Dosage regimen for the treatment of cancer

Abstract

This specification relates to AZD9833 for use in the treatment of cancer and to methods of treating cancer comprising the administration of AZD9833, in each case administered orally once daily at a dose of 25 mg to 450 mg. AZD9833 can be administered alone or in combination with an additional anti-cancer agent such as a CDK inhibitor, everolimus, or an AKT inhibitor.

Description

Technical Field

[0001] This specification relates to N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridine-3-amine (AZD9833, compound (I) below) for use in the treatment of cancer, which is characterized in that it is for once-daily oral administration at a defined dose. This specification also relates to a treatment method comprising oral administration of AZD9833 once daily at a defined dose to a patient in need thereof, the use of AZD9833 for the manufacture of a medicament for once-daily oral administration at a defined dose, a pharmaceutical composition comprising a specific amount of AZD9833, and a kit of such a pharmaceutical composition.

Chemical Formula

Background Art

[0002] Estrogen receptor alpha (ERα, ESR1, NR3A) and estrogen receptor beta (ERβ, ESR2, NR3B) are steroid hormone receptors that are members of the large nuclear receptor family. Structurally similar to all nuclear receptors, ERα is composed of six functional domains (named A - F) (Non - Patent Document 1), and after association with a specific ligand (the female sex steroid hormone 17β - estradiol (E2)), the complex binds to a genomic sequence named estrogen receptor element (ERE) and interacts with co - regulatory factors to regulate the transcription of target genes, thus being classified as a ligand - dependent transcription factor. The ERα gene is located at 6q25.1, encodes a 595AA protein, and multiple isoforms can be produced due to alternative splicing and translation start sites. This receptor contains an N - terminal (A / B) domain, a hinge (D) domain that links the C and E domains, and a C - terminal extension (F domain) in addition to the DNA - binding domain (domain C) and the ligand - binding domain (domain E). The C and E domains of ERα and ERβ are completely conserved (96% and 55% amino acid identity respectively), while the A / B, D, and F domains are not well conserved (less than 30% amino acid identity). Both receptors are involved in the regulation and development of female reproductive organs and further play roles in the central nervous system, cardiovascular system, and bone metabolism. The genomic action of ER occurs in the nucleus of cells when this receptor binds directly (direct activation or classical pathway) or indirectly (indirect activation or non - classical pathway) to ERE. In the absence of ligand, ER associates with heat - shock proteins Hsp90 and Hsp70, and the associated chaperone mechanism stabilizes the ligand - binding domain (LBD) and enables contact with the ligand. Ligand - bound ER dissociates from the heat - shock proteins, resulting in a conformational change of the receptor, allowing dimer formation, DNA binding, interaction with co - activators or co - repressors, and regulation of target gene expression. In the non - classical pathway, AP - 1 and Sp - 1 are alternative regulatory DNA sequences used by both isoforms of the receptor to regulate gene expression.In this example, ER interacts through association with other DNA-binding transcription factors, such as c-Jun or c-Fos, rather than directly with DNA (Non-Patent Document 2). The exact mechanism by which ER acts on gene transcription has not been fully elucidated, but it is thought to be mediated by a number of nuclear factors recruited by DNA-binding receptors. Recruitment of co-regulatory factors is mainly mediated by two protein surfaces, AF2 and AF1, located in the E domain and A / B domain, respectively. AF1 is regulated by growth factors, and its activity depends on the cellular environment and promoter environment. On the other hand, the activity of AF2 depends entirely on ligand binding. These two domains can act independently, but maximal ER transcriptional activity is achieved through synergistic interactions via these two domains (Non-Patent Document 3). Although ER is regarded as a transcription factor, it can also act through non-genomic mechanisms, as is evident from the rapid ER effects on a time scale that is too early for genomic effects in tissues after E2 administration. It is unclear whether the receptor responsible for the rapid action of estrogen is the same nuclear ER or another G-protein-coupled steroid receptor (Non-Patent Document 4), but an increase in the number of pathways induced by E2, such as the MAPK / ERK pathway, and activation of endothelial nitric oxide synthase and the PI3K / Akt pathway have been confirmed. In addition to ligand-dependent pathways, ERα has been shown to have ligand-independent activity via AF-1, which is associated with stimulation of MAPK through growth factor signaling, such as insulin-like growth factor 1 (IGF-1) and epidermal growth factor (EGF). The activity of AF-1 depends on phosphorylation of Ser118, and an example of cross-talk between ER and growth factor signaling is phosphorylation of Ser118 by MAPK in response to growth factors such as IGF-1 and EGF (Non-Patent Document 5).

[0003] Many structurally different compounds have been shown to bind to the ER. There are compounds that act as receptor agonists, such as the endogenous ligand E2, and there are also compounds that competitively inhibit E2 binding and act as receptor antagonists. These compounds can be divided into two classes according to their functional effects. Selective estrogen receptor modulators (SERMs), such as tamoxifen, have the ability to act as both receptor agonists and antagonists depending on the cellular context, promoter context, and the targeted ER isoform. For example, tamoxifen acts as an antagonist in the breast but as a partial agonist in bone, the cardiovascular system, and the uterus. All SERMs seem to act as AF2 antagonists and derive their partial agonist properties via AF1. A second group, of which fulvestrant is an example, is classified as a complete antagonist and can block estrogen activity by completely inhibiting the AF1 and AF2 domains through the induction of a specific conformational change in the ligand-binding domain (LBD) upon compound binding, which completely prevents the interaction between helix 12 and the rest of the LBD and blocks cofactor recruitment (Non-Patent Document 6; Non-Patent Document 7).

[0004] The intracellular level of ERα is downregulated via the ubiquitin / proteasome (Ub / 26S) pathway in the presence of E2. Polyubiquitination of ligand-bound ERα is catalyzed by at least three enzymes. Ubiquitin activated by ubiquitin-activating enzyme E1 is conjugated to lysine residues by E2 through an isopeptide bond by an E3 ubiquitin ligase, and then polyubiquitinated ERα is directed to the proteasome for degradation. ER-dependent transcriptional regulation and proteasome-mediated ER degradation are linked (Non-Patent Document 8), but transcription per se is not required for ERα degradation, and assembly of the transcription initiation complex is sufficient to target ERα for nuclear proteasomal degradation. This E2-induced degradation process is thought to be necessary for its ability to rapidly activate transcription in response to demands regarding cell growth, differentiation, and metabolism (Non-Patent Document 9). Fulvestrant is also classified as a selective estrogen receptor degrader (SERD), a subset of antagonists that can also induce rapid downregulation of ERα via the 26S proteasome pathway. In contrast, SERMs such as tamoxifen can increase ERα levels, but the effect on transcription is similar to that seen with SERDs.

[0005] Approximately 70% of breast cancers express ER and / or progesterone receptors, suggesting that the growth of these tumor cells is hormone-dependent. Other cancers, such as those of the ovary and endometrium, are also thought to have growth that is dependent on ERα signaling. Treatment options for such patients can inhibit ER signaling by any of the following: antagonizing the ligand that binds to ER, such as tamoxifen, which is used to treat early and advanced ER-positive breast cancer in both premenopausal and postmenopausal settings; antagonizing and downregulating ERα, such as fulvestrant, which is used to treat breast cancer in women who have progressed despite treatment with tamoxifen or an aromatase inhibitor; or blocking estrogen synthesis, such as an aromatase inhibitor, which is used to treat early and advanced ER-positive breast cancer. These treatments have had a very beneficial impact on breast cancer treatment, but a significant number of patients whose tumors express ER develop new resistance to existing ER therapies or develop resistance to these therapies over time. Several different mechanisms have been described to explain resistance to initial tamoxifen therapy. This mainly includes a switch from the antagonistic to the agonistic action of tamoxifen due to a lower affinity of specific cofactor binding to the tamoxifen-ERα complex (offset by overexpression of these cofactors), or due to the formation of secondary sites that promote the interaction of the tamoxifen-ERα complex with cofactors that normally do not bind to this complex. Thus, resistance can occur as a result of the growth of cells expressing specific cofactors that promote tamoxifen-ERα activity. There is also a possibility that other growth factor signaling pathways directly activate the ER receptor or coactivator, promoting cell growth independent of ligand signaling.

[0006] More recently, mutations in ESR1 have been identified as resistance mechanisms that can occur at variable frequencies of 17-25% in tumor samples and patient-derived xenograft models (PDX) from metastatic ER-positive patients. These mutations are predominant but not exclusive in the ligand-binding domain and result in mutated functional proteins. Examples of amino acid changes include Ser463Pro, Val543Glu, Leu536Arg, Tyr537Ser, Tyr537Asn, and Asp538Gly, and changes at amino acids 537 and 538 constitute the majority of the changes described to date. These mutations have not been detected to date in the genomes of primary breast cancer samples characterized in the Cancer Genome Atlas database. Among 390 primary breast cancer samples that were ER expression positive, no mutations were detected in ESR1 (Non-Patent Document 10). Mutations in the ligand-binding domain are thought to occur as a response to resistance to aromatase inhibitor endocrine therapy because these mutant receptors exhibit basal transcriptional activity in the absence of estradiol. The crystal structures of ER mutated at amino acids 537 and 538 showed that both mutations shift the position of helix 12, enabling coactivator recruitment, and thereby favorably acting on the agonist conformation of ER by mimicking wild-type ER activated by an agonist. Published data indicate that endocrine therapies, such as tamoxifen and fulvestrant, can still bind to ER mutants and can inhibit transcriptional activation to some extent, and that fulvestrant can degrade Try537Ser, but higher doses may be required for complete receptor inhibition (Non-Patent Document 11; Non-Patent Document 12; Non-Patent Document 13). Therefore, at this stage, it is unclear whether ESR1 mutations are associated with changes in clinical outcomes, but there is a possibility that compound (I) or a pharmaceutically acceptable salt thereof (described later) can downregulate mutant ER and antagonize mutant ER.

