WO2024006207A1 - Inhibiteur du récepteur des androgènes à domaine n-terminal et utilisations associées - Google Patents

Inhibiteur du récepteur des androgènes à domaine n-terminal et utilisations associées Download PDF

Info

Publication number
WO2024006207A1
WO2024006207A1 PCT/US2023/026227 US2023026227W WO2024006207A1 WO 2024006207 A1 WO2024006207 A1 WO 2024006207A1 US 2023026227 W US2023026227 W US 2023026227W WO 2024006207 A1 WO2024006207 A1 WO 2024006207A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
subject
pharmaceutically acceptable
solvate
prodrug
Prior art date
Application number
PCT/US2023/026227
Other languages
English (en)
Inventor
Peter Virsik
Original Assignee
Essa Pharma Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Essa Pharma Inc. filed Critical Essa Pharma Inc.
Publication of WO2024006207A1 publication Critical patent/WO2024006207A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • the present disclosure generally relates to therapeutic use of an androgen receptor (AR) N-terminal domain inhibitor (NTD) Compound A.
  • AR androgen receptor
  • NTD N-terminal domain inhibitor
  • the present disclosure relates to the use of Compound A for treatment of cancers, such as prostate cancer.
  • Androgens mediate their effects through the androgen receptor (AR). Androgens play a role in a wide range of developmental and physiological responses and are involved in male sexual differentiation, maintenance of spermatogenesis, and male gonadotropin regulation (R. K. Ross, G. A. Coetzee, C. L. Pearce, J. K. Reichardt, P. Bretsky, L. N. Kolonel, B. E. Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol 35, 355-361 (1999); A. A. Thomson, Reproduction 121, 187-195 (2001); N. Tanji, K. Aoki & M.
  • Androgen receptor (AR) is a transcription factor that plays dual roles in breast cancer cells: promoting or inhibiting proliferation depending on expression and activity of estrogen receptor-alpha.
  • TNBC triple-negative breast cancer
  • AR plays a role in the proliferation of breast cancer cells by either promoting proliferation or inhibiting proliferation depending on the expression of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2).
  • ER estrogen receptor
  • HER2 human epidermal growth factor receptor 2
  • AR expression is detected in up to 90% of all breast cancers and in up to approximately 35% of TNBC.
  • AR-Vs have been detected in primary breast cancer specimens and in breast cancer cell lines.
  • AR-V7 expression was detected in circulating-tumor cells of patients with metastatic breast cancer and was associated with bone metastases.
  • Targeting AR is a potential therapeutic strategy for AR-positive TNBC.
  • Androgens also play a role in female diseases such as polycystic ovary syndrome as well as cancers.
  • ovarian cancer where elevated levels of androgens are associated with an increased risk of developing ovarian cancer (K. J. Helzlsouer, A. J. Alberg, G. B. Gordon, C. Longcope, T. L. Bush, S. C. Hoffman & G. W. Comstock, JAMA 274, 1926-1930 (1995); R. J. Edmondson, J. M. Monaghan & B. R. Davies, Br J Cancer 86, 879-885 (2002)).
  • the AR has distinct functional domains that include the carboxy-terminal ligand-binding domain (LBD), a DNA-binding domain (DBD) comprising two zinc finger motifs, and an N-terminus domain (NTD) that contains two transcriptional activation units (taul and tau5) within activation function-1 (AF-1). Binding of androgen (ligand) to the LBD of the AR results in its activation such that the receptor can effectively bind to its specific DNA consensus site, termed the androgen response element (ARE), on the promoter and enhancer regions of “normally” androgen regulated genes, such as PSA, to initiate transcription.
  • LBD carboxy-terminal ligand-binding domain
  • DBD DNA-binding domain
  • NTD N-terminus domain
  • AF-1 activation function-1
  • the AR can be activated in the absence of androgen by stimulation of the cAMP-dependent protein kinase (PKA) pathway, with interleukin-6 (IL-6) and by various growth factors (Culig et al 1994 Cancer Res. 54, 5474-5478; Nazareth el a! 1996 J. Biol. Chem. 271, 19900-19907; Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J. Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 38087-38094).
  • PKA cAMP-dependent protein kinase pathway
  • IL-6 interleukin-6
  • the mechanism of ligand-independent transformation of the AR has been shown to involve: 1) increased nuclear AR protein suggesting nuclear translocation; 2) increased AR/ARE complex formation; and 3) the AR-NTD (Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J. Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 38087-38094).
  • the AR can be activated in the absence of testicular androgens by alternative signal transduction pathways in castrationresistant disease, which is consistent with the finding that nuclear AR protein is present in secondary prostate cancer tumors (Kim et al 2002 Am. J. Pathol. 160, 219-226; and van der Kwast et al 1991 Inter. J. Cancer 48, 189-193).
  • Clinically available inhibitors of the AR include nonsteroidal antiandrogens such as bicalutamide (CasodexTM), nilutamide (Anandron®, Nilandron®), flutamide (Eulexin®), enzalutamide (Xtandi®), apalutamide (Erleada®), and darolutamide (Nubeqa®).
  • nonsteroidal antiandrogens such as bicalutamide (CasodexTM), nilutamide (Anandron®, Nilandron®), flutamide (Eulexin®), enzalutamide (Xtandi®), apalutamide (Erleada®), and darolutamide (Nubeqa®).
  • steroidal antiandrogens such as cyproterone acetate and spironolactone.
  • Both steroidal and non-steroidal antiandrogens target the LBD of the AR and predominantly fail presumably due to poor affinity and mutations that lead to activation of the AR by these same antiandrogens (Taplin, M.E., Bubley, G.J., Kom Y.J., Small E.J., Uptonm M., Rajeshkumarm B., Balkm S.P., Cancer Res., 59, 2511-2515 (1999)), and constitutively active AR splice variants.
  • Antiandrogens have no effect on the constitutively active AR splice variants that lack the ligand-binding domain (LBD) and are associated with castration-recurrent prostate cancer (Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ., Cancer Res 68, 5469-77, 2008; Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, Kung HJ, Brodie AM, Edwards J, Qiu Y., Cancer Res. 69, 2305-13, 2009; Hu et al 2009 Cancer Res. 69, 16-22; Sun et al 2010 J Clin Invest.
  • LBD ligand-binding domain
  • AR degraders such as niclosamide (Liu C et al 2014), galeterone (Njar et al 2015; Yu Z at al 2014), and ARV-330/Androgen receptor PROTAC (Neklesa et al 2016 J Clin Oncol 34 suppl 2S; abstr 267); ARDBD inhibitor VPC- 14449 (Dalal K et al 2014 J Biol Chem.
  • the AR-NTD is also a target for drug development (e.g. WO 2000/001813; Myung et al. J. Clin. Invest 2013, 123, 2948), since the NTD contains Activation-Function- 1 (AF-1) which is the essential region required for AR transcriptional activity (Jenster et al 1991. Mol Endocrinol. 5, 1396-404).
  • AF-1 Activation-Function- 1
  • the AR-NTD importantly plays a role in activation of the AR in the absence of androgens (Sadar, M.D. 1999 J. Biol. Chem. 274, 7777-7783; Sadar MD et al 1999 Endocr Relat Cancer. 6, 487-502; Ueda et al 2002 J. Biol. Chem.
  • the AR-NTD is important in hormonal progression of prostate cancer as shown by application of decoy molecules (Quayle et al 2007, Proc Natl Acad Sci USA. 104,1331-1336).
  • Compounds that modulate AR, potentially through interaction with NTD domain include the bisphenol compounds disclosed in published PCT Nos: WO 2010/000066, WO 2011/082487; WO 2011/082488; WO 2012/145330; WO 2012/139039; WO 2012/145328; WO 2013/028572; WO 2013/028791; WO 2014/179867; WO 2015/031984; WO 2016/058080; WO 2016/058082; WO 2016/112455; WO 2016/141458; WO 2017/177307; WO 2017/210771; WO 2018/045450; and WO 2020/081999, and which are hereby incorporated by reference in their entireties.
  • AR mechanisms of resistance to ADT include: overexpression of AR (Visakorpi, T. et al Nature Genetics 1995, 9, 401-406; Koivisto, P. et al Scandinavian Journal of Clinical and Laboratory Investigation Suppiementum 1996, 226, 57-63); gain-of-function mutations in the AR LBD (Culig Z.
  • AR-Vs AR splice variants
  • LBD ligand-binding domain
  • Anti -androgens such as bicalutamide and enzalutamide target AR LBD, but have no effect on truncated constitutively active AR-Vs such as AR-V7 (Li Y. etal Cancer Research 2013, 73, 483-489). Expression of AR-V7 is associated with resistance to current hormone therapies (Li Y. et al Cancer Research 2013, 73, 483-489; Antonarakis E. S. et al The New England Journal of Medicine 2014, 371, 1028-1038).
  • the present disclosure relates to methods for treating cancer comprising Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at a daily dose in the range of about 50 mg to about 2000 mg.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at a daily dose of about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, about 1,100 mg, about 1,200 mg, about 1,300 mg, about 1,400 mg, about 1,500 mg, about 1,600 mg, about 1,700 mg, or about 1,800 mg.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered once a day. In some embodiments, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at once a day at a dose of about 200 mg, about 400 mg, about 600 mg, about 800 mg, or about 1,000 mg.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered twice a day.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered twice a day at a daily dose of about 200 mg, about 400 mg, about 600 mg, about 800 mg, about 1,000 mg, about 1,200 mg, about 1,400 mg, or about 1,600 mg.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at about 200 mg twice a day, about 400 mg twice a day, about 600 mg twice a day, about 800 mg twice a day, or about 1,000 mg twice a day.
  • cancer is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, or salivary gland carcinoma.
  • cancer is prostate cancer.
  • prostate cancer is primary or localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, advanced prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer, non-metastatic castrationresistant prostate cancer, and hormone-sensitive prostate cancer.
  • prostate cancer is metastatic castration-resistant prostate cancer.
  • prostate cancer is non-metastatic castration-resistant prostate cancer.
  • prostate cancer expresses full-length androgen receptor or truncated androgen receptor splice variant.
  • prostate cancer is resistant to at least one anti-androgen therapeutic agent other than Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the resisted anti-androgen therapeutic agent is abiraterone acetate, enzalutamide, apalutamide, or darolutamide.
  • prostate cancer is resistant to enzalutamide monotherapy.
  • the subject received at least one line of prior therapy for treating the prostate cancer. In some embodiments, the subject received one to fifteen lines of prior therapy for treating the prostate cancer. In some embodiments, the subject received one to three lines of prior therapy for treating the prostate cancer.
  • the subject was previously treated with at least one anti-androgen therapeutic agent or chemotherapy prior to monotherapeutic administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the anti-androgen therapeutic agent used in previous treatment is abiraterone acetate, enzalutamide, apalutamide, or darolutamide.
  • the subject was previously treated with abiraterone acetate prior to monotherapeutic administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the subject was previously treated with enzalutamide prior to monotherapeutic administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the subject was previously treated with (i) abiraterone acetate and (ii) enzalutamide, darolutamide or apalutamide, prior to monotherapeutic administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the subject was previously treated with darolutamide or apalutamide prior to monotherapeutic administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the subject was previously treated with at least one line of chemotherapy prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof. In some embodiments, the subject was previously treated with one line of chemotherapy or no chemotherapy prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the subject is treated with a combination of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof in combination with a nonsteroidal antiandrogen such as bicalutamide (CasodexTM), nilutamide (Anandron®, Nilandron®), flutamide (Eulexin®), enzalutamide (Xtandi®), apalutamide (Erleada®), and darolutamide (Nubeqa®).
  • a nonsteroidal antiandrogen such as bicalutamide (CasodexTM), nilutamide (Anandron®, Nilandron®), flutamide (Eulexin®), enzalutamide (Xtandi®), apalutamide (Erleada®), and darolutamide (Nubeqa®).
  • a nonsteroidal antiandrogen such as bicalutamide (CasodexTM), nilu
  • the subject has visceral metastases. In some embodiments, the subject does not have visceral metastases.
  • the subject expresses one or more androgen receptor-associated molecular alterations.
  • the androgen receptor-associated molecular alteration is androgen receptor amplification or gain, androgen receptor mutation, or androgen receptor structural alteration.
  • the subject expresses one or more non-androgen receptor-associated molecular alterations.
  • the nonandrogen receptor-associated molecular alteration is PI3K pathway amplification, WNT pathway alteration, DNA repair alteration, loss of TP53, or loss of Rbl.
  • the administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof does not produce a Grade 3 treatment-related adverse event (TRAE) to the subject.
  • TEE Treatment-related adverse event
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject for at least about 4 weeks. In some embodiments, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject for at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, or at least about 20 weeks.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject orally. In some embodiments, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject in a tablet or a capsule. [0029] In some embodiments of the methods described herein, the method provides increase in the subject’s plasma or serum low-density lipoprotein (LDL) cholesterol level.
  • LDL serum low-density lipoprotein
  • the subject’s plasma or serum LDL cholesterol level increases in the range of about 5% to about 60% compared to the subject’s plasma or serum LDL cholesterol level prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the method provides reduction or stabilization in the subject’s prostate-specific antigen (PSA) level compared to the subject’s PSA level prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • PSA prostate-specific antigen
  • the method provides decrease in the subject’s circulating tumor DNA (ctDNA) level compared to the subject’s ctDNA level prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • ctDNA circulating tumor DNA
  • the method provides decrease in the subject’s tumor volume compared to the subject’s tumor volume prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the present disclosure also provides a method for treating non-metastatic castration resistant prostate cancer, comprising administering Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof to a subject in need thereof.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at a daily dose in the range of about 50 mg to about 2000 mg.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at a daily dose of about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, about 1,100 mg, about 1,200 mg, about 1,300 mg, about 1,400 mg, about 1,500 mg, about 1,600 mg, about 1,700 mg, or about 1,800 mg.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered once a day. In some embodiments, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered once a day at a dose of about 200 mg, about 400 mg, about 600 mg, about 800 mg, or about 1,000 mg.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered twice a day.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered twice a day at a daily dose of about 200 mg, about 400 mg, about 600 mg, about 800 mg, about 1,000 mg, about 1,200 mg, about 1,400 mg, or about 1600 mg.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at about 200 mg twice a day, about 400 mg twice a day, about 600 mg twice a day, about 800 mg twice a day, or about 1,000 mg twice a day.
  • prostate cancer expresses full- length androgen receptor or truncated androgen receptor splice variant.
  • the subject received no prior therapy for treating the prostate cancer.
  • the administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof does not produce a Grade 3 treatment-related adverse event (TRAE) to the subject.
  • TEE Treatment-related adverse event
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject for at least about 4 weeks. In some embodiments, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject for at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, or at least about 20 weeks.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject orally.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject in a tablet or a capsule.
  • the method provides decrease or stabilization in the subject’s prostate-specific antigen (PSA) level compared to the subject’s PSA level prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • PSA prostate-specific antigen
  • the method provides decrease in the subject’s circulating tumor DNA (ctDNA) level compared to the subject’s ctDNA level prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • ctDNA circulating tumor DNA
  • the method provides decrease in the subject’s tumor volume compared to the subject’s tumor volume prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the present disclosure relates to a pharmaceutical combination comprising a therapeutically effective amount of a first therapeutically active agent Compound A or a pharmaceutically acceptable salt, or solvate thereof, and a second therapeutically active agent, darolutamide, in at least one pharmaceutical composition.
  • the combination of Compound A and darolutamide is in a single dosage form. In one embodiment, the combination of Compound A and darolutamide is in at least two dosage forms.
  • the at least two dosage forms are co-packaged together into a single kit.
  • a daily dosage amount of Compound A is between about 50 mg and about 2000 mg, or between about 100 mg and about 1500 mg, or between about 200 mg and about 1000 mg, or between about 300 mg and about 600 mg.
  • Compound A is included in at least one tablet and the amount of Compound A per tablet is between about 5 mg and about 1000 mg, or between about 10 mg and about 500 mg, or between about 20 mg and about 400 mg, or between about 75 mg and about 300 mg, or between about 150 mg and about 250 mg.
  • Compound A is included in at least one tablet and amount of Compound A per tablet is about 200 mg.
  • the dosage amount of darolutamide in the pharmaceutical combinations is about 200 mg to about 3000 mg, or about 300 mg to about 2000 mg, or about 400 mg to about 1700 mg, or about 800 mg to about 1500 mg, or about 1100 mg to about 1300 mg.
  • the daily dosage amount of darolutamide is about 1200 mg.
  • the amount of darolutamide per dosage is about 20 mg to about 2000 mg, or about 100 mg to about 1000 mg, or about 300 mg to about 800 mg, or about 500 mg to about 700 mg.
  • the amount of darolutamide per dosage is about 600 mg. In another specific embodiment, the 600 mg dosage of darolutamide is provided in at least two pharmaceutical compositions.
  • the pharmaceutical composition comprises about 20 mg to about 2000 mg darolutamide, or about 50 mg to about 1000 mg darolutamide, or about 100 mg to about 500 mg darolutamide, or about 200 mg to about 400 mg darolutamide. In a specific embodiment, the pharmaceutical composition comprises about 300 mg of darolutamide.
  • the pharmaceutical composition may be a tablet.
  • Compound A and darolutamide and are in the same composition.
  • Compound A and darolutamide are in different pharmaceutical compositions as a kit.
  • the kit comprises 1 to 6 compositions for each therapeutically active agent to be administered per day.
  • the pharmaceutical combinations when administered to a subject, do not produce any serious adverse event to the subject.
  • the serious adverse event is as determined by the U.S Food & Drug Administration.
  • the serious adverse event is determined as provided https://www.fda.gov/safety/reporting-serious-problems-fda/what-serious-adverse-event.
  • administration of said comginations does not produce a treatment- emergent adverse event (TEAE) of Grade 3 or less or a treatment-emergent serious adverse event (TESAE) of Grade 3 or less.
  • TEAE treatment- emergent adverse event
  • TESAE treatment-emergent serious adverse event
  • Fig. 1 shows molecular alterations of 29 patients from Part la study of Example 1 on QD dosing regimen at baseline as well as their baseline circulating tumor DNA (ctDNA) percentage.
  • Fig. 2 shows area under the concentration-time curve from zero to 24 hours (AUC0-24) of Compound A on day 28 of cycle 1 by different cohort groups from Part la study of Example 1.
  • Fig. 3 shows patient status of patients from Part la study of Example 1.
  • Fig. 4 shows relationship between patient’s cholesterol (LDL level) and Compound A plasma concentration at steady state (Part la study of Example 1).
  • Fig. 5 shows patient’s best % PSA change from baseline and patient’s androgen receptor (AR)-associated and non- AR associated genomic aberrations (Part la study of Example 1).
  • AR androgen receptor
  • FIG. 6A shows relationship between ctDNA% and tumor burden of patients receiving QD dosing of Compound A in Part la study of Example 1.
  • Fig. 6B shows relationship between PSA level and ctDNA fraction % of patients receiving QD dosing of Compound A in Part la study of Example 1.
  • Fig. 7 shows patient’s ctDNA % change from baseline and patient’s androgen receptor (AR)-associated and non- AR associated genomic aberrations (QD dosing patients from Part la study of Example 1).
  • AR androgen receptor
  • Fig. 8 shows patient’s best % change in measurable disease and patient’s androgen receptor (AR)-associated and non- AR associated genomic aberrations (Part la study of Example 1).
  • AR androgen receptor
  • Fig. 9A shows PSA levels of Patient A from Part 1 a study of Example 1.
  • Fig. 9B shows CT scan of Patient A from Part la study of Example 1 conducted for serial volumetric analysis.
