria, for at least 8 weeks.50. The method aspect 38 or 47, wherein the cancer exhibits stable disease (SD), as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria, for at least 12 weeks.51. The method aspect 38 or 47, wherein the cancer exhibits stable disease (SD), as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria, for at least 26 weeks.52. The method aspect 38 or 47, wherein the cancer exhibits stable disease (SD), as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria, for at least 52 weeks.53. The method aspect 38 or 47, wherein the cancer exhibits stable disease (SD), as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria, for at least 78 weeks.Example

[0141] Study Design

[0142] A first-in-human, first-in-class, phase 1, multicenter, open-label, dose escalation / dose exploration study of Compound I monotherapy and in combination with docetaxel was conducted in patients with SM ARC A4 -mutated solid tumors.

[0143] This study has four parts: Compound I monotherapy dose escalation, with up to 11 dose levels; Compound I monotherapy backfill cohorts; Compound I in combination with docetaxel dose escalation, with up to five dose levels; and Compound I and docetaxel combination backfill cohorts at select dose levels.

[0144] The study design is depicted in FIG. 3.

[0145] Patients with any solid tumor and a SMARCA4 mutation or deletion with progressive disease on standard therapy, ECOG-PS 0-1, and adequate organ function are eligible.105807.001154

[0146] Patients with any solid tumor, any SMARCA4 mutation and evaluable disease were eligible for dose escalation cohorts. Backfill cohorts required a loss-of-function SMARCA4 mutation, measurable disease and were enriched for NSCLC. Key eligibility criteria included age >18 years old, with locally advanced, recurrent, or metastatic solid tumors, locally determined SMARCA4-mutation by NGS, or absence of SMARCA4 / BRG1 protein expression by IHC. Patients must have either progressed on standard-of-care therapy or be ineligible for standard-of-care therapy to be eligible for enrollment in the study. Patients with NSCLC and treatable driver mutations in oncogenes (e.g., EGFR, RET, MET, ALK, BRAF, KRAS, ROS1) were eligible only after progression on approved targeted therapies. Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) and thoracic sarcomatoid tumors were excluded because these rare tumor types frequently have dual loss of SMARCA4 and SMARCA2, and so, are unlikely to respond to SMARCA2 / BRM degradation. Patients were required to have archival or fresh tumor tissue samples for IHC analysis of SMARCA2 / BRM and SMARCA4 / BRG1.

[0147] Primary Outcome Measures1. Dose limiting toxicity (DLT) of Compound 1 monotherapy and in combination with docetaxel. Dose-limiting toxi cities are evaluated over the 21 -day observation period.2. Safety and tolerability of Compound Imonotherapy and in combination with docetaxel: AEs, CTCAE Assessments. Safety and tolerability are evaluated by incidence of DLTs, laboratory measurements, dose interruption, modification, and discontinuation due to adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).3. Maximum tolerated dose (MTD) / Recommended phase 2 dose (RP2D) of Compound 1 monotherapy and in combination with docetaxel.

[0148] Secondary Outcome Measures1. Efficacy of Compound 1 monotherapy and in combination with docetaxel: Objective response rate (ORR). Best overall response of either complete response (CR) or partial response (PR), as assessed by the investigator per RECIST vl.l.105807.0011542. Efficacy of Compound 1 monotherapy and in combination with docetaxel: Progression-free survival (PFS). Duration from Day 1 to the earliest date of first disease progression, as assessed by the investigator per RECIST vl.l, discontinuation because of disease progression, or death due to any cause.3. Efficacy of Compound 1 monotherapy and in combination with docetaxel: Clinical benefit rate (CBR). Best overall response of CR, PR, or durable stable disease (24 weeks or longer duration), as assessed by the investigator per RECIST vl.l.4. Efficacy of Compound 1 monotherapy and in combination with docetaxel: Duration of response (DOR). Duration from time of first observed response (CR or PR) to the earliest date of disease progression, as assessed by the investigator per RECIST vl .1, or death due to any cause.5. Pharmacokinetic profile of Compound 1 monotherapy and in combination with docetaxel: Maximum observed plasma concentration. Pharmacokinetics are calculated including the maximum observed plasma concentration.6. Pharmacokinetic profile of Compound 1 monotherapy and in combination with docetaxel: Area under the curve. Pharmacokinetics will be calculated including the area under the plasma concentration versus time curve (AUC).7. Pharmacodynamic effect of Compound 1 monotherapy and in combination with docetaxel: Target engagement. Pharmacodynamic effect of Compound 1 monotherapy and in combination with docetaxel demonstrating target engagement by assessment of SMARCA2 protein in peripheral blood mononuclear cells (PBMCs) and tumor tissue.

