Dosage regimen for treating cancer

Abstract

The present application relates to dosage regimens for the treatment of cancer. The present specification relates to AZD9833 for use in the treatment of cancer and a method of cancer treatment comprising administration of AZD9833 wherein, in each case, the AZD9833 is orally administered once a day at a dose of 25 mg to 450 mg. AZD9833 can be administered alone and can also be used in combination with additional anti-cancer agents such as a CDK inhibitor, everolimus or an AKT inhibitor.

Description

[0001] This application is a divisional application of the invention patent application with the application date of April 22, 2021, application number 202180030426.X, and invention name "Dosing Regimens for the Treatment of Cancer". Technical Field

[0002] 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)pyridin-3-amine (AZD9833, hereinafter compound (I)) for the treatment of cancer, which is characterized in that the compound is orally administered once daily at a specified dose. This specification also relates to a treatment method, which involves orally administering AZD9833 once daily at a specified dose to a patient in need thereof, the use of AZD9833 in the preparation of a medicament (wherein the medicament is orally administered once daily at a specified dose), a pharmaceutical composition comprising a certain amount of AZD9833, and a kit of such a pharmaceutical composition.

[0003] Background Art

[0004] Estrogen receptor α (ERα, ESR1, NR3A) and estrogen receptor β (ERβ, ESR2, NR3b) are steroid hormone receptors, and these steroid hormone receptors are members of the large nuclear receptor family. Structurally similar to all nuclear receptors, ERα is composed of six functional domains (named A-F) (Dahlman-Wright et al., Pharmacol.Rev. Pharmacological Reviews , 2006, 58 ​: 773 - 781) and is classified as a ligand - dependent transcription factor because after its association with a specific ligand (the female sex steroid hormone 17β - estradiol (E2)), the complex binds to genomic sequences named estrogen receptor elements (EREs) and interacts with co - regulators to regulate the transcription of target genes. The ERα gene is located on 6q25.1 and encodes a 595AA protein, and due to alternative splicing and translation start sites, multiple isoforms can be produced. In addition to the DNA - binding domain (domain C) and ligand - binding domain (domain E), the receptor also contains an N - terminal (A / B) domain, a hinge (D) domain connecting domains C and E, and a C - terminal extension (F domain). Although the C and E domains of ERα and ERβ are quite conserved (96% and 55% amino - acid identity, respectively), the A / B, D, and F domains are poorly conserved (less than 30% amino - acid identity). Both receptors are involved in the regulation and development of the female reproductive tract and, in addition, play roles in the central nervous system, cardiovascular system, and bone metabolism. The genomic action of ER occurs in the nucleus of the cell, where the receptor binds to EREs either directly (direct activation or classical pathway) or indirectly (indirect activation or non - classical pathway). In the absence of ligand, ER associates with heat - shock proteins Hsp90 and Hsp70, and this associated molecular - chaperone mechanism stabilizes the ligand - binding domain (LBD) such that it is accessible to ligand. Ligand - bound ER dissociates from the heat - shock proteins, resulting in a conformational change of the receptor, which allows dimerization, 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 two isoforms of the receptor to regulate gene expression. In this instance, ER does not directly interact with DNA but associates with other DNA - binding transcription factors such as c - Jun or c - Fos (Kushner et al., PureApplied Chemistry Pure and Applied Chemistry 2003, 75 : 1757 - 1769). The precise mechanism by which ER affects gene transcription is poorly understood but appears to be mediated by multiple nuclear factors recruited by the DNA - bound receptor. The recruitment of co - regulators is mainly mediated by two protein surfaces, AF2 and AF1, which are located in the E - domain and A / B domain, respectively. AF1 is regulated by growth factors and its activity depends on the cellular and promoter environment, whereas AF2 is completely ligand - binding - activity - dependent. Although the two domains can function independently, maximal ER transcriptional activity is achieved through both domains (Tzukerman et al., Mol.Endocrinology Molecular Endocrinology , 1994, 8 ​​:(21 - 30). Although ERs are considered transcription factors, they can also act through non-genomic mechanisms, as demonstrated by rapid ER action in tissues on a timescale following E2 administration that is considered too fast for genomic action. It remains unclear whether the receptor responsible for rapid estrogen responses is the same nuclear ER or a different G protein-coupled steroid receptor (Warner et al., Steroids Steroids 2006 71 :91 - 95), but an increasing number of E2-induced pathways have been identified, such as the activation of the MAPK / ERK pathway and endothelial nitric oxide synthase and the PI3K / Akt pathway. In addition to ligand-dependent pathways, ERα has also been shown to have ligand-independent activity through AF-1, which is associated with the 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 the phosphorylation of Ser 118 and an example of the interaction between ER and growth factor signaling is the phosphorylation of Ser118 by MAPK in response to growth factors such as IGF-1 and EGF (Kato et al., Science science ,1995, 270 :1491 - 1494).