  • Fig. 10A shows plasma concentration of Compound A for Patient B on various days of treatment cycle 1.
  • Fig. 10B shows change in PSA level for Patient B during the course of 24 weeks of treatment.
  • the range “from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).
  • a androgen receptor modulator refers to one or more androgen receptor modulators or at least one androgen receptor modulator.
  • the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein.
  • reference to “an inhibitor” by the indefinite article “a” or “an” does not exclude the possibility that more than one of the inhibitors is present, unless the context clearly requires that there is one and only one of the inhibitors.
  • salts includes both acid and base addition salts.
  • Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.
  • acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • treating means one or more of relieving, alleviating, delaying, reducing, improving, or managing at least one symptom of a condition in a subject.
  • the term “treating” may also mean one or more of arresting, delaying the onset (i.e., the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition.
  • the compounds of the invention, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids.
  • the present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms whether or not they are specifically depicted herein.
  • Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the present disclosure includes tautomers of any said compounds.
  • a “prodrug” refers to a derivative of a compound of the present disclosure that will be converted to the compound in vivo.
  • a prodrug includes a compound of for example abiraterone having a free hydroxyl group (-OH) that is acetylated (-OCOMe) or acylated at one or more positions.
  • An “effective amount” means the amount of a formulation according to the invention that, when administered to a patient for treating a state, disorder or condition is sufficient to effect such treatment. The “effective amount” will vary depending on the active ingredient, the state, disorder, or condition to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated.
  • terapéuticaally effective applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.
  • combination therapy refers to a first therapy that includes Compound A in conjunction with a second therapy (e.g., therapy, surgery and/or an additional pharmaceutical agent) useful for treating, stabilizing, preventing, and/or delaying the disease or condition.
  • a second therapy e.g., therapy, surgery and/or an additional pharmaceutical agent
  • Administration in "conjunction with” another therapeutically active agent includes administration in the same or different composition(s) and/or combinations, either sequentially, simultaneously, or continuously, through the same or different routes.
  • the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and/or inert substances.
  • pharmaceutical combination refers to a single dosage form comprising at least two therapeutically active agents, or separate dosage forms comprising at least two therapeutically active agents together or separately for use in a combination therapy.
  • one therapeutically active agent may be formulated into one dosage form and the other therapeutically active agent may be formulated into a single or different dosage forms.
  • one therapeutically active agent may be formulated into a solid oral dosage form whereas the second therapeutically active agent may be formulated into a solution dosage form for parenteral administration, including as a kit, or from two kits.
  • a “fixed dosage form” as used herein means a dosage formulation in which one or more therapeutically active agents are combined in a single dosage formulation.
  • a “co-packaged form” as used herein means that the therapeutically active agents are taken together, more than one dosage forms wherein the therapeutically active agents are taken together, or more than one dosage forms wherein the therapeutically active agents are taken separately in two or more pharmaceutical compositions, /. ⁇ ., such as two or more separate tablets, capsules, gel capsules, pellets, etc, but typically the separate compositions are as a single kit.
  • pharmaceutical composition refers to a formulation comprising at least one therapeutically active agent and a pharmaceutically acceptable excipient or carrier.
  • a non-limiting example of pharmaceutical compositions includes tablets, capsules, gel capsules, syrup, liquid, gel, suspension, solid dispersion, or combinations thereof.
  • a dosage form refers to one or more pharmaceutical compositions which provides a specific amount of a therapeutically active agent, such as a unit dose.
  • a dosage form can be provided in one or more pharmaceutical compositions.
  • a dosage form can comprise two tablets each containing 100 mg of the therapeutically active agent, wherein the two tablets are the same pharmaceutical composition.
  • solid dispersion is a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components (homogenous mix).
  • a solid dispersion formulation of a therapeutically active agent(s) refers to a dispersion mixture of the therapeutically active agent(s) in an inert carrier.
  • Inert carriers can be a crystalline carrier (such as sugars), a polymeric carrier (such as HPMCAS), or a mixture of surfactants and polymers.
  • a solid dispersion of a therapeutically active agent increases the surface area of the therapeutically active agent and enhances drug solubility and/or dissolution rate.
  • a “subject” can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like.
  • the subject can be suspected of having or at risk for having a cancer, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, or suspected of having or at risk for having acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.
  • a cancer such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, or suspected of having or at risk for having acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy
  • Diagnostic methods for various cancers such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, salivary gland carcinoma, or endometrial cancer, and diagnostic methods for acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration and the clinical delineation of cancer, such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, salivary gland carcinoma, or endometrial cancer, diagnoses and the clinical delineation of acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration are known to those of ordinary skill in the art.
  • “Mammal” includes humans and both domestic animals such as laboratory animals (e.g., mice, rats, monkeys, dogs, etc.) and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
  • laboratory animals e.g., mice, rats, monkeys, dogs, etc.
  • household pets e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits
  • non-domestic animals such as wildlife and the like.
  • mutation refers to a change in the gene of a protein that leads to substituted, inserted, or deleted amino acids in the amino acid sequence of a protein, one or more base pair insertions, deletion, or substitutions, gene amplification, gene promoter or enhancer modifications, changes to the 3’ or 5’ untranslated regions of the mRNA, chromosome translocations, or any other changes, including epigenetic changes, that result in altered expression of a protein, wherein altered expression includes increasing activity of the protein, reducing activity of a protein, altering the activity of the protein, or eliminating activity of the protein.
  • mutated or abnormal androgen receptor (AR) activity can be associated to a mutation in the AR protein, a mutation in the regulatory sequences controlling expression of AR, a mutation in a protein that regulates AR activity or a mutation in a gene or protein that alters the expression and/or activity of AR.
  • AR mutated or abnormal androgen receptor
  • a “Structural ariation” or “structural variants” herein relates to genomic alterations, and in particular, genomic alterations between individuals, that involve DNA segments larger than 1 kilo base (kb) and includes copy number variants such as insertions and deletions, inversions, and/or balanced translocations.
  • substantially refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result.
  • an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed.
  • the exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking, the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained.
  • the use of “substantially” is equally applicable when used in a negative connotation to refer to the complete or near complete lack of action, characteristic, property, state, structure, item, or result.
  • compositions that is "substantially free of other active agents would either completely lack other active agents, or so nearly completely lack other active agents that the effect would be the same as if it completely lacked other active agents.
  • a composition that is "substantially free of an ingredient or element or another active agent may still contain such an item as long as there is no measurable effect thereof
  • compositions comprising N-(4-((4-(2- (3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2- yl)methanesulfonamide (Compound A), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
  • Compound A has the following structure:
  • Compound A is an androgen receptor modulator.
  • Compound A binds to androgen receptor.
  • Compound A is an androgen receptor N-terminal domain inhibitor.
  • Related androgen receptor modulators are disclosed in W02020/081999, which is incorporated by reference in its entirety for all purposes.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is in a crystalline form.
  • Compound A is crystalline Form A as disclosed in WO2021/212032, which is incorporated by reference in its entirety for all purposes.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is in an amorphous form, as disclosed in WO2021/212032, which is incorporated by reference in its entirety for all purposes.
  • the amorphous form has a purity in the range of about 80% to about 99.9%. In some embodiments, the amorphous form has a purity in the range of about 80% to about 99%. In some embodiments, the amorphous form has a purity of about 95% or higher. In some embodiments, the amorphous form has a purity of about 99% or higher.
  • the amorphous form of Compound A or a pharmaceutically acceptable salt, solvate, or solvate salt thereof has a purity of at least about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0 %, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90%.
  • the amorphous form comprises less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5% by weight of a crystalline form of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. In some embodiments, the amorphous form comprises less than about 10% by weight of a crystalline form of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. In some embodiments, the amorphous form comprises less than about 5% by weight of a crystalline form of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
  • mCRPC Metastatic castration-resistant prostate cancer
  • Darolutamide is an AR inhibitor (ARi) that targets the C-terminal ligand binding domain (LBD) of the AR.
  • ARi an AR inhibitor
  • LBD C-terminal ligand binding domain
  • a drug to be studied in combination with darolutamide, Compound A is a novel, N-terminal domain (NTD) ARi that can block AR transcriptional activity even in the presence of LBD-driven resistance.
  • NTD N-terminal domain
  • Dual blockade of the AR by darolutamide and Compound may thus show effective suppression of the AR by simultaneously targeting both ends of the AR and in addition may delay the development of AR C-terminal-driven resistance mechanisms such as AR V7 splice variants.
  • the present disclosure thus relates to pharmaceutical combinations and/or compositions comprising Compound A and darolutamide.
  • the pharmaceutical combinations and/or composition of the present disclosure is useful for treating various diseases and conditions including, but not limited to, cancer.
  • the pharmaceutical combinations and/or composition of the present disclosure is useful for treating prostate cancer.
  • the pharmaceutical combinations and/or composition of the present disclosure can be used for administering to a subject or patient at various stages of the disease or treatment regimen of the subject or patient.
  • the pharmaceutical combinations and/or composition of the present disclosure can be administered during advanced or metastatic cancer.
  • the pharmaceutical combinations and/or composition of the present disclosure can be administered before or after the patient undergoes prostatectomy for any localized prostate cancer.
  • the pharmaceutical combinations and/or composition of the present disclosure can be administered as a neoadjuvant therapy, i.e., before any chemotherapy, before any radiation therapy, any hormone therapy, and any surgery which would be considered the main or primary treatment to the subject or patient.
  • the main or primary treatment is surgery.
  • the surgery is a prostatectomy.
  • the prostatectomy may include partial or complete removal of the prostate.
  • the present disclosure relates to pharmaceutical compositions and combinations comprising Compound A or a pharmaceutically acceptable salt, or solvate, thereof, and at least darolutamide.
  • the composition and/or combination comprises a third therapeutically active agent.
  • the present disclosure relates to a pharmaceutical combination comprising a therapeutically effective amount of a first therapeutically active agent Compound A or a pharmaceutically acceptable salt, or solvate, thereof, and a darolutamide in at least one pharmaceutical composition.
  • the pharmaceutical combination relates to Compound A or a pharmaceutically acceptable salt, or solvate thereof, and darolutamide.
  • the present disclosure relates to methods of treating cancer or a condition associated with cell proliferation, comprising administering Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof to a subject in need thereof.
  • the present disclosure also relates to methods of treating cancer, comprising administering Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof to a subject in need thereof, wherein Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at a daily dose in the range of about 50 mg to about 2,000 mg.
  • the present disclosure also relates to methods of treating prostate cancer, comprising administering Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof to a subject in need thereof.
  • the present disclosure also relates to methods of treating non-metastatic castrationresistant prostate cancer, comprising administering Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof to a subject in need thereof.
  • cancer is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, or salivary gland carcinoma.
  • the method is for treating prostate cancer.
  • prostate cancer is primary or localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, advanced prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, and hormone-sensitive prostate cancer.
  • the prostate cancer is metastatic castration-resistant prostate cancer.
  • the prostate cancer is non-metastatic castration-resistant prostate cancer.
  • the prostate cancer expresses full-length androgen receptor or truncated androgen receptor splice variant.
  • prostate cancer is resistant to at least one anti-androgen therapeutic agent other than Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the antiandrogen therapeutic agent is abiraterone acetate, enzalutamide, apalutamide, or darolutamide.
  • prostate cancer is resistant to enzalutamide monotherapy.
  • the method is for treating breast cancer.
  • the breast cancer is triple negative breast cancer.
  • the present disclosure also relates to methods of reducing, inhibiting, or ameliorating cell proliferation, comprising administering Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof to a subject in need thereof.
  • the reducing, inhibiting, or ameliorating in the method disclosed herein is in vivo.
  • the reducing, inhibiting, or ameliorating is in vitro.
  • the cells in the method disclosed herein are cancer cells.
  • the cancer cells are prostate cancer cells.
  • the prostate cancer cells are cells of primary/localized prostate cancer (newly diagnosed or early stage), locally advanced prostate cancer, recurrent prostate cancer (e.g., prostate cancer which was not cured with primary therapy), metastatic prostate cancer, advanced prostate cancer (e.g., after castration for recurrent prostate cancer), metastatic castration-resistant prostate cancer (mCRPC), non-metastatic castration-resistant prostate cancer (nmCRPC), or hormonesensitive prostate cancer.
  • the prostate cancer cells are cells of a metastatic castration-resistant prostate cancer.
  • the prostate cancer cells are androgen-dependent prostate cancer cells or androgen-independent prostate cancer cells.
  • the cancer cells are breast cancer cells.
  • the condition or disease associated with cell proliferation is cancer.
  • the cancer is selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration.
  • the condition or disease is prostate cancer.
  • prostate cancer is selected from primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, metastatic castrationresistant prostate cancer (mCRPC), non-metastatic castration-resistant prostate cancer (nmCRPC), or hormone-sensitive prostate cancer.
  • the prostate cancer is a metastatic castration-resistant prostate cancer.
  • the prostate cancer is a non-metastatic castration-resistant prostate cancer.
  • the prostate cancer is an androgen-dependent prostate cancer cells or an androgen-independent prostate cancer.
  • the condition or disease is breast cancer.
  • the breast cancer is AR-positive triple negative breast cancer.
  • the present disclosure also relates to methods for reducing or preventing tumor growth, comprising contacting tumor cells with Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • reducing or preventing tumor growth includes reduction in tumor volume. In one embodiment, reducing or preventing tumor growth includes complete elimination of tumors. In one embodiment, reducing or preventing tumor growth includes stopping or halting the existing tumor to grow. In one embodiment, reducing or preventing tumor growth includes reduction in the rate of tumor growth. In one embodiment, reducing or preventing tumor growth includes reduction in the rate of tumor growth such that the rate of tumor growth before treating a patient with the methods disclosed herein (rl) is faster than the rate of tumor growth after said treatment (r2) such that rl > r2. [0115] In one embodiment, the reducing or preventing in the methods disclosed herein is in vivo. In another embodiment, the treating is in vitro.
  • the tumor cell in the method disclosed herein is selected from prostate cancer, breast cancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma.
  • the tumor cells are prostate cancer tumor cells.
  • the prostate cancer tumor cells are tumor cells of primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), non-metastatic castration-resistant prostate cancer (nmCRPC), or hormone-sensitive prostate cancer.
  • the prostate cancer is a metastatic castration-resistant prostate cancer.
  • the prostate cancer is a non-metastatic castration-resistant prostate cancer.
  • the prostate cancer is androgen-dependent prostate cancer or androgenindependent prostate cancer.
  • the tumor cells are is breast cancer tumor cells.
  • the present disclosure also relates to methods for modulating androgen receptor (AR), comprising administering Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
  • modulating androgen receptor (AR) activity is in a mammalian cell.
  • modulating androgen receptor (AR) can be in a subject in need thereof (e.g., a mammalian subject) and for treatment of any of the described conditions or diseases.
  • the modulating AR is binding to AR. In other embodiments, the modulating AR is inhibiting AR.
  • the modulating AR is modulating AR N-terminal domain (NTD). In one embodiment, the modulating AR is modulating AR NTD and AR ligand-binding domain (LBD). In one embodiment, the modulating AR is binding to AR NTD. In one embodiment, the modulating AR is binding to AR NTD and AR LBD. In other embodiments, the modulating AR is inhibiting AR NTD. In other embodiments, the modulating AR is inhibiting AR NTD and AR LBD. In some embodiments, modulating the AR is inhibiting transactivation of androgen receptor N-terminal domain (NTD).
  • NTD androgen receptor N-terminal domain
  • modulating androgen receptor (AR) activity is for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, age related macular degeneration, and combinations thereof.
  • the indication is prostate cancer.
  • the prostate cancer is primary /localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), non-metastatic castration-resistant prostate cancer (nmCRPC), or hormone-sensitive prostate cancer (also known as castrationsensitive prostate cancer).
  • the prostate cancer is the prostate cancer is selected from one or more of primary or localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, advanced prostate cancer, metastatic prostate cancer, metastatic and non-metastatic castration-resistant prostate cancer, and metastatic and non- metastatic hormone-sensitive prostate cancer.
  • the prostate cancer is androgen dependent prostate cancer.
  • the spinal and bulbar muscular atrophy is Kennedy’s disease.
  • the cancer is prostate cancer
  • the methods of treatment include administering to a subject or patient at various stages of the disease or treatment regimen of the subject or patient.
  • the methods include treatment during advanced or metastatic cancer.
  • the methods include treatment before or after the patient undergoes prostatectomy for any localized prostate cancer.
  • the pharmaceutical combinations and/or composition of the present disclosure can be administered as a neoadjuvant therapy, i.e., before any chemotherapy, before any radiation therapy, any hormone therapy, and any surgery which would be considered the main or primary treatment to the subject or patient.
  • the main or primary treatment is surgery.
  • the surgery is a prostatectomy.
