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WO2021163273A1 - Utilisations d'antagonistes du récepteur des glucocorticoïdes - Google Patents

Utilisations d'antagonistes du récepteur des glucocorticoïdes Download PDF

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Publication number
WO2021163273A1
WO2021163273A1 PCT/US2021/017581 US2021017581W WO2021163273A1 WO 2021163273 A1 WO2021163273 A1 WO 2021163273A1 US 2021017581 W US2021017581 W US 2021017581W WO 2021163273 A1 WO2021163273 A1 WO 2021163273A1
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Prior art keywords
compound
administered
pharmaceutically acceptable
acceptable salt
treating
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PCT/US2021/017581
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English (en)
Inventor
Pratik Multani
Edna CHOW MANEVAL
Rongda XU
Haiying Zhou
Melissa Junttila
Anneleen Daemen
Jae Chang
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Oric Pharmaceuticals Inc
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Oric Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/46—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of glucocorticosteroids

Definitions

  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered in an amount that is between about 10 mg and about 500 mg. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 50 mg and about 400 mg. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 40 mg and about 480 mg. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 80 mg and about 250 mg.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered in an amount that is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg,
  • the chemotherapy is nab-paclitaxel, pacbtaxel, docetaxel, cabazitaxel, tesetaxel, cisplatin, carboplatin, gemcitabine, capecitabine, or pemetrexed.
  • the chemotherapy is nab-paclitaxel.
  • the chemotherapy is administered in an amount that is between about 10 mg/m 2 and about 200 mg/m 2 . In some embodiments of a method of treating a solid tumor, the chemotherapy is administered in an amount that is about 75 mg/m 2 .
  • the chemotherapy is administered in an amount that is about 125 mg/m 2 . In some embodiments of a method of treating a solid tumor, the chemotherapy is administered in 28-day cycles. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered for multiple 28-day cycles. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered for at least one 28- day cycle. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered for at least two 28-day cycles. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered for at least three 28-day cycles.
  • the chemotherapy is administered on days 1, 8, and 15 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered on days 1 and 8 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered on days 8 and 15 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered on days 1-7 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered on day 1 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered in 21 -day cycles.
  • the chemotherapy is administered for multiple 21 -day cycles. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered for at least one 21 -day cycle. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered for at least two 21-day cycles. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered for at least three 21 -day cycles. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered on days 1, 8, and 15 of each 21-day cycle. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered on days 1 and 8 of each 21 -day cycle.
  • the chemotherapy is administered on days 8 and 15 of each 21-day cycle. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered on days 1-7 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered on day 1 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered in 28 -day cycles. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered for multiple 28-day cycles.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered for at least one 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least two 28-day cycles. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least three 28-day cycles. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 28-day cycle.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered on days 1-21 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1, 8, and 15 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1 and 15 of each 28-day cycle.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered on days 8 and 15 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1 and 8 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 7, and 14 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1 and 7 of each 28-day cycle.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered on days -1 and 14 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 7 and 14 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2, 9, and 16 of each 28 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2 and 16 of each 28-day cycle.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered on days 9 and 16 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2 and 9 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-3, 8-10, and 15-17 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1, 2, 7-9, and 14-16 of each 28-day cycle.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered on days 1-4, 8-11, and 15-18 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1-3, 7-10, and 14- 17 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-5, 8-12, and 15-19 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1-4, 7-11, and 14-18 of each 28-day cycle.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered on days 1-6, 8-13, and 15-20 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1-5, 7-12, and 14-19 of each 28-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered in 21- day cycles. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered for multiple 21 -day cycles.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered for at least one 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least two 21 -day cycles. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least three 21 -day cycles. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 21-day cycle.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1, 8, and 15 of each 21-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1 and 15 of each 21 -day cycle.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered on day 1 and 8 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 8 and 15 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2, 9, and 16 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2 and 9 of each 21 -day cycle.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered on days 2 and 16 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 9 and 16 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-3, 8-10, and 15-17 of each 21- day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-3 and 8-10 of each 21-day cycle.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered on days -1, 1, 2, 7-9, and 14-16 of each 21-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1, 2, and 7-9 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1, 2 and 7-9 of each 21-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-4, 8-11, and 15-18 of each 21-day cycle.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered on days 1-4 and 8-11 of each 21-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1-3, 7-10, and 14-17 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1-3, and 7-10 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-5, 8-12, and 15-19 of each 21-day cycle.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered on days 1-5 and 8-12 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1-4, 7-11, and 14-18 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1-4, and 7-11 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-6, 8-13, and 15-20 of each 21-day cycle.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered on days 1-6 and 8-13 of each 21-day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1-5, 7-12, and 15-19 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1-5 and 7-12 of each 21 -day cycle. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered three times a day. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered between about 2 hours before and about 2 hours after administration of the chemotherapy.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered about 2 hours before administration of the chemotherapy. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered about 30 mins after administration of the chemotherapy. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered at the same time as the chemotherapy. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered the day after administration of the chemotherapy. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered two days after administration of the chemotherapy.
  • a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof is administered the day before administration of the chemotherapy. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered two days before administration of the chemotherapy. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered first thing in the morning. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered just before sleep. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.
  • a method of treating a solid tumor is administered as an injection. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered as an infusion. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered orally. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered as an injection. In some embodiments of a method of treating a solid tumor, the chemotherapy is administered as an infusion. In some embodiments of a method of treating a solid tumor, compound 1, or a pharmaceutically acceptable salt thereof, is administered with food.
  • a method of treating a solid tumor compound 1, or a pharmaceutically acceptable salt thereof, is administered without food.
  • the solid tumor is prostate cancer, breast cancer, endometrial cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, non-small cell lung cancer, squamous head & neck cancer, hepatocellular cancer, esophageal cancer, ovarian cancer, or gastric cancer.
  • the solid tumor is prostate cancer.
  • the prostate cancer is metastatic prostate cancer.
  • the prostate cancer is castration- resistant prostate cancer (CRPC). In some embodiments of a method of treating a solid tumor, the prostate cancer is castration-sensitive prostate cancer. In some embodiments of a method of treating a solid tumor, the solid tumor is breast cancer. In some embodiments of a method of treating a solid tumor, the breast cancer is metastatic breast cancer. In some embodiments of a method of treating a solid tumor, the breast cancer is triple negative breast cancer. In some embodiments of a method of treating a solid tumor, the breast cancer is ER negative breast cancer. In some embodiments of a method of treating a solid tumor, the subject in need thereof has been previously treated with an anti -cancer agent.
  • CRPC castration- resistant prostate cancer
  • the anti -cancer agent is a chemotherapy agents comprising taxanes, antimetabolites, and platinum agents. In some embodiments of a method of treating a solid tumor, the anti -cancer agent is an androgen receptor modulator. In some embodiments of a method of treating a solid tumor, the subject in need thereof is refractory to the previously used anti cancer agent. [0005] Also disclosed herein is a method of treating prostate cancer; the method comprising administering:
  • compound 1, or a pharmaceutically acceptable salt thereof is administered in an amount that is between about 10 mg and about 500 mg. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 50 mg and about 400 mg. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 80 mg and about 250 mg. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 40 mg and about 480 mg.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered in an amount that is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about
  • the androgen receptor modulator is enzalutamide, apalutamide, darolutamide, abiraterone, or bicalutamide. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is enzalutamide. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is apalutamide. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered in an amount that is between about 60 mg and about 400 mg.
  • the androgen receptor modulator is administered in an amount that is between about 160 mg and about 240 mg. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered in an amount that is about 80 mg. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered in an amount that is about 120 mg. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered in an amount that is about 160 mg. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered in an amount that is about 180 mg.