[0007] Regardless of which resistance mechanism or combination of mechanisms occurs, much still relies on ER-dependent activity, and removing the receptor via the SERD mechanism provides the best way to remove the ERα receptor from cells. Fulvestrant is currently the only SERD approved for clinical use, but despite its mechanistic properties, its current monthly dose is limited to 500 mg, which results in less than 50% receptor turnover in patient samples compared to the complete downregulation of receptors seen in in vitro breast cell line experiments, thus limiting the efficacy of this drug (Non-Patent Document 14).

[0008] AZD9833, namely N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine (optionally provided as its pharmaceutically acceptable salt), has been identified as a compound having the ability to act as a selective estrogen receptor degrader (SERD). AZD9833 is described as Example 17 of Patent Document 1, which discloses the synthesis method of the compound and its biological activity in in vitro and in vivo experiments. Furthermore, in contrast to fulvestrant, the only SERD currently approved for clinical use and administered by intramuscular injection, AZD9833 has been shown in preclinical studies to have a physicochemical profile compatible with oral administration.

[0009] Given its advantageous properties, it was hypothesized that daily oral administration of AZD9833 may achieve better estrogen receptor degradation than that achieved by fulvestrant. As described for the first time herein, preliminary results of clinical trials on daily oral administration of AZD9833 led to the identification of a dose range that resulted in a partial response demonstrated according to the RECIST criteria (e.g., according to the RECIST 1.1 criteria (https: / / recist.eortc.org / ; see Non-Patent Document 15)) in patients who received heavy pre-treatment.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Non-Patent Documents

[0011]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

[0012] The object of the present specification is to provide an appropriate dosage and administration regimen for the use of AZD9833 in the treatment of cancer, for example, for use in the treatment of breast cancer. [[Means for Solving the Problems]]

[0013] In a first aspect of the present specification, AZD9833 for use in the treatment of cancer is provided, and AZD9833 is orally administered once a day at a dosage of 25 mg to 450 mg.

[0014] In a second aspect of the present specification, there is provided a method for treating cancer, which includes administering AZD9833 once a day to a patient in need thereof at a dose of 25 mg to 450 mg.

[0015] In a third aspect of the present specification, there is provided the use of AZD9833 in the manufacture of a medicament for treating cancer, and AZD9833 is orally administered once a day at a dose of 25 mg to 450 mg.

[0016] In a fourth aspect of the present specification, there is provided a pharmaceutical composition for once-daily oral administration, which includes 25 mg to 450 mg of AZD9833 and a pharmaceutically acceptable excipient.

[0017] In a fifth aspect of the present specification, there is provided a pharmaceutical composition for once-daily oral administration, which includes 25 mg to 450 mg of AZD9833 for use in treating cancer and a pharmaceutically acceptable excipient.

[0018] In a sixth aspect of the present specification, there is provided a kit including a pharmaceutical composition including AZD9833 and at least one pharmaceutically acceptable excipient, and instructions for use of the pharmaceutical composition in the treatment of cancer, wherein AZD9833 is for administration once a day at a dose of 25 mg to 450 mg.

[0019] For a better understanding of the present specification, reference is made to the following drawings.

Brief Description of the Drawings

[0020]

Figure 1

Figure 2

Figure 3

Figure 4

[0021] The invention detailed herein should not be construed as being limited to any of the recited embodiments or examples. Other embodiments will be readily apparent to the reader, who is skilled in the art.

[0022] "A" or "an" means "at least one". In any embodiment where "a" or "an" is used to denote a given element, "a" or "an" may mean one. In any embodiment where "a" or "an" is used to denote a given element, "a" or "an" may mean 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0023] When reference is made to "in some embodiments", a particular feature may be present, and that feature may be present not only in the appropriate embodiments of the same section or text area of this specification, but also in the appropriate embodiments in any part of this specification.

[0024] The claims are embodiments.

[0025] Therapeutic Use In one embodiment, AZD9833 for use in the treatment of cancer is provided, and AZD9833 is administered orally once a day at a dose of 25 mg to 450 mg.

[0026] In one embodiment, AZD9833 for use in producing an anti-proliferative effect is provided, and AZD9833 is administered orally once a day at a dose of 25 mg to 450 mg.

[0027] In one embodiment, AZD9833 for selectively inhibiting ERα is provided, and AZD9833 is orally administered once a day at a dose of 25 mg to 450 mg.

[0028] In one embodiment, the use of AZD9833 in the manufacture of a medicament for the treatment of cancer is provided, and AZD9833 is orally administered once a day at a dose of 25 mg to 450 mg.

[0029] In one embodiment, the use of AZD9833 in the manufacture of a medicament for producing an anti-proliferative effect is provided, and AZD9833 is orally administered once a day at a dose of 25 mg to 450 mg.

[0030] In one embodiment, the use of AZD9833 in the manufacture of a medicament for selectively inhibiting ERα is provided, and AZD9833 is orally administered once a day at a dose of 25 mg to 450 mg.

[0031] In one embodiment, a method for treating cancer in a human or animal patient in need of cancer treatment is provided, the method comprising orally administering AZD9833 to the patient once a day at a dose of 25 mg to 450 mg.

[0032] In one embodiment, a method for producing such an effect in a human or animal patient in need of an anti-proliferative effect is provided, the method comprising orally administering AZD9833 to the patient once a day at a dose of 25 mg to 450 mg.

[0033] In one embodiment, a method for selectively inhibiting ERα in a human or animal patient in need of such an effect is provided, the method comprising orally administering AZD9833 to the patient once a day at a dose of 25 mg to 450 mg.

[0034] Compound In some embodiments, AZD9833 can be N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine or a pharmaceutically acceptable salt thereof. N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine has the structure of compound (I) described above.

[0035] In some embodiments, AZD9833 can be N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine in free salt form (e.g., in neutral form or zwitterionic form, or in free base form for example).

[0036] In some embodiments, AZD9833 can be a pharmaceutically acceptable salt of N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine.

[0037] The term "pharmaceutically acceptable" is used to indicate that the subject (e.g., salt, dosage form, or excipient) is suitable for use in a patient. An exemplary list of pharmaceutically acceptable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use", P.H. Stahl and C.G. Wermuth, editors, Weinheim / Zurich: Wiley-VCH / VFiCA, 2002 or subsequent editions.

[0038] Suitable pharmaceutically acceptable salts of N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine are, for example, acid addition salts. The acid addition salts of N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine can be formed by contacting the compound with a suitable inorganic or organic acid under conditions known to those skilled in the art.

[0039] The acid addition salts can be formed, for example, using inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. The acid addition salts can also be formed using organic acids selected from acetic acid, adipic acid, benzenesulfonic acid, benzoic acid, cinnamic acid, citric acid, D,L-lactic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, hydrochloric acid, L-tartaric acid, maleic acid, malic acid, malonic acid, methanesulfonic acid, napadisylic acid, phosphoric acid, saccharin, succinic acid, sulfuric acid, p-toluenesulfonic acid, toluenesulfonic acid, and trifluoroacetic acid.

[0040] Further suitable pharmaceutically acceptable salts of N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine are, for example, salts formed in the body of a human or animal after administration of N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine into the body of the human or animal.

[0041] Dosage level In some embodiments, the dosage of AZD9833 can be selected from 25 mg, 75 mg, 150 mg, 300 mg, and 450 mg.

[0042] In some embodiments, the dosage of AZD9833 can be 25 mg.

[0043] In some embodiments, the dosage of AZD9833 can be 75 mg.

[0044] In some embodiments, the dosage of AZD9833 can be 150 mg.

[0045] In some embodiments, the dosage of AZD9833 can be 300 mg.

[0046] In some embodiments, the dosage of AZD9833 can be 450 mg.

[0047] In some embodiments, the dosage of AZD9833 can be an oral daily dosage.

[0048] "Oral daily dosage" is the amount of AZD9833 administered orally within 24 hours.

[0049] In some embodiments, AZD9833 can be administered as a single dose.

[0050] In some embodiments, AZD9833 can be administered as a divided dose.

[0051] "Divided dose" is a dosage in which the total dosage (e.g., oral daily dosage) is administered in multiple (e.g., 1, 2, 3, 4, or 5) portions.

[0052] In some embodiments, AZD9833 can be administered as a single-dose unit or multiple-dose units.

[0053] The "administration unit" is an individual dosage form, for example, a specific number (e.g., 1, 2, 3, 4, or 5) of tablets or capsules.

[0054] In some embodiments, AZD9833 can be administered as a single tablet.

[0055] In some embodiments, AZD9833 can be administered once daily as a single tablet.

[0056] In some embodiments, AZD9833 can be administered orally once daily as a single tablet.

[0057] For the sake of clarity, when the dosage range of AZD9833 is indicated herein, for example, at a dosage of 25 mg to 450 mg, the range includes the dosages at the endpoints of the range, and the dosages in between those endpoints, i.e., 25 mg and 450 mg and the amounts in between.