  • the prostatectomy is partial or complete removal of the prostate.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at a daily dose in the range of about 50 mg to about 2,000 mg, including all values and subranges therebetween.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at a daily dose of about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, about 1,100 mg, about 1,200 mg, about 1,300 mg, about 1,400 mg, about 1,500 mg, about 1,600 mg, about 1,700 mg, or about 1,800 mg, including all values therebetween.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered once a day.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at once a day at a dose of about 200 mg, about 400 mg, about 600 mg, about 800 mg, about 1000 mg, about 1200 mg, about 1400 mg, about 1600 mg, about 1800 mg or about 2,000 mg, including all values therebetween.
  • a daily dosage amount of Compound A is about 100 mg QD (once a day), about 150 mg QD, about 200 mg QD, about
  • a daily dosage amount of Compound A is about 200 mg QD, about 400 mg QD, about 600 mg QD, about 800 mg QD, about 1000 mg QD, about 1200 mg QD, about 1400 mg QD, about 1600 mg QD, about 1800 mg QD or about 2000 mg QD, or any values therebetween.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered twice a day.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered twice a day at a daily dose of about 200 mg, about 400 mg, about 600 mg, about 800 mg, about 1,000 mg, about 1,200 mg, about 1,400 mg, 1,600 mg, 1,400 mg, 1,800 mg, 2,000 mg, or about 2,200 mg, including all values therebetween.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at about 200 mg twice a day, about 400 mg twice a day, about 600 mg twice a day, about 800 mg twice a day, or about 1,000 mg twice a day, including all values therebetween. In some embodiments, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at about 400 mg twice a day or about 600 mg twice a day. In some embodiments, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered at a dose in the range between about 400 mg twice a day to about 600 mg twice a day.
  • a daily dosage amount of Compound A is about 100 mg BID (twice a day), about 150 mg BID, about 200 mg BID, about 250 mg BID, about 300 mg BID, about 350 mg BID, about 400 mg BID, about 450 mg BID, about 500 mg BID, about 550 mg BID, about 600 mg BID, about 650 mg BID, about 700 mg BID, about 750 mg BID, about 800 mg BID, about 850 mg BID, about 900 mg BID, about 950 mg BID, about 1,000 mg BID, about 1,050 mg BID, about 1,100 mg BID, about 1,150 mg BID, or about 1,200 mg BID, or any values therebetween.
  • a daily dosage amount of Compound A is about 400 mg BID, about 600 mg BID, or about 800 mg BID, or any values therebetween.
  • the daily dosage amount of darolutamide is about 200 mg to about 3000 mg, or about 300 mg to about 2000 mg, or about 400 mg to about 1500 mg, or about 700 mg to about 1200 mg, or any values or subranges therebetween.
  • the daily dosage amount of darolutamide is about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, about 1,050 mg, about 1,100 mg, about 1,150 mg, about 1,200 mg, about 1,250 mg, about 1,300 mg, about 1,350 mg, about 1,400 mg, about 1,450 mg, about 1,500 mg, about 1,550 mg, about 1,600 mg, about 1,650 mg, about 1,700 mg, about 1,750 mg, about 1,800 mg, about 1,850 mg, about 1,900 mg, about 1,950 mg, about 2,000 mg, about 2,050 mg, about 2,100 mg, about 2,150 mg, about 2,200 mg, about 2,250 mg, about 2,300 mg, about 2,350 mg, about 2,400 mg, about 2,450 mg, about 2,500 mg, about 2,550 mg,
  • the daily dosage amount of darolutamide is about 1200 mg. In one embodiment, the daily dose of darolutamide is administered once a day, or divided into twice-a-day or three times a day doses. In one embodiment, the daily dose of darolutamide is provided in one tablet or one capsule, or the daily dose is divided into two, three, four, five, or six tablets or capsules. In a specific embodiment, 600 mg of darolutamide is provided in each administration. In another embodiment, the administration is provided twice daily.
  • the amount of darolutamide per a dosage form is about 20 mg to about 2000 mg, or about 50 mg to about 1000 mg, or about 100 mg to about 500 mg, or about 200 mg to about 300 mg, or any values or subranges therebetween.
  • the amount of darolutamide per a dosage form is about 5 mg, about 10 mg, about 15 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 150 mg, about 200 mg, about 200 mg to about 3000 mg, or about 300 mg to about 2000 mg, or about 400 mg to about 1500 mg, or about 700 mg to about 1200 mg, or any values or subranges therebetween.
  • the amount per a dosage form is about 600 mg.
  • the dosage form is separated into two pharmaceutical compositions, and specifically, into two tablets.
  • the an amount of darolutamide per one tablet or one capsule form is about 20 mg to about 2000 mg, or about 50 mg to about 1000 mg, or about 100 mg to about 500 mg, or about 200 mg to about 300 mg, or any values or subranges therebetween.
  • the amount of darolutamide per one tablet or one capsule is about 5 mg, about 10 mg, about 15 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 150 mg, about 200 mg, about 300 mg, about 200 mg to about 3000 mg, or about 300 mg to about 2000 mg, or about 400 mg to about 1500 mg, or about 700 mg to about 1200 mg, or any values or subranges therebetween. In one embodiment, the amount of darolutamide per one tablet or one capsule is about 300 mg.
  • Compound A and darolutamide are in the same composition. In one embodiment, Compound A and darolutamide in the same composition is formulated together or formulated separately. In one embodiment, Compound A and darolutamide are in different compositions. In one embodiment, the composition comprising darolutamide comprises one or more pharmaceutically acceptable carrier or excipient selected from calcium hydrogen phosphate, croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone K 30, hypromellose 15 cP, macrogol 3350, or titanium dioxide. In one embodiment, the composition comprising darolutamide is a tablet. In one embodiment, the tablet comprising darolutamide has a film-coat. Examples of formulations of darolutamide are disclosed in WO2019/032840 Al, the disclosures of which are hereby incorporated by reference in their entirety.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject for at least one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, or ten weeks.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject for at least about 4 weeks. In some embodiments, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject for at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, or at least about 20 weeks.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to a subject for at least one cycle, two cycles, three cycles, four cycles, five cycles, six cycles, seven cycles, eight cycles, nine cycles, ten cycles, 11 cycles, 12 cycles, 13 cycles, 14 cycles, 15 cycles, 16 cycles, 17 cycles, 18 cycles, 19 cycles, or 20 cycles.
  • one cycle is about 7 days, about 14 days, abut 21 days, about 28 days, or about 35 days. In some embodiments, one cycle is about 28 days.
  • the administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof does not produce a Grade 3 treatment-related adverse event (TRAE) to the subject.
  • TEE Treatment-related adverse event
  • Compound A is administered with darolutamide in combination within the cycles and dosing schedules described herein.
  • the subject received at least one line of prior therapy for treating the prostate cancer. In some embodiments, the subject received one to fifteen lines of prior therapy for treating the prostate cancer. In some embodiments, the subject received one to ten lines of prior therapy for treating the prostate cancer. In some embodiments, the subject received one to three lines of prior therapy for treating the prostate cancer. In some embodiments, the subject received three or less lines of prior therapy for treating the prostate cancer.
  • the subject has mCRPC and failed standard of care therapy prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the subject was previously treated with at least one anti-androgen therapeutic agent or chemotherapy prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the previously treated antiandrogen therapeutic agent is abiraterone acetate, enzalutamide, apalutamide, or darolutamide.
  • the subject was previously treated with abiraterone acetate prior to monotherapeutic administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the subject was previously treated with enzalutamide prior to monotherapeutic administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the subject was previously treated with (i) abiraterone acetate and (ii) enzalutamide, darolutamide or apalutamide, prior to monotherapeutic administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the subject was previously treated with darolutamide or apalutamide prior to monotherapeutic administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the subject was previously treated with at least one line of chemotherapy prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof. In some embodiments, the subject was treated with one line of chemotherapy or no chemotherapy prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof. In some embodiments, the subject was treated with no chemotherapy prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the subject had neuron specific enolase (NSE) value of about 10 ng/mL or greater prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • NSE neuron specific enolase
  • the subject hadNSE value of>10 ng/mL or greater prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the subject had NSE value of ⁇ 10 ng/mL or greater prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof. In some embodiments of the methods for treating prostate cancer as described herein, the subject had NSE value of ⁇ 5 ng/mL or greater prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the subject has visceral metastases. In some embodiments, the subject does not have visceral metastases.
  • the subject has lung, liver, and/or brain metastases.
  • the subject received three or less lines of prior therapy for treating the prostate cancer and does not have visceral metastases. In some embodiments of the methods described herein, the subject received three or less lines of prior therapy and no prior chemotherapy for treating the prostate cancer. In some embodiments of the methods described herein, the subject received no prior chemotherapy for treating the prostate cancer and does not have visceral metastases. In some embodiments of the methods described herein, the subject received three or less lines of prior therapy and no prior chemotherapy for treating the prostate cancer, and does not have visceral metastases.
  • the subject has prostate cancer naive to one or more second generation anti-androgens.
  • the second generation anti-androgen is abiraterone acetate, enzalutamide, apalutamide or darolutamide.
  • the subject received no prior therapy for treating the prostate cancer.
  • the subject comprises one or more androgen receptor-associated molecular alterations.
  • the subject comprises one or more alterations in a protein associated with androgen receptor (AR).
  • the molecular alteration is one or more gene amplifications, one or more genetic mutations, and/or one or more structural variations.
  • the alteration relates to alteration in genetic copy number, such as amplification, gain deletion or deep deletion.
  • the androgen receptor- associated molecular alteration is androgen receptor amplification or gain, androgen receptor mutation, or androgen receptor structural alteration.
  • the subject has as least one mutation in a gene or protein associated with AR.
  • the mutation associated with AR is selected from one or more of the group consisting of missense, frameshift, stopgain, non-frameshift, and splice site.
  • the mutant form is at least one point mutation.
  • the point mutation is on only one allele.
  • the point mutation is on two alleles.
  • the mutation is on AR, NCOA2, FOXA1, and/or FOXP1.
  • the subject has as least one structural variation associated with AR.
  • the structural variant (SV) is selected from one or more of the group consisting of duplication, deletion, insertion, inversion, translocation, and combinations thereof.
  • the SV associated with AR has a copy number variation (CNV) of 1 or greater than 2.
  • the SV has CNV1, CNV3, CNV4, CNV5, CNV6, CNV7, CNV8, CNV9, or CNV10.
  • the CNV is due to gene amplification, gene gain, gene deletion and/or gene deep deletion.
  • the CNV is due to copy number (CN) amplification, CN gain, CN deletion and/or CN deep deletion.
  • the subject has one or more SVs in the protein associated with AR.
  • the subject has one or more CNV with AR due to CN amplification or CN gain.
  • the at least one structural variation associated with AR is copy number variation number of greater than 2, gene amplification, and/or chromosome translocation.
  • the subject comprises an amplification of androgen receptor (AR) genes.
  • the subject comprises gain of function of AR genes.
  • the subject comprises truncation of AR genes.
  • the subject harbors AR mutation selected from one or more of p.L702H, p.W742C, p.H875Y, or p.T878A/S.
  • the subject harbors one or more AR point mutations.
  • the point mutation is on only one allele. In another embodiment, the point mutation is on two alleles.
  • the subject comprises one or more non-androgen receptor-associated molecular alterations.
  • the subject comprises one or more alterations in a protein associated with non-androgen receptor proteins.
  • the molecular alteration is one or more gene amplifications, one or more genetic mutations, and/or one or more structural variations.
  • the alteration relates to alteration in genetic copy number, such as amplification, gain deletion or deep deletion.
  • the non-androgen receptor-associated molecular alteration is androgen receptor amplification or gain, androgen receptor mutation, or androgen receptor structural alteration.
  • the non-androgen receptor-associated molecular alteration is associated with: cell cycle regulation, PI3K pathway, WNT pathway, DNA repair pathway, or chromatin modifier.
  • the non-androgen receptor-associated molecular alteration is in a protein selected from SPOP, NKX3-1, or ZFHX3.
  • the molecular alteration is in TP53 or Rbl. In some embodiments, the molecular alteration is loss of TP53 or loss of Rbl.
  • the alteration in a protein associated with cell cycle regulation pathway is one or more mutations in a protein associated with the cell cycle regulation pathway or one or more structural variations in a protein associated with the cell cycle regulation pathway.
  • the subject has as least one mutation associated with the cell cycle regulation.
  • the mutation associated with the cell cycle regulation is selected from one or more of the group consisting of missense, frameshift, stopgain, non-frameshift, and splice site.
  • the mutant form is at least one point mutation.
  • the point mutation is on only one allele. In another embodiment, the point mutation is on two alleles.
  • the protein associated with the cell cycle regulation in the subject is a wild type.
  • the protein associated with the cell cycle regulation is TP53, RBI, MDM2, CDK4, CDK6, CDKN2A, CDKN1B, MYC, or CCND1.
  • the mutation association with the cell cycle regulation is selected from one or more of the group consisting of TP53, RBI, MDM2, CDK4, CDK6, CDKN2A, CDKN1B, MYC, and CCND1.
  • the subject harbors mutations in one or more genes selected from the group consisting of TP53, RBI, MDM2, CDK4, CDK6, CDKN2A, CDKN1B, MYC, and CCND1.
  • the subject has at least one structural variation in a protein associated with the cell cycle regulation.
  • the structural variant (SV) is selected from one or more of the group consisting of duplication, deletion, insertion, inversion, translocation, and combinations thereof.
  • the SV associated with the cell cycle regulation has a copy number variation (CNV) of 1 or greater than 2.
  • the SV has CNV1, CNV3, CNV4, CNV5, CNV6, CNV7, CNV8, CNV9, or CNV10.
  • the CNV is due to gene amplification, gene gain, gene deletion and/or gene deep deletion.
  • the CNV is due to copy number (CN) amplification, CN gain, CN deletion and/or CN deep deletion.
  • the at least one structural variation in a protein associated with the cell cycle regulation is copy number variation number of greater than 2, gene amplification, and/or chromosome translocation.
  • the alteration is associated with PI3K pathway in one or more mutations associated with the PI3K pathway or one or more structural variations associated with the PI3K pathway.
  • the subject has as least one mutation associated with the PI3K pathway.
  • the mutation in a protein associated with the PI3K pathway is selected from one or more of the group consisting of missense, frameshift, stopgain, non-frameshift, and splice site.
  • the mutant form of protein is in at least one point mutation.
  • the point mutation is on only one allele. In another embodiment, the point mutation is on two alleles.
  • the protein associated with the PI3K pathway in the subject is a wild type.
  • the protein associated with the PI3K pathway is PTEN, PIK3R1, PIK3CA, or PIK3CB.
  • the mutated protein associated with the PI3K pathway is selected from one or more of the group consisting of PTEN, PIK3R1, PIK3CA, and PIK3CB.
  • the subject harbors mutations in one or more genes selected from the group consisting of PTEN, PIK3R1, PIK3CA, and PIK3CB.
  • the mutation associated with the PI3K pathway further comprises one or more structural variations.
  • the subject has as least one structural variation associated with the PI3K pathway.
  • the structural variant (SV) is selected from one or more of the group consisting of duplication, deletion, insertion, inversion, translocation, and combinations thereof.
  • the SV of the protein associated with the PI3K pathway has a copy number variation (CNV) of 1 or greater than 2.
  • the SV has CNV1, CNV3, CNV4, CNV5, CNV6, CNV7, CNV8, CNV9, or CNV10.
  • the CNV is due to gene amplification, gene gain, gene deletion and/or gene deep deletion.
  • the CNV is due to copy number (CN) amplification, CN gain, CN deletion and/or CN deep deletion.
  • the subject has one or more CNV associated with the PI3K pathway due to CN amplification or CN gain.
  • the at least one structural variation in a protein associated with the PI3K pathway is copy number variation number of greater than 2, gene amplification, and/or chromosome translocation.
  • the alteration is associated with WNT pathway.
  • the subject has as least one mutation associated with the WNT pathway.
  • the mutation associated with the WNT pathway is selected from one or more of the group consisting of missense, frameshift, stopgain, non-frameshift, and splice site.
  • the mutant is at least one point mutation.
  • the point mutation is on only one allele.
  • the point mutation is on two alleles.
  • the protein associated with the WNT pathway in the subject is a wild type.
  • the protein associated with the WNT pathway is APC, CTNNB1, or RNF43.
  • the mutated protein associated with the WNT pathway is selected from one or more of the group consisting of APC, CTNNB1, and RNF43.
  • the subject harbors mutations in one or more genes selected from the group consisting of APC, CTNNB1, and RNF43.
  • the mutation associated with the WNT pathway further comprises one or more structural variations.
  • the subject has as least one structural variation associated with the WNT pathway.
  • the structural variant (SV) is selected from one or more of the group consisting of duplication, deletion, insertion, inversion, translocation, and combinations thereof.
  • the SV associated with the WNT pathway has a copy number variation (CNV) of 1 or greater than 2.
  • the SV has CNV1, CNV3, CNV4, CNV5, CNV6, CNV7, CNV8, CNV9, or CNV10.
  • the CNV is due to gene amplification, gene gain, gene deletion and/or gene deep deletion.
  • the CNV is due to copy number (CN) amplification, CN gain, CN deletion and/or CN deep deletion.
  • the at least one structural variation associated with the WNT pathway is copy number variation number of greater than 2, gene amplification, and/or chromosome translocation.
  • the alteration in a protein associated with DNA repair pathway is one or more mutations associated with the DNA repair pathway or one or more structural variations associated with the DNA repair pathway.
  • the subject has as least one mutation associated with the DNA repair pathway.
  • the mutation associated with the DNA repair pathway is selected from one or more of the group consisting of missense, frameshift, stopgain, non-frameshift, and splice site.
  • the mutant form of protein is in at least one point mutation.
  • the point mutation is on only one allele.
  • the point mutation is on two alleles.
  • the protein associated with the DNA repair pathway in the subject is a wild type.
  • the protein associated with the DNA repair pathway is APC, CTNNB 1 , or RNF43.
  • the mutated protein associated with the DNA repair pathway is selected from one or more of the group consisting of APC, CTNNB 1, and RNF43.
  • the subject harbors mutations in one or more genes selected from the group consisting of APC, CTNNB1, and RNF43.
  • the subject has as least one structural variation associated with the DNA repair pathway.
  • the structural variant (SV) is selected from one or more of the group consisting of duplication, deletion, insertion, inversion, translocation, and combinations thereof.
  • the SV of the protein associated with the DNA repair pathway has a copy number variation (CNV) of 1 or greater than 2.
  • the SV has CNV1, CNV3, CNV4, CNV5, CNV6, CNV7, CNV8, CNV9, or CNV10.
  • the CNV is due to gene amplification, gene gain, gene deletion and/or gene deep deletion.
  • the CNV is due to copy number (CN) amplification, CN gain, CN deletion and/or CN deep deletion.
  • the at least one structural variation associated with the DNA repair pathway is copy number variation number of greater than 2, gene amplification, and/or chromosome translocation.
  • the alteration associated with chromatin modifier is one or more mutations associated with the chromatin modifier or one or more structural variations associated with the chromatin modifier.
  • the subject has as least one mutation associated with the chromatin modifier.
  • the mutation associated with the chromatin modifier is selected from one or more of the group consisting of missense, frameshift, stopgain, non-frameshift, and splice site.