  • the androgen receptor modulator is administered in an amount that is about 240 mg. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered once a day. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered twice a day. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered three times a day. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered three times a day.
  • the androgen receptor modulator is administered for multiple 28-day cycles.
  • the androgen receptor modulator is administered for at least one 28- day cycle.
  • the androgen receptor modulator is administered for at least two 28-day cycles.
  • the androgen receptor modulator is administered for at least three 28-day cycles.
  • the androgen receptor modulator is administered on days 128-7 of each 28-day cycle.
  • the androgen receptor modulator is administered on days 128-14 of each 28-day cycle. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered on days 128-21 of each 28-day cycle. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered on days 128-28 of each 28-day cycle. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered in 28-day cycles. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered for multiple 28-day cycles.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered for at least one 28-day cycle. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least two 28-day cycles. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least three 28-day cycles. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 28-day cycle. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1- 6 of each 28-day cycle.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each 28-day cycle. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1-13 of each 28-day cycle. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 28-day cycle. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days -1, 1-20 of each 28- day cycle. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 28-day cycle.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered on days -1, 1-27 of each 28-day cycle. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered between about 2 hours before and about 2 hours after administration of the androgen receptor modulator. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered about 2 hours before administration of the androgen receptor modulator. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered about 30 mins after administration of the androgen receptor modulator.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered at the same time as the androgen receptor modulator. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered first thing in the morning. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered just before sleep. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered first thing in the morning. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered just before sleep. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered as an injection. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered as an infusion. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered orally. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered as an injection. In some embodiments of a method of treating prostate cancer, the androgen receptor modulator is administered as an infusion. In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered with food.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered without food.
  • the androgen receptor modulator is administered with food.
  • the androgen receptor modulator is administered without food.
  • the prostate cancer is metastatic prostate cancer.
  • the prostate cancer is castration-resistant prostate cancer (CRPC).
  • the prostate cancer is castration-sensitive prostate cancer.
  • the subject in need thereof has been previously treated with an anti-cancer agent.
  • the anti-cancer agent is a chemotherapy agents comprising taxanes, antimetabolites, and platinum agents.
  • the anti -cancer agent is radiation therapy.
  • the anti -cancer agent is androgen deprivation therapy.
  • the anti cancer agent is an androgen receptor modulator.
  • the anti -cancer agent is surgery.
  • the subject in need thereof is refractory to the previously used anti -cancer agent.
  • the subject in need thereof is undergoing chemical castration.
  • the subject in need thereof has undergone surgical castration.
  • Alkyl refers to a straight or branched chain hydrocarbon monoradical, which may be fully saturated or unsaturated, having from one to about ten carbon atoms, or from one to six carbon atoms.
  • saturated hydrocarbon monoradical include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1 -propyl, 2-methyl-2-propyl, 2-methyl- 1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2, 2-dimethyl- 1 -propyl, 2-methyl- 1 -pentyl, 3-methyl- 1 -pentyl, 4-methyl- 1 -pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl- 1 -butyl, 3,3-dimethyl-l-butyl, 2-ethyl- 1 -
  • alkyl means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a Ci-Cio alkyl, a Ci- C 9 alkyl, a Ci-C 8 alkyl, a C 1 -C 7 alkyl, a Ci-C 6 alkyl, a C 1 -C 5 alkyl, a Ci-C 4 alkyl, a C 1 -C 3 alkyl, a Ci-C 2 alkyl, or a Ci alkyl.
  • the alkyl refers to an unsaturated straight or branched chain hydrocarbon monoradical it is known as an “alkenyl” or an “alkynyl”.
  • alkenyl may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
  • C2-C6 alkenyl means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • the alkenyl is a C 2 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.
  • alkynyl include, but are not limited to ethynyl, 2- propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • C2-C6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • the alkynyl is a C 2 -C 10 alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
  • an alkyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or - NO 2 .
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or - OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10-membered aryl.
  • the aryl is a 6-membered aryl.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as- indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • the aryl is phenyl.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2.
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl).
  • the cycloalkyl is a 3- to 6-membered cycloalkyl.
  • the cycloalkyl is a 5- to 6-membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, decalinyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Heterocycloalkyl refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrol
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH2, or -NO2.
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -G, heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)- ), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, - OMe, -NH2, or -NO2.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidolyl
  • a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH2, or -NO2.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or - OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • terapéutica means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient.
  • a therapeutic agent such as a compound 1 is directed to the treatment and/or the amelioration of cancers.
  • administering when used in conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted.
  • administering when used in conjunction with a composition described herein, can include, but is not limited to, providing a composition into or onto the target tissue; providing a composition systemically to a patient by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells.
  • administering a composition may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques.
  • the term “animal” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals.
  • the terms “patient,” “subject” and “individual” are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof.
  • the patient is a primate.
  • the primate or subject is a human.
  • the human is an adult.
  • the human is child.
  • the human is under the age of 12 years.
  • the human is elderly.
  • the human is 60 years of age or older.
  • Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows.
  • the experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with hypertensive pathology.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • composition shall mean a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • a mammal for example, without limitation, a human.
  • a “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or
  • treat refers to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • a prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition.
  • “treat,” “treated,” “treatment,” or “treating” includes prophylaxis in some embodiments.
  • formulations comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
  • R 1 is -NR 4a R 5a ; each R 2 is independently -NR 4 R 5 , halo, -OR 6 , -OH, optionally substituted alkyl, or haloalkyl;
  • R 3 is optionally substituted C2-8 alkyl, halo, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, -Si(R 6 ) 3 , -OR 6 , or -S(0) 2 R 7 ;
  • R 4a is C2-8 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
  • R 5a is -H, optionally substituted alkyl, or haloalkyl; or R 4a and R 5a are taken together with the N atom to which they are attached to form an optionally substituted heterocycloalkyl;
  • R 4 and R 5 are each independently -H, optionally substituted alkyl, or haloalkyl; or R 4 and R 5 are taken together with the N atom to which they are attached to form an optionally substituted heterocycloalkyl; each R 6 is independently optionally substituted alkyl or haloalkyl;
  • R 7 is optionally substituted alkyl or haloalkyl
  • R 8 and R 9 are each independently -H, optionally substituted alkyl, haloalkyl, or halo;
  • R 10 and R 11 are each independently -H, optionally substituted alkyl, halo, or haloalkyl;
  • R 12 is hydrogen, optionally substituted alkyl, haloalkyl, hydroxy, or halo; n is 0, 1, or 2.
  • R 12 is Ci- 6 alkyl or hydrogen. In some embodiments of compounds of Formula (I), R 12 is methyl. In some embodiments of compounds of Formula (I), R 12 is H. In some embodiments of compounds of Formula (I), ring A is phenyl. In some embodiments of compounds of Formula (I), R 4a is C 2-8 alkyl. In some embodiments of compounds of Formula (I), R 4a is C 3-6 alkyl. In some embodiments of compounds of Formula (I), R 4a is C 2-4 alkyl. In some embodiments of compounds of Formula (I), R 4a is ethyl, i-propyl, or t-butyl.
  • R 5a is -H, optionally substituted alkyl, or haloalkyl. In some embodiments of compounds of Formula (I), R 5a is -H or alkyl. In some embodiments of compounds of Formula (I), R 5a is Ci- 6 alkyl. In some embodiments of compounds of Formula (I), n is 0 or 1. In some embodiments of compounds of Formula (I), each R 2 is independently halo. In some embodiments of compounds of Formula (I), R 3 is optionally substituted C 2-8 alkyl, haloalkyl, or optionally substituted cycloalkyl. In some embodiments of compounds of Formula (I), R 3 is C 4-8 alkyl. In some embodiments of compounds of Formula (I), R 8 and R 9 are -H. In some embodiments of compounds of Formula (I), R 10 and R 11 are each -H.