[0149] Key Inclusion and Exclusion Criteria:

[0150] Inclusion Criteria:

[0151] Minimum Age: 18 Years.

[0152] Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations (including contraception requirements), and other study procedures.

[0153] Histologically confirmed advanced, recurrent, or metastatic solid tumor malignancy with any mutation of SMARCA4 (dose escalation and combination cohorts) and105807.001154 loss of function mutation of SMARCA4 (backfill cohorts) by local testing that have either progress on or ineligible for standard of care therapy.

[0154] Must have measurable or non-measureable (but evaluable) disease per RECIST vl.l for dose escalation and combination cohorts.

[0155] Must have measureable diseases per RECIST vl.l for backfill cohort Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

[0156] Willing to provide either archival or fresh tumor tissue sample.

[0157] Adequate organ function (hematology, renal, and hepatic).

[0158] Exclusion Criteria:

[0159] Participants with solid tumors with known concomitant SMARCA2 mutation or loss of protein expression.

[0160] Clinically significant or uncontrolled cardiac disease, uncontrolled electrolyte disorders, uncontrolled or symptomatic central nervous system (CNS) metastases or leptomeningeal disease.

[0161] History of another malignancy within 3 years except for adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancies, or malignancies previously treated with curative intent and not on active therapy or expected to require treatment or recurrence during the study.

[0162] Concurrent treatment with strong or moderate CYP3 A4 inhibitor or inducer.

[0163] Compound I Administration

[0164] Compound I was administered as an intravenous infusion once weekly at doses ranging from 24 mg to 500 mg. Doses <283 mg were infused over 1 hour, 376 mg was infused over 1.5 hours, and 500 mg was infused over 2 hours. Treatment with Compound I was continued until disease progression or unacceptable toxicity was observed.

[0165] Primary objectives were safety and recommended phase 2 dose. Secondary objectives included pharmacokinetics, pharmacodynamics, and preliminary antitumor activity measured by RECIST vl. l. Primary endpoints were DLTs, incidence of treatment-emergent adverse events, changes in clinical laboratory parameters and incidence of dose interruptions, dose modifications, and discontinuations due to treatment-emergent adverse events. The severity of all adverse events was assessed according to Common Terminology Criteria for105807.001154Adverse Events version 5.0 (CTCAE v5.0). Secondary endpoints included objective response rate based on RECIST 1.1 by investigator assessment, duration of response, clinical benefit rate, PFS, pharmacokinetic parameters, and pharmacodynamic biomarkers demonstrating target engagement by assessment of SMARCA2 / BRM protein in PBMCs and tumor tissue. Exploratory endpoints included molecular analysis of tumor tissue and / or blood ctDNA over time of treatment and correlation with efficacy measures.

[0166] Statistical analysis

[0167] The efficacy-evaluable patient population consisted of patients with NSCLC or upper gastrointestinal cancers and loss-of-function SMARCA4 mutations who completed at least one post-baseline tumor assessment or discontinued the study due to death or progressive disease. Descriptive statistics were provided for selected demographics, safety, efficacy, pharmacokinetics, and biomarker data by dose groups. The overall response rate (ORR) was estimated along with a corresponding exact 95% confidence interval (CI) using the Clopper- Pearson method. Dose escalation and de-escalation decisions were guided by a Bayesian optimal interval (BOIN) method. See Liu, S.Y.Y. Bayesian optimal interval designs for phase I clinical trials. JR Stat Soc Ser C Appl Stat 64, 507-523 (2015). The BOIN method uses a non-informative prior, which assumes that each dose has equal prior probability of being at, below or above the MTD. The optimal escalation / de-escalation boundaries (0.256, 0.359) associated with the target DLT rate of 0.30 were used with the over-dose control (the probability that the DLT rate is greater than 0.3, given the data) of 0.95. Three was the default number of DLT-evaluable patients in a cohort at each dose escalation / de-escalation step.