  • the mutant form of protein is in at least one point mutation.
  • the point mutation is on only one allele. In another embodiment, the point mutation is on two alleles.
  • the protein associated with the chromatin modifier in the subject is a wild type.
  • the protein associated with the chromatin modifier is KMT2C, KMT2D, CHD1, or KDM6A.
  • the mutated protein associated with the chromatin modifier is selected from one or more of the group consisting of KMT2C, KMT2D, CHD1, and KDM6A.
  • the subject harbors mutations in one or more genes selected from the group consisting of KMT2C, KMT2D, CHD and KDM6A.
  • the mutated protein associated with the chromatin modifier further comprises one or more structural variations.
  • the subject has as least one structural variation in a protein associated with the chromatin modifier.
  • the structural variant (SV) is selected from one or more of the group consisting of duplication, deletion, insertion, inversion, translocation, and combinations thereof.
  • the SV of the protein associated with the chromatin modifier has a copy number variation (CNV) of 1 or greater than 2.
  • the SV has CNV1, CNV3, CNV4, CNV5, CNV6, CNV7, CNV8, CNV9, or CNV10.
  • the CNV is due to gene amplification, gene gain, gene deletion and/or gene deep deletion.
  • the CNV is due to copy number (CN) amplification, CN gain, CN deletion and/or CN deep deletion.
  • the at least one structural variation in a protein associated with the chromatin modifier is copy number variation number of greater than 2, gene amplification, and/or chromosome translocation.
  • the alteration in SPOP is one or more mutations or one or more structural variations.
  • the subject has a mutation in SPOP.
  • the mutation is selected from one or more of the group consisting of missense, frameshift, stopgain, non-frameshift, and splice site.
  • the mutant form SPOP is in at least one point mutation.
  • the point mutation is on only one allele.
  • the point mutation is on two alleles.
  • SPOP in the subject is a wild type.
  • the subject harbors mutations in SPOP.
  • the mutated SPOP further comprises one or more structural variations.
  • the subject has as least one structural variation in SPOP.
  • the structural variant (SV) is selected from one or more of the group consisting of duplication, deletion, insertion, inversion, translocation, and combinations thereof.
  • the SV of the protein associated with the chromatin modifier has a copy number variation (CNV) of 1 or greater than 2.
  • the SV has CNV1, CNV3, CNV4, CNV5, CNV6, CNV7, CNV8, CNV9, or CNV10.
  • the CNV is due to gene amplification, gene gain, gene deletion and/or gene deep deletion.
  • the CNV is due to copy number (CN) amplification, CN gain, CN deletion and/or CN deep deletion.
  • the at least one structural variation in a protein associated with the chromatin modifier is copy number variation number of greater than 2, gene amplification, and/or chromosome translocation.
  • the alteration in NKX3-1 is one or more mutations or one or more structural variations.
  • the subject has a mutation in NKX3-1.
  • the mutation is selected from one or more of the group consisting of missense, frameshift, stopgain, non-frameshift, and splice site.
  • the mutant form NKX3-1 is in at least one point mutation.
  • the point mutation is on only one allele.
  • the point mutation is on two alleles.
  • NKX3-1 in the subject is a wild type.
  • the subject harbors mutations in NKX3-1.
  • the mutated SPOP further comprises one or more structural variations.
  • the subject has as least one structural variation in NKX3-1.
  • the structural variant (SV) is selected from one or more of the group consisting of duplication, deletion, insertion, inversion, translocation, and combinations thereof.
  • the SV of the protein associated with the chromatin modifier has a copy number variation (CNV) of 1 or greater than 2.
  • the SV has CNV1, CNV3, CNV4, CNV5, CNV6, CNV7, CNV8, CNV9, or CNV10.
  • the CNV is due to gene amplification, gene gain, gene deletion and/or gene deep deletion.
  • the CNV is due to copy number (CN) amplification, CN gain, CN deletion and/or CN deep deletion.
  • the at least one structural variation in a protein associated with the chromatin modifier is copy number variation number of greater than 2, gene amplification, and/or chromosome translocation.
  • the alteration in ZFHX3 is one or more mutations or one or more structural variations.
  • the subject has a mutation in ZFHX3.
  • the mutation is selected from one or more of the group consisting of missense, frameshift, stopgain, non-frameshift, and splice site.
  • the mutant form ZFHX3 is in at least one point mutation.
  • the point mutation is on only one allele.
  • the point mutation is on two alleles.
  • ZFHX3 in the subject is a wild type.
  • the subject harbors mutations in ZFHX3.
  • the mutated SPOP further comprises one or more structural variations.
  • the subject has as least one structural variation in ZFHX3.
  • the structural variant (SV) is selected from one or more of the group consisting of duplication, deletion, insertion, inversion, translocation, and combinations thereof.
  • the SV of associated with the chromatin modifier has a copy number variation (CNV) of 1 or greater than 2.
  • the SV has CNV1, CNV3, CNV4, CNV5, CNV6, CNV7, CNV8, CNV9, or CNV10.
  • the CNV is due to gene amplification, gene gain, gene deletion and/or gene deep deletion.
  • the CNV is due to copy number (CN) amplification, CN gain, CN deletion and/or CN deep deletion.
  • the at least one structural variation in a protein associated with the chromatin modifier is copy number variation number of greater than 2, gene amplification, and/or chromosome translocation.
  • the subject harbors mutations in RBI. In some embodiments, the subject harbors mutations in TP53. In some embodiments, the subject harbors mutations in MYC. In some embodiments, the subject harbors mutations in PI3K pathway genes. In some embodiments, the subject harbors mutations in WNT pathway genes. In some embodiments, the subject harbors mutations in AR-associated genes. In some embodiments, the subject harbors mutations in Chromatin modifier genes. In some embodiments, the subject harbors mutations in DNA repair genes. In some embodiments, the subject harbors mutations in SPOP.
  • the subject harbors mutations in NKX3-P In some embodiments, the subject harbors mutations in ZFHX3. In some embodiments, the mutation is missense, frameshift, stopgain, non- frameshift, or splice site.
  • the subject harbors alterations in RBI. In some embodiments, the subject harbors alterations in TP53. In some embodiments, the subject harbors alterations in MYC. In some embodiments, the subject harbors alterations in PI3K pathway genes. In some embodiments, the subject harbors alterations in WNT pathway genes. In some embodiments, the subject harbors alterations in AR-associated genes. In some embodiments, the subject harbors alterations in Chromatin modifier genes. In some embodiments, the subject harbors alterations in DNA repair genes. In some embodiments, the alteration is amplification, gain, deletion, deep deletion, or a structural variant.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject for at least about 4 weeks. In some embodiments, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject for at least about 12 weeks. In some embodiments, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject for about 4 weeks to about 12 weeks, including all values and subranges therebetween, before the subject begins standard of care treatment for prostate cancer.
  • the subject has histologically, pathologically, or cytologically confirmed prostate cancer. In some embodiments of the methods of the present disclosure, the subject has histologically, pathologically, or cytologically confirmed prostate cancer without small cell or neuroendocrine features.
  • the subject has PSA levels >1 ng/mL while on androgen deprivation therapy (ADT) or following surgical castration.
  • ADT androgen deprivation therapy
  • the subject has PSA levels >1 ng/mL while on ADT or following surgical castration and documentation of three rising PSA levels taken at least 1 week apart.).
  • the subject has castration-resistant prostate cancer demonstrated during continuous androgen deprivation therapy (ADT)/post orchiectomy, defined as 3 consecutive rises of PSA, at least 1 week apart with the last PSA > 2 ng/mL.
  • ADT continuous androgen deprivation therapy
  • the subject has one or more bone lesions on bone scan or by soft tissue disease observed by CT/MRI.
  • the subject has nodal or visceral progression.
  • the subject is on ADT with luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy.
  • LHRH luteinizing hormone-releasing hormone
  • the subject has a history of bilateral orchiectomy with castrate level testosterone.
  • the subject has serum testosterone ⁇ 1.73 nmol/L (50 ng/dL).
  • the method provides increase in the subject’s plasma or serum low-density lipoprotein (LDL) cholesterol level.
  • the subject’s plasma or serum LDL cholesterol level increases in the range of about 5% to about 60% compared to the subject’s plasma or serum LDL cholesterol level prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the method provides reduction or stabilization in the subject’s prostate-specific antigen (PSA) level compared to the subject’s PSA level prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • PSA prostate-specific antigen
  • the method provides PSA90 (prostate-specific antigen decline of >90%) response rate of about 30% or greater, about 40% or greater, about 50% or greater, about 60% or greater, about 65% or greater, about 70% or greater, or about 75% or greater, including all values therebetween. In some embodiments, the method provides PSA90 response rate of about 60% or greater or about 65% or greater.
  • the method provides PSA30 (PSA decline of >30%) response rate of about 30% or greater, about 40% or greater, about 50% or greater, about 60% or greater, about 65% or greater, about 70% or greater, about 75% or greater, about 80% or greater, about 85% or greater, or about 90% or greater, including all values therebetween.
  • the method provides PSA50 response rate of about 60% or greater, about 70% or greater, or about 80% or greater.
  • the method provides PSA50 (PSA decline of >50%) response rate of about 30% or greater, about 40% or greater, about 50% or greater, about 60% or greater, about 65% or greater, about 70% or greater, about 75% or greater, about 80% or greater, about 85% or greater, or about 90% or greater, including all values therebetween. In some embodiments, the method provides PSA50 response rate of about 60% or greater, about 70% or greater, or about 80% or greater.
  • the method provides PSA ⁇ 2 ng/mL rate of about 10% or greater, about 15% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 35% or greater, about 40% or greater, about 45% or greater, about 50% or greater, about 55% or greater, or about 60% or greater, including all values therebetween.
  • the method provides AUC0-24 (area under the concentration-time curve from 0 to 24 hours) for Compound A in the range of about 50,000 ng hr/mL to about 800,000 ng hr/mL, including all subranges and values therebetween. In some embodiments, the method provides AUC0-24 for Compound A in the range of about 75,000 ng hr/mL to about 750,000 ng hr/mL, including all subranges and values therebetween. In some embodiments, the method provides AUC0-24 for Compound A in the range of about 100,000 ng hr/mL to about 700,000 ng hr/mL, including all subranges and values therebetween.
  • the method provides AUC0-24 for Compound A in the range of about 125,000 ng hr/mL to about 700,000 ng hr/mL, including all subranges and values therebetween. In some embodiments, the method provides AUC0-24 for Compound A in the range of about 150,000 ng hr/mL to about 700,000 ng hr/mL, including all subranges and values therebetween. In some embodiments, the method provides AUC0-24 for Compound A in the range of about 150,000 ng hr/mL to about 650,000 ng hr/mL, including all subranges and values therebetween.
  • the method provides AUC0-24 for Compound A in the range of about 150,000 ng hr/mL to about 600,000 ng hr/mL, including all subranges and values therebetween. In some embodiments, the method provides AUC0-24 for Compound A in the range of about 150,000 ng hr/mL to about 550,000 ng hr/mL, including all subranges and values therebetween. In some embodiments, the method provides AUC0-24 for Compound A in the range of about 150,000 ng hr/mL to about 400,000 ng hr/mL, including all subranges and values therebetween.
  • the method provides AUC0-24 for Compound A in the range of about 150,000 ng hr/mL to about 350,000 ng hr/mL, including all subranges and values therebetween. In some embodiments, the method provides AUC0-24 for Compound A in the range of about 150,000 ng hr/mL to about 300,000 ng hr/mL, including all subranges and values therebetween. In some embodiments, the method provides AUC0-24 for Compound A of at least 75,000 ng hr/mL. In some embodiments, the method provides AUC0-24 for Compound A of at least 90,000 ng hr/mL.
  • the method provides AUC0-24 for Compound A of at least 100,000 ng hr/mL. In some embodiments, the method provides AUCo- 24 for Compound A of at least 125,000 ng hr/mL. In some embodiments, the method provides AUCo-24 for Compound A of at least 150,000 ng hr/mL. In some embodiments, AUC0-24 is measured on day 28 of cycle 1. In some embodiments, AUCo-24 for Compound A is measured in the subject’s blood or plasma.
  • the method provides decrease in the subject’s circulating tumor DNA (ctDNA) level compared to the subject’s ctDNA level prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • ctDNA circulating tumor DNA
  • the method provides decrease in the subject’s tumor volume compared to the subject’s tumor volume prior to administration of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject orally. In some embodiments, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered to the subject in a tablet or a capsule. [0199] In some embodiments of the methods described herein, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered in combination with one or more additional therapeutically active agent. In some embodiments, the one or more additional therapeutically active agent is administered together, sequentially, or separately from Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.
  • the one or more additional therapeutically active agent is administered during the same treatment cycle as Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, but on a different dosing schedule (e.g., Compound A is administered BID and another therapeutically active agent is administered QD).
  • the one or more additional therapeutically active agent is administered during the same treatment cycle as Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, but on different dosing days or times.
  • the one or more additional therapeutically active agent is useful for treating cancer, treating symptoms associated with cancer, or treating side effects caused by one or more therapeutically active agents.
  • the one of more additional therapeutically active agents is a metabolic inhibitor that may be beneficial to alter the dosing frequency or dosing amounts of Compound A and/or other therapeutically active agents.
  • the one or more additional therapeutically active agent is an androgen receptor ligand-binding domain inhibitor, anti -androgen, a steroid, a CYP17 inhibitor, a CYP3A4 inhibitor, or an inhibitor of UGT enzymes.
  • the additional therapeutically active agent is an androgen receptor ligand-binding domain inhibitor.
  • the androgen receptor ligand-binding domain inhibitor is bicalutamide, nilutamide, flutamide, ODM-204, or TAS3681, or a pharmaceutically acceptable salt or solvate thereof.
  • the additional therapeutically active agent is a steroid.
  • steroid is aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide
  • the additional therapeutically active agent is a CYP17 inhibitor.
  • the CYP17 inhibitor is galeterone.
  • the additional therapeutically active agent is a CYP3 A4 inhibitor.
  • the CYP3 A4 inhibitor is clarithromycin, telithromycin, erythromycin, nefazodone, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, ritonavir, ketoconazole, itraconazole, fluconazole, verapamil, or cobicistat, or a pharmaceutically acceptable salt or solvate thereof.
  • the additional therapeutically active agent is an uridine 5'- diphospho-glucuronosyltransferase (UDP-glucurono-syltransferase, UGT) inhibitor.
  • the inhibitor of UGT enzyme is atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, silybin, ritonavir, quinidine, diclofenac, everolimus, gemfibrozil, androsterone, phenylbutazone, ketoconazole, nilotinib, deoxyschizandrin, hecogenin, niflumic acid, efavirenz, or amitriptyline, or a pharmaceutically acceptable salt or solvate thereof.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof can be formulated into a pharmaceutical composition with one or more pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition can be a solid, a liquid, an emulsion, a suspension, a dispersion, or combinations thereof.
  • the pharmaceutical composition can be suitable for administration orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, intraportally, parenterally, or locally, e.g., topical, intra-tumor and peri-tumor.
  • the pharmaceutical composition for the methods of the present disclosure is an oral composition.
  • the pharmaceutical composition is a tablet or a capsule.
  • the pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is a solid dispersion composition.
  • the solid dispersion is formed by solvent evaporation (also known as solvent processing), hot-melt extrusion or spray drying methods.
  • the solid dispersion is a spray-dried dispersion (SDD).
  • the solid dispersion is prepared by solvent evaporation where after the therapeutically active agent and the polymeric carrier are both dissolved in the same solvent or a solvent mixture, the solvent or the solvent mixture is rapidly removed by evaporation or by mixing with a non-solvent.
  • Rapid removal of the solvent or the solvent mixture can be achieved using spray-drying, spray-coating (pan-coating, fluidized bed coating, etc.), and precipitation by rapid mixing of the polymer and drug solution with CO2, water, or other nonsolvent.
  • the solid dispersion is a supersaturated solid solution where the concentration of the therapeutically active agent in the polymeric carrier is above its equilibrium value.
  • the solid dispersion has a single glass transition temperature.
  • a single glass transition temperature for a solid dispersion indicates a high degree of homogeneity.
  • the solid dispersion comprises one or more water-soluble polymer. In one embodiment, the solid dispersion comprises one or more cellulose derivatives. In one embodiment, the solid dispersion comprises one or more water-soluble cellulosic polymer. In one embodiment, the solid dispersion comprises one or more cellulosic or non-cellulosic polymer. In one embodiment, the solid dispersion comprises one or more polymer that are neutral or ionizable in aqueous solution. In one embodiment, the solid dispersion comprises one or more polymers that are ionizable and cellulosic. In one embodiment, the solid dispersion comprises one or more polymers that are ionizable cellulosic polymers. In one embodiment, the solid dispersion comprises one or more amphiphilic polymers. In one embodiment, the solid dispersion comprises one or more hydrophilic polymer. In one embodiment, the solid dispersion comprises one or more water-soluble hydrophilic polymer.
  • the solid dispersion comprises one or more polymers or polymeric carriers selected from polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP), polyethyleneoxide (PEO), poly(vinyl pyrrolidone-co-vinyl acetate) (PVP-VA), polymethacrylate, polyoxyethylene alkyl ether, polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-glycolic)acid, lipid, cellulose, pullulan, dextran, dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate,
  • one or more polymers or polymeric carriers is PEG, polyvinyl pyrrolidone, polyethyleneoxide, poly(vinyl pyrrolidone-co-vinyl acetate), polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oils, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-glycolic)acid, lipids, cellulose, pullulan, dextran, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, spirulan, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, 10 carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate (including grades L, M, H, LF and/or LG HPMCAS) cellulose acetate phthalate, cellulose acetate trim
  • one or more polymers or polymeric carriers is hydroxypropyl methylcellulose acetate succinate.
  • hydroxypropyl methylcellulose acetate succinate HPMCAS
  • the polymer or polymeric carrier is HPMCAS-H.
  • one or more polymers or polymeric carriers selected from the group consisting of polyethylene glycol (PEG), polyvinyl caprolactam, polyvinyl acetate, polyvinyl pyrrolidone (PVP), poly(vinyl pyrrolidone-co-vinyl acetate) (PVP-VA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(methacrylic acid-co-methyl methacrylate) 1 : 1, and poly(methacrylic acid- co-methyl methacrylate) 1 :2.
  • PEG polyethylene glycol
  • PVP polyvinyl caprolactam
  • PVP polyvinyl pyrrolidone
  • PVP-VA poly(vinyl pyrrolidone-co-vinyl acetate)
  • HPMC hydroxypropyl methylcellulose
  • HPMCAS hydroxypropyl methylcellulose acetate succinate
  • a neutral non-cellulosic polymer or polymeric carrier is selected from vinyl polymers and copolymers having substituents of hydroxyl, alkylacyloxy, and cyclicamido polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl pyrrolidone; polyvinylpyrrolidone vinyl acetate; or polyethylene polyvinyl alcohol copolymers.
  • an ionizable non-cellulosic polymer or polymeric carrier is selected from carboxylic acid-functionalized vinyl polymers, such as the carboxylic acid functionalized polymethacrylates and carboxylic acid functionalized polyacrylates such as the Eudragit® polymers; amine-functionalized polyacrylates and polymethacrylates; proteins; or carboxylic acid functionalized starches such as starch glycolate.
  • an amphiphilic non-cellulosic polymer or polymeric carrier is acrylate and methacrylate copolymers.