  • the compound has the structure of Formula (la):
  • a method of a solid tumor in a subject in need thereof; the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1, or a pharmaceutically acceptable salt thereof), and chemotherapy.
  • the solid tumor is prostate cancer, breast cancer, endometrial cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, non-small cell lung cancer, squamous head & neck cancer, hepatocellular cancer, esophageal cancer, ovarian cancer, or gastric cancer.
  • the solid tumor is prostate cancer.
  • the prostate cancer is metastatic prostate cancer.
  • the solid tumor is breast cancer.
  • the breast cancer is metastatic breast cancer.
  • the breast cancer is triple negative breast cancer.
  • the breast cancer is ER negative breast cancer.
  • Disclosed herein is a method of treating non-small cell lung cancer, triple negative breast cancer, ovarian cancer, melanoma, pancreatic cancer, prostate cancer, renal cancer, melanoma, hepatocellular carcinoma, or bladder cancer, in a subject in need thereof; the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1, or a pharmaceutically acceptable salt thereof) and chemotherapy.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound 1, or a pharmaceutically acceptable salt thereof) and chemotherapy.
  • Prostate cancer is the second most common cause of cancer death in men in the United States, and approximately one in every six American men will be diagnosed with the disease during his lifetime. Treatment aimed at eradicating the tumor is unsuccessful in 30% of men.
  • One embodiment provides a method of treating prostate cancer in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1, or a pharmaceutically acceptable salt thereof).
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound 1, or a pharmaceutically acceptable salt thereof).
  • the prostate cancer is chemoresistant cancer, radio resistant cancer, antiandrogen resistant, or refractory cancer. In some embodiments, the prostate cancer is relapsed cancer, persistent cancer, or recurrent cancer.
  • the prostate cancer is acinar adenocarcinoma, atrophic carcinoma, foamy carcinoma, colloid carcinoma, or signet ring carcinoma.
  • the prostate cancer is ductal adenocarcinoma, transitional cell cancer, urothelial cancer, squamous cell cancer, carcinoid cancer, small cell cancer, sarcoma cancer, or sarcomatoid cancer.
  • the prostate cancer is metastatic castration-resistant prostate cancer, doubly-resistant prostate cancer, castration- resistant prostate cancer, hormone-resistant prostate cancer, androgen-independent, or androgen- refractory cancer.
  • the prostate cancer is castration-resistant prostate cancer (CRPC). In some embodiments, the prostate cancer is castration-sensitive prostate cancer.
  • antiandrogens are useful for the treatment of prostate cancer during its early stages.
  • prostate cancer cells depend on androgen receptor (AR) for their proliferation and survival.
  • AR androgen receptor
  • Some prostate cancer patients are physically castrated or chemically castrated by treatment with agents that block production of testosterone (e.g. GnRH agonists), alone or in combination with antiandrogens, which antagonize effects of any residual testosterone.
  • prostate cancer advances to a hormone-refractory state in which the disease progresses despite continued androgen ablation or antiandrogen therapy.
  • the hormone -refractory state to which most patients eventually progresses in the presence of continued androgen ablation or anti androgen therapy is known as “castration resistant” prostate cancer (CRPC).
  • CRPC is associated with an overexpression of AR.
  • AR is expressed in most prostate cancer cells and overexpression of AR is necessary and sufficient for androgen-independent growth of prostate cancer cells. Failure in hormonal therapy, resulting from development of androgen-independent growth, is an obstacle for successful management of advanced prostate cancer.
  • Resistant prostate cancer occurs when cancer cells overexpress androgen receptors (AR).
  • AR target gene expression is inhibited when the cells are treated with a second generation antiandrogen.
  • increased signaling through the glucocorticoid receptor (GR) compensates for inhibition of androgen receptor signaling in resistant prostate cancer.
  • Double resistant prostate cancer develops when expression of a subset of those AR target genes is restored.
  • GR activation is responsible for this target gene activation.
  • GR transcription is activated in patients susceptible to or suffering from resistant prostate cancer (e.g., doubly resistant and castration resistant prostate cancers).
  • GR upregulation in cancer cells confers resistance to antiandrogens.
  • Some embodiments provided herein describe the use of the GR inhibitors for treating prostate cancer in a subject in need thereof, including doubly resistant prostate cancer and castration resistant prostate cancer.
  • the subject in need has elevated tumor GR expression.
  • the GR inhibitor is also an AR signaling inhibitor or antiandrogen.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is used in combination with an anti -cancer agent or an AR signaling inhibitor or antiandrogen.
  • the second or additional agent is an AR signaling inhibitor or antiandrogen.
  • the AR signaling inhibitor is an AR antagonist.
  • the second or additional therapeutic agent is selected from finasteride, dutasteride, alfatradiol, cyproterone acetate, spironolactone, danazol, gestrinone, ketoconazole, abiraterone acetate, enzalutamide, apalutamide, darolutamide, danazol, gestrinone, danazol, simvastatin, aminoglutethimide, atorvastatin, simvastatin, progesterone, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, drospirenone, estradiol, ethinyl estradiol, diethylstilbestrol,
  • the second or additional therapeutic agent is selected from flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, darolutamide, cyproterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, cimetidine, or any combinations or any salts thereof.
  • the AR signaling inhibitor is 3,3 ’-diindolylm ethane (DIM), abiraterone acetate, apalutamide, darolutamide, bexlosteride, bicalutamide, dutasteride, epristeride, enzalutamide, finasteride, flutamide, izonsteride, ketoconazole, N-butylbenzene- sulfonamide, nilutamide, megestrol, steroidal antiandrogens, turosteride, or any combinations thereof.
  • the AR signaling inhibitor is flutamide, nilutamide, bicalutamide, or megestrol.
  • the AR signaling inhibitor is apalutamide.
  • the AR signaling inhibitor is enzalutamide.
  • the anti-cancer agent is mitoxantrone, estramustine, etoposide, vinblastine, carboplatin, vinorelbine, paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin.
  • the anti-cancer agent is paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin.
  • the anti-cancer agent is docetaxel.
  • Breast cancer is the second leading cause of cancer among women in the United States. Triple negative breast cancers are among the most aggressive and difficult to treat of all the breast cancer types. Triple-negative breast cancer is a form of the disease in which the three receptors that fuel most breast cancer growth - estrogen, progesterone and the HER-2 - are not present. Because the tumor cells lack these receptors, treatments that target estrogen, progesterone and HER-2 are ineffective. Approximately 40,000 women are diagnosed with triple-negative breast cancer each year. It is estimated that more than half of these women’s tumor cells express significant amounts of GR.
  • GR expression is associated with a poor prognosis in estrogen receptor (ER)- negative early stage breast cancer.
  • ER estrogen receptor
  • GR activation in triple-negative breast cancer cells initiates an anti-apoptotic gene expression profile that is associated with inhibiting chemotherapy- induced tumor cell death.
  • GR activity in these cancer cells correlate with chemotherapy resistance and increased recurrence of cancer.
  • a GR inhibitor described herein is used in combination with a second therapeutic agent (e.g., a chemotherapeutic agent) for treating breast cancer.
  • a second therapeutic agent e.g., a chemotherapeutic agent
  • the combination of the GR inhibitor with the second therapeutic agent e.g., a chemotherapeutic agent
  • the breast cancer is chemoresistant cancer, radio resistant cancer, or refractory cancer.
  • the breast cancer is relapsed cancer, persistent cancer, or recurrent cancer.