[0168] Pharmacokinetics and pharmacodynamics

[0169] Plasma concentrations of Compound I were analyzed using a validated liquid chromatographic-tandem mass spectrometry (LC / MS-MS) method. The lower limit of quantification of the assay was 5 nM. Pharmacokinetic parameters were derived from noncompartmental analysis (Phoenix 8.5, Certara Corporation, USA) from the plasma concentration-time data of Compound I.

[0170] Immunohistochemistry

[0171] IHC staining for SMARCA2 / BRM (BRM, Abeam ab240648 clone EPR23103-44, 0.5 pg / mL) and SMARCA4 / BRG1 (BRG-1, Abeam abl 10641 clone EPNCIR111 A, 0.5 pg / mL) on formalin-fixed, paraffin-embedded tumor tissue was105807.001154 performed on the Leica BOND III automated IHC staining platform. Semi -quantitative H- score was used to assess protein expression in tumor cells (H-score was defined as weighted sum of % 1 + cells, twice % 2 + cells, and three times % 3 + cells; range, 0-300) and scored by a board-certified pathologist. SMARCA2 / BRM and SMARCA4 / BRG1 expressions were considered deficient when there was a complete absence or severe diffuse reduction of staining in the background of intact positive cells (H-score <20). Sufficient tumor tissue (>100 cells) for IHC analysis was available for 80% of patients (78 of 97) at baseline. Paired tumor tissue was obtained from selected patients prior to treatment and while on treatment (usually between Cycle 2 Day 1 and the end of Cycle 3).

[0172] Next-generation sequencing

[0173] Tumor NGS was conducted centrally using the Tempus xT assay (Tempus Al, Inc., Chicago, IL, USA). See, e.g., Beaubier, N, et al. Clinical validation of the tempus xT next-generation targeted oncology sequencing assay. Oncotarget 10, 2384-2396 (2019). Briefly, Tempus xT is a targeted, tumor-normal-matched DNA panel that detects singlenucleotide variants, insertions and / or deletions, and copy number variants in 595-648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Tempus xF+, a targeted cell-free DNA (cfDNA) panel spanning ~1.8 Mb that detects singlenucleotide variants and insertions and / or deletions in 523 genes, along with gene rearrangements in 10 genes and copy number gains in seven genes, was used for analysis of ctDNA. Local testing data from varied NGS sources was used to supplement central data or used solely in three patients where central testing data were unavailable.

[0174] Results

[0175] With >12 weeks of follow-up from first dose of study treatment, 73 patients received Compound I monotherapy in nine dose escalation cohorts from 24 mg to 500 mg and five backfill cohorts from 120 mg to 376 mg. Among the 73 patients, 54.8% were male, the median age was 62.0 years (range: 40-79 years), and 76.7% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1. Patients were heavily pretreated with 25 patients (34.2%) receiving four or more prior lines of therapy; median prior lines of therapy were 3 (Table 1.1). The most common tumor types were NSCLC (46.6) and pancreatic cancer (11.0%). Eligibility required either a SMARCA4 mutation identified by local next-generation sequencing (NGS) testing or loss of SMARCA4 / BRG1 protein by local immunohistochemistry (IHC) testing. In 39 patients (53.4%), tumors were classified locally105807.001154 as SMARCA4 class 1 mutations and local IHC results indicated loss of SMARCA4 / BRG1 protein in eight additional patients (11.0%).

[0176] Demographics and disease characteristics of patients enrolled in the monotherapy dose escalation study are shown in Table 1.1.Table 1.1 | Baseline demographics and disease characteristics - Monotherapy105807.001154ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry; NSCLC, non-small cell lung cancer; PD-1, programmed cell death 1; PDL-1, programmed cell death ligand-1; IHC, immunohistochemistry; VUS, variant of uncertain significance.

[0177] Safety

[0178] Patients received a median of 6 weeks of Compound I monotherapy (range: 1-78.6) with no dose-limiting toxicities (DLTs). Compound I at doses up to 500 mg weekly was very well tolerated with a low rate of discontinuation due to adverse events.

[0179] Adverse events were reported in 71 patients (97.3%) and grade >3 adverse events in 37 patients (50.7%). The most common adverse events (>10%) were fatigue and nausea (24.7% each), decreased appetite (20.5%), anemia (19.2%), constipation (17.8%), abdominal pain (16.4%), back pain (12.3%), and dyspnea and pyrexia (11.1% each) (Table 1.2).