  • Commercial grades of such copolymers include the Eudragit® polymers, which are copolymers of methacrylates and acrylates; and graft copolymers of polyethyleneglycol, polyvinylcaprolactam, and polyvinylacetate, such as Soluplus®.
  • a neutral non-ionizable cellulosic polymer or polymeric carrier is selected from hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, or hydroxyethyl ethyl cellulose.
  • a neutral amphiphilic cellulosic polymer or polymeric carrier is selected from hydroxypropyl methyl cellulose or hydroxypropyl cellulose acetate, where cellulosic repeat units that have relatively high numbers of methyl or acetate substituents relative to the unsubstituted hydroxyl or hydroxypropyl substituents constitute hydrophobic regions relative to other repeat units on the polymer.
  • a cellulosic polymer or polymeric carrier is selected from hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate succinate succinate, hydroxypropyl methyl cellulose acetate succinate
  • cellulosic polymers or polymeric carriers are selected from cellulose acetate phthalate (CAP), methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxylpropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate phthalate (HPMCAP), hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose a
  • a cellulosic ionizable polymer or polymeric carrier is selected from hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, or hydroxyethyl cellulose acetate succinate.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is present in about 10% to about 90% by weight of the total composition (which can include one or more additional therapeutically active agents and/or other pharmaceutically acceptable excipients and/or coatings), including all values and subranges therebetween.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is present in about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% by weight of the total composition, including all values therebetween.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is present in about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 15% to about 85%, about 15% to about 75%, about 15% to about 65%, about 15% to about 55%, about 15% to about 45%, about 15% to about 35%, about 15% to about 25%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 25% to about 85%, about 25% to about 75%, about 25% to about 65%, about 25% to about 55%, about 25% to about 45%, about 25% to about 35%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 35% to about 85%, about 35% to about 75%, about 35% to about 35% to about 30%
  • the weight ratio of the polymer or the polymeric carrier and Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is about 90: 10, about 85: 15, about 80:20, about 75:25, about 70:30, about 65:35, about 60:40, about 55:45, about 50:50, about 45:55, about 40:60, about 35:65, about 30: 70, about 25:75, about 20:80, or about 10:90, including all values therebetween.
  • the solid dispersion has a D50 particle size in the range of about 40 microns to about 130 microns, including all values therebetween. In one embodiment, the solid dispersion has a D50 particle size in the range of about 70 microns to about 100 microns, including all values therebetween.
  • the solid dispersion has a D50 particle size of about 10 microns, about 15 microns, about 20 microns, about 25 microns, about 30 microns, about 35 microns, about 40 microns, about 45 microns, about 50 microns, about 55 microns, about 60 microns, about 65 microns, about 70 microns, about 75 microns, about 80 microns, about 85 microns, about 90 microns, about 95 microns, or about 100 microns, including all values therebetween.
  • the solid dispersion has a D90 particle size in the range of about 10 microns to about 100 microns, including all values therebetween. In one embodiment, the solid dispersion has a D90 particle size in the range of about 30 microns to about 60 microns, including all values therebetween.
  • the solid dispersion has a D90 particle size of about 40 microns, about 45 microns, about 50 microns, about 55 microns, about 60 microns, about 65 microns, about 70 microns, about 75 microns, about 80 microns, about 85 microns, about 90 microns, about 95 microns, about 100 microns, about 105 microns, about 110 microns, about 115 microns, about 120 microns, about 125 microns, or about 130 microns, including all values therebetween.
  • the solid dispersion has a bulk density in the range of about 0.1 g/mL to about 0.6 g/mL, including all values therebetween. In one embodiment, the solid dispersion has a bulk density of about 0.1 g/mL, about 0.2 g/mL, about 0.3 g/mL, about 0.4 g/mL, about 0.5 g/mL, or about 0.6 g/mL, including all values therebetween.
  • the solid dispersion has a tap density in the range of about 0.2 g/mL to about 0.7 g/mL, including all values therebetween. In one embodiment, the solid dispersion has a tap density of about 0.2 g/mL, about 0.3 g/mL, about 0.4 g/mL, about 0.5 g/mL, about 0.6 g/mL, or about 0.7 g/mL, including all values therebetween.
  • the solid dispersion comprises any solvent in less than about 10% by weight. In one embodiment, the solid dispersion comprises any organic solvent in less than about 8% by weight. In one embodiment, the solid dispersion comprises any organic solvent in less than: about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, about 1%, or about 0.5% by weight, including all values therebetween.
  • the solid dispersion comprises dichloromethane in less than about 5% by weight. In one embodiment, the solid dispersion comprises dichloromethane in less than about 0.01% by weight. In one embodiment, the solid dispersion comprises dichloromethane in less than: about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% by weight, including all values therebetween.
  • the solid dispersion comprises water in less than about 1% by weight. In one embodiment, the solid dispersion comprises water in less than about 0.5% by weight. In one embodiment, the solid dispersion comprises water in less than: about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, or about 0.5% by weight, including all values therebetween.
  • the solid dispersion exhibits a glass transition temperature (Tg) in the range of about 60 °C to about 180 °C as measured by differential scanning calorimeter, including all values therebetween. In some embodiments, the solid dispersion exhibits a glass transition temperature (Tg) in the range of about 60 °C to about 90 °C as measured by differential scanning calorimeter, including all values therebetween. In one embodiment, the solid dispersion exhibits a glass transition temperature (Tg) in the range of about 70 °C to about 80 °C as measured by differential scanning calorimeter, including all values therebetween.
  • the solid dispersion exhibits a glass transition temperature (Tg) of about 55°C to about 180 °C, about 60 °C to about 170 °C, about 60 °C to about 160 °C, about 60 °C to about 150 °C, about 60 °C to about 140 °C, about 60 °C to about 130 °C, about 60 °C to about 120 °C, about 60 °C to about 110 °C, about 60 °C to about 100 °C, about 60 °C to about 95°C, or about 60 °C to about 85 °C, including all values and subranges therebetween.
  • Tg glass transition temperature
  • the solid dispersion exhibits a glass transition temperature (Tg) of about 70 °C, about 71 °C, about 72 °C, about 73 °C, about 74 °C, about 75 °C, about 76 °C, about 77 °C, about 78 °C, about 79 °C, or about 80 °C as measured by differential scanning calorimeter, including all values therebetween.
  • the differential scanning calorimeter is modulated differential scanning calorimeter (mDSC). Tg is determined under dry conditions (0%RH).
  • the solid dispersion exhibits a glass transition temperature (Tg) in the range of about 30 °C to about 100 °C as measured by differential scanning calorimeter under 50% RH, including all values therebetween. In some embodiments, the solid dispersion exhibits a glass transition temperature (Tg) in the range of about 40 °C to about 80 °C as measured by differential scanning calorimeter under 50% RH, including all values therebetween. In some embodiments, solid dispersion exhibits a glass transition temperature (Tg) in the range of about 50 °C to about 70 °C as measured by differential scanning calorimeter under 50% RH, including all values therebetween. In one embodiment, the differential scanning calorimeter is modulated differential scanning calorimeter (mDSC).
  • mDSC modulated differential scanning calorimeter
  • the solid dispersion exhibits a glass transition temperature (Tg) in the range of about 30 °C to about 100 °C as measured by differential scanning calorimeter under 75% RH, including all values therebetween. In some embodiments, the solid dispersion exhibits a glass transition temperature (Tg) in the range of about 40 °C to about 80 °C as measured by differential scanning calorimeter under 75% RH, including all values therebetween. In some embodiments, solid dispersion exhibits a glass transition temperature (Tg) in the range of about 50 °C to about 70 °C as measured by differential scanning calorimeter under 75% RH, including all values therebetween. In one embodiment, the differential scanning calorimeter is modulated differential scanning calorimeter (mDSC).
  • mDSC modulated differential scanning calorimeter
  • the solid dispersion exhibits a glass transition temperature (Tg) in the range of about 30 °C to about 100 °C, as measured by differential scanning calorimeter after being stored at 25 °C/60% RH for about one month or about two months. In some embodiments, the solid dispersion exhibits a glass transition temperature (Tg) in the range of about 50 °C to about 90 °C, as measured by differential scanning calorimeter, after being stored at 25 °C/60% RH for about one month or about two months.
  • the solid dispersion exhibits a glass transition temperature (Tg) in the range of about 60 °C to about 80 °C, as measured by differential scanning calorimeter after being stored at 25 °C/60% RH for about one month or about two months.
  • Tg glass transition temperature
  • the differential scanning calorimeter is modulated differential scanning calorimeter (mDSC).
  • the solid dispersion exhibits a glass transition temperature (Tg) in the range of about 30 °C to about 100 °C, as measured by differential scanning calorimeter after being stored at 40 °C/75% RH for about one month or about two months. In some embodiments, the solid dispersion exhibits a glass transition temperature (Tg) in the range of about 50 °C to about 90 °C, as measured by differential scanning calorimeter, after being stored at 40 °C/75% RH for about one month or about two months.
  • the solid dispersion exhibits a glass transition temperature (Tg) in the range of about 60 °C to about 80 °C, as measured by differential scanning calorimeter after being stored at 40 °C/75% RH for about one month or about two months.
  • Tg glass transition temperature
  • the differential scanning calorimeter is modulated differential scanning calorimeter (mDSC).
  • the solid dispersion reaches a solubility of about 40 pg of Compound A/mL (pgA/mL) to about 50 pgA/mL in intestinal buffer (IB) media within about 30 minutes. In some embodiments, the solid dispersion reaches a solubility of about 45 pgA/mL in intestinal buffer (IB) media within about 30 minutes.
  • the solid dispersion reaches a solubility of about 35 pgA/mL, about 36 pgA/mL, about 37 pgA/mL, about 38 pgA/mL, about 39 pgA/mL, about 40 pgA/mL, about 41 pgA/mL, about 42 pgA/mL, about 43 pgA/mL, about 44 pgA/mL, about 45 pgA/mL, about 46 pgA/mL, about 47 pgA/mL, about 48 pgA/mL, about 49 pgA/mL, about 50 pgA/mL, about 51 pgA/mL, about 52 pgA/mL, about 53 pgA/mL, about 54 pgA/mL, or about 55 pgA/mL in IB media within about 30 minutes.
  • IB media has a pH of 6.5. In one embodiment, IB media is a 0.5%wt simulated intestinal fluid (SIF) in a pH 6.5 phosphate buffer saline (PBS).
  • SIF simulated intestinal fluid
  • PBS pH 6.5 phosphate buffer saline
  • the solid dispersion is physically stable when stored under 25 °C/60% RH for about one month. In some embodiments, the solid dispersion is physically stable when stored under 25 °C/60% RH for about two months. In some embodiments, the solid dispersion is physically stable when stored under 25 °C/60% RH for about three months. In some embodiments, the solid dispersion is physically stable when stored under 25 °C/60% RH for up to about three months.
  • the solid dispersion is physically stable when stored under 25 °C/60% RH for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months.
  • the solid dispersion is a spray dried dispersion.
  • the solid dispersion comprises less than 1 wt% water after being stored at 25 °C/60% RH for about one month. In some embodiments, the solid dispersion comprises less than 1 wt% water after being stored at 25 °C/60% RH for about two months. In some embodiments, the solid dispersion comprises less than 0.5 wt% water after being stored at 25 °C/60% RH for about one month. In some embodiments, the solid dispersion comprises less than 0.5 wt% water after being stored at 25 °C/60% RH for about two months.
  • the solid dispersion comprises less than 1 wt% water or less than 0.5 wt% water after being stored under 25 °C/60% RH for at least about 1 month, at least about 2 months, or at least about 3 months. In some embodiments, the solid dispersion gains less than 1 wt% water after being stored at 25 °C/60% RH for about one month or about two months. In some embodiments, the solid dispersion gains less than 0.5 wt% water after being stored at 25 °C/60% RH for about one month or about two months. In some embodiments, the solid dispersion gains less than 0.3 wt% water after being stored at 25 °C/60% RH for about one month or about two months.
  • the solid dispersion gains less than 1 wt%, less than 0.5 wt%, or less than 0.3% water after being stored under 25 °C/60% RH for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months.
  • the solid dispersion is a spray dried dispersion.
  • the solid dispersion is physically stable when stored under 40 °C/75% RH for about one month. In some embodiments, the solid dispersion is physically stable when stored under 40 °C/75% RH for about two months. In some embodiments, the solid dispersion is physically stable when stored under 40 °C/75% RH for about three months. In some embodiments, the solid dispersion is physically stable when stored under 40 °C/75% RH for up to about three months. In some embodiments, the solid dispersion is physically stable when stored under 40 °C/75% RH for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months.
  • the solid dispersion is a spray dried dispersion.
  • the solid dispersion comprises less than 1 wt% water after being stored at 40 °C/75% RH for about one month. In some embodiments, the solid dispersion comprises less than 1 wt% water after being stored at 40 °C/75% RH for about two months. In some embodiments, the solid dispersion comprises less than 0.5 wt% water after being stored at 40 °C/75% RH for about one month. In some embodiments, the solid dispersion comprises less than 0.5 wt% water after being stored at 40 °C/75% RH for about two months.
  • the solid dispersion comprises less than 1 wt% water or less than 0.5 wt% water after being stored under 40 °C/75% RH for at least about 1 month, at least about 2 months, or at least about 3 months. In some embodiments, the solid dispersion gains less than 1 wt% water after being stored at 40 °C/75% RH for about one month or about two months. In some embodiments, the solid dispersion gains less than 0.5 wt% water after being stored at 40 °C/75% RH for about one month or about two months. In some embodiments, the solid dispersion gains less than 0.3 wt% water after being stored at 40 °C/75% RH for about one month or about two months.
  • the solid dispersion gains less than 1 wt%, less than 0.5 wt%, or less than 0.3% water after being stored under 40 °C/75% RH for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months.
  • the solid dispersion is a spray dried dispersion.
  • the solid dispersion has a potency of about 90 mg of Compound A per a gram of the solid dispersion (mgA/g) to about 700 mgA/g, including all values therebetween. In some embodiments, the solid dispersion has a potency of about 100 mgA/g to about 500 mgA/g, including all values therebetween. In some embodiments, the solid dispersion has a potency of about 150 mgA/g to about 400 mgA/g, including all values therebetween. In some embodiments, the solid dispersion has a potency of about 200 mgA/g to about 375 mgA/g, including all values therebetween.
  • the solid dispersion is formulated into a tablet.
  • the tablet is in a fixed dosage form.
  • a capsule is filled with the solid dispersion.
  • the capsule is in a fixed dosage form.
  • each tablet or capsule comprises Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, in about 5 mg and about 1000 mg, or between about 10 mg and about 500 mg, or between about 20 mg and about 250 mg, or between about 30 mg and about 300 mg, or between about 50 mg and about 200 mg, including all values therebetween.
  • each tablet or capsule comprises Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, in about 50 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg, including all values therebetween.
  • an amount of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, per one tablet or one capsule is about 5 mg, about 10 mg, about 15 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 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1,000 mg, or any values therebetween.
  • an amount of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, per a dosage form is between about 5 mg and about 1000 mg, or between about 10 mg and about 500 mg, or between about 20 mg and about 250 mg, or between about 30 mg and about 300 mg, or between about 50 mg and about 200 mg, or any values or subranges therebetween.
  • an amount of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, per a dosage form is about 5 mg, about 10 mg, about 15 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 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1,000 mg, or any values therebetween. In one embodiment, an amount of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, per a dosage form is about 50 mg, about 100 mg, or about 200 mg, or any values therebetween.
  • a daily dosage amount of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is between about 50 mg and about 2000 mg, or between about 50 mg and about 1500 mg, or between about 100 mg and about 1000 mg, or between about 200 mg and about 800 mg, or between about 300 mg and about 600 mg, or any values or subranges therebetween.
  • the daily dosage amount of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, about 1,050 mg, about 1,100 mg, about 1,150 mg, about 1,200 mg, about 1,250 mg, about 1,300 mg, about 1,350 mg, about 1,400 mg, about 1,450 mg, about 1,500 mg, about 1,550 mg, or about 1,600 mg, or any values therebetween.
  • the daily dose of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is administered once a day, or divided into twice-a-day or three times a day dose.
  • the daily dose of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is provided in one tablet or one capsule, or the daily dose is divided into two, three, four, five, or six tablets or capsules.
  • compositions are also available.
  • Appropriate form of the pharmaceutical compositions useful for the methods of the present disclosure can be determined according to any clinically-acceptable route of administration of the composition to the subject.
  • the manner in which the composition is administered is dependent, in part, upon the cause and/or location.
  • One skilled in the art will recognize the advantages of certain routes of administration.
  • the method includes administering an effective amount of the agent or compound (or composition comprising the agent or compound) to achieve a desired biological response, e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, a symptom of a condition to be treated, e.g., oncology and neurology disorders.
  • the route of administration is systemic, e.g., oral or by injection.
  • the compositions of the disclosure are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, intraportally, and parenterally.
  • the route of administration is local, e.g., topical, intra-tumor and peri-tumor.
  • the composition is administered orally.
  • the pharmaceutical composition is prepared for oral administration.
  • a pharmaceutical composition is formulated by combining one or more agents and pharmaceutically acceptable carriers. Certain of such carriers enable pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, gel capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject.
  • the pharmaceutical composition comprises intragranular excipients and extragranular excipients. In some embodiments, extragranular excipients are blended with the solid dispersion prior to being blended with the extragranular excipients.
  • the pharmaceutical composition comprises intragranular excipients selected from a filler, a disintegrant, a glidant, and/or a lubricant. In some embodiments, the pharmaceutical composition comprises extragranular excipients selected from a filler, a disintegrant, a glidant, and/or a lubricant.
  • the pharmaceutical composition can comprise one or more additional therapeutically active agents.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and the additional therapeutically active agent is provided in at least two dosage forms or at least two pharmaceutical compositions.
  • the at least two dosage forms or the at least two pharmaceutical compositions are co-packaged together into a single kit.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is provided in one dosage form or one pharmaceutical composition and the additional therapeutically active agent is provided in another dosage form or another pharmaceutical composition.
  • a single kit comprises Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, in one dosage form or a pharmaceutical composition and the additional therapeutically active agent in another dosage form or a pharmaceutical composition.
  • a single kit comprises Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, formulated into one or more tablets or capsules and the additional therapeutically active agent in different tablets or capsules.
  • a single kit comprises Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, formulated into one or more tablets and the additional therapeutically active agent in different tablets.
  • the tablet is an immediate release tablet. In some embodiments, the tablet has a film coating.