  • Breast cancers may include, but are not limited to, ductal carcinoma, invasive ductal carcinoma, tubular carcinoma of the breast, medullary carcinoma of the breast, mecinous carcinoma of the breast, papillary carcinoma of the breast, cribriform carcinoma of the breast, invasive lobular carcinoma, inflammatory breast cancer, lobular carcinoma in situ, male breast cancer, Paget disease of the nipple, phyllodes tumor of the breast, recurrent and metastatic breast cancer, triple -negative breast cancer, or combinations thereof.
  • the breast cancer is recurrent and metastatic breast cancer, triple-negative breast cancer, or combinations thereof.
  • the breast cancer is chemoresistant triple negative breast cancer or estrogen receptor (ER) negative breast cancer.
  • the breast cancer is chemoresistant triple-negative breast cancer.
  • the breast cancer is estrogen receptor (ER) negative breast cancer.
  • the breast cancer is GR+ triple negative breast cancer.
  • the breast cancer is GR+ estrogen receptor (ER) negative breast cancer.
  • GR inhibitors inhibit the anti-apoptotic signaling pathways of GR and increase the cytotoxic efficiency of secondary chemotherapeutic agents.
  • the GR inhibitors described herein enhance the efficacy of chemotherapy in breast cancer patients, such as triple negative breast cancer patients.
  • the breast cancer patient has elevated tumor GR expression.
  • the formulation comprising a GR inhibitor described herein is used in combination with a second therapeutic agent, such as chemotherapy or immunotherapy.
  • a GR inhibitor described herein is used in combination with one or more additional therapeutic agents.
  • the second or additional chemotherapeutic agent is cisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin, melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide, doxorubicin, liposomal doxorubicin, camptothecin, pemetrexed, topotecan, vinorelbine, vinblastine, daunorubicin, 5-fluorouracil, mitomycin, thiotepa, vincristine, everolimus, veliparib, glembatumumab vedotin, pertuzumab, trastuzumab, or any combinations or any salts thereof.
  • the second or additional therapeutic agent is an anti-PD-L 1 agent.
  • the anti-PD-Ll agent is MPDL3280A or avelumab.
  • the second or additional therapeutic agent is an anti -PD 1 agent.
  • the anti -PD 1 agent is nivolumab or permbrolizumab.
  • the second or additional therapeutic agent is an anti an anti-CTLA-4 agent.
  • the second or additional therapeutic agent is a CAR-T cell therapy.
  • the second or additional therapeutic agent is an IDO-1 inhibitor.
  • the second or additional therapeutic agent is a cancer vaccine.
  • Some embodiments provided herein describe methods of treating estrogen positive breast cancer.
  • estrogen positive breast cancer patients become resistant to estrogen receptor modulators.
  • the GR inhibitors described herein enhance the efficacy of estrogen receptor modulators in estrogen positive breast cancer patients.
  • the breast cancer patient has elevated tumor GR expression.
  • a GR inhibitor described herein is used in combination with an estrogen receptor modulator.
  • the estrogen receptor modulator is tamoxifen, raloxifene, toremifene, tibolone, fulvestrant, lasofoxifene, clomifene, ormeloxifene, or ospemifene.
  • the estrogen receptor modulator is tamoxifen, raloxifene, toremifene, tibolone, or fulvestrant. In some embodiments, the estrogen receptor modulator is tamoxifen, raloxifene, or toremifene. In certain embodiments, the estrogen receptor modulator is tamoxifen.
  • Ovarian cancer is the leading cause of death from gynecologic malignancies.
  • Some ovarian cancers e.g., high grade serous ovarian cancer
  • platinum -based therapy but relapse rates remain high.
  • One embodiment provides a method of treating ovarian cancer in a patient in need thereof, comprising administering to the patient a formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1, or a pharmaceutically acceptable salt thereof).
  • a formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof e.g., compound 1, or a pharmaceutically acceptable salt thereof
  • a second therapeutic agent e.g., a chemotherapeutic agent
  • the combination of the GR inhibitor with the second therapeutic agent provides a more effective initial therapy for treating ovarian cancer compared to the second therapeutic agent (e.g., a chemotherapeutic agent) administered alone.
  • GR activation increases resistance to chemotherapy in ovarian cancer (e.g., high-grade serous ovarian cancer). In some instances, GR activation significantly inhibits chemotherapy induced apoptosis in ovarian cancer cells.
  • a GR inhibitor e.g., GR antagonist
  • the ovarian cancer has become resistant to chemotherapy.
  • the ovarian cancer cells are resistant to cisplatin, paclitaxel, carboplatin, gemcitabine, alone or in combination.
  • the GR inhibitor or antagonist reverses the cell survival effect.
  • Ovarian cancers may include, but are not limited to, epithelial ovarian cancers, such as serous epithelial ovarian cancer, endometrioid epithelial ovarian cancer, clear cell epithelial ovarian cancer, mucinous epithelial ovarian cancer, undifferentiated or unclassifiable epithelial ovarian cancer, refractory ovarian cancer, sex cord-stromal tumors, Sertoli and Sertoli-Leydig cell tumors, germ cell tumors, such as dysgerminoma and nondysgerminomatous tumors, Brenner tumors, primary peritoneal carcinoma, fallopian tube cancer, or combinations thereof.
  • epithelial ovarian cancers such as serous epithelial ovarian cancer, endometrioid epithelial ovarian cancer, clear cell epithelial ovarian cancer, mucinous epithelial ovarian cancer, undifferentiated or unclassifiable epithelial
  • the formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1, or a pharmaceutically acceptable salt thereof) is used in combination with at least a second therapeutic agent, such as chemotherapy or immunotherapy.
  • a second therapeutic agent such as chemotherapy or immunotherapy.
  • the second or additional chemotherapeutic agent is cisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin, melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide, doxorubicin, liposomal doxorubicin, camptothecin, pemetrexed, topotecan, vinorelbine, vinblastine, daunorubicin, 5-fluorouracil, mitomycin, thiotepa, vincristine, everolimus, veliparib, glembatumumab vedotin, pertuzumab, trastuzumab, or any combinations or any salts thereof.
  • the second or additional chemotherapeutic agent is gemcitabine. In some embodiments, the second or additional chemotherapeutic agent is carboplatin. In some embodiments, the second or additional chemotherapeutic agent is cisplatin. In some embodiments, the second or additional agent is paclitaxel. In some embodiments, the GR inhibitor is used in combination with gemcitabine and carboplatin. In some embodiments, the GR inhibitor is used in combination with carboplatin and cisplatin. In some embodiments, the second or additional therapeutic agent is an anti-PD-Ll agent. In certain embodiments, the anti-PD-Ll agent is MPDL3280A or avelumab.
  • the second or additional therapeutic agent is an anti -PD 1 agent.
  • the anti -PD 1 agent is nivolumab or permbrolizumab.
  • the second or additional therapeutic agent is an anti an anti-CTLA-4 agent.
  • the second or additional therapeutic agent is a CAR-T cell therapy.
  • the second or additional therapeutic agent is an IDO-1 inhibitor.
  • the second or additional therapeutic agent is a cancer vaccine.
  • One embodiment provides a method of treating non-small cell lung cancer (NSCLC) in a patient in need thereof, comprising administering to the patient a formulation provided herein.
  • the patient has elevated tumor GR expression.
  • a GR inhibitor described herein is used in combination with a second therapeutic agent (e.g., a chemotherapeutic agent) for treating NSCLC.
  • the combination of the GR inhibitor with the second therapeutic agent e.g., a chemotherapeutic agent
  • the formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof is used in combination with at least a second therapeutic agent, such as a chemotherapeutic agent or immunotherapy.
  • the second or additional chemotherapeutic agent is cisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin, melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide, doxorubicin, liposomal doxorubicin, camptothecin, pemetrexed, topotecan, vinorelbine, vinblastine, daunorubicin, 5-fluorouracil, mitomycin, thiotepa, vincristine, everolimus, veliparib, glembatumumab vedotin, pertuzumab, trastuzumab, or any combinations or any salts thereof.