[0058] Cancer "Cancer" is used interchangeably with tumor and lesion herein. Cancer may include not only primary cancer but also secondary cancer and metastases.

[0059] "Treatment of cancer", "treating cancer" and similar terms encompass treating existing cancer and / or preventing cancer.

[0060] In some embodiments, treatment of cancer or treating cancer may mean treating cancer and preventing cancer.

[0061] In some embodiments, treatment of cancer or treating cancer may mean treating cancer.

[0062] In some embodiments, treatment of cancer or treating cancer may mean preventing cancer.

[0063] In some embodiments, cancer can be selected from breast cancer and gynecological cancers.

[0064] "Gynecological cancers" include uterine cancer, ovarian cancer, cervical cancer, vulvar cancer, and vaginal cancer.

[0065] In some embodiments, the cancer can be selected from breast cancer, uterine cancer, ovarian cancer, cervical cancer, vulvar cancer, and vaginal cancer.

[0066] In some embodiments, the cancer can be ER-positive HER2-negative breast cancer.

[0067] "ER-positive HER2-negative breast cancer" includes tumors that have estrogen receptors (ER-positive) and do not have high levels of the HER2 gene or HER2 protein (HER2-negative). The ER-positive and HER2-negative status can be measured by methods known in the art, including the use of commercially available kits.

[0068] In some embodiments, the breast cancer can be ER-positive breast cancer.

[0069] In some embodiments, the breast cancer can be HER2-negative breast cancer.

[0070] In some embodiments, the cancer can be ER-positive HER2-negative advanced breast cancer.

[0071] In some embodiments, the breast cancer can be ER-positive advanced breast cancer.

[0072] In some embodiments, the breast cancer can be HER2-negative advanced breast cancer.

[0073] Patient Selection In some embodiments, AZD9833 can be administered to premenopausal or postmenopausal women.

[0074] In some embodiments, AZD9833 can be administered to premenopausal women.

[0075] In some embodiments, AZD9833 can be administered to postmenopausal women.

[0076] In some embodiments, AZD9833 can be administered to premenopausal or postmenopausal women with ER-positive cancer.

[0077] In some embodiments, AZD9833 can be administered to premenopausal or postmenopausal women with HER2-negative cancer.

[0078] In some embodiments, AZD9833 can be administered to premenopausal or postmenopausal women with ER-positive and HER2-negative cancer.

[0079] In some embodiments, AZD9833 can be administered to premenopausal or postmenopausal women with cancer having an ESR1 mutation.

[0080] In some embodiments, AZD9833 can be administered to premenopausal or postmenopausal women with cancer not having an ESR1 mutation.

[0081] In some embodiments, AZD9833 can be administered to patients whose cancer has been treated with 1 to 15 prior anti-cancer therapies.

[0082] In some embodiments, AZD9833 can be administered to patients whose cancer has been treated with 1 to 10 prior anti-cancer therapies.

[0083] In some embodiments, AZD9833 can be administered to patients whose cancer has been treated with 1 to 5 prior anti-cancer therapies.

[0084] In some embodiments, AZD9833 can be administered to patients whose cancer has been treated with 5 to 10 prior anti-cancer therapies.

[0085] If a patient has been "previously treated", this refers to any treatment administered to the patient prior to administration of AZD9833. "Previous treatment" does not mean that the treatment was successful or curative, but simply that the patient received treatment with that treatment method (for example, as a result of the treatment method being prescribed by a qualified healthcare provider).

[0086] "Anticancer therapy" includes agents, drugs, compounds, or other medical techniques (for example, treatment using the patient's own immunological agents) aimed at treating cancer. Examples of anticancer therapy are endocrine therapy and chemotherapy.

[0087] "Endocrine therapy" acts by modulating the patient's hormonal pathways. Examples include estrogen inhibitors (such as tamoxifen or fulvestrant), aromatase inhibitors (such as letrozole, anastrozole, vorazole, or exemestane), progestogens (such as megestrol acetate), and luteinizing hormone blockers (such as leuprolide or goserelin).

[0088] "Chemotherapy" is a cancer therapy that is not endocrine therapy. Chemotherapy includes, for example, the following: i. Conventional anti-proliferative / anti-cancer drugs and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea); antimetabolites (e.g., gemcitabine and folic acid antimetabolites, such as fluoropyrimidines (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines (e.g., adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mitramycin)); mitotic inhibitors (e.g., vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), and taxoids (e.g., taxol and taxotere), and polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins (e.g., etoposide and tenoposide), amsacrine, topotecan, and camptothecin); ii. Inhibitors of growth factor function and downstream signaling pathways thereof, such as any growth factor or Ab modulator of a growth factor receptor target, such as those reviewed by Stern et al., Critical Reviews in Oncology / Haematology, 2005, 54, pp11 - 29; small molecule inhibitors of such targets, such as kinase inhibitors. Specific examples include the anti - erbB2 antibodies trastuzumab [Herceptin (trademark)] and pertuzumab [Perjeta (trademark)], the antibody - drug conjugates trastuzumab deruxtecan [Enhertu (trademark)] and trastuzumab emtansine [Kadcyla (trademark)] targeting HER - 2, the anti - EGFR antibody panitumumab, the anti - EGFR antibody cetuximab [Erbitux, C225], and tyrosine kinase inhibitors (inhibitors of the erbB receptor family, such as the epidermal growth factor family receptor (EGFR / erbB1), tyrosine kinase inhibitors such as gefitinib, osimertinib, or erlotinib, erbB2 tyrosine kinase inhibitors such as lapatinib, and mixed inhibitors of erb1 / 2 such as afatinib). Other exemplary classes of growth factors and their receptor modulators include, for example, inhibitors of the hepatocyte growth factor family or their receptors (including c - met and ron); inhibitors of the insulin and insulin - like growth factor family or their receptors (IGFR, IR), inhibitors of the platelet - derived growth factor (PDGFR) family or their receptors, and inhibitors of signal transduction mediated by other receptor tyrosine kinases, such as c - kit, AnLK, and CSF - 1R; modulators targeting signal transduction proteins of the PI3 - kinase signaling pathway, such as inhibitors of PI3 - kinase isoforms (e.g., PI3K - α, PI3K - β).PI3K-γ and PI3K-δ, and serine / threonine kinases, such as AKT (e.g., capivasertib, afuresertib, miransertib, ARQ751, ipataserib, MK-2206, or perifosine), mTOR (e.g., AZD2014 or everolimus), PDK, SGK, PI4K, or PIP5K; inhibitors of serine / threonine kinases not listed above, such as raf inhibitors like vemurafenib, MEK inhibitors like selumetinib (AZD6244), Abl inhibitors like imatinib or nilotinib, Btk inhibitors like ibrutinib, acalabrutinib, and zanubrutinib, Syk inhibitors like fostamatinib, aurora kinase inhibitors (e.g., AZD1152), inhibitors of other serine / threonine kinases (e.g., JAK, STAT, and IRAK4), and cyclin-dependent kinases, such as CDK1, CDK4, CDK6, CDK7, CDK9, and inhibitors of CDK4 / 6 (e.g., palbociclib, ribociclib, abemaciclib, lerociclib, and trilaciclib); iii. Modulators of the DNA damage signaling pathway, such as PARP inhibitors (e.g., olaparib, rucaparib, niraparib, and talazoparib), ATR inhibitors (e.g., AZD6738), or ATM inhibitors; iv. Modulators of the apoptosis pathway and cell death pathway, such as Bcl family modulators (e.g., ABT-263 / Navitoclax, ABT-199); v. Anti-angiogenic agents, such as those that inhibit the effect of vascular endothelial growth factor, such as the anti-vascular endothelial growth factor antibody bevacizumab (Avastin (trademark)), or VEGF receptor tyrosine kinase inhibitors, such as sorafenib, axitinib, pazopanib, sunitinib, or vandetanib (and compounds that act by other mechanisms (e.g., linomid, inhibitors of integrin function, and angiostatin); vi. Vascular damaging agents, such as combretastatin A4; vii. Anti-infiltrating agents, such as c-Src kinase family inhibitor-like (dasatinib, J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloprotease inhibitors (such as marimastat), inhibitors of urokinase plasminogen activator receptor function, or antibodies against heparanase); viii. Immunotherapy (e.g., ex vivo and in vivo techniques for increasing the immunogenicity of patient tumor cells, such as transfection with cytokines (e.g., interleukin 2, interleukin 4, or granulocyte macrophage colony-stimulating factor), techniques for reducing T cell anergy, techniques using transfected immune cells such as cytokine-transfected dendritic cells, techniques using cytokine-transfected tumor cell lines, and techniques using anti-idiotype antibodies). Specific examples include monoclonal antibodies targeting PD-1 (e.g., pembrolizumab, nivolumab, cemiplimab), monoclonal antibodies targeting PD-L1 (e.g., durvalumab, atezolizumab, or avelumab), or monoclonal antibodies targeting CTLA4 (e.g., ipilimumab and tremelimumab); ix. Antisense or RNAi-based therapies, such as those targeting the targets listed herein; and x. Gene therapy techniques (e.g., techniques for replacing abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy), such as techniques using cytosine deaminase, thymidine kinase, or bacterial nitroreductase enzymes, and techniques for increasing the patient's resistance to chemotherapy or radiotherapy, such as multidrug resistance gene therapy).