  • the tablet has an average hardness of about 10 kP to about 40 kP, including all subranges and values therebetween. In some embodiments, the tablet has an average hardness of about 15 kP to about 35 kP, or about 15 kP to about 30 kP, including all subranges and values therebetween.
  • the tablet has an average hardness of about 10 kP, about 11 kP, about 12 kP, about 13 kP, about 14 kP, about 15 kP, about 16 kP, about 17 kP, about 18 kP, about 19 kP, about 20 kP, about 21 kP, about 22 kP, about 23 kP, about 24 kP, about 25 kP, about 26 kP, about 27 kP, about 28 kP, about 29 kP, about 30 kP, about 31 kP, about 32 kP, about 33 kP, about 34 kP, about 35 kP, about 36 kP, about 37 kP, about 38 kP, about 39 kP, about or 40 kP.
  • the tablet has an average tensile strength of about 1 MPa to about 5 MPa, including all subranges and values therebetween. In some embodiments, the tablet has an average tensile strength of about 1 MPa, about 1.5 MPa, about 2 MPa, about 2.5 MPa, or about 3 MPa.
  • the tablet has a friability of no more than 1.0% weight loss at 100 drops. In some embodiments, the tablet has a friability of no more than about 0.5% weight loss at 100 drops. In some embodiments, the tablet has a friability of no more than about 0.2% weight loss at 100 drops. In some embodiments, the tablet has a friability of no more than about 0.1% weight loss at 100 drops.
  • the tablet has a friability of no more than 1.0% weight loss at 300 drops. In some embodiments, the tablet has a friability of no more than about 0.5% weight loss at 300 drops. In some embodiments, the tablet has a friability of no more than about 0.4% weight loss at 300 drops. In some embodiments, the tablet has a friability of no more than about 0.2% weight loss at 300 drops.
  • the tablet has a friability of no more than 1.0% weight loss at 500 drops. In some embodiments, the tablet has a friability of no more than about 0.6% weight loss at 500 drops. In some embodiments, the tablet has a friability of no more than about 0.4% weight loss at 500 drops. In some embodiments, the tablet has a friability of no more than about 0.3% weight loss at 500 drops.
  • the tablet friability is measured on uncoated tablets (e.g., tablets without film coating or release modifying coating).
  • the tablet has an average disintegration time of less than about 300 seconds in an acidic media. In some embodiments, the tablet has an average disintegration time of less than about 250 seconds in an acidic media. In some embodiments, the tablet has an average disintegration time of less than about 200 seconds in an acidic media. In some embodiments, the tablet has an average disintegration time of less than about 160 seconds in an acidic media. In some embodiments, the tablet has an average disintegration time of less than about 100 seconds in an acidic media. In some embodiments, the tablet has an average disintegration time of less than about 60 seconds in an acidic media. In some embodiments, the disintegration test is performed in a USP ⁇ 701> style basket rack assembly using 0.01N HC1 at about 37 °C as the disintegration media.
  • a single kit comprises a single dose of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and the additional therapeutically active agent.
  • a single kit comprises a daily dose of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and the additional therapeutically active agent.
  • a daily dose may comprise one or more single doses of Compound A and/or the second therapeutically active agent to be taken at one, two, three, or four different times of the day.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and the additional therapeutically active agent has the same dosing frequency (e.g., once a day, twice a day, once a week). In one embodiment, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and the additional therapeutically active agent has the same dosing frequency but taken at different times of the day. In one embodiment, Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and the additional therapeutically active agent has the same dosing frequency and taken at the same time of the day.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and the additional therapeutically active agent has a different dosing frequency (e.g., Compound A is taken once a day and the additional therapeutically active agent is taken twice a day).
  • the combination of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and the additional therapeutically active agent is in a single fixed dosage form.
  • a single tablet or a single capsule fixed dosage form comprises unit doses of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and the additional therapeutically active agent.
  • a single dosage form comprises two or more tablets or capsules, each comprising a fixed-dose of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and the second therapeutically active agent.
  • the pharmaceutical composition of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and the additional therapeutically active agent is provided in at least two dosage forms or at least two pharmaceutical compositions.
  • the composition is provided in at least three dosage forms.
  • the at least two dosage forms or the at least two pharmaceutical compositions are co-packaged together into a single kit.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof is provided in one dosage form or one pharmaceutical composition and the additional therapeutically active agent is provided in another dosage form or another pharmaceutical composition.
  • a single kit comprises Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, in one dosage form or a pharmaceutical composition and the additional therapeutically active agent in another dosage form or a pharmaceutical composition.
  • a single kit comprises Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and the second therapeutically active agent formulated into one or more tablets or capsules.
  • the pharmaceutical composition can comprise a kit comprising, one, two or three different dosage forms co-packaged together. Different dosage forms in a single co-package can comprise different therapeutically active agents. In some embodiments, all therapeutically active agents (Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, the second, optionally the third, optionally the fourth therapeutically active agents, and so forth) are provided in different dosage forms. In some embodiments, two or more therapeutically active agents are formulated into the same dosage form. In one embodiment, the kit can comprise 1, 2, 3, 4, 5, or 6 pharmaceutical compositions of each dosage form.
  • all pharmaceutical compositions are co-packaged for daily administration.
  • each pharmaceutical composition of each dosage form is for administration to a subject once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 5 hours, or once every 4 hours.
  • different therapeutically active agents can have different dosing schedule.
  • Compound A and the additional therapeutically active agent are in different compositions but provided in a single kit.
  • the kit comprises 1, 2, 3, 4, 5, or 6 compositions for each therapeutically active agent to be administered per day.
  • the kit comprises 1, 2, 3, 4, 5, or 6 tablets or capsules or mixtures of tablets and capsules for each therapeutically active agent.
  • At least one composition is a tablet.
  • Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and the additional therapeutically active agent are in different layers or compartments of the same tablet composition.
  • the layers or compartments comprising the different therapeutically active agent is adjacent to one another.
  • the layers or compartments comprising the different therapeutically active agent are separated by one or more coatings or compartments such that the two therapeutically active agents do not come in contact.
  • the one or more coatings or compartments separating the different therapeutically active agents can be functional (e.g., modifies release) or inert (e.g., just providing physical separation).
  • the Compound A layer or the Compound A compartment is about 10% to about 70% by weight of the composition, or about 20% to about 50% by weight of the composition, or about 30% to about 40% by weight of the composition, or any values or subranges therebetween. In one embodiment, the Compound A layer or the Compound A compartment is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% weight of the composition, or any values therebetween.
  • the layer or the compartment of the composition comprising the second therapeutically active agent is about 10% to about 70% by weight of the composition or about 20% to about 50% by weight of the composition, or about 30% to about 40% by weight of the composition, or any values or subranges therebetween. In one embodiment, the layer or the compartment of the composition comprising the second therapeutically active agent is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% weight of the composition, or any values therebetween.
  • compositions as disclosed herein can further comprise a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition as disclosed herein comprises a pharmaceutically acceptable carrier, excipient or adjuvant is provided.
  • the pharmaceutically acceptable carriers, excipients and adjuvants are added to the composition or formulation for a variety of purposes.
  • a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and/or diluent.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical compositions of the present disclosure may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels.
  • the pharmaceutical compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • additional materials useful in physically formulating various dosage forms of the compositions of the present invention such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • such materials when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention.
  • the formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/
  • the therapeutic agents disclosed herein can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compounds disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the compounds disclosed herein can also be formulated as a preparation for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.
  • a pharmaceutical composition of the present disclosure is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05M phosphate buffer or 0.8% saline.
  • Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions.
  • non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers suitable for use in the present application include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media.
  • Oral carriers can be elixirs, syrups, capsules, tablets and the like.
  • Liquid carriers suitable for use in the present application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration.
  • the liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
  • Solid carriers suitable for use in the present application include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like.
  • a solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier can be a finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active compound.
  • suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Parenteral carriers suitable for use in the present application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
  • Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like.
  • Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
  • Carriers suitable for use in the present application can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.
  • the carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art.
  • Diluents may be added to the formulations of the present invention. Diluents increase the bulk of a solid pharmaceutical composition and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., AVICEL®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
  • microcrystalline cellulose e.g., AVICEL®
  • microfine cellulose lactose
  • starch pregelatinized starch
  • a pharmaceutical composition of the present invention is a solid (e.g., a powder, tablet, a capsule, granulates, and/or aggregates).
  • a solid pharmaceutical composition comprising one or more ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., Carbopol®), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, gum tragacanth, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCELTM), hydroxypropyl methyl cellulose (e.g., METHOCELTM), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON®, PLASDONETM), pregelatinized starch, sodium alginate, and starch.
  • carbomer e.g., Carbopol®
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient’s stomach may be increased by the addition of a disintegrant to the composition.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL® and PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON® and POLYPLASDONETM), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB®), potato starch, and starch.
  • the disintegrant is crospovidone or arboxymethylcellulose sodium.
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • a dosage form such as a tablet is made by the compaction of a powdered composition
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • the lubricant is magnesium stearate.
  • flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid pharmaceutical compositions can optionally have different types of coating.
  • Coatings can be applied to the entire dosage form (e.g. a tablet) or a component of a dosage form (e.g., core, granules, beads, pellets, microparticles, etc).
  • a coating can be used to improve patient compliance (e.g., taste-masking coating, flavor coating, coating to provide smooth surface for easy swallowing), to improve the stability of the compositions (e.g., protection from light, moisture, gas, acid protection, or to divide different layers or compartments to avoid a drug from interacting with different ingredients in a different layer/compartment), alter release profile of the drug (e.g., enteric coating, pH-dependent polymer coating, etc), or improve cosmetic considerations.
  • the tablet has a cosmetic coating.
  • the tablet has a film coating.
  • the tablet has a coating comprising Opadry®.
  • a coating can be a thin film-coating comprising one or more polymers or water soluble materials including but are not limited to, hypromellose, macrogol, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol, polyvinyl alcohol, and cellulose acetate phthalate.
  • film coating can comprise one or more pharmaceutically acceptable excipients, including but not limited to titanium dioxide, ferric oxide, coloring agents, talc, or lecithin.
  • a coating that modifies release of the active ingredient can comprise a pH-dependent polymer (e.g., enteric polymer) or a pH-independent polymer.
  • a release-modifying coating can comprise one or more polymers selected from methacrylic copolymers, aminoalkyl methacrylate copolymers, methacrylate copolymers, or ammonioalkyl methacrylate copolymers.
  • a release-modifying coating can comprise one or more cationic polymer, anionic polymer, or neutral polymer.
  • Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • a pharmaceutical composition of the present invention is a liquid (e.g., a suspension, elixir and/or solution).
  • a liquid pharmaceutical composition is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • Liquid pharmaceutical compositions can be prepared where the solid or amorphous components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylenepolyoxypropylene copolymers can be useful excipients to control the release of active compounds.
  • Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, poly oxy ethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.
  • Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
  • Liquid pharmaceutical compositions can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
  • Sweetening agents such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition can also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
  • a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
  • injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.
  • compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • such suspensions may also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • Formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer.
  • the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent.
  • the compound is to be administered by infusion, it can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water.
  • an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • Suitable formulations further include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
  • a pharmaceutical composition of the present invention is formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example an emulsion in an acceptable oil
  • ion exchange resins for example an emulsion in an acceptable oil
  • sparingly soluble derivatives for example, as a sparingly soluble salt.
  • a pharmaceutical composition of the present invention comprises a delivery system.
  • delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.
  • a pharmaceutical composition of the present invention comprises a co-solvent system.
  • co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • co-solvent systems are used for hydrophobic compounds.
  • VPD co-solvent system is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80 and 65% w/v polyethylene glycol 300.
  • co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.
  • identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • a pharmaceutical composition of the present invention comprises a sustained-release system.
  • a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers.
  • sustained-release systems may, depending on their chemical nature, release pharmaceutical agents over a period of hours, days, weeks or months.
  • a pharmaceutical composition of the present disclosure is prepared for oral administration.
  • a pharmaceutical composition is formulated by combining one or more agents and pharmaceutically acceptable carriers.
  • suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, lactose monohydrate, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, microcrystalline cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • fillers such as sugars, including lactose, lactose monohydrate, sucrose, mannitol, or sorbitol
  • cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, microcrystalline cellulose, hydroxy
  • such a mixture is optionally ground and auxiliaries are optionally added.
  • pharmaceutical compositions are formed to obtain tablets or dragee cores.
  • disintegrating agents e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate
  • the filler is microcrystalline cellulose and/or lactose monohydrate.
  • dragee cores are provided with coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to tablets or dragee coatings.
  • compositions for oral administration are push- fit capsules made of gelatin. Certain of such push-fit capsules comprise one or more pharmaceutical agents of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • pharmaceutical compositions for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • one or more pharmaceutical agents of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • pharmaceutical compositions are prepared for buccal administration. Certain of such pharmaceutical compositions are tablets or lozenges formulated in conventional manner.
  • a pharmaceutical composition is prepared for transmucosal administration.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • a pharmaceutical composition is prepared for administration by inhalation.
  • Certain of such pharmaceutical compositions for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer.
  • Certain of such pharmaceutical compositions comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined with a valve that delivers a metered amount.
  • capsules and cartridges for use in an inhaler or insufflator may be formulated.
  • Certain of such formulations comprise a powder mixture of a pharmaceutical agent of the invention and a suitable powder base such as lactose or starch.
  • the compound and the compositions of the present disclosure are administered by the intravenous route.
  • the parenteral administration may be provided in a bolus or by infusion.
  • a pharmaceutical composition is prepared for rectal administration, such as a suppository or retention enema.
  • Certain of such pharmaceutical compositions comprise known ingredients, such as cocoa butter and/or other glycerides.
  • a pharmaceutical composition is prepared for topical administration.
  • Certain of such pharmaceutical compositions comprise bland moisturizing bases, such as ointments or creams.
  • ointments or creams include, but are not limited to, petrolatum, petrolatum plus volatile silicones, and lanolin and water in oil emulsions.
  • suitable cream bases include, but are not limited to, cold cream and hydrophilic ointment.
  • the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
  • one or more therapeutically active agents, or a pharmaceutically acceptable salt or solvate thereof are formulated as a prodrug.
  • a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically more active form.
  • prodrugs are useful because they are easier to administer than the corresponding active form.
  • a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form.
  • a prodrug may have improved solubility compared to the corresponding active form.
  • prodrugs are less water soluble than the corresponding active form.
  • a prodrug is an ester.
  • the ester is metabolically hydrolyzed to carboxylic acid upon administration.
  • the carboxylic acid containing compound is the corresponding active form.
  • a prodrug comprises a short peptide (polyaminoacid) bound to an acid group.
  • the peptide is cleaved upon administration to form the corresponding active form.
  • a prodrug is produced by modifying a pharmaceutically active compound such that the active compound will be regenerated upon in vivo administration.
  • the prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • the androgen receptor modulators in the pharmaceutical composition as disclosed herein can be administered at about 0.001 mg/kg to about 100 mg/kg body weight (e.g., about 0.01 mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 5 mg/kg).