[0180] Table 1.2 - Treatment-emergent adverse events105807.001154ALT, alanine aminotransferase increased; AST, aspartate aminotransferase increased; TEAE, treatment-emergent adverse event.

[0181] Treatment-related adverse events were reported in 43 patients (58.9%), with nausea being the most commonly reported (16.4%) (Table 1.3). Infusion-related reactions occurred in 4.1% of the patients and were characterized by pyrexia, chills, flushing, and in some cases, transient dyspnea. Serious adverse events were reported in 20 patients (27.4%), none of which were treatment-related. Six patients (6.7%) had adverse events leading to dose reduction. Adverse events leading to dose holds occurred in 23 patients (31.5%) and were considered related in six patients (8.2%). The most common adverse events leading to dose hold were abdominal pain and COVID-19 (4.1% each) and anemia, constipation, hypoxia, and pain (2.7% each). Adverse events leading to permanent treatment discontinuation were observed in five patients (6.8%) and included events of abdominal pain,105807.001154 cerebrovascular accident, dysphagia, esophageal hemorrhage and urinary tract infection in one patient each. There were no fatal adverse events.

[0182] Table 1.3 Treatment-related adverse events

[0183] Lab oratory -related adverse events included transient elevations in aspartate aminotransferase (AST, 9.6%), and alanine aminotransferase (ALT) and blood creatinine increased (8.2% each) that were observed across all dose levels (Table 1.2). These events typically appeared early in Cycle 1, resolved without treatment modification, and in most cases did not recur in subsequent cycles. Peripheral sensory neuropathy was observed in four patients (5.5%), presenting as mild to moderate events (grade 1-2), with no severe (grade >3) events. All four patients received prior platinum- and / or taxane-containing regimens and had a prior history of peripheral neuropathy. Some cases appeared dose-dependent or worsened over time, leading to dose reductions but not treatment discontinuation.

[0184] See also, FIG 4.

[0185] Dose-related decreases in AUC of SMARCA2 over time were observed. Dose dependent decreases in SMARCA2 levels were seen at all doses with a trend for increasing depth and duration with increasing doses; minimal effects on SMARCA4 levels were seen.105807.001154

[0186] Pharmacokinetics:

[0187] Mean Compound I plasma concentration-time profiles after the first dose on Cycle 1, Day 1 are presented in Fig. 10. Overall exposure as measured by area under the curve (AUC) of Compound I trended higher with increasing doses. Maximum concentrations (Cmax) were generally observed at the end of infusion. Cmax was lower at 500 mg owing to longer infusion time (2 hours) at this dose. Mean pharmacokinetic concentrations of Compound I exceeded the half-maximal degradation concentration (DCso; 21 nM) for SMARCA2 / BRM degradation by approximately 8 hours at the 500-mg dose level. The halflife of Compound I was approximately 5 hours. Consistent with the half-life and weekly administration, no accumulation was observed with repeat dosing of Compound I.

[0188] Pharmacodynamics:

[0189] SMARCA2 / BRM protein levels in peripheral blood mononuclear cells (PBMCs) were assessed at various timepoints on treatment and compared with pre-dose levels. SMARCA2 / BRM degradation was observed at all doses, with greater depth and consistency of maximal SMARCA2 / BRM degradation seen at higher dose levels (Fig. 12). Duration of SMARCA2 / BRM degradation demonstrated a dose-dependent increase over the first four dose levels, and there was consistent and robust degradation at dose levels of 160 mg and higher (Fig. 11). At doses >160 mg, SMARCA2 / BRM levels remained decreased at Day 8 prior to the second Compound I infusion (60.2% median degradation, n=41).

[0190] SMARCA2 / BRM degradation was also confirmed in tumor tissue using paired pretreatment and on-treatment biopsies. As an example, a patient with a SMARCA4 splice site mutation receiving Compound 1283 mg who experienced a partial response demonstrated a total protein loss of SMARCA2 / BRM in tumor tissue, with a drop in SMARCA2 / BRM H-score from 280 (pretreatment) to 0 (Cycle 5 Day 2) (FIG 13 A). Selectivity of Compound I for SMARCA2 / BRM degradation relative to SMARCA4 / BRG1 was demonstrated in tumor tissue by measuring protein levels in paired pretreatment and on- treatment tumor tissue samples. As an example, in samples from a patient with a SMARCA4 missense mutation receiving Compound I 665 mg (Cycle 2, Day 2), levels of SMARCA2 / BRM decreased (H-score 70 predose vs 1 on treatment), whereas levels of SMARCA4 / BRG1 remained the same (H-score 300 predose vs 295 on treatment), confirming selective degradation of SMARCA2 / BRM in the tumor (FIG 13B). This patient was not efficacy evaluable at the time of data cutoff.105807.001154

[0191] Pharmacodynamic effect is more prolonged than pharmacokinetic effect.