[0089] In some embodiments, AZD9833 can be administered to patients whose cancer has been treated previously with one or more endocrine therapies and two or fewer chemotherapy regimens.

[0090] In some embodiments, AZD9833 can be administered to patients whose cancer has previously been treated with one or more endocrine therapies for ER-positive HER2-negative breast cancer and one or two chemotherapies.

[0091] "Chemotherapy for ER-positive HER2-negative breast cancer" can include any anti-cancer regimen that includes at least one cytotoxic agent administered for 21 days or more.

[0092] In some embodiments, AZD9833 can be administered to patients whose cancer has previously been treated with one or more endocrine therapies for ER-positive HER2-negative advanced breast cancer and one or two chemotherapies.

[0093] In some embodiments, the one or more endocrine therapies can be selected from estrogen inhibitors, aromatase inhibitors, progestogens, and luteinizing hormone blockers.

[0094] In some embodiments, the one or more endocrine therapies can be selected from tamoxifen, toremifene, raloxifene, droloxifene, idoxifene, fulvestrant, letrozole, anastrozole, vorazole, exemestane, megestrol acetate, leuprolide, and goserelin.

[0095] In some embodiments, the one or two chemotherapies can be selected from CDK inhibitors (e.g., CD4 inhibitors, CDK6 inhibitors, or CDK4 / CDK6 dual inhibitors), and mTOR inhibitors.

[0096] In some embodiments, the one or two chemotherapies can be selected from palbociclib, ribociclib, abemaciclib, trilaciclib, lerociclib, and everolimus.

[0097] In some embodiments, AZD9833 can be administered to patients whose cancer is resistant to aromatase inhibitors.

[0098] In some embodiments, AZD9833 can be administered to patients in whom the cancer is resistant to non-steroidal aromatase inhibitors.

[0099] In some embodiments, AZD9833 can be administered to patients in whom the cancer is resistant to aromatase inhibitors selected from letrozole and anastrozole.

[0100] When a patient's cancer is "resistant" (or refractory) to a particular drug or treatment, the cancer no longer responds adequately to that treatment, and that treatment is no longer considered an appropriate medical option. In such cases, the attending physician will recommend an alternative treatment approach.

[0101] In some embodiments, AZD9833 can be administered to patients in whom the cancer is resistant to tamoxifen.

[0102] In some embodiments, AZD9833 can be administered to patients in whom the cancer is resistant to fulvestrant.

[0103] In some embodiments, AZD9833 can be administered to patients in whom the cancer is resistant to CDK inhibitors.

[0104] Pharmacokinetic and pharmacodynamic properties In one embodiment, AZD9833 for use in the treatment of cancer is provided, wherein AZD9833 is administered orally once daily at a dose of 25 mg to 450 mg and reaches an average maximum plasma concentration of 10 to 1000 ng / mL in cancer patients.

[0105] "Average maximum plasma concentration" refers to the maximum amount of AZD9833 that reaches the patient's plasma after treatment.

[0106] In one embodiment, AZD9833 for use in the treatment of cancer is provided, wherein AZD9833 is administered orally once daily at a dose of 25 mg to 450 mg and reaches a median terminal phase half-life of 8 to 14 hours in cancer patients.

[0107] In one embodiment, AZD9833 for use in the treatment of cancer is provided, and AZD9833 is orally administered once a day at a dose of 25 mg to 450 mg and reaches the median terminal-phase half-life in cancer patients.

[0108] The "median terminal-phase half-life" is the median time for the drug plasma concentration in the patient to be halved after reaching pseudo-equilibrium.

[0109] Clinical Characteristics In one embodiment, AZD9833 for use in the treatment of cancer is provided, and AZD9833 is orally administered once a day at a dose of 25 mg to 450 mg and achieves an objective response rate of 10% to 20%.

[0110] The "objective response rate" refers to the proportion of patients who have a measurable disease at baseline and whose response measured by the RECIST criteria is confirmed 17 weeks or more after the first dose or 15 weeks or more after the post-treatment scan date.

[0111] In one embodiment, AZD9833 for use in the treatment of cancer is provided, and AZD9833 is orally administered once a day at a dose of 25 mg to 450 mg and achieves a clinical utility rate of 25% to 100%.

[0112] The "clinical utility rate" refers to the proportion of patients who show confirmation or stabilization of response measured by the RECIST criteria for more than 23 weeks after treatment, 25 weeks or more after the first dose or 23 weeks or more after the post-treatment scan date.

[0113] In one embodiment, AZD9833 for use in the treatment of cancer is provided, and AZD9833 is orally administered once a day at a dose of 25 mg to 450 mg and achieves a clinical utility rate of more than 25%.

[0114] In one embodiment, AZD9833 for use in the treatment of cancer is provided, and AZD9833 is orally administered once a day at a dose of 25 mg to 450 mg and achieves a clinical utility rate of 25% to 90%.

[0115] In one embodiment, AZD9833 for use in the treatment of cancer is provided, and AZD9833 is administered orally once a day at a dose of 25 mg to 450 mg, achieving a clinical utility rate of 25% to 80%.

[0116] In one embodiment, AZD9833 for use in the treatment of cancer is provided, and AZD9833 is administered orally once a day at a dose of 25 mg to 450 mg, achieving a clinical utility rate of 25% to 75%.

[0117] In one embodiment, AZD9833 for use in the treatment of cancer is provided, and AZD9833 is administered orally once a day at a dose of 25 mg to 450 mg, and does not cause any serious side effects in cancer patients.

[0118] In some embodiments, serious side effects can be defined as grade 4 or 5 adverse events.

[0119] "Grade 4 or 5 adverse events" can be classified according to the Common Terminology Criteria for Adverse Events (CTCAE).

[0120] Combination therapy In one embodiment, AZD9833 for use in the treatment of cancer is provided, and AZD9833 is administered orally once a day at a dose of 25 mg to 450 mg in combination with a further anti-cancer therapy.

[0121] When a drug is administered "in combination with" AZD9833, the combination can include separate, sequential, or simultaneous administration of the drugs. If the treatments are separate and / or sequential, the interval between the dose of AZD9833 and the dose of the further anti-cancer therapy can be selected such that the combined treatment effect is ensured.

[0122] In some embodiments, the administration of AZD9833 and the administration of the further anti-cancer therapy are separate.

[0123] In some embodiments, the administration of AZD9833 and the administration of a further anti-cancer therapy are sequential.

[0124] In some embodiments, the administration of AZD9833 and the administration of a further anti-cancer therapy are separate and sequential.

[0125] In some embodiments, the further anti-cancer therapy can be a CDK inhibitor.

[0126] In some embodiments, the further anti-cancer therapy can be a CDK4 inhibitor.

[0127] In some embodiments, the further anti-cancer therapy can be a CDK6 inhibitor.

[0128] In some embodiments, the further anti-cancer therapy can be a CDK4 / CDK6 dual inhibitor.

[0129] In some embodiments, the further anti-cancer therapy can be a CDK inhibitor selected from palbociclib, ribociclib, abemaciclib, lerociclib, or trilaciclib.

[0130] In some embodiments, the further anti-cancer therapy can be palbociclib.

[0131] In some embodiments, the further anti-cancer therapy can be an mTOR inhibitor.

[0132] In some embodiments, the further anti-cancer therapy can be an mTOR inhibitor selected from sirolimus, deforolimus, everolimus, and temsirolimus.

[0133] In some embodiments, the further anti-cancer therapy can be everolimus.

[0134] In some embodiments, the further anti-cancer therapy can be everolimus orally administered once daily at a dose of up to 10 mg.

[0135] In some embodiments, the additional anti-cancer therapy may be selected from palbociclib, ribociclib, abemaciclib, lerociclib, trilaciclib, and everolimus.

[0136] In some embodiments, the additional anti-cancer therapy may be selected from palbociclib, ribociclib, abemaciclib, lerociclib, and trilaciclib.

[0137] In some embodiments, the additional anti-cancer therapy may be an AKT inhibitor.

[0138] In some embodiments, the additional anti-cancer therapy may be selected from capivasertib, afuresertib, milciclib, ARQ751, ipatasertib, MK-2206, or perifosine.

[0139] Composition In one embodiment, a composition for once-daily oral administration is provided, comprising 25 mg to 450 mg of AZD9833 and a pharmaceutically acceptable excipient.

[0140] In some embodiments, the pharmaceutically acceptable excipient may be selected from inert diluents (such as microcrystalline cellulose or dicalcium phosphate anhydrous), granulating agents, disintegrants (such as sodium starch glycolate), binders, lubricants (such as magnesium stearate), preservatives, antioxidants, and chelating agents.

[0141] In some embodiments, the composition for once-daily oral administration comprises 25 mg to 450 mg of AZD9833, such as 25 mg, 75 mg, or 100 mg of AZD9833, and at least one diluent selected from microcrystalline cellulose (MCC), dicalcium phosphate anhydrous (DCPA), mannitol, lactose, dicalcium phosphate, calcium sulfate dihydrate, tribasic calcium phosphate, dibasic calcium phosphate dihydrate, siliconized microcrystalline cellulose, their co-processed combinations, polydextrose, trehalose, sucrose, glucose, cyclodextrin, and hydroxypropyl cellulose.

[0142] The composition for once-daily oral administration may further comprise at least one disintegrant selected from croscarmellose sodium, crospovidone, sodium starch glycolate (SSG), and low-substituted hydroxypropyl cellulose (L-HPC).