[0005] A large number of structurally different compounds have been shown to bind to ER. Some compounds such as the endogenous ligand E2 act as receptor agonists, whereas others competitively inhibit E2 binding and act as receptor antagonists. These compounds can be divided into two categories depending on 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 and promoter environment 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 appear to act as AF2 antagonists and derive their partial agonist characteristics through AF1. The second group (exemplified by fulvestrant) is classified as a complete antagonist and can block estrogen activity by complete inhibition of both the AF1 and AF2 domains through the induction of unique conformational changes in the ligand-binding domain (LBD) for compound binding, which results in the complete elimination of the interaction between helix 12 and the rest of the LBD, thereby blocking cofactor recruitment (Wakeling et al., CancerRes . Cancer Research ,1991, 51 :3867 - 3873; Pike et al., Structure structure ,2001, 9 ​​​(: 145 - 153).

[0006] The intracellular level of ERα is downregulated in the presence of E2 via the ubiquitin / proteasome (Ub / 26S) pathway. Polyubiquitination of liganded ERα is catalyzed by at least three enzymes; ubiquitin activated by ubiquitin-activating enzyme E1 is conjugated via an isopeptide bond to E2 with a lysine residue by an E3 ubiquitin ligase, and then polyubiquitinated ERα is targeted to the proteasome for degradation. Although ER-dependent transcriptional regulation and proteasome-mediated degradation of ER are related (Lonard et al., Mol.Cell Molecular Cell , 2000 5 : 939 - 948), transcription itself is not required for ERα degradation, and assembly of the transcriptional initiation complex is sufficient to target ERα for nuclear proteasomal degradation. This E2-induced degradation process is thought to be required for its ability to rapidly activate transcription in response to the demands of cell proliferation, differentiation, and metabolism (Stenoien et al., Mol.CellBiol . point Daughter Cell Biology , 2001, 21 : 4404 - 4412). Fulvestrant is also classified as a selective estrogen receptor downregulator (SERD), which is 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, although the effect on transcription is similar to that seen for SERDs.

[0007] ​Approximately 70% of breast cancers express ER and / or progesterone receptors, meaning that these tumor cells are hormone-dependent for growth. Other cancers such as ovarian and endometrial cancers are also thought to be dependent on ERα signaling for growth. Therapies for such patients can inhibit ER signaling by: antagonizing ligand binding to the ER, such as tamoxifen, which is used to treat early and late-stage ER-positive breast cancer in both pre- and post-menopausal settings; antagonizing and downregulating ERα, such as fulvestrant, which is used to treat breast cancer in women with disease progression despite tamoxifen or aromatase inhibitor therapy; or blocking estrogen synthesis, such as aromatase inhibitors, which are used to treat early and late-stage ER-positive breast cancer. Although these therapies have an extremely positive impact on breast cancer treatment, a significant number of patients with tumors expressing ER show de novo resistance to the ER therapies present or develop resistance to these therapies over time. Several different mechanisms have been described to explain resistance to first-line tamoxifen therapy, which mainly involves a shift of tamoxifen from acting as an antagonist to acting as an agonist, either by lower affinity binding of certain cofactors to the tamoxifen-ERα complex that is offset by overexpression of these cofactors, or by formation of a second site that promotes interaction of the tamoxifen-ERα complex with cofactors that do not normally bind to this complex. Resistance may thus arise due to overgrowth of cells expressing specific cofactors that drive tamoxifen-ERα activity. It is also possible that other growth factor signaling pathways directly activate the ER receptor or coactivators to drive cell proliferation independent of ligand signaling.

[0008] Recently, mutations in ESR1 have been identified as a possible resistance mechanism in metastatic ER-positive patient-derived tumor samples and patient-derived xenograft models (PDX) at frequencies varying from 17%-25%. These mutations are predominantly, but not exclusively, in the ligand-binding domain resulting in mutant functional proteins; examples of amino acid changes include Ser463Pro, Val543Glu, Leu536Arg, Tyr537Ser, Tyr537Asn, and Asp538Gly, where changes at amino acids 537 and 538 constitute the majority of currently described changes. These mutations were not detected previously in the genomes of primary breast samples characterized in the Cancer Genome Atlas database. In 390 primary breast cancer samples positive for ER expression, no single mutation was detected in ESR1 (Cancer Genome Atlas Network, 2012 Natur e nature(490:61 - 70). These ligand - binding domain mutations are thought to have evolved as a resistance response to aromatase inhibitor endocrine therapy because in the absence of estradiol, these mutant receptors display basal transcriptional activity. The crystal structures of ER mutants at amino acids 537 and 538 show that both mutants favor the agonist conformation of ER, which is achieved by altering the position of helix 12 to allow co - activator recruitment and thereby mimic agonist - activated wild - type ER. Published data have shown that endocrine therapies such as tamoxifen and fulvestrant can still bind to ER mutants and to some extent inhibit transcriptional activation, and fulvestrant is able to degrade Try537Ser, but may require higher doses for complete receptor inhibition (Toy et al., Nat.Genetics Natural heritage Transmission 2013, 45:1439 - 1445; Robinson et al., Nat.-Genetics Nature Genetics 2013, 45:1446 - 1451; Li, S. et al. CellRep. Cell Reports 4, 1116–1130 (2013)). Thus, it is feasible that compound (I) or its pharmaceutically acceptable salts (as described below) will be able to down - regulate and antagonize mutant ER, although at this time it is unknown whether ESR1 mutations are associated with altered clinical outcomes.