[0192] Increasing doses show deeper and more prolonged pharmacodynamic effect.

[0193] Selective degradation of SMARCA2 over SMARCA4 was observed.

[0194] Efficacy

[0195] The target patient population for the efficacy analysis was not pre-specified and was guided by observed antitumor activity during the course of the study. Antitumor activity of Compound I at doses ranging from 24 to 500 mg included partial responses by Response Evaluation Criteria in Solid Tumors (RECIST), tumor shrinkage not meeting at least a partial response per RECIST, and prolonged stable disease in patients with advanced, heavily pretreated NSCLC and upper gastrointestinal (esophageal and gastric) cancers.

[0196] The change in size of target lesions patients with NSCLC or upper gastrointestinal cancer and SMARCA4 loss of function who have post-baseline tumor assessment («=30) is shown in FIG 5. SMARCA4 loss of function was defined as tumors with class 1 SMARCA4 mutations, loss of SMARCA4 / BRG1 expression by H4C, or missense SMARCA4 mutations with literature evidence of loss of protein function. Best overall response and duration of treatment in efficacy-evaluable patients with NSCLC or upper gastrointestinal cancer ( / / =30) are shown in FIG 6. Among efficacy-evaluable patients with NSCLC or upper gastrointestinal cancer with a SMARCA4 loss-of-function mutation who were treated with doses >283 mg (w=15), the confirmed objective response rate was 20.0% (95% CI: 4.3, 48.1). The durations of response for the three responders at Compound I doses >283 mg were 19.3, 25.3, and 12.1 weeks each, and three patients continue with tumor responses as of the data cutoff. One patient with NSCLC treated with Compound I at 48 mg demonstrated prolonged stable disease (maximal sum of longest diameter reduction of - 29.2%) and treatment through Cycle 27.

[0197] Four patients with NSCLC who were treated at Compound I doses <283 mg demonstrated prolonged stable disease. One patient with NSCLC and a loss-of-function SMARCA4 mutation treated with Compound 148 mg demonstrated prolonged stable disease for >78 weeks. Two patients with NSCLC and loss-of-function SMARCA4 mutations treated with Compound I (at 120 mg and 160 mg weekly) and one patient with NSCLC and a missense / non-deleterious mutation treated at 212 mg weekly demonstrated prolonged stable disease >24 weeks.105807.001154

[0198] Of the 73 patients included in this analysis, 47 had enrolled in the study with local tumor NGS and / or IHC results denoting class 1 SMARCA4 mutations or loss of SMARCA4 / BRG1 expression. Central NGS on 26 patients with class 1 mutation confirmed deleterious SMARCA4 mutation in 23 (88%) patients. Ten patients did not have sufficient tissue for NGS testing, but IHC results demonstrated loss of SMARCA4 / BRG1 in seven of these patients. Taken together, class 1 SMARCA4 mutations were centrally confirmed in 30 of 36 participants (83%). Twenty-six patients with class 2 SMARCA4 mutations enrolled in the study, including 10 with missense mutations and literature evidence of loss of function.

[0199] Paired central IHC and tumor NGS performed on archival or baseline fresh tumor biopsies from 35 patients demonstrated that all (10 of 10) tumors with class 2 SMARCA4 mutations expressed SMARCA4 / BRG1 protein. Sixty-four percent of tumors (16 of 25) with confirmed class 1 SMARCA4 mutations lacked SMARCA4 / BRG1 protein expression. The majority of tumors (30 of 35, 85.7%) expressed SMARCA2 / BRM protein at baseline. Three patients with paired central IHC and NGS had concomitant loss of SMARCA2 / BRM and SMARCA4 / BRG1 protein: one patient with thoracic SMARCA4 / BRG1 -deficient undifferentiated tumor and two patients with NSCLC. Another four patients had loss of SMARCA2 / BRM with retained SMARCA4 / BRG1 expression.