[0143] The composition for once-daily oral administration may further comprise at least one lubricant selected from magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate, and stearic acid.

[0144] Dosage form In one embodiment, a pharmaceutical composition is provided that comprises 25 mg to 450 mg of AZD9833 and a pharmaceutically acceptable excipient in the form of a tablet or capsule for once-daily oral administration.

[0145] The tablet formulation may or may not be coated, or may be coated to adjust its disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve its stability and / or appearance, and in any case, conventional coating agents and procedures known in the art are used. For example, the tablet formulation may be processed to release the active ingredient immediately.

[0146] In one embodiment, a pharmaceutical composition is provided that comprises AZD9833 in an amount of 25 mg to 450 mg, such as 25 to 100 mg of AZD9833, and a pharmaceutically acceptable excipient, and the composition is an immediate release composition.

[0147] In one embodiment, a pharmaceutical composition is provided that comprises AZD9833 in an amount of 25 mg to 450 mg, such as 25 to 100 mg of AZD9833, and a pharmaceutically acceptable excipient, in the form of a single tablet for once-daily oral administration.

[0148] In addition to tablets, the composition for oral use may alternatively be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil.

[0149] In one embodiment, a pharmaceutical composition is provided that comprises AZD9833 in an amount of 25 mg to 450 mg, such as 25 to 100 mg of AZD9833, and a pharmaceutically acceptable excipient, in the form of a single capsule for once-daily oral administration.

[0150] In one embodiment, the use of a pharmaceutical composition is provided that comprises AZD9833 in an amount of 25 mg to 450 mg, such as 25 to 100 mg of AZD9833, and a pharmaceutically acceptable excipient, in the treatment of cancer, and the pharmaceutical composition is administered once daily.

[0151] Kit In one embodiment, a kit is provided that comprises a pharmaceutical composition comprising AZD9833 and at least one pharmaceutically acceptable excipient, and instructions for the use of the pharmaceutical composition in the treatment of cancer, wherein the AZD9833 is for once-daily administration at a dose of 25 mg to 450 mg.

[0152] In one embodiment, - a pharmaceutical composition comprising AZD9833 and at least one pharmaceutically acceptable excipient; - an additional anti-cancer agent for administration in combination with AZD9833; - An instruction manual for the use of a pharmaceutical composition in the treatment of cancer, and a kit is provided, wherein AZD9833 is for once-daily administration at a dose of 25 mg to 450 mg.

[0153] In one embodiment, - A pharmaceutical composition comprising AZD9833 and at least one pharmaceutically acceptable excipient; - An additional anti-cancer agent for administration in combination with AZD9833; - An instruction manual for the use of a pharmaceutical composition in the treatment of cancer, and a kit is provided, wherein AZD9833 is for once-daily administration at a dose of 25 mg to 450 mg.

[0154] In one embodiment, - A pharmaceutical composition comprising AZD9833 and at least one pharmaceutically acceptable excipient; - An additional anti-cancer agent selected from palbociclib, ribociclib, abemaciclib, or trilaciclib for administration in combination with AZD9833; - An instruction manual for the use of a pharmaceutical composition in the treatment of cancer, and a kit is provided, wherein AZD9833 is for once-daily administration at a dose of 25 mg to 450 mg.

Example

[0155] Clinical Trial Protocol Summary: To determine the optimal dosing regimen of AZD9833, a Phase 1 dose escalation and dose expansion were conducted in ER-positive, HER2-negative advanced breast cancer patients according to the following basic protocol.

[0156] Rationale: AZD9833 may provide clinical benefits superior to existing endocrine therapies through improved bioavailability (compared to intramuscular fulvestrant) and improved target (estrogen receptor) binding and modulation in estrogen receptor-positive (ER+) breast cancer patients. The primary objective of this study is to determine the safety and tolerability of AZD9833 in women with ER+ human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Additionally, the pharmacokinetics and preliminary antitumor activity of AZD9833 will be investigated.

[0157] Primary Objectives and Endpoints:

[0158]

Table 1

[0159] Secondary Objectives and Endpoints:

[0160]

Table 2

[0161] Exploratory Objectives and Endpoints:

[0162]

Table 3

[0163] Overall Design: This study is a first-in-human, multi-center, dose-escalation and dose-expansion trial (Parts A and B) designed to evaluate the safety and tolerability of AZD9833 alone in women with endocrine-resistant ER+HER2- breast cancer who are ineligible for curative-intent treatment.

[0164] In Part A of the trial, dose escalation of AZD9833 alone is possible. For these parts, a "cohort" consists of all patients administered at that particular dose level in the dose escalation scheme shown in Figure 1. In Part B (expansion) of the trial, eligible subjects are randomized to receive a selected dose of AZD9833 based on the findings in Part A.

[0165] Throughout the trial, premenopausal subjects take AZD9833 with LHRH agonist basal therapy (see basal therapy drug).

[0166] Part A: Administer AZD9833 to eligible premenopausal and postmenopausal subjects. For the first administration, the first patient in each cohort is followed up until day 8, after which additional patients are assigned to the cohort at that dose level. See Section 6.1.5.5. If there are sufficient evaluable subjects (3 - 6 subjects) for a decision on dose escalation, optionally, the cohort can be expanded to include additional subjects (up to a maximum of 12 evaluable subjects per cohort), and / or a cohort can be opened at the next dose level. In Part A of the trial, a maximum of 8 dose level cohorts are anticipated. Stop escalation at MTD / MFD. Part A includes at least 2 subjects with paired tumor biopsy material at each dose level.

[0167] In the dose escalation phase of the trial, determine the MTD or MFD of AZD9833 based on the evaluation of safety, tolerability, and PK data collected during the first 28 days of daily dosing. The dose escalation and de-escalation plan for evaluating AZD9833 follows a Bayesian flow adaptive design scheme (Neuenschwander et al., Stat Med. 2008, 15:2420) that combines prior expectations regarding the dose - toxicity relationship, applies the data at the end of each cohort, and recommends the dose for the next cohort. After establishing safety and tolerability after treating the first subject in each dose level cohort for at least 7 days, incorporate up to 3 additional subjects to ensure at least 3 evaluable subjects in 28 days.

[0168] Optional expansion with increasing doses is included at the doses of AZD9833, and these doses are such that the preclinically predicted pharmacodynamic effects on ER are greater than those of fulvestrant, which is the appropriate standard of care for this disease situation. This allows subjects to obtain early the opportunity to be administered the drug at therapeutically possible doses and the opportunity to further investigate the safety, tolerability, and pharmacological and biological activity profiles of AZD9833. The expanded dose levels are based on newly obtained data and are approved by the Safety Review Committee (SRC).

[0169] The expansion of part A of the trial also involves enrolling at least two subjects suitable for paired in-trial tumor biopsies to enable a preliminary assessment of the tumor pharmacodynamic effects over a wider range of doses than considered in part B.

[0170] Part B: Eligible premenopausal subjects (n = 12) are administered AZD9833 300 mg (the highest of the three selected dose levels in part A), and postmenopausal subjects (n = 36) are randomized 1:1:1 to receive either AZD9833 300 mg, AZD9833 150 mg, or AZD9833 75 mg. Part B includes at least five subjects in each of the four treatment groups (premenopausal with dose 300 mg, postmenopausal with dose 300 mg, postmenopausal with dose 150 mg, postmenopausal with dose 75 mg) for whom paired biopsy material is evaluable.

[0171] In Part B, it will be possible to further evaluate the safety profile of AZD9833 at three different dose levels in a larger group of postmenopausal subjects. The purpose of examining the three dose levels is to ensure that in future AZD9833 trials, the dose recommended for further clinical investigation can be reliably selected in both the context of advanced breast cancer and, in some cases, early disease / adjuvant therapy settings. A randomized design will be applied to the allocation of 36 subjects to one of the three tolerated dose levels in Part A, facilitating a reliable comparison of the safety profiles by avoiding allocation bias or any other potential experimental bias. In Part B, up to 12 premenopausal subjects can also be allocated to the highest dose (300 mg) of the three doses that were considered safe and well-tolerated in Part A.

[0172] Part B also includes enrolling a subset of subjects suitable for paired on-treatment tumor biopsies (n = 15 postmenopausal (i.e., 5 per dose level) and n = 5 premenopausal at the 300 mg dose level) to enable further evaluation of the pharmacodynamic effects.

[0173] Study Population: Future approval of protocol deviations from the inclusion and incorporation criteria, also known as protocol waivers or exemptions, is not permitted. To be assigned / randomized to AZD9833, each subject must meet all selection criteria and none of the exclusion criteria. Under no circumstances can an exception be made to this rule. Subjects who do not meet the registration requirements are screening failures.

[0174] Included subjects are defined as those who have signed the informed consent. Treated subjects are those who have received at least one dose of AZD9833. In Parts B and D, included subjects will be randomized to treatment groups. Randomized subjects are defined as those who have been randomized and have received a randomization number.