  • the second or additional chemotherapeutic agent is gemcitabine. In some embodiments, the second or additional chemotherapeutic agent is carboplatin. In some embodiments, the second or additional chemotherapeutic agent is cisplatin. In some embodiments, the second or additional agent is paclitaxel. In some embodiments, the GR inhibitor is used in combination with gemcitabine and carboplatin. In some embodiments, the GR inhibitor is used in combination with carboplatin and cisplatin. In some embodiments, the second or additional therapeutic agent is an anti-PD-Ll agent. In certain embodiments, the anti-PD-Ll agent is MPDL3280A or avelumab.
  • the second or additional therapeutic agent is an anti -PD 1 agent.
  • the anti -PD 1 agent is nivolumab or permbrolizumab.
  • the second or additional therapeutic agent is an anti an anti-CTLA-4 agent.
  • the second or additional therapeutic agent is a CAR-T cell therapy.
  • the second or additional therapeutic agent is an IDO-1 inhibitor.
  • the second or additional therapeutic agent is a cancer vaccine.
  • compositions described herein are used for the treatment of diseases and conditions described herein.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of compositions in therapeutically effective amounts to said subject.
  • Dosages of compositions described herein can be determined by any suitable method.
  • Maximum tolerated doses (MTD) and maximum response doses (MRD) for a compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1, or a pharmaceutically acceptable salt thereof) can be determined via established animal and human experimental protocols as well as in the examples described herein.
  • toxicity and therapeutic efficacy of a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via the protocols.
  • the amount of a given compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 1, or a pharmaceutically acceptable salt thereof) formulation that corresponds to such an amount varies depending upon factors such as the particular salt or form, disease condition and its severity, the identity (e.g., age, weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in an amount between about 10 mg to 500 mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is between about 50 mg and about 400 mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is between about 100 mg and about 400 mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is between about 100 mg and about 300 mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is between about 200 mg and about 400 mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in an amount that is between about 200 mg and about 300 mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in an amount that is between about 40 mg and about 480 mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in an amount that is between about 100 mg and about 480 mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in an amount that is between about 200 mg and about 480 mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in an amount that is between about 80 mg and about 250 mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in an amount that is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about
  • Administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) described is at a dosage described herein or at other dose levels and compositions determined and contemplated by a medical practitioner.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered for prophylactic and/or therapeutic treatments.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered to a patient already suffering from a disease in an amount sufficient to cure the disease or at least partially arrest or ameliorate the symptoms.
  • Amounts effective for this use depend on the age of the patient, severity of the disease, previous therapy, the patient's health status, weight, and response to the compositions, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial.
  • compositions described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, e.g., cancer.
  • a patient susceptible to or otherwise at risk of a particular disease e.g., cancer.
  • Such an amount is defined to be a “prophylactically effective amount or dose.”
  • the precise amounts also depend on the patient's age, state of health, weight, and the like.
  • effective amounts for this use will depend on the risk or susceptibility of developing the particular disease, previous therapy, the patient's health status and response to the compositions, and the judgment of the treating physician.
  • the administration of a composition described herein are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease. In other embodiments, administration of a composition continues until complete or partial response of a disease.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered twice a day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered three times a day.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a subject who is in a fasted state.
  • a fasted state refers to a subject who has gone without food or fasted for a certain period of time.
  • General fasting periods include at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours and at least 16 hours without food.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered to a subject who is in a fasted state for at least 8 hours.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a subject who is in a fasted state for at least 10 hours. In yet other embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered to a subject who is in a fasted state for at least 12 hours. In other embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered to a subject who has fasted overnight.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a subject who is in a fed state.
  • a fed state refers to a subject who has taken food or has had a meal.
  • a composition is administered to a subject in a fed state 5 minutes post-meal, 10 minutes post-meal, 15 minutes post-meal, 20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutes post-meal, 1 hour post-meal, or 2 hours post-meal.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a subject in a fed state 30 minutes post-meal. In other instances, the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered to a subject in a fed state 1 hour post-meal. In yet further embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered to a subject with food.
  • the methods described herein further comprise administering the compositions and formulations comprising a compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent to the subject or patient in need thereof in multiple cycles repeated on a regular schedule with periods of rest in between each cycle. For example, in some instances, treatment is given for one week followed by three weeks of rest is one treatment cycle.
  • the length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle ranges from two to six weeks. In some embodiments, the length of a treatment cycle ranges from three to six weeks. In some embodiments, the length of a treatment cycle ranges from three to four weeks. In some embodiments, the length of a treatment cycle is three weeks (or 21 days). In some embodiments, the length of a treatment cycle is four weeks (28 days). In some embodiments, the length of a treatment cycle is 56 days. In some embodiments, a treatment cycle lasts one, two, three, or four weeks. In some embodiments, a treatment cycle lasts three weeks. In some embodiments, a treatment cycle lasts four weeks. The number of treatment doses scheduled within each cycle also varies depending on the drugs being given.
  • Disclosed herein is a method of treating a solid tumor in a subject in need thereof; the method comprising administering to the subject in need thereof:
  • Formula (I) e.g., compound pharmaceutically acceptable salt thereof; and (b) a chemotherapy.
  • the solid tumor is prostate cancer, breast cancer, endometrial cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, non-small cell lung cancer, squamous head & neck cancer, hepatocellular cancer, esophageal cancer, ovarian cancer, or gastric cancer.
  • the solid tumor is prostate cancer.
  • the solid tumor is prostate cancer.
  • the prostate cancer is metastatic prostate cancer.
  • the prostate cancer is castration-resistant prostate cancer (CRPC).
  • the prostate cancer is castration-sensitive prostate cancer.
  • the solid tumor is breast cancer.
  • the breast cancer is metastatic breast cancer.
  • the breast cancer is triple negative breast cancer.
  • the breast cancer is ER negative breast cancer.
  • the chemotherapy is nab-paclitaxel, paclitaxel, docetaxel, cabazitaxel, tesetaxel, cisplatin, carboplatin, gemcitabine, capecitabine, or pemetrexed.
  • the chemotherapy is nab-paclitaxel.
  • the chemotherapy is administered in an amount that is between about 10 mg/m 2 and about 200 mg/m 2 .
  • the chemotherapy is administered in an amount that is about 75 mg/m 2 .
  • the chemotherapy is administered in an amount that is about 125 mg/m 2 .
  • the compound of Formula (I) e.g., compound 1
  • pharmaceutically acceptable salt thereof and the chemotherapy are both administered in 28-day cycles.
  • the chemotherapy is administered for multiple 28-day cycles.
  • the chemotherapy is administered for at least one 28-day cycle.
  • the chemotherapy is administered for at least two 28-day cycles.
  • the chemotherapy is administered for at least three 28-day cycles.
  • the chemotherapy is administered on days 1, 8, and 15 of each 28-day cycle.
  • the chemotherapy is administered on days 1 and 8 of each 28-day cycle. [00101] In some embodiments, the chemotherapy is administered on days 8 and 15 of each 28-day cycle. [00102] In some embodiments, the chemotherapy is administered on days 1-7 of each 28-day cycle. [00103] In some embodiments, the chemotherapy is administered on day 1 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for multiple 28-day cycles.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least two 28-day cycles.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least three 28-day cycles.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1, 8, and 15 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1 and 15 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 8 and 15 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1 and 8 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 7, and 14 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1 and 7 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1 and 14 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 7 and 14 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 2, 9, and 16 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 2 and 16 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 9 and 16 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 2 and 9 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-3, 8-10, and 15-17 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1, 2, 7-9, and 14-16 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-4, 8-11, and 15-18 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-3, 7-10, and 14-17 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-5, 8-12, and 15-19 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-4, 7-11, and 14-18 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-6, 8-13, and 15-20 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1-5, 7-12, and 14-19 of each 28-day cycle.