[0200] In biopsies from patients with NSCLC, esophageal or gastric cancer, loss- of-function SMARCA4 mutation type frequencies included 43.3% truncation mutations, 26.6% frameshift, 13.3% splice site, 13.3% loss-of-function missense, and 3.3% gene deletion. In patients with NSCLC, NGS analysis revealed co-mutations in genes commonly associated with this cancer type. Among patients with NSCLC and loss-of-function SMARCA4 mutations, commonly observed pathogenic co-mutations included TP53 (83.3%), CDKN2A (26.7%), STK11 (23.3%), KEAP1 (23.3%), DNMT3A (16.7%), and KRAS (16.7%). No significant associations were observed between co-mutations and efficacy.

[0201] Individual Outcomes

[0202] Patient 1

[0203] A 72-year-old man with metastatic, poorly differentiated carcinoma of the lung with squamous differentiation. SMARCA4 splice-site alteration (cl 246-2 A>G). Prior therapy included carboplatin / paclitaxel and carboplatin / docetaxel / pembrolizumab, followed by progression. Started on Compound 1 , 283 mg. RECISTvl. l PR on second follow-up scan, with reduction in liver, adrenal, and lymph nodes. See FIG 8.105807.001154

[0204] Patient 2

[0205] A 72-year-old man with moderately well-differentiated lung adenocarcinoma. Metastases to brain and malignant pleural effusion and ascites. SMARCA4 splice variant (c3874-lG>T). Prior therapy included carboplatin, pemetrexed, pembrolizumab, followed by progression. Started on Compound I 283 mg. RECISTvl.l PR on first follow-up scan, with reduction in lung, lymph node, pelvic lesions, and resolution of ascites. See FIG 8.

[0206] Patient 3

[0207] A 53-year-old man with metastatic, poorly differentiated carcinoma of the esophagus with squamous differentiation. SMARCA4 deletion-frameshift (c2732delG, pG911fs). Prior therapy included cisplatin-platinum, 5-fluorouracil, pembrolizumab, followed by progression. Started on Compound 1 , 24 mg. RECISTvl .1 PR on first followup scan, with reduction in liver, adrenal, and lymph node lesions. See FIG 9.

[0208] Patient 4

[0209] A 41 -year-old female with ovarian cancer with missense SMARCA4 mutation receiving 500mg Compound I monotherapy. Fresh baseline and on-treatment lung biopsies taken 23 days apart. On-treatment biopsy taken on C2D2, 1 day post dose. Shows Selective degradation of SMARCA2 in tumor tissue. 99% decrease in SMARCA2 expression (H-score) with treatment. See FIG 14.

[0210] Combination with Docetaxel

[0211] Study Scheme and Enrollment- Compound I as a combination therapy with Docetaxel

[0212] A clinical study was designed with Dose Escalation cohorts and Backfill cohorts. In the study Compound I was dosed intravenously, weekly. Docetaxel was dosed either weekly or every 3 weeks. The eligibility criteria for the dose escalation cohorts included patients with any solid tumor, any SMARCA4 mutation, and an evaluable disease. The eligibility criteria for the backfill cohorts included: patients having enriched NSCLC, having a loss-of-function (LOF) SMARCA4 mutation, and having a measurable disease. The dose escalation scheme is outlined in FIG. 17.

[0213] Demographics and disease characteristics of patient enrolled in the combined dose escalation study are shown in Table 1.4. A summary of the adverse events recorded over the combined dose escalation study include are shown in Table 1.5 with the105807.001154 most frequently occurring adverse events being shown in FIG. 18. Fatigue was the most commonly observed adverse event recorded.

[0214] Results-Combined Therapy — Compound I + Docetaxel

[0215] Preliminary PK data was available from 6 patients in the 120 mg cohort. Compound I PK in combination with docetaxel appeared to be consistent with monotherapy at 120 mg.

[0216] Compound I dosing is intravenous (intravenous infusion), weekly.Docetaxel dosing is intravenous (intravenous infusion) either weekly or every 3 weeks per standard practice. Dose escalation is ongoing at Compound I (500 mg) + Docetaxel.Table 1.4 - Demographics and Disease Characteristics - Compound I + Docetaxel105807.001154Table 1.5 - Summary of Adverse Events- Compound I + Docetaxel

[0217] Patient 5

[0218] A 42-year-old Caucasian male with large cell neuroendocrine cancer.Comp. I 120 mg + docetaxel cohort. 88% decrease in SMARCA2 expression (H-score) on105807.001154C2D3, 2 days post-dose. Shift in cells from high intensity SMARCA2 staining to weak or absent staining. SMARCA2 levels in PBMCs show 65% degradation on C2D1 pre-dose relative to baseline, suggesting sustained SMARCA2 decrease over time. See FIGS 15 and 16.