[0009] Regardless of which resistance mechanism or combination of mechanisms occurs, many are still ER - dependent activities, and removing the receptor via the SERD mechanism provides the best way to remove the ERα receptor from the cell. Fulvestrant is currently the only SERD approved for clinical use, and yet despite its mechanistic properties, the pharmacological properties of the drug have limited efficacy due to the current monthly 500 mg dose limit, which results in less than 50% turnover of the receptor in patient samples compared to complete down - regulation of the receptor seen in in vitro breast cell line experiments (Wardell et al., Biochem.Pharm. Biochemical Pharmacy 2011, 82 :122 - 130).

[0010] ​​​​AZD9833, 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 a pharmaceutically acceptable salt thereof, has been identified as a compound with the ability to act as a selective estrogen receptor degrader (SERD). AZD9833 is described as Example 17 in WO 2018 / 077630A1, which discloses the synthesis method of the compound and its biological activities in in vitro and in vivo experiments. In addition, compared with fulvestrant (the only SERD currently approved for clinical use and administered by intramuscular injection), preclinical studies have shown that AZD9833 has physicochemical properties compatible with oral administration.

[0011] Given the favorable properties of AZD9833, it is conceivable that oral administration of AZD9833 once daily can achieve superior estrogen receptor degradation compared to that provided by fulvestrant. As described for the first time herein, the preliminary results of a clinical trial of oral administration of AZD9833 once daily have led to the discovery of a range of doses that have caused partial remission established according to the RECIST criteria (e.g., according to the RECIST 1.1 criteria, see https: / / recist.eortc.org / ; Eur.J.Cancer European Journal of Cancer 2016, 62 , pp. 132-137) in heavily pretreated patients. Summary of the Invention

[0012] The object of the present specification is to provide an appropriate dose and dosing regimen of AZD9833 for cancer treatment (e.g., for the treatment of breast cancer).

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

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

[0015] In a third aspect of the present specification, there is provided the use of AZD9833 in the preparation of a medicament for the treatment of cancer, wherein AZD9833 is orally administered once daily 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, the pharmaceutical composition comprising 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, the pharmaceutical composition comprising 25 mg to 450 mg of AZD9833 and a pharmaceutically acceptable excipient for use in the treatment of cancer.

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

[0019] For a better understanding of the present specification, please refer to the following drawings.

[0020] Figure 1 : Schematic diagram of the dose escalation phase of a Phase I clinical trial conducted in heavily pretreated breast cancer patients, which breast cancer patients are suitable for demonstrating the benefits of AZD9833 treatment across a dose range.

[0021] Figure 2 : Swimmer plot of patient responses after treatment with escalating doses of AZD9833.

[0022] Figure 3 : Composite waterfall plot showing the best change in tumor size compared to baseline in patients treated with different doses of AZD9833.

[0023] Figure 4 : Plot of mean plasma concentration over time after administration of AZD9833 at different doses. Detailed Description of the Invention

[0024] The invention detailed in the present specification should not be construed as limited to any one of the examples or instances. For those skilled in the art, other examples will be obvious.

[0025] "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 denote one. In any embodiment where "a" or "an" is used to denote a given element, "a" or "an" may denote 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0026] When referring to "in some embodiments...", there may be a feature that can be present in suitable embodiments in any part of the specification, not just in the same part or text area of the specification.

[0027] The claims are embodiments.

[0028] Therapeutic use

[0029] In one embodiment, AZD9833 is provided for use in treating cancer, wherein AZD9833 is administered orally once a day at a dose of 25 mg to 450 mg.

[0030] In one embodiment, AZD9833 is provided for producing an anti - proliferative effect, wherein AZD9833 is administered orally once a day at a dose of 25 mg to 450 mg.