  • the compound of Formula (I) e.g., compound 1
  • pharmaceutically acceptable salt thereof and the chemotherapy are both administered in 21 -day cycles.
  • the chemotherapy is administered for multiple 21-day cycles.
  • the chemotherapy is administered for at least one 21 -day cycle.
  • the chemotherapy is administered for at least two 21-day cycles.
  • the chemotherapy is administered for at least three 21-day cycles.
  • the chemotherapy is administered on days 1, 8, and 15 of each 21 -day cycle.
  • the chemotherapy is administered on days 1 and 8 of each 21 -day cycle. [00139] In some embodiments, the chemotherapy is administered on days 8 and 15 of each 21-day cycle. [00140] In some embodiments, the chemotherapy is administered on days 1-7 of each 21-day cycle. [00141] In some embodiments, the chemotherapy is administered on day 1 of each 21-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for multiple 21-day cycles.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least one 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least two 21 -day cycles.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least three 21 -day cycles.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1, 8, and 15 of each 21-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1 and 15 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on day 1 and 8 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 8 and 15 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 2, 9, and 16 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 2 and 9 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 2 and 16 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 9 and 16 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-3, 8-10, and 15-17 of each 21-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-3 and 8-10 of each 21-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1, 2, 7-9, and 14-16 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1, 2, and 7-9 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1, 2 and 7-9 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-4, 8-11, and 15-18 of each 21-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-4 and 8-11 of each 21-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-3, 7-10, and 14-17 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-3, and 7-10 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-5, 8-12, and 15-19 of each 21-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-5 and 8-12 of each 21-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-4, 7-11, and 14-18 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-4, and 7-11 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-6, 8-13, and 15-20 of each 21-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-6 and 8-13 of each 21-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-5, 7-12, and 15-19 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-5 and 7-12 of each 21 -day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered between about 2 hours before and about 2 hours after administration of the chemotherapy.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered about 2 hours before administration of the chemotherapy.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered about 30 mins after administration of the chemotherapy.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered at the same time as the chemotherapy.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered first thing in the morning. In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered just before sleep.
  • PDAC pancreatic ductal adenocarcinoma
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof PDAC
  • nab-paclitaxel nab-paclitaxel
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least one 28 -day cycle.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least two 28-day cycles.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof PDAC
  • nab-paclitaxel are both administered to the subject for at least three 28-day cycles.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least four 28-day cycles.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof PDAC
  • nab-paclitaxel are both administered to the subject for at least five 28-day cycles.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least six 28-day cycles.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least seven 28 -day cycles.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least eight 28-day cycles.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least nine 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 1028 -day cycles.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 15 28 -day cycles.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 2028-day cycles.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 25 28-day cycles.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • pancreatic ductal adenocarcinoma PDAC
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • a method of treating ovarian cancer in a subject in need thereof comprising administering to the subject in need thereof: (Compound 1) or a pharmaceutically acceptable salt thereof; and
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject in 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least one 28-day cycle.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least two 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least three 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least four 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least five 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least six 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least seven 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least eight 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least nine 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 1028-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 15 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 2028-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 25 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle and nab- paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m 2 per day.
  • Disclosed herein is a method of treating in a subject in need thereof; the method comprising administering to the subject in need thereof: (Compound 1) or a pharmaceutically acceptable salt thereof; and
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject in 28- day cycles.
  • TNBC triple negative breast cancer
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least one 28 -day cycle.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least two 28-day cycles.
  • TNBC triple negative breast cancer
  • compound 1 , or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least three 28-day cycles.
  • compound 1 , or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least four 28-day cycles.
  • TNBC triple negative breast cancer
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least five 28 -day cycles.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least six 28-day cycles.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least seven 28-day cycles.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least eight 28 -day cycles.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least nine 28-day cycles.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 1028-day cycles.
  • TNBC triple negative breast cancer
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 15 28-day cycles.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 2028-day cycles.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 25 28-day cycles.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.
  • TNBC triple negative breast cancer
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • TNBC triple negative breast cancer
  • compound 1 or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • TNBC triple negative breast cancer
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered in 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least one 28-day cycle.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least two 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least three 28- day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least four 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least five 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least six 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least seven 28- day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least eight 28- day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least nine 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least 1028-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least 15 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least 2028-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and the chemotherapy are both administered for at least 25 28- day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject in 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least one 28-day cycle.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least two 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least three 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least four 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least five 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least six 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least seven 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least eight 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least nine 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 1028-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 15 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 2028-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 25 28-day cycles.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle and nab- paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-21 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m 2 per day.
  • compound 1, or pharmaceutically acceptable salt thereof is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m 2 per day.
  • the androgen receptor modulator is enzalutamide, apalutamide, darolutamide, abiraterone, or bicalutamide. In some embodiments, the androgen receptor modulator is enzalutamide. In some embodiments, the androgen receptor modulator is apalutamide. In some embodiments, the androgen receptor modulator is administered in an amount that is between about 60 mg and about 400 mg. In some embodiments, the androgen receptor modulator is administered in an amount that is between about 160 mg and about 240 mg. In some embodiments, the androgen receptor modulator is administered in an amount that is about 80 mg. In some embodiments, the androgen receptor modulator is administered in an amount that is about 120 mg.
  • the androgen receptor modulator is administered in an amount that is about 160 mg. In some embodiments, the androgen receptor modulator is administered in an amount that is about 180 mg. In some embodiments, the androgen receptor modulator is administered in an amount that is about 240 mg. In some embodiments, the androgen receptor modulator is enzalutamide and is administered to the subject once per day at a dose of 160 mg.
  • the prostate cancer is metastatic prostate cancer.
  • the prostate cancer is castration-resistant prostate cancer (CRPC).
  • the prostate cancer is castration-sensitive prostate cancer.
  • the prostate cancer is metastatic prostate cancer progressing on AR-inhibitors, including, but not limited to, enzalutamide.
  • the prostate cancer is metastatic prostate cancer progressing on enzalutamide [00297]
  • the compound of Formula (I) e.g., compound 1), or pharmaceutically acceptable salt thereof, and the androgen receptor modulator are administered daily.
  • the compound of Formula (I) e.g., compound 1
  • the androgen receptor modulator are administered in 28-day cycles. [00298] In some embodiments, the androgen receptor modulator is administered for multiple 28-day cycles.
  • the androgen receptor modulator is administered for at least one 28-day cycle.
  • the androgen receptor modulator is administered for at least two 28-day cycles.
  • the androgen receptor modulator is administered for at least three 28-day cycles.
  • the androgen receptor modulator is administered on days 1-7 of each 28- day cycle.
  • the androgen receptor modulator is administered on days 1-14 of each 28- day cycle.
  • the androgen receptor modulator is administered on days 1-21 of each 28- day cycle.
  • the androgen receptor modulator is administered on days 1-28 of each 28- day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered in 28-day cycles.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for multiple 28-day cycles.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least two 28-day cycles.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least three 28-day cycles.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-6 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-13 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-20 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-27 of each 28-day cycle.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered between about 2 hours before and about 2 hours after administration of the androgen receptor modulator.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered about 2 hours before administration of the androgen receptor modulator.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered about 30 mins after administration of the androgen receptor modulator.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered at the same time as the androgen receptor modulator.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered first thing in the morning.
  • the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered just before sleep.
  • the androgen receptor modulator is administered first thing in the morning.
  • the androgen receptor modulator is administered just before sleep.