[0175] Selection Criteria: A patient is eligible for inclusion in this trial only if they meet all of the following selection criteria and none of the exclusion criteria. 1. Provide signed and dated written informed consent prior to any required study-specific procedures, sample collection, and analyses. If a subject refuses to participate in optional exploratory research and / or genetic components of the trial, there will be no penalty or loss of benefits to the subject, nor will the subject be excluded from other aspects of the trial. 2. Be at least 18 years of age. 3. Be in one of the following postmenopausal states. (a) Premenopausal women must have initiated treatment with an LHRH agonist at least 4 weeks prior to starting AZD9833 and must intend to continue LHRH agonist therapy throughout the study period. (b) Postmenopausal as defined by meeting at least one of the following criteria: (i) Have had bilateral oophorectomy. (ii) Be 60 years of age or older. (iii) Be 50 years of age or older, have had no regular menses for 12 months or more, have a healthy uterus, and have not received oral contraception or hormone replacement therapy prior to breast cancer diagnosis. (iv) Be less than 60 years of age, have had no regular menses for 12 months or more, and have follicle-stimulating hormone (FSH) and estradiol levels in the postmenopausal range (using the range by the local clinical laboratory). (c) Those who do not meet the definition of postmenopausal are considered premenopausal. 4. Histological or cytological confirmation of breast adenocarcinoma. 5. The estrogen receptor positive status of the documented primary or metastatic tumor tissue according to local clinical examination parameters (such that those clinical examination parameters comply with acceptable diagnostic guidelines, for example, American Society of Clinical Oncology / College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer (Hammond et.al.2010)). HER2- defined as an immunohistochemistry (IHC) score of 0 or 1+, or negative for in situ hybridization (ISH; FISH / CISH / SISH). In the case of IHC2+, ISH must be negative. The evaluation of the ER and HER2 status, if available, shall be based on the most recent tumor biopsy sample. 6. Metastatic disease or locally recurrent disease refractory or intolerant to existing therapies known to provide clinical benefit. 7. Prior chemotherapy, endocrine therapy, and other therapies as follows. (a) Two or fewer lines of chemotherapy for progressive disease. (b) Recurrence or progression on at least one line of endocrine therapy in the setting of progressive / metastatic disease. (c) There is no limit to the number of prior lines of endocrine therapy. (d) Prior treatment with CDK4 / 6 inhibitors is permitted. The chemotherapy line for progressive disease is an anticancer regimen that includes at least one cytotoxic chemotherapy agent and is administered for 21 days or more. If the cytotoxic chemotherapy regimen was discontinued for reasons other than disease progression and the continuation was less than 21 days, this regimen does not count as a prior line of chemotherapy. Repeated administration of the same anticancer regimen at distant times does not count as a new line of chemotherapy. 8. Metastatic or locally recurrent disease that is refractory or intolerant to existing therapies known to provide clinical benefit. 9. Women of childbearing potential must agree to use one highly effective method of contraception (as defined by the contraception methods in Section 5.3.1) from the time of screening until 4 weeks after discontinuation of AZD9833, must not be breastfeeding, and must have a negative pregnancy test before initiation of dosing. 10. At least one lesion (measurable and / or non-measurable according to the Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1], accurately evaluable at baseline, suitable for repeated evaluation by computed tomography (CT), magnetic resonance imaging (MRI), or plain X-ray; or by clinical examination). Lesions that are only blastic in bone are not considered evaluable. 11. Eastern Cooperative Oncology Group (ECOG) / World Health Organization (WHO) performance status of 0 - 1, no worsening in the past 2 weeks, and a minimum life expectancy of 12 weeks.

[0176] Exclusion Criteria: Patients must not participate in the study if they meet any of the following exclusion criteria. 1. Therapeutic intervention by any of the following: (a) Any cytotoxic chemotherapy, investigational agent, or other anti-cancer drug for the treatment of advanced breast cancer by a past treatment regimen or clinical trial within 14 days of the first dose of AZD9833. (b) Pharmaceuticals or herbal supplements known to be strong inhibitors / inducers of cytochrome P450 3A4 / 5 (CYP3A4 / 5) substrates and highly sensitive cytochrome P450 2B6 (CYP2B6) substrates (commonly prescribed drugs are listed in Appendix B), or pharmaceuticals or herbal supplements that cannot be discontinued within the washout period defined in Appendix B before the first dose of AZD9833 is administered. (c)Drugs known to prolong QT and known to have a risk of torsade de pointes. (d)Palliative radiotherapy to a limited radiation field within 1 week of the first dose of AZD9833, except for patients who receive radiation to more than 30% of the bone marrow or to a wide radiation field within 4 weeks of the first dose of AZD9833. (e)Major surgical procedures or significant trauma judged by the principal investigator within 4 weeks of the first dose of AZD9833, or the need for any surgery requiring major surgery and / or general anesthesia is anticipated during the trial. 2.Any unresolved toxicity (excluding alopecia) from previous therapies that exceeds Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the start of AZD9833. 3.The presence of life-threatening metastatic visceral disease or uncontrolled central nervous system (CNS) metastatic disease judged by the principal investigator. Patients with spinal cord compression and / or brain metastases can be included if they have been treated radically (e.g., surgery or radiotherapy) and are stable off steroids for at least 4 weeks prior to the start of AZD9833. 4.Severe or uncontrolled systemic diseases (including uncontrolled hypertension and active bleeding diathesis), or infections requiring, for example, intravenous antibiotic therapy, that in the opinion of the principal investigator are not desirable for the patient to participate in the trial, or that threaten compliance with the protocol, or any evidence of active infections (requiring antiviral treatment) including hepatitis B, hepatitis C, and human immunodeficiency virus (HIV). 5.Any of the following cardiac criteria: (a)The mean of the resting QT intervals corrected by Fridericia's formula (QTcF) obtained from three electrocardiograms (ECGs) exceeds 470 milliseconds. (b)Any clinically significant abnormalities in the rhythm, conduction, or morphology of the resting ECG (e.g., complete left bundle branch block, second-degree heart block, and third-degree heart block), or clinically significant sinus arrest. Patients with controlled atrial fibrillation can be included. (c) Any factor that increases the risk of QTc prolongation or arrhythmic events, such as symptomatic heart failure, hypokalemia, congenital long QT syndrome, direct family history (family history of long QT syndrome or sudden unexplained death under 40 years of age). Hypertrophic cardiomyopathy and clinically significant valvular stenosis disease. (d) Experience of any of the following procedures or conditions in the past 6 months: coronary artery bypass grafting, angioplasty, vascular stent, myocardial infarction, unstable angina, New York Heart Association (NYHA) class 2 or higher congestive heart failure, cerebrovascular disorder, or transient ischemic attack. (e) Poorly controlled hypertension. Although hypertensive patients may be eligible, blood pressure needs to be appropriately controlled at baseline. The patient may be rescreened regarding blood pressure requirements. 6. Insufficient bone marrow reserve or organ function indicated by any of the following clinical laboratory values: (a) Absolute neutrophil count (ANC) < 1.5 × 10^9 / L. (b) Platelet count < 100 × 10^9 / L. (c) Hemoglobin < 90 g / L. (d) Alanine aminotransferase (ALT) > 2.5 times the upper limit of normal (ULN). (e) Aspartate aminotransferase (AST) > 2.5 times the ULN. (f) Total bilirubin (TBL) > 1.5 times the ULN or > 3 times the ULN in the presence of Gilbert syndrome (unconjugated hyperbilirubinemia) documented in the medical record. (g) Glomerular filtration rate (GFR) < 50 mL / min. 7. Involvement in the planning and conduct of this trial. 8. Refractory nausea and vomiting, poorly controlled chronic gastrointestinal (GI) disease, the prescribed product being dysphagic, or a past major bowel resection that prevents adequate absorption of AZD9833. A history of hypersensitivity to the active or inactive excipients of AZD9833, or a drug having a chemical structure or class similar to AZD9833. 9. The judgment of the principal investigator that the patient should not participate in the trial if the patient is unlikely to comply with the procedures, restrictions, and requirements of the trial. 10. Male subjects are excluded from this study.

[0177] Investigational treatment: AZD9833 administered as 25 mg and 100 mg tablets. AZD9833 is administered orally once daily initially. AZD9833 should be taken at approximately the same time each morning, regardless of food intake. The SRC may decide to require administration of AZD9833 with food or in the fasting state (i.e., fast for at least 2 hours before and 1 hour after each AZD9833 dose) depending on newly available study data. Another dosing frequency or intermittent schedule of AZD9833 may be initiated according to the recommendations of the SRC based on newly available safety, tolerability, and PK data.

[0178] Dosing starts at 75 mg once daily. At each dose level, one subject is exposed and monitored until Day 8. For details, after each dose level during the dose escalation phase of the study, the SRC evaluates all available safety information. After reviewing the data for each cohort, the SRC agrees to a decision to stop dosing or enrollment of subsequent cohorts. Dose escalation and de-escalation are determined by the SRC. In the proposed dose escalation scheme, it is possible in principle to double the dose in each cohort (e.g., 75 mg, 150 mg, 300 mg, etc.). However, the SRC may test another or intermediate dose level after reviewing the safety data.

[0179] At least 2 subjects at each dose level in Part A and at least 5 subjects in each cohort in Part B are selected as suitable and willing to provide paired biopsy samples, one pre-treatment and one during treatment. If subjects are selected for provision of paired biopsy materials and this becomes clinically infeasible during their treatment, individual cohorts may be expanded by recruiting additional biopsy-eligible subjects until the required number of evaluable biopsy pairs are collected in each cohort.

[0180] There is no maximum treatment period, and the subject may continue to receive AZD9833 as long as the treating investigator determines that there is continued clinical benefit. If AZD9833 is discontinued for reasons other than disease progression, the subject must continue tumor assessments until disease progression or until further lines of anti-cancer therapy are administered.