  • the concentration of a therapeutically active agent in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound to be administered, the pharmacokinetic characteristics of the compound(s) employed, and the route of administration.
  • the agent may be administered in a single dose or in repeat doses.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. Treatments may be administered daily or more frequently depending upon a number of factors, including the overall health of a patient, and the formulation and route of administration of the selected compound(s). An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • compositions as disclosed herein may be manufactured and/or administered in single or multiple unit dose forms.
  • Embodiment 1 A pharmaceutical combination comprising a therapeutically effective amount of a first therapeutically active agent Compound A having the structure: , or a pharmaceutically acceptable salt, or solvate thereof, and darolutamide in at least one pharmaceutical composition.
  • Embodiment 2 The pharmaceutical combination of Embodiment 1, wherein the combination of Compound A and darolutamide are in at least two pharmaceutical compositions.
  • Embodiment 3 The pharmaceutical combination of Embodiment 3, wherein the combination of Compound A and darolutamide are in the at least two pharmaceutical compositions are at least two different dosage forms.
  • Embodiment 4 The pharmaceutical combination of Embodiment 2 or 3, wherein the at least two pharmaceutical compositions or dosage forms are co-packaged together into a single kit.
  • Embodiment 5 The pharmaceutical combination of any one of Embodiments 1-4, wherein a daily dosage amount of Compound A is between about 50 mg and about 2000 mg, or between about 100 mg and about 1500 mg, or between about 200 mg and about 1000 mg, or between about 300 mg and about 600 mg.
  • Embodiment 6 The pharmaceutical combination of any one of Embodiments 1-5, wherein Compound A is included in at least one tablet and the amount of Compound A per tablet is between about 5 mg and about 1000 mg, or between about 10 mg and about 500 mg, or between about 20 mg and about 400 mg, or between about 75 mg and about 300 mg, or between about 150 mg and about 250 mg.
  • Embodiment 7 The pharmaceutical combination of any one of Embodiments 1-6, wherein a daily dosage amount of darolutamide is about 200 mg to about 3000 mg, or about 300 mg to about 2000 mg, or about 400 mg to about 1700 mg, or about 800 mg to about 1500 mg, or about 1100 mg to about 1300 mg.
  • Embodiment 8 The pharmaceutical combination of any one of Embodiments 1-7, wherein the amount of darolutamide per dosage is about 20 mg to about 2000 mg, or about 100 mg to about 1000 mg, or about 300 mg to about 800 mg, or about 500 mg to about 700 mg.
  • Embodiment 9 A method for treating cancer, comprising administering the pharmaceutical combination of any one of Embodiments 1-8 to a subject in need thereof.
  • Embodiment 10 The method of Embodiment 9, wherein the cancer is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, or salivary gland carcinoma.
  • Embodiment 11 The method of Embodiment 10, wherein the cancer is prostate cancer.
  • Embodiment 12 The method of Embodiment 11, wherein the prostate cancer is selected from one or more of the group consisting of primary or localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, advanced prostate cancer, metastatic prostate cancer, metastatic and non-metastatic castration-resistant prostate cancer, and metastatic and non-metastatic hormone-sensitive prostate cancer.
  • Embodiment 13 The method of Embodiment 12, wherein the prostate cancer is metastatic castration-resistant prostate cancer.
  • Embodiment 14 The method of Embodiment 13, wherein the prostate cancer expresses full-length androgen receptor or truncated androgen receptor splice variant.
  • Embodiment 15 The method of any one of Embodiments 9-14, wherein the administration of the pharmaceutical combination does not produce any serious adverse event to the subject.
  • Embodiment 16 The method of any one of Embodiments 9-14, wherein the administration of the pharmaceutical combination does not produce a treatment-emergent adverse event (TEAE) of Grade 3 or less or a treatment-emergent serious adverse event (TESAE) of Grade 3 or less to the subject.
  • TEAE treatment-emergent adverse event
  • TESAE treatment-emergent serious adverse event
  • Embodiment 17 The method of any one of Embodiments 9-16, wherein the pharmaceutical combination is administered before or after the patient undergoes prostatectomy for any localized prostate cancer.
  • Embodiment 18 The method of any one of Embodiments 9-17, wherein the pharmaceutical combination is administered as a neoadjuvant therapy.
  • Embodiment 19 The method of Embodiment 18, wherein the pharmaceutical combination is administered before any chemotherapy, before any radiation therapy, any hormone therapy, and/or any surgery which would be considered the main or primary treatment to the subject.
  • Embodiment 20 The method of Embodiment 19, wherein the main or primary treatment is surgery.
  • Embodiment 21 The method of Embodiment 20, wherein the surgery is a prostatectomy.
  • Example 1 Open-label Study to Evaluate the Safety, Pharmacokinetics, and AntiTumor Activity of Oral Compound A in Patients with Castration-Resistant Prostate Cancer - Phase 1
  • the overall objective of this Phase 1 study is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of daily oral dosing with Compound A in patients with progressive castration-resistant prostate cancer (CRPC).
  • PK pharmacokinetics
  • PD pharmacodynamics
  • CRPC progressive castration-resistant prostate cancer
  • Part la of the study is to evaluate the safety and tolerability of orally administered Compound A.
  • CTC circulating tumor cell
  • ctDNA circulating tumor DNA fraction
  • the exploratory objectives are aimed to molecularly characterize the disease by:
  • CgA chromogranin A
  • NSE neuron specific enolase
  • pro-GRP pro-gastrin releasing peptide
  • Part la was an open-label, multiple dose, standard 3 + 3 design study.
  • the initial dosing and evaluation period for dose-limiting toxicity (DLT) determination consisted of 28 days.
  • the dose cohorts included dose levels of 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, and 1,000 mg/day administered QD. Additional dose cohort include 400 mg BID, 600 mg BID, and 800 mg BID.
  • BID cohorts patients were limited to ⁇ 3 prior lines of therapy and one line of prior chemotherapy. Also for BID cohorts, patients with visceral metastases were excluded.
  • Dose-escalation decisions are made by the Safety Review Board (SRB). At a minimum, treatment-emergent adverse events (TEAEs), vital signs, 12-lead electrocardiogram (ECG) results, physical examination findings, clinical laboratory test results, and concomitant medications will be assessed in addition to any available PK data prior to dose-escalation decisions Dose escalation will occur by cohort until the MTD has been determined or until a consistent exposure at least comparable to the one resulting in maximum anti-tumor activity in animal models in a minimum of 3 dosed patients has been reached in the absence of DLTs.
  • SRB Safety Review Board
  • the study follows a standard 3 + 3 design in which, at a minimum, 3 patients are enrolled in each cohort sequentially until an MTD or RP2D is reached.
  • An MTD is defined according to the following standard criteria: [0363] If none of the first 3 patients in a dosing cohort experiences a protocol-defined DLT during the DLT assessment period, dose escalation will proceed with the next planned cohort.
  • RP2D(s) to be used in Part lb will be selected after review of all available safety, PK, PD, and anti -tumor activity data from Part la of the study. A 30-day safety follow-up visit will be requested 30 days from the date of the last dose.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • Enrolled patients will be allowed to escalate sequentially to a higher dose cohort if all the following are met:
  • the patient has completed 28 days of treatment at the assigned dose
  • the patient has not experienced a DLT at a lower dose
  • the patient has not met any of the criteria for study drug discontinuation; and [0375] the SRB approves the intra-patient dose-escalation. [0376] Patients may undergo more than 1 dose escalation (must meet all the above criteria for each escalation).
  • the primary safety variable for Part la of the study is the incidence of protocol-defined DLT during the DLT assessment period (first 28 days of dosing).
  • the DLTs will be characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for AEs [NCI CTCAE version 5.0]), timing, seriousness, and relationship to study drug.
  • Secondary safety variables include:
  • TEAEs characterized by type, frequency, severity, timing, seriousness, and relationship to study drug.
  • PK parameters of Compound A following single and multiple dosing including but not limited to plasma area under the concentration-time curve (AUC), maximum concentration (Cmax), observed pre-dose plasma concentration during multiple dosing (Ctrough), time to reach Cmax (T ma x), apparent terminal elimination half-life (t’ ), apparent volume of distribution during the terminal phase after extravascular administration (V z /F), apparent clearance after extravascular administration (CL/F).
  • Secondary anti-tumor variables include:
  • the Part lb is an open-label, two cohort study (two cohorts enrolling in parallel).
  • Cohort A Dose Expansion: multiple-dose expansion at the MTD or RP2D identified from Part la conducted in a patient population enrolled under the same eligibility criteria as Phase la. More than one RP2D level can be evaluated in the Dose Expansion cohort.
  • the primary objective of Cohort A is to further evaluate the safety, tolerability, PK, and preliminary anti -tumor activity of Compound A at the MTD or RP2D (as measured by changes in tumor burden measured by imaging and changes in PSA levels over time) in a patient population enrolled under the same eligibility criteria of Phase 1 Part la (Version 7.0, Amendment 6.0).
  • the primary efficacy variable for Cohort A is the proportion of patients with a decline from baseline in PSA blood concentrations of >50% and > 90% at any time point during daily dosing with Compound A.
  • Additional efficacy variables include:
  • the safety variables include:
  • TEAEs [0405] PK parameters of Compound A and any major metabolites following multiple dosing, including but not limited to plasma AUC, Cmax, Ctrough, Tmax, t’/2, Vz/F, and CL/F.
  • Cohort B (Window of Opportunity Study): a window of opportunity with clinical endpoint cohort at the MTD or RP2D identified in Part la is conducted in a small number of patients (up to 10) with nmCRPC naive to second generation anti-androgen and chemotherapy.
  • Compound A is administered orally with tablets having 50 mg, 100 mg, or 200 mg strengths, with or without food.
  • Cohort B The primary objective of Cohort B is to assess the anti -tumor activity (as measured by changes of PSA over time) of Compound A administered at the RP2D for a limited window of time (up to 12 weeks before patients start standard of care therapy) in non-metastatic CRPC (nmCRPC) unperturbed by previous second-generation anti-androgen therapies or chemotherapy.
  • nmCRPC non-metastatic CRPC
  • the primary efficacy variable for Cohort B is the proportion of patients with a decline from baseline in PSA blood concentrations of >50% and > 90% at any time point during daily dosing with Compound A at the RP2D up to Week 12.
  • the safety variables include:
  • PK parameters of Compound A and any major metabolites following multiple dosing including but not limited to plasma AUC, Cmax, Ctrough, Tmax, t’/2, Vz/F, and CL/F.
  • CRPC castration-resistant prostate cancer
  • ADT on androgen deprivation therapy
  • 3 successive rising PSA levels taken at least 1 week apart, or as defined by evidence of radiologic progression.
  • Patients may have received prior docetaxel for mCSPC or mCRPC but must not have had disease progression during, or within 6 months of completing chemotherapy. In some instances for Part la study, only one line of prior chemotherapy is allowed. In some instances for Part lb Cohort A, prior chemotherapy is not allowed.
  • PSA >1 ng/mL that has increased on at least 3 successive measurements taken at least 1 week apart;
  • Bon-sparing agents e.g., bisphosphonates, denosumab must be on stable doses for at least 4 weeks prior to enrollment.
  • Biologic anti-cancer therapy e.g., sipuleucel-T, monoclonal antibodies
  • a cytotoxic chemotherapy such as docetaxel, cabazitaxel, and estramustine
  • b Uncontrolled angina within 3 months prior to study entry;
  • c Congestive heart failure New York Heart Association (NYHA) class III or IV, or a history of congestive heart failure NYHA class III or IV unless a screening echocardiogram or multi-gated acquisition scan performed within 3 months prior to study entry results in a left ventricular ejection fraction that is > 45%;
  • NYHA New York Heart Association
  • ventricular arrhythmias e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes
  • CYP2C8 substrates e.g., daprobustat, dasabuvir, repaglinide, paclitaxel
  • sensitve substrates for CYP3A e.g., alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir, ebastine, everolimus, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, vardenafil) and CYP2B6 (e.g., bupropion).
  • CYP2B6 e.g., bupropion
  • Exclusion Criteria - for Part lb Cohort B [0493] 1. Presence of distant metastases, including visceral, nodal and bones involvement. Exception: pelvic lymph nodes ⁇ 2 cm in short axis (Nl) located below the iliac bifurcation are allowed.
  • Symptomatic loco-regional disease requiring medical intervention such as moderate or severe urinary obstruction or hydronephrosis due to primary tumor (e.g., tumor obstruction of bladder trigone).
  • CYP17 inhibitors e.g., abiraterone, orteronel, galeterone, ketoconazole.
  • Radiopharmaceutical agents e.g., Strontium-89
  • immunotherapy e.g., sipuleucel-T
  • any other investigational agent for nmCRPC e.g., sipuleucel-T
  • Herbal and non-herbal products that may decrease PSA levels (i.e., saw palmetto, pomegranate juice);
  • ventricular arrhythmias e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes
  • ventricular arrhythmias e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes
  • f History of Mobitz II second-degree or third-degree heart block.
  • narrow therapeutic index sensitive CYP2C8 substrates e.g., daprobustat, dasabuvir, repaglinide, paclitaxel
  • sensitve substrates for CYP3A e.g., alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir, ebastine, everolimus, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, vardenafil) and CYP2B6 (e.g., bupropion).
  • CYP2B6 e.g., bupropion
  • Active infection such as human immunodeficiency virus (HIV).
  • HAV human immunodeficiency virus
  • PSA progression is defined as a PSA level increase of >25% and 1 ng/mL above the nadir. A second confirmatory PSA measurement meeting the same criteria performed 3 or more weeks later is required. Patients who only have PSA progression (without radiologic or clinical progression) and who are continuing to derive some clinical benefit per Investigator’s assessment and have an acceptable safety profile may continue to receive treatment (as per PCWG3 recommendations).
  • Clinical disease progression is defined as a skeletal -related event, or an event due to metastatic prostate cancer requiring intervention (e.g., a malignant pleural effusion).
  • Skeletal-related events are defined as the following events due to bone metastatic prostate cancer: [0522] Radiation therapy to bone metastases (external beam or injected radionuclides),
  • Exclusion Criteria - for Part lb Cohort A The discontinuation criteria for patients in Part lb Cohort A are the same as Part la with the following clarification for discontinuation due to AEs:
  • Grade 3 related or possibly related AEs do not require discontinuation if the AE(s) resolve to baseline or Grade 1 within 7 days with conservative medical management, dose interruption and/or dose reductions, and restart of study drug.
  • Exclusion Criteria - for Part lb Cohort B The discontinuation criteria for patients enrolled in Part lb Cohort B are the same as listed in Part lb Cohort A. In addition, patients enrolled in this cohort will remain in study until Week 12 or development of clinical, or PSA progression, unacceptable toxicity or withdrawal of consent, whichever occurs first. Patients who withdraw consent before Week 12 in absence of disease progression and/or toxicity can be replaced.
  • Granulocyte colony stimulating factor is allowed if used per clinical guidelines (e.g., American Society of Clinical Oncology or European Society for Medical Oncology guidelines) but should not be used to meet eligibility required for hematologic laboratory parameters and cannot be used within 7 days of screening laboratories.
  • Drugs used to control bone loss are allowed if started at least 4 weeks prior to the start of study drug and continued on a stable dose throughout the study. They may not be changed or initiated during study treatment but may be stopped per standard of care.
  • Not-allowed therapies or therapies to be taken with special consideration during the study include concomitant medications that prolong the QT interval (QT) and/or the corrected QT interval (QTc).
  • Safety data including AEs coded by System Organ Class and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) and graded using NCI CTCAE version 5.0, will be summarized for Part la and Part lb separately using the safety analysis set (SAS), which consists of all patients who received at least one dose of study drug.
  • SAS safety analysis set
  • For Part la data will be presented by dose group.
  • For Part lb Cohort A data will be presented for all patients dosed at the selected dose, including patients from Part la dosed at that dose level.
  • Part lb Cohort B data will be presented for all patients dosed at the selected dose level.
  • safety data will be assessed with descriptive statistics only (i.e., no formal statistical testing will be performed on these data).
  • NSE neuron-specific enolase
  • ctDNA circulating tumor DNA Table 3.
  • n 29
  • Five patients enrolled in the Part la part of this study, receiving twice a day (BID) dose of Compound A were selected to have less advanced disease than the QD patient cohorts (Tables 4-6).
  • the patients enrolled under the BID dosing thus far have a history of fewer lines of previous therapy, longer PSA doubling time, significantly lower median baseline of % ctDNA, and do not have obvious neuroendocrine differentiation as judged by biomarkers.
  • SAEs Serious adverse events
  • Table 8 Compound A was found to be safe and well-tolerated at all dose levels studied.
  • Anti -turn or effects of Compound A in patient population were measured by: (i) changes in circulating PSA levels, (ii) changes in ctDNA levels, and (iii) radiographic changes in disease burden (CT and bone scans).
  • PSA reduction or PSA stabilization was observed in Part la patients with: no visceral disease, less DNA genomic aberrations in the non- AR oncogenic pathways, and/or those receiving less than 3 prior lines of therapy (Fig. 5).
  • the patient with the deepest PSA decline had no detectable ctDNA at baseline, consistent with a relatively low tumor burden. Molecular information for this particular patient is unavailable.
  • Circulating tumor DNA is tumor-derived fragmented DNA that is shed into a patient’s bloodstream.
  • ctDNA fraction of cell free DNA indirectly reflects the overall tumor volume/growth in a patient but also varies by tumor type and disease stage.
  • baseline tumor burden correlated with % ctDNA but not with PSA.
  • PSA is an imperfect biomarker in mCRPC, especially in late stage patients.
  • Part la QD patients demonstrated good correlation between ctDNA and overall tumor burden as measured by imaging (Fig. 6A) while a similar relationship was not observed with PSA levels (Fig. 6B). This demonstrates the complexity of interpreting PSA changes in late stage patients.
  • radiographic imaging is the primary objective measure in mCRPC and not PSA levels.
  • ctDNA levels were detected in 17 Part la QD patients. It was observed that ctDNA declined in a subset of Part la patients including patients whose PSA levels were stable or increasing and these declines were observed even in patients with wildtype AR and patients harboring AR point mutations, AR gain/amplification, and/or AR truncations, as well as with some patients with non AR mutations (Fig. 7).
  • Fig. 8 Tumor volume changes in Part la patients who were on therapy for more than 12 weeks (10 patients) and had measurable disease and scan measurements (5 patients) are shown in Fig. 8. Decreases in measurable disease were observed in all of these 5 patients even in absence of parallel PSA reduction. Decreases in measurable target lesions was observed in patients whose tumors had AR amplification and/or mutations. Of the remaining 5 patients, 4 patients had bone disease only (the fifth patient had no scan measurement available).
  • Patient A was a 79-year-old male who had previously progressed on two second- generation anti- androgens for his mCRPC (Table 9).
  • Patient A enrolled in Part la study he began treatment at the 200 mg QD level and progressively escalated dose levels up to 1000 mg QD during 18 cycles of treatment.
  • his PSA levels declined progressively reaching a nadir PSA80 between weeks 32 and 36 (Fig. 9A).
  • PSA levels continually increased despite intra-patient dose escalation as permitted by protocol. During this time he reported a good quality of life until finally progressing radiographically and discontinuing therapy around 18 months.
  • Patient B was a 71 year old male who had been previously treated with docetaxel and abiraterone (Table 10).
  • Patient B was received Compound A at 400 mg BID dosing regimen.
  • Patient B had a PSA doubling time of three months indicating aggressive disease but with a low baseline PSA level, had no circulating tumor cells, and had a relatively low ctDNA percentage of 7%.
  • Patient B’s plasma concentration of Compound A during cycle 1 on day 1 (C1D1), day 8 (C1D8), day 15 (C1D15), and day 28 (C1D28) are shown in Fig. 10A.
  • Patient B’s Compound A AUC at steady state was approximately 500,000 ng h/mL.
  • SD stable disease
  • CR complete response
  • PD progressive disease