  • a method of treating prostate cancer in a subject in need thereof comprising administering to the subject in need thereof: (compound 1), or a pharmaceutically acceptable salt thereof; and
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one week.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two weeks.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three weeks.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one month.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least four months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least five months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least six months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one year.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two years.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject until disease progression.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 120 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 160 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 240 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 320 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one week.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two weeks.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three weeks.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one month.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least four months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least five months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least six months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one year.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two years.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject until disease progression.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 120 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 160 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 240 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 320 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • a method of treating metastatic prostate cancer in a subject in need thereof, wherein the prostate cancer has progressed after treatment with an androgen receptor modulator comprising administering to the subject in need thereof: (compound 1) or a pharmaceutically acceptable salt thereof; and (b) enzalutamide.
  • the androgen receptor modulator is enzalutamide, apalutamide, darolutamide, abiraterone, or bicalutamide. In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, the androgen receptor modulator is enzalutamide. In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, the androgen receptor modulator is apalutamide.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one week.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two weeks.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three weeks.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one month.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least four months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least five months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least six months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one year.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two years.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject until disease progression.
  • compound 1 is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 120 mg per day.
  • compound 1 is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1 is administered to the subject at a dose of 160 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1 is administered to the subject at a dose of 240 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1 is administered to the subject at a dose of 320 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one week.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two weeks.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three weeks.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one month.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least four months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least five months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least six months.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one year.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two years.
  • compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject until disease progression.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 120 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 160 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 240 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 320 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.
  • the dose of compound 1, or a pharmaceutically acceptable salt thereof, administered to the subject in need thereof may be administered to the subject as a single dose, or two doses, or three doses, or four doses, or five doses, or 6 doses.
  • the dose of compound 1, or a pharmaceutically acceptable salt thereof, administered to the subject in need thereof is administered to the subject as a single dose.
  • a dose of 80 mg, or 160 mg, or 240 mg, or 320 mg of compound 1, or a pharmaceutically acceptable salt thereof, to be administered to the subject may be administered in the form of one or more dosage units, such as one or more capsules or tablets.
  • each dosage unit may contain the same amount or different amounts of compound 1, or a pharmaceutically acceptable salt thereof.
  • each dosage unit may be administered to the subject at the same time or as close in time as is convenient for the subject.
  • a dose of 160 mg of compound 1, or a pharmaceutically acceptable salt thereof, to be administered to the subject once per day may be administered to the subject as two dosage units, each containing 80 mg of compound 1, or a pharmaceutically acceptable salt thereof, each of which is administered to the subject at the same time or as close in time as is convenient for the subject.
  • a dose of 160 mg of compound 1, or a pharmaceutically acceptable salt thereof, to be administered to the subject once per day may be administered to the subject as two dosage units, each containing 80 mg of compound 1, or a pharmaceutically acceptable salt thereof, and each of which is administered to the subject during the same 24-hour period but with some period of time in between the administration of each, such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 11 hours, or 12 hours.
  • the dose of compound 1, or a pharmaceutically acceptable salt thereof, to be administered to the subject daily is administered as a single dose (e.g., two capsules, each containing 80 mg of compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject at the same time or as close in time as is convenient for the subject).
  • Described herein are methods for assessing a clinical or a biochemical response to a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, in a subject in need thereof.
  • Described herein are methods for treating a solid tumor cancer patient by administering a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, by assessing the clinical or the biochemical response to the compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, in the solid tumor cancer patient.
  • the method for assessing a clinical or biochemical response to a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, in a human subject includes: a) measuring a first amount, or activity of FKBP5, GILZ, PERI, and/or KLK3 protein or a first expression level of a gene encoding FKBP5, GILZ, PERI and/or KLK3 protein in a first sample from the subject, wherein i) the first sample comprises primary cells; and ii) the first sample is obtained before administering the compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, to the subject; b) administering the compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, to the subject; c) measuring a second amount or activity of FKBP5, GILZ, PERI, and/or KLK3 protein or a second expression level of a gene
  • the sample is obtained by any means known in the art.
  • the sample is obtained by collecting a blood sample (e.g., a sample of whole blood or a fraction thereof).
  • the sample is obtained by scraping epithelial cells (e.g., nasal epithelial cells) of a subject.
  • Samples include, but are not limited to samples of human cells and tissues, such as blood samples (e.g., peripheral blood mononuclear cell (PBMC)), cerebrospinal fluid samples, synovial tissue samples, synovial fluid samples, brain tissue samples, blood vessel samples, or tumor samples.
  • the sample is peripheral blood mononuclear cell (PBMC) and the FKBP5, GILZ, and/or PERI genes are quantified.
  • the quantified amount, activity, expression that indicates a biochemical or clinical response to the compound of Formula (I) is equal to about, or less than about, 25%, 30%, 40%, 50%, 75%, 100%, 110%, 125%, or 150% of the positive control or threshold value. In some cases, the quantified amount, activity, or expression that indicates a lack of a biochemical or clinical response to the compound of Formula (I)
  • control or threshold value is a negative control or threshold value that indicates a lack of a response (e.g. , biochemical or clinical) to the compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, or a value that is typically obtained without, or prior to, administration of a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof.
  • a quantified amount, activity, or expression level that is below the negative control or threshold value indicates a clinical or biochemical response or a strong clinical or biochemical response to the compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof.
  • a quantified amount, activity, or expression level that is near, equal to, or above the negative control or threshold value indicates a lack of a clinical response, a lack of biochemical response, a lack of a strong clinical response, or a lack of a strong biochemical response to the compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof.
  • the quantified amount, activity, or expression that indicates a clinical response to the compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, or a biochemical response to the compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof is equal to about or less than about 0.25%, 0.5%, 1 %, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 25%, 30%, 40%, or 50% of the negative control or threshold value.
  • the quantified amount, activity, or expression that indicates a lack of a clinical response or a lack of a biochemical response to the compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof is at least about 75%, 100%, 110%, 125%, 150%, 200%, 300%, or 400% of the negative control or threshold value.
  • the methods described herein are employed to assess or predict the effect of administration of a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, therapy on the cancer cells of the subject.
  • cancer cells are obtained from a subject and assayed for FKBP5, GILZ, PERI, and/or KLK3 amount or activity or the expression level of a gene encoding FKBP5, GILZ, PERI, and/or KLK3.
  • a high level of FKBP5, GILZ, PERI, and/or KLK3 relative to a control suggests that the cells express a high level of GR and administration of a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, is indicated.
  • a low level of FKBP5, GILZ, PERI, and/or KLK3 relative to a control suggests that the cells express a low level of GR and administration of a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof is not indicated.
  • a low level of FKBP5, GILZ, PERI, and/or KLK3 relative to a control suggests that the FKBP5, GILZ, PERI, and/or KLK3 feedback mechanism is inoperative, and thus continued administration of a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, is indicated.
  • a compound of Formula (I) e.g., compound 1
  • a reduction in FKBP5, GILZ, PERI, and/or KLK3 in tumor cells after administration of a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, as compared to a pre-administration value suggests that administration of a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, therapy is indicated.
  • FKBP5, GILZ, PERI, and/or KLK3 amount, activity, or expression level are assessed in combination with GR amount, activity, or expression level.
  • low GR amount, activity, or expression level and low FKBP5, GILZ, PERI, and/or KLK3 amount, activity, or expression level predict that administration of a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, is not beneficial for this cancer type, cell, or tumor.
  • high GR amount, activity, or expression level and high FKBP5, GILZ, PERI, and/or KLK3 amount, activity, or expression level indicate that administration of a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, is beneficial for this cancer type, cell, or tumor.