[0181] Dose-limiting toxicity (DLT): DLT is defined as an AE or abnormal clinical laboratory value occurring from the first administration of AZD9833 through day 28 of cycle 1 (DLT period), is evaluated to be unrelated to disease progression, concurrent illness, or concomitant medications, and meets any of the following criteria despite optimal therapeutic intervention: (a) Any death not clearly attributable to underlying disease or external causes (b) The following hematologic toxicities (CTCAE): (i) Any grade 4 or greater hematologic toxicity present continuously for more than 4 days or requiring transfusion, G-CSF, or erythropoietin. (ii) Any grade 3 or greater neutropenia with fever of 38.5°C or higher and / or systemic infection for any duration. (iii) Any grade 3 or greater thrombocytopenia with bleeding for any duration. (iv) Grade 4 thrombocytopenia (regardless of duration or bleeding) (c) Any non-hematologic toxicity of CTCAE grade 3 or greater, provided the following conditional provisions are met: (i) Grade 3 or greater nausea of CTCAE continuously for more than 3 days despite maximum anti-emetic therapy. (ii) Grade 3 or greater vomiting of CTCAE continuously for more than 3 days despite maximum anti-emetic therapy. (iii) Grade 4 or greater vomiting of CTCAE (regardless of duration) (iv) Grade 3 or greater diarrhea of CTCAE continuously for more than 3 days despite maximum anti-diarrheal therapy. (v) Grade 4 or greater diarrhea of CTCAE (regardless of duration) (vi) Grade 3 or greater fatigue of CTCAE lasting more than 4 days. (vii) An increase in creatinine of CTCAE grade 3 or higher. (d) Other toxicities: (i) A QTcF value exceeding 500 milliseconds, or a QTcF prolongation from baseline of 60 milliseconds and a QTcF value exceeding 480 milliseconds, confirmed by at least two separate ECGs. (ii) An ECG QT corrected interval prolongation of CTCAE grade 4 or higher. (iii) An increase in serum / plasma AST, or a TBL of 2 times or more the ULN simultaneously with an ALT of 3 times or more the ULN. (e) Any other of the following toxicities: (i) Those that exceed baseline, are clinically significant and / or unacceptable despite optimal therapeutic intervention, and are judged by the SRC to be DLTs, or (ii) Those for which the dosing schedule is interrupted for more than 14 days despite optimal therapeutic intervention.

[0182] Baseline treatment medications: Premenopausal women need to initiate treatment with an LHRH agonist at least 4 weeks before starting AZD9833 and need to continue LHRH agonist therapy throughout the study period.

[0183] Efficacy evaluation: Antitumor activity is evaluated using RECIST 1.1 by the evaluation of the principal investigator of the trial. The baseline tumor evaluation needs to include all known predilection sites for metastases in the disease under evaluation and needs to further investigate areas that may be affected based on the signs and symptoms of individual subjects. The baseline evaluation is to be carried out within 28 days before the start of AZD9833, ideally as close as possible to the start of AZD9833. The evaluation method used at baseline is to be used in each subsequent evaluation during the treatment part and follow-up part of the trial. Any other sites where a new disease is suspected are also to be appropriately imaged.

[0184] If unscheduled assessments are conducted and the subject has not progressed, or if the subject is continuing to take AZD9833, or until the subject progresses, all attempts will be made to conduct subsequent assessments at the scheduled visit. The classification of objective tumor response assessments is based on the RECIST 1.1 guidelines for response (Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD)). For subjects who have only non-measurable disease at baseline, the classification of objective tumor response assessments is based on the RECIST 1.1 guidelines for response in non-target lesions (NTL) (CR, PD, and non-CR / non-PD). If the principal investigator is unsure whether progression has occurred (especially in the presence of a response to NTL or the appearance of new lesions), it is recommended that AZD9833 be continued and the subject's status be reassessed at the next scheduled assessment or earlier if clinically necessary. To reach "unequivocal progression" based on non-target disease, even if there is SD or PR in the target disease, the overall level in the non-target disease needs to deteriorate substantially to the extent that the total tumor burden has increased sufficiently to warrant treatment discontinuation. A slight increase in the size of one or more NTL is usually not sufficient to be considered a state of obvious disease progression.

[0185] Safety and Clinical Assessments: The safety and tolerability of AZD9833 are the primary objectives of this study. The relevant outcome measures are DLT, AE / SAE, vital signs, clinical chemistry / hematology, and ECG.

[0186] Clinical Laboratory Assessments of Clinical Safety: Clinical chemistry, hematology, urine tests, and coagulation will be performed at the clinical laboratory of the principal investigator's trial site or a local clinical laboratory near it. The sample tubes and sample sizes may vary depending on the testing methods used and the daily practices at the trial site.

[0187] Pharmacokinetics: The characterization of the pharmacokinetics of single and multiple doses of AZD9833 is a secondary objective of this study. If there are residual samples remaining after PK analysis, they may be used to identify, characterize, and establish the concentrations of AZD9833 metabolites and drug-related products in plasma and / or to conduct exploratory biomarker studies. The analysis of AZD9833 in plasma and urine will be performed using appropriate bioanalytical methods. All details regarding the methods to be used are described in a separate bioanalytical report.

[0188] Analyze all samples that are within the known stability of the analyte of interest at the time the biological laboratory receives them. Additionally, PK samples can be subjected to further analysis to identify, characterize, and establish the concentrations of metabolites in plasma. The results of such analysis will be reported separately from the clinical study report. If there is a reproducibility analysis of incurred samples, it will be performed along with the bioanalysis of the study samples. The results of the evaluation will not be reported in the clinical study report but will be reported separately in the bioanalytical report.

[0189] Pharmacodynamics: Pharmacodynamic measurements will be performed on several biomarkers (e.g., optional tumor biopsy material, ctDNA in plasma, CTC, and archived tumor tissue). Biological samples (archived tumor tissue, mandatory and optional biopsy material if applicable) will be collected for the analysis of tumor DNA as an exploratory objective of this study. 2 mL of blood samples for DNA isolation will be collected from subjects who have consented to participate in the genetic analysis component of this study, prior to the administration of the first dose of AZD9833. If for any reason the samples are not collected prior to dosing, they may be collected at any visit up to the final study visit. During the study, only one sample for genetic research will be collected per subject. Participation is optional. Subjects who do not wish to participate in the genetic research can still participate in this study.

[0190] Biomarkers: The following samples for exploratory biomarker studies are either optional or mandatory as indicated and will be collected from appropriate subjects.

[0191] In Part A, paired tumor biopsy samples are collected from at least two subjects at each dose level. In Part B, these biopsy materials are collected from at least five postmenopausal subjects for each dose level of AZD9833 (300 mg, 150 mg, and 75 mg), as well as from at least five premenopausal subjects at 300 mg. If a subject wishes to participate in this part of the trial, the subject signs a biopsy-specific written informed consent. The paired tumor biopsy materials are obtained from subjects with accessible tumors who have consented to the biopsy. An accessible lesion is defined as a tumor lesion that is biopsyable and suitable for repeat biopsies.

[0192] Pre-treatment biopsy materials are collected during screening as close as possible to the start of treatment. Samples during treatment are to be collected on Day 1 (±7 days) of Cycle 2, but may be collected outside of this time frame if there is agreement with AstraZeneca. At disease progression or at the end of treatment, additional (optional) tumor biopsy materials are also to be collected. Biomarkers to be investigated using the tumor samples may include, but are not necessarily limited to, ER, PgR, Ki67, genomic / gene changes, and other ER regulatory gene expression. Where feasible, collection of tumor biopsy materials at disease progression is encouraged. This sample is used to investigate changes in pathway signaling and potential mechanisms of resistance (i.e., evidence of gene changes or alternative pathway activation).

[0193] If available, formalin-fixed tumor tissues for storage, embedded in paraffin blocks, are collected from all subjects. If baseline biopsy samples can also be collected, recovery of diagnostic tumor material for storage is still necessary to provide data on how the tumor has developed since diagnosis. Storage samples can be obtained from the primary tumor and / or metastatic sites, and if possible, the most recently obtained storage sample is required. If tumor blocks cannot be submitted, unstained slides newly prepared from the stored tumor blocks are acceptable. Cores can be removed from the submitted stored tumor blocks to construct tissue microarrays for subsequent biomarker analysis. The remainder of the tumor blocks may be returned to the facility.

[0194] For the evaluation of cancer antigen CA15, one 2-mL blood sample is collected at each time point.

[0195] Blood samples are collected at each time point. These samples are collected to obtain a preliminary assessment of the AZD9833 activity of the tumor by evaluating changes in pharmacodynamic biomarkers (which may include, but are not limited to, the total number and expression levels of ER, Ki67 protein, and ER-regulated genes).

[0196] One 10-mL blood sample is collected at the following time points to obtain two plasma samples and one serum sample for each time point. Samples are collected and stored to enable retrospective exploratory biomarker analysis, and the samples are analyzed for a series of oncology biomarkers that may correlate with drug response.

[0197] For the preparation of RNA and microRNA / RNA samples, two 2.5-mL whole blood samples are collected in PAXgene tubes. RNA analysis can be performed to generate hypotheses related to the mechanism of action of the molecules evaluated in the study and, in some cases, to identify changes in gene expression that correlate with treatment response.