[0219] Summary

[0220] Compound I monotherapy and in combination with docetaxel demonstrated an acceptable safety profile, with no dose-limiting toxicities or study drug-related SAEs. Pharmacokinetic analysis shows increases in exposure (Cmax, AUC) with dose. The pharmacodynamic effect is more prolonged than pharmacokinetic effect. Degradation of SMARCA2 was observed in PBMCs and tumor tissue confirming target modulation. Increasing doses show deeper and more prolonged pharmacodynamic effect. Proof-of- concept has been demonstrated by tumor responses and prolonged stable disease in patients with NSCLC and esophageal cancer.

[0221] The optimal recommended phase 2 dose of Compound I of 500 mg was selected based on the totality of clinical, PK, and PD data. Although data at 665 mg are not included in this analysis due to the data cutoff date, the number of patients with grade 3 adverse events and serious adverse events was generally higher among patients receiving Compound I at 665 mg compared with the lower dose levels. Additionally, one patient experienced a transient DLT consisting of a grade 3 serious adverse event (ALT increased and AST increased) while no DLTs were observed at the lower dose levels. Further, no increase in PD effects was observed at doses higher than 283 mg and no additional antitumor activity was observed at doses >500 mg.

[0222] The clinical activity of Compound I included RECIST partial responses, tumor shrinkage not meeting at least partial response per RECIST, and prolonged stable disease in patients with advanced, heavily pretreated NSCLC and upper gastrointestinal cancers. Prolonged stable disease may be significant in the context of an aggressive mutation phenotype such as SMARCA4 -mutated cancers, because it indicates that the cancer, despite its typically aggressive and treatment-resistant nature, has been effectively controlled.

[0223] Although Compound I demonstrated excellent tolerability, several adverse events appeared to be potentially associated with Compound I therapy. These adverse events included infusion-related reactions, gastrointestinal signs and symptoms, transient elevations105807.001154 in transaminases, (particularly ALT), and possibly worsening of peripheral neuropathy. All patients who developed neuropathy had baseline peripheral neuropathy from prior therapies and had worsening neuropathy for many months into treatment with Compound I (median onset approximately 4 months post first Compound I dose). Elevations in ALT and AST typically occurred early in Cycle 1, were mostly grade 1 and 2, resolved without dose modification, and rarely recurred in later cycles. Although some instances of liver function test elevation may be confounded by liver metastases, this was not true for all patients. No Hy’s law cases were observed / reported. The transient increases in transaminases, especially ALT, may represent an adaptive response to Compound I therapy, a phenomenon observed across multiple drug classes. Infusion-related reactions were seen in 4.1% of cases characterized by symptoms of fever, chills, rash, and dyspnea. All infusion-related reactions were grade 1 or 2 and were effectively treated and prevented with standard medications including acetaminophen, diphenhydramine, and occasionally low-dose glucocorticoids. Gastrointestinal adverse events included nausea (24.7%), decreased appetite (20.5%), constipation (17.8%), and diarrhea (9.6%). These events were grade 1 or 2 in severity and did not result in treatment modification or discontinuation.

[0224] When this study began, it was not known which tumors or types of SMARCA4 mutations would respond best to Compound I therapy. As the study progressed, antitumor activity in patients with NSCLC, esophageal, and gastric cancer was observed. This antitumor activity included RECIST partial responses, tumor responses that did not meet the criteria for partial responses, and prolonged stable disease. The most robust antitumor activity was seen in patients with class 1 SMARCA4 mutant tumors; however antitumor activity was also observed in patients with class 2 SMARCA4 loss-of-function missense mutations, including a patient with gastric cancer who demonstrated a confirmed partial response. This study shows that SMARCA2 / BRM degrader therapy may be a treatment option for some SMARCA4 / BRG1 -deficient cancers.