  • high GR amount, activity, or expression level and low FKBP5, GILZ, PERI, and/or KLK3 amount, activity, or expression level indicate a defective cortisol counter regulation mechanism and administration of a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof, is beneficial treatment.
  • a compound of Formula (I) e.g., compound 1
  • a pharmaceutically acceptable salt thereof is beneficial treatment.
  • circulating tumor DNA is found in the bloodstream and is DNA that comes from cancerous cells and tumors.
  • ctDNA are small pieces of DNA, usually comprising fewer than 200 building blocks (nucleotides) in length.
  • detection of ctDNA is useful, for example, for detecting and diagnosing a tumor. Because tumor DNA has acquired multiple genetic mutations, leading to tumor development, ctDNA is not an exact match to the individual’s DNA. Finding DNA with genetic differences aids in tumor detection. Diagnosing the type of tumor using ctDNA can reduce the need for getting a sample of the tumor tissue (tumor biopsy), which can be challenging when a tumor is difficult to access, such as a tumor in the brain or lung.
  • a decrease in the quantity of ctDNA suggests the solid tumor is shrinking and treatment with a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof is effective.
  • a lack of ctDNA in the bloodstream indicates that the cancer has not returned after treatment with a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof.
  • the genomic profiling is performed after each treatment cycle with a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof.
  • the gene mutations indicate that the cancer is becoming resistant to the treatment with a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof.
  • the lack of gene mutations indicate that the cancer is not becoming resistant to the treatment with a compound of Formula (I) (e.g., compound 1), or a pharmaceutically acceptable salt thereof.
  • Example 1 Open-Label Phase lb Study of Compound 1 in Combination with Nab-Paclitaxel in Patients with Advance or Metastatic Solid Tumors
  • Compound 1 in the form of a pharmaceutical composition was administered to subjects having solid tumors in an open-label, uncontrolled, multi-center, dose-finding study. After the screening period, eligible subjects were enrolled and treated with the pharmaceutical composition comprising compound 1 in combination with nab-paclitaxel until disease progression, unacceptable toxicity, or meeting another criterion for stopping treatment.
  • Compound 1 was supplied as a pharmaceutical composition in the form of an 80 mg capsule for oral administration.
  • the capsule contained 80 mg of compound 1 with the inactive excipients caprylic acid, ascorbyl palmitate and alpha tocopherol, which was filled into a hard gelatin capsule.
  • Compound 1 80 mg capsules were packaged in an induction-sealed HDPE bottle with a child resistant cap. All study medications were stored at 2°C to 8°C and protected from heat, light, and humidity in a secure, environmentally controlled, and monitored (manual or automated) area in accordance with the labelled storage conditions with access limited to the investigator and authorized site staff.
  • Nab-paclitaxel (Abraxane®) was supplied as lyophilized powder in single-use vials for reconstitution.
  • compound 1 was administered orally to subjects as the 80 mg capsules described above once per day at Dose Level 1A (80 mg once per day), Dose Level 2A (160 mg once per day), or Dose Level 3A (240 mg once per day) on days 1 to 5, 8 to 12, and 15 to 19 of the 28-day cycle, in combination with the administration to the subjects of nab-paclitaxel at a dose of 75 mg/m 2 on days 1, 8, and 15 of each 28-day cycle.
  • Dose Level 1A 80 mg once per day
  • Dose Level 2A 160 mg once per day
  • Dose Level 3A 240 mg once per day
  • compound 1 was administered orally to subjects as the 80 mg capsules described above once per day at Dose Level 2B (160 mg once per day) on days 1 to 21 of the 28-day dosing cycle, in combination with the administration to the subjects of nab-paclitaxel at a dose of 75 mg/m 2 on days 1, 8, and 15 of each 28- day cycle.
  • Dose Level 2B 160 mg once per day
  • the dose levels of compound 1 that were evaluated are described in the table below.
  • Example 2 Open-Label Phase lb Study of Compound 1 in Combination with Enzalutamide in Patients with Metastatic Prostate Cancer Progressing on Enzalutamide
  • the study evaluated the administration of compound 1 in the form of 80 mg capsules in an overall 28-day dosing cycle to subjects having metastatic prostate cancer progressing on enzalutamide.
  • Compound 1 in the form of 80 mg capsules was administered orally to the subjects once per day in combination with the administration of enzalutamide once per day at a dose of 160 mg.
  • Compound 1 was supplied as a pharmaceutical composition in the form of an 80 mg capsule for oral administration.
  • the capsule contained 80 mg of compound 1 with the inactive excipients caprylic acid, ascorbyl palmitate and alpha tocopherol, which was fdled into a hard gelatin capsule.
  • Enzalutamide (Xtandi®) was supplied as 40 mg capsules.
  • Compound 1 in the form of the 80 mg capsules described above was administered orally to the subjects once per day at Dose Level 1 (80 mg once per day), Dose Level 2 (160 mg once per day), or Dose Level 3 (240 mg once per day), in combination with the administration to the subjects once per day of enzalutamide at a dose of 160 mg in 28-day cycles.
  • Dose Level 1 80 mg once per day
  • Dose Level 2 160 mg once per day
  • Dose Level 3 240 mg once per day

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Abstract

La présente invention concerne de manière générale l'utilisation d'un antagoniste du récepteur des glucocorticoïdes pour le traitement du cancer, en particulier des tumeurs solides et du cancer de la prostate.
PCT/US2021/017581 2020-02-12 2021-02-11 Utilisations d'antagonistes du récepteur des glucocorticoïdes Ceased WO2021163273A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023043632A1 (fr) * 2021-09-16 2023-03-23 Corcept Therapeutics Incorporated Dosage intermittent de modulateurs du récepteur des glucocorticoïdes pour le traitement des cancers de l'ovaire et d'autres cancers
US12109272B2 (en) 2021-09-16 2024-10-08 Corcept Therapeutics Incorporated Intermittent dosing of glucocorticoid receptor modulators for the treatment of ovarian and other cancers

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6512130B1 (en) * 2000-09-05 2003-01-28 Council Of Scientific And Industrial Research Mifepristone analogue, process for the preparation thereof and use thereof
US20140364600A1 (en) * 2013-06-05 2014-12-11 Klaus Nickisch Imidazolyl progesterone antagonists
US20160289261A1 (en) * 2013-12-11 2016-10-06 Sloan-Kettering Institute For Cancer Research Glucocorticoid inhibitors for treatment of prostate cancer
US20190218246A1 (en) * 2016-10-07 2019-07-18 Oric Pharmaceuticals, Inc. Inhibitors of glucocorticoid receptor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6512130B1 (en) * 2000-09-05 2003-01-28 Council Of Scientific And Industrial Research Mifepristone analogue, process for the preparation thereof and use thereof
US20140364600A1 (en) * 2013-06-05 2014-12-11 Klaus Nickisch Imidazolyl progesterone antagonists
US20160289261A1 (en) * 2013-12-11 2016-10-06 Sloan-Kettering Institute For Cancer Research Glucocorticoid inhibitors for treatment of prostate cancer
US20190218246A1 (en) * 2016-10-07 2019-07-18 Oric Pharmaceuticals, Inc. Inhibitors of glucocorticoid receptor

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023043632A1 (fr) * 2021-09-16 2023-03-23 Corcept Therapeutics Incorporated Dosage intermittent de modulateurs du récepteur des glucocorticoïdes pour le traitement des cancers de l'ovaire et d'autres cancers
US12109272B2 (en) 2021-09-16 2024-10-08 Corcept Therapeutics Incorporated Intermittent dosing of glucocorticoid receptor modulators for the treatment of ovarian and other cancers
AU2022344984B2 (en) * 2021-09-16 2025-04-24 Corcept Therapeutics Incorporated Intermittent dosing of glucocorticoid receptor modulators for the treatment of ovarian and other cancers

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