[0198] Collect one 20 mL blood sample at the time of screening and 10 mL blood samples at all other time points to obtain plasma. This is used for the extraction and analysis of ctDNA to analyze predictive biomarkers and pharmacodynamic biomarkers and to examine changes in gene changes and potential mechanisms of resistance.

[0199] Results of clinical trials A clinical trial was conducted using 60 patients according to the above protocol. The results can be summarized as follows.

[0200] Sixty patients (median age 61 years (range 39 - 79 years)) were treated over 5 administrations (25 mg QD n = 12, 75 mg QD n = 12, 150 mg QD n = 13, 300 mg QD n = 13, 50 mg QD n = 10). Exposure to AZD9833 was proportional to the dose after multiple administrations, and the median terminal phase t1 / 2 was 12 hours.

[0201] Treatment-related AEs experienced by more than 10% of patients were visual impairment (53%; 91% G1, 6% G2, 3% G3), bradycardia / sinus bradycardia (45%; 93% G1, 7% G2), nausea (18%; 46% G1, 55% G2), fatigue (13%; 38% G1, 63% G2), dizziness (10%; 83% G1, 17% G3), vomiting (10%; 50% G1, 33% G2, 17% G3), and asthenia (10%; 67% G1, 33% G2). Three patients experienced DLTs, which were G3 QTcF prolongation (300 mg); G3 vomiting (450 mg); and the co-occurrence of G2 visual impairment, G2 headache, and G2 gait disturbance (450 mg). DLT cases were managed by dose reduction. There were no reports of G4 or 5 AEs. None of the observed AEs were considered clinically significant.

[0202] Efficacy data (objective response rate (ORR) and clinical benefit rate (CBR) at the 24-week time point) are shown in the following table.

[0203]

Table 4

[0204] Regulation of the ER signaling pathway was observed in all dose cohorts. In patients in whom clinical efficacy occurred and paired biopsy materials were obtained, a 98% decrease in Ki67 was measured.

[0205] These data indicate that AZD9833 has promising efficacy and a dose-dependent safety profile. Evidence of clinical benefit and target engagement was observed at all dose levels in all women with ER+ABC, including patients pretreated with CDK4 / 6 inhibitors and fulvestrant, and patients with ESR1 mutations. The present invention includes the following aspects. [Item 1] AZD9833 for use in the treatment of cancer, which is orally administered once a day at a dose of 25 mg to 450 mg. [Item 2] AZD9833 for use according to Item 1, wherein the dose of AZD9833 is selected from 25 mg, 75 mg, 150 mg, 300 mg, and 450 mg. [Item 3] AZD9833 for use according to Item 1 or 2, wherein the AZD9833 is administered as a single-dose unit or multiple-dose units. [Item 4] AZD9833 for use according to Item 3, wherein the AZD9833 is administered as a single tablet. [Item 5] AZD9833 for use according to any one of Items 1 to 4, wherein the AZD9833 is administered in combination with a further anti-cancer therapy. [Item 6] AZD9833 for use according to any one of Items 1 to 5, wherein the AZD9833 is administered in combination with a CDK inhibitor. [Item 7] AZD9833 for use according to Item 6, wherein the AZD9833 is administered in combination with palbociclib, ribociclib, abemaciclib, lerociclib, or trilaciclib. [Item 8] AZD9833 for use according to any one of Items 1 to 7, wherein the AZD9833 is administered in combination with palbociclib. [Item 9] AZD9833 for use according to any one of Items 1 to 5, wherein the AZD9833 is administered in combination with an mTOR inhibitor. [Item 10] AZD9833 for use according to Item 9, wherein the AZD9833 is administered in combination with everolimus. [Item 11] AZD9833 for use according to any one of Items 1 to 10, wherein the cancer is selected from breast cancer and gynecological cancer. [Item 12] AZD9833 for use according to Item 11, wherein the cancer is ER-positive HER2-negative advanced breast cancer. [Item 13] AZD9833 for use according to any one of Items 1 to 12, wherein the AZD9833 is administered to pre-menopausal or post-menopausal women. [Item 14] AZD9833 for use according to any one of Items 1 to 13, wherein the cancer has been treated with one or more endocrine therapies and two or fewer chemotherapies for ER-positive HER2-negative advanced breast cancer. [Item 15] AZD9833 for use according to any one of Items 1 to 14, wherein the AZD9833 is administered to a patient in whom cancer is resistant to non-steroidal aromatase inhibitors. [Item 16] AZD9833 for use according to any one of Items 1 to 15, wherein the dose of AZD9833 reaches an average maximum plasma concentration of 10 to 1000 ng / mL in cancer patients. [Item 17] AZD9833 for use according to any one of Items 1 to 16, wherein the dose of AZD9833 reaches a median terminal phase half-life of 8 to 14 hours in cancer patients. [Item 18] AZD9833 for use according to any one of Items 1 to 17, wherein the dose of AZD9833 reaches a median terminal phase half-life of 12 hours in cancer patients. [Item 19] AZD9833 for use according to any one of Items 1 to 18, wherein the dose of AZD9833 achieves an objective response rate of 10% to 20%. [Item 20] AZD9833 for use according to any one of Items 1 to 19, wherein the dose of AZD9833 does not cause severe side effects in cancer patients. [Item 21] A method for treating cancer in a human or animal patient in need of cancer treatment, the method comprising orally administering AZD9833 to the patient once a day at a dose of 25 mg to 450 mg. [Item 22] Use of AZD9833 in the manufacture of a medicament for the treatment of cancer, wherein the AZD9833 is orally administered once a day at a dose of 25 mg to 450 mg. [Item 23] A pharmaceutical composition for once-daily oral administration, comprising 25 mg to 450 mg of AZD9833 and a pharmaceutically acceptable excipient. [Item 24] The pharmaceutical composition according to Item 23, wherein the amount of AZD9833 is selected from 25 mg, 75 mg, 150 mg, 300 mg, and 450 mg. [Item 25] The pharmaceutical composition according to Item 23 or Item 24, which is in the form of a single tablet. [Item 26] The pharmaceutical composition according to any one of Items 23 to 25 for use in the treatment of cancer. [Item 27] A kit comprising a pharmaceutical composition comprising AZD9833 and at least one pharmaceutically acceptable excipient, and instructions for use of the pharmaceutical composition in the treatment of cancer, wherein the AZD9833 is for once-daily administration at a dose of 25 mg to 450 mg. The kit according to item 27, further comprising an additional anti-cancer agent for administration in combination with AZD9833.

Claims

1. A medicament for treating cancer, comprising N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridine-3-amine (AZD9833): 【Chemical 1】 The medicament, wherein the AZD9833 is orally administered once a day at a dose of 75 mg or 150 mg.

2. The medicament according to claim 1, wherein the AZD9833 is administered as a single-dose unit or multiple-dose units.

3. The medicament according to claim 2, wherein the AZD9833 is administered as a single tablet.

4. The medicament according to any one of claims 1 to 3, wherein the AZD9833 is administered in combination with a CDK inhibitor.

5. The medicament according to claim 4, wherein the CDK inhibitor is palbociclib, ribociclib, abemaciclib, lerociclib, or trilaciclib.

6. The medicament according to any one of claims 1 to 5, wherein the AZD9833 is administered in combination with palbociclib.

7. The medicament according to any one of claims 1 to 3, wherein the AZD9833 is administered in combination with an mTOR inhibitor.

8. The medicament according to claim 7, wherein the mTOR inhibitor is everolimus.

9. The medicament according to any one of claims 1 to 8, wherein the cancer is selected from breast cancer and gynecological cancer.

10. The medicament according to claim 9, wherein the cancer is ER-positive HER2-negative advanced breast cancer.

11. The medicament according to any one of claims 1 to 10, wherein the AZD9833 is administered to premenopausal or postmenopausal women.

12. The medicament according to any one of claims 1 to 11, wherein the cancer has been treated with one or more endocrine therapies and two or fewer chemotherapies for ER-positive HER2-negative advanced breast cancer.

13. The medicament according to any one of claims 1 to 12, wherein the AZD9833 is administered to a patient in whom the cancer is resistant to non-steroidal aromatase inhibitors.

14. The dosage of AZD9833 reaches: i) an average maximum plasma concentration of 10 to 1000 ng / mL in cancer patients; and / or ii) a median terminal phase half-life of 8 to 14 hours in cancer patients; and / or iii) a median terminal phase half-life of 12 hours in cancer patients, the medicament according to any one of claims 1 to 13.

15. The dosage of AZD9833 achieves an objective response rate of at least 10%, the medicament according to any one of claims 1 to 14.

16. The dosage of AZD9833 does not cause severe side effects in cancer patients, the medicament according to any one of claims 1 to 15.

17. 75 mg or 150 mg of N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine (AZD9833): 【Chemical 2】 and a pharmaceutically acceptable excipient, a pharmaceutical composition for once-daily oral administration.

18. The pharmaceutical composition according to claim 17, which is in the form of a single tablet.

19. N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine (AZD9833): 【Chemical 3】 and at least one pharmaceutically acceptable excipient, a kit comprising a pharmaceutical composition and instructions for use of the pharmaceutical composition in the treatment of cancer, wherein the AZD9833 is for once-daily administration at a dosage of 75 mg or 150 mg.

20. The kit according to claim 19, further comprising an additional anti-cancer agent for administration in combination with AZD9833.

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