[0225] Compound I represents a first-in-class, novel, targeted therapeutic designed to induce synthetic lethality in SMARCA4 / BRG1 -deficient cancer while sparing normal tissue. Compound I has demonstrated an acceptable safety profile, with no DLTs or treatment-related serious adverse events to date. Proof-of-concept was demonstrated by tumor responses and prolonged stable disease in patients with NSCLC and esophageal and gastric cancers.

Claims

105807.001154What is Claimed:

1. A method of treating cancer in a human subj ect in need thereof, comprising administering to the human subject Compound I,(Compound I), or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the human subject is administered Compound I.

3. The method of claim 1, wherein the human subject is administered a pharmaceutically acceptable salt of Compound I.

4. The method of any one of the preceding claims, wherein the Compound I, or pharmaceutically acceptable salt thereof, is administered intravenously.

5. The method of any one of the preceding claims, wherein Compound I, or pharmaceutically acceptable salt thereof, is administered once per week.

6. The method of any one of the preceding claims, wherein the Compound I, or pharmaceutically acceptable salt thereof, is administered in an amount (on a Compound I basis) of 20 mg - 1000 mg per dose.

7. The method of claim 6, wherein the Compound I, or pharmaceutically acceptable salt thereof, is administered in an amount (on a Compound I basis) of 24 mg - 500 mg per dose.

8. The method of claim 6, wherein the Compound I, or pharmaceutically acceptable salt thereof, is administered in an amount (on a Compound I basis) of 120 mg - 500 mg per dose.

9. The method of claim 6, wherein the Compound I, or pharmaceutically acceptable salt thereof, is administered in an amount (on a Compound I basis) of 283 mg - 500 mg per dose.

10. The method of claim 6, wherein the Compound I, or pharmaceutically acceptable salt thereof, is administered in an amount (on a Compound I basis) of 283 mg per dose.105807.00115411. The method of claim 6, wherein the Compound I, or pharmaceutically acceptable salt thereof, is administered in an amount (on a Compound I basis) of 500 mg per dose.

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

13. The method of claim 12, wherein the cancer has a mutated SMARCA4 gene.

14. The method of claim 13, wherein the mutated SMARCA4 gene has a Class 1 mutation.

15. The method of claim 13, wherein the mutated SMARCA4 gene has a Class 2 mutation.

16. The method of any one of the preceding claims, wherein the cancer is non-small cell lung cancer, esophageal cancer, or gastric cancer.

17. The method of claim 16, wherein the cancer is non-small cell lung cancer or esophageal cancer.

18. The method of claim 16, wherein the cancer is non-small cell lung cancer.

19. The method of claim 16, wherein the cancer is esophageal cancer.

20. The method of claim 16, wherein the cancer is gastric cancer.

21. The method of any preceding claim further comprising administering to the human subject docetaxel in combination with Compound I, or pharmaceutically acceptable salt thereof.

22. The method of claim 21, wherein the docetaxel is administered intravenously.

23. The method of claim 21 or claim 22, wherein the docetaxel is administered by intravenous infusion over about 0.5 hr - about 3 hours.

24. The method of any one of claims 21-23, wherein the docetaxel is administered once per week.

25. The method of any one of claims 21-23, wherein the docetaxel is administered once every three weeks.

26. The method of any one the preceding claims, wherein the cancer exhibits a complete response (CR), a partial response (PR), or a stable disease (SD) as a result of the administration of Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl. l criteria.

27. The method of any one the preceding claims, wherein the cancer exhibits a complete response (CR) as a result of the administration of Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.105807.00115428. The method of any one the preceding claims, wherein the cancer exhibits a partial response (PR) as a result of the administration of Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.

29. The method of any one the preceding claims, wherein the cancer exhibits stable disease (SD) as a result of the administration of Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl. l criteria.

30. The method of any one of claims 21-25, wherein the cancer exhibits a complete response (CR), a partial response (PR), or a stable disease (SD) as a result of the administration of docetaxel in combination with Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl. l criteria.

31. The method of any one of claims 21-25, wherein the cancer exhibits a complete response (CR) as a result of the administration of docetaxel in combination with Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl. l criteria.

32. The method of any one of claims 21-25, wherein the cancer exhibits a partial response (PR) as a result of the administration of docetaxel in combination with Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.

33. The method of any one of claims 21-25, wherein the cancer exhibits stable disease (SD) as a result of the administration of docetaxel in combination with Compound I, or pharmaceutically acceptable salt thereof, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria.

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