Abstract

La présente divulgation concerne en général l'utilisation thérapeutique de N-(4-((4-(2-(3-chloro-4-(2-chloroéthoxy)-5-cyanophényl)propan-2-yl)phénoxy)méthyl)pyrimidin-2-yl)méthanesulfonamide ou d'un sel, solvate, stéréoisomère ou promédicament pharmaceutiquement acceptable de celui-ci dans le traitement du cancer. La présente divulgation concerne en particulier le traitement du cancer de la prostate, tel que le cancer de la prostate métastatique résistant à la castration .
PCT/US2023/026227 2022-06-26 2023-06-26 Inhibiteur du récepteur des androgènes à domaine n-terminal et utilisations associées WO2024006207A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263355623P 2022-06-26 2022-06-26
US63/355,623 2022-06-26

Publications (1)

Publication Number Publication Date
WO2024006207A1 true WO2024006207A1 (fr) 2024-01-04

Family

ID=89381239

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/026227 WO2024006207A1 (fr) 2022-06-26 2023-06-26 Inhibiteur du récepteur des androgènes à domaine n-terminal et utilisations associées

Country Status (1)

Country Link
WO (1) WO2024006207A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200247763A1 (en) * 2018-10-18 2020-08-06 Essa Pharma, Inc. Androgen receptor modulators and methods for their use
WO2020198710A1 (fr) * 2019-03-28 2020-10-01 Essa Pharma, Inc. Compositions et associations pharmaceutiques comprenant des inhibiteurs du récepteur des androgènes et leurs utilisations
WO2020198711A1 (fr) * 2019-03-28 2020-10-01 Essa Pharma, Inc. Modulateurs du récepteur des androgènes et méthodes associées à utiliser en tant que ligands chimères ciblant la protéolyse
US20210323931A1 (en) * 2020-04-17 2021-10-21 Essa Pharma, Inc. Solid forms of an n-terminal domain androgen receptor inhibitor and uses thereof
US20220105093A1 (en) * 2020-09-16 2022-04-07 Essa Pharma, Inc. Pharmaceutical compositions and combinations comprising inhibitors of the androgen receptor and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200247763A1 (en) * 2018-10-18 2020-08-06 Essa Pharma, Inc. Androgen receptor modulators and methods for their use
WO2020198710A1 (fr) * 2019-03-28 2020-10-01 Essa Pharma, Inc. Compositions et associations pharmaceutiques comprenant des inhibiteurs du récepteur des androgènes et leurs utilisations
WO2020198711A1 (fr) * 2019-03-28 2020-10-01 Essa Pharma, Inc. Modulateurs du récepteur des androgènes et méthodes associées à utiliser en tant que ligands chimères ciblant la protéolyse
US20210323931A1 (en) * 2020-04-17 2021-10-21 Essa Pharma, Inc. Solid forms of an n-terminal domain androgen receptor inhibitor and uses thereof
US20220105093A1 (en) * 2020-09-16 2022-04-07 Essa Pharma, Inc. Pharmaceutical compositions and combinations comprising inhibitors of the androgen receptor and uses thereof

Similar Documents

Publication Publication Date Title
US20220105093A1 (en) Pharmaceutical compositions and combinations comprising inhibitors of the androgen receptor and uses thereof
Molife et al. Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC)
US11491149B2 (en) Anti-androgens for the treatment of non-metastatic castration-resistant prostate cancer
JP2002128696A (ja) 肺高血圧の治療
JP2009511569A (ja) チピファルニブの新規ｉｖ調合物
WO2022221661A1 (fr) Compositions pharmaceutiques comprenant des inhibiteurs du récepteur des androgènes et leurs utilisations
WO2024006207A1 (fr) Inhibiteur du récepteur des androgènes à domaine n-terminal et utilisations associées
US20210038578A1 (en) Method of treating cancer
WO2023034916A1 (fr) Compositions et associations pharmaceutiques comprenant des inhibiteurs du récepteur des androgènes et leurs utilisations
US11723898B2 (en) Androgen receptor inhibitors for the treatment of non-metastatic castration-resistant prostate cancer in subjects with severe hepatic impairment
US20230218717A1 (en) Administration of CEBP-Beta Antagonist and Methods of Use
KR20200013644A (ko) 간세포 암종의 치료
CN118055763A (zh) 包含雄激素受体抑制剂的药物组合物和组合及其用途
EP4364742A1 (fr) Composition pharmaceutique pour le traitement de tumeurs solides
WO2023148345A1 (fr) Niraparib et acétate d'abiratérone plus prednisone pour améliorer des résultats cliniques chez des patients ayant un cancer de la prostate résistant à la castration métastatique et des modifications de hrr
TW202329970A (zh) 包含cdk4抑制劑之用於治療癌症之方法及給藥方案
EP4301356A1 (fr) Traitement du cancer du sein au moyen d'amcenestrant et de palbociclib
WO2024076626A1 (fr) Méthodes de traitement de troubles médiés par le récepteur des oestrogènes
WO2024039691A1 (fr) N-(1-((r)-1-acryloylazépan-3-yl)-7-chloro-6-(((r)-tétrahydrofuran-3-yl)oxy)-1h-benzo[d]imidazol-2-yl)-2-méthylisonicotinamide (nx-019) destiné à être utilisé dans le traitement du cancer à mutation de l'egfr

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23832202

Country of ref document: EP

Kind code of ref document: A1