[0031] In one embodiment, AZD9833 is provided for selectively inhibiting ERα, wherein AZD9833 is administered orally once a day at a dose of 25 mg to 450 mg.

[0032] In one embodiment, the use of AZD9833 in the preparation of a medicament for treating cancer is provided, wherein AZD9833 is administered orally once a day at a dose of 25 mg to 450 mg.

[0033] In one embodiment, the use of AZD9833 in the preparation of a medicament for producing an anti - proliferative effect is provided, wherein AZD9833 is administered orally once a day at a dose of 25 mg to 450 mg.

[0034] In one embodiment, the use of AZD9833 in the preparation of a medicament for selectively inhibiting ERα is provided, wherein AZD9833 is administered orally once a day at a dose of 25 mg to 450 mg.

[0035] In one embodiment, a method of treating cancer in a human or animal patient in need of such treatment is provided, the method comprising administering AZD9833 orally to the patient once a day at a dose of 25 mg to 450 mg.

[0036] In one embodiment, a method of producing such an anti - proliferative effect in a human or animal patient in need of an anti - proliferative effect is provided, the method comprising administering AZD9833 orally to the patient once a day at a dose of 25 mg to 450 mg.

[0037] In one embodiment, there is provided a method for selectively inhibiting ERα in a human or animal patient in need of selective inhibition of ERα, the method comprising orally administering AZD9833 to the patient once daily at a dose of 25 mg to 450 mg.

[0038] Compound

[0039] 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) above.

[0040] 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 a salt-free form (e.g., a neutral or zwitterionic form, or e.g., a free base form).

[0041] 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.

[0042] The term "pharmaceutically acceptable" generally refers to an entity (e.g., a salt, dosage form, or excipient) that is suitable for use in a patient. A list of examples of pharmaceutically acceptable salts can be found in: Handbook of Pharmaceutical Salts: Properties, Selection and Use, edited by P.H. Stahl and C.G. Wermuth, Weinheim / Zurich: Wiley-VCH / VFiCA, 2002 or subsequent editions.

[0043] 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.

[0044] Acid addition salts can be formed, for example, using inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Acid addition salts can also be formed using the following organic acids: 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, 1,5-naphthalenedisulfonic acid, phosphoric acid, saccharin, succinic acid, sulfuric acid, p-toluenesulfonic acid, toluenesulfonic acid, and trifluoroacetic acid.

[0045] Another suitable 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 is, for example, a salt formed in a human or animal body 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 to the human or animal body.

[0046] Dose levels

[0047] In some embodiments, the dose of AZD9833 can be selected from 25 mg, 75 mg, 150 mg, 300 mg, and 450 mg.

[0048] In some embodiments, the dose of AZD9833 can be 25 mg.

[0049] In some embodiments, the dose of AZD9833 can be 75 mg.

[0050] In some embodiments, the dose of AZD9833 can be 150 mg.

[0051] In some embodiments, the dose of AZD9833 can be 300 mg.

[0052] In some embodiments, the dose of AZD9833 can be 450 mg.

[0053] In some embodiments, the dose of AZD9833 can be an oral daily dose.

[0054] "Oral daily dose" means the amount of AZD9833 administered orally within 24 hours.

[0055] In some embodiments, AZD9833 can be administered as a single dose.

[0056] In some embodiments, AZD9833 can be administered in divided doses.

[0057] "Divided doses" are doses in which the total dose (e.g., the oral daily dose) is administered in multiple (e.g., 1, 2, 3, 4, or 5) portions.

[0058] In some embodiments, AZD9833 can be administered as a single dosage unit or multiple dosage units.

[0059] "Dosage unit" is a discrete dosage form, such as a specified number (e.g., 1, 2, 3, 4, or 5) of tablets or capsules.

[0060] In some embodiments, AZD9833 can be administered as a single tablet.

[0061] In some embodiments, AZD9833 can be administered once a day as a single tablet.

[0062] In some embodiments, AZD9833 can be administered orally once a day as a single tablet.

[0063] For the avoidance of doubt, when a dose range of AZD9833 is given herein, for example, a dose of 25 mg to 450 mg, the range includes the doses at the endpoints of the range as well as the doses falling between these endpoints, i.e., 25 mg and 450 mg and the amounts in between.

[0064] Cancer

[0065] In this specification, "cancer" is used synonymously with tumor and lesion. Cancer may include primary cancer as well as secondary and metastatic cancers.

[0066] "Treatment of cancer", "treating cancer" and similar terms include treating existing cancer and / or preventing cancer.

[0067] In some embodiments, treatment of cancer or treating cancer can mean treating and preventing cancer.

[0068] In some embodiments, treating cancer or the treatment of cancer can mean treating cancer.

[0069] In some embodiments, treating cancer or the treatment of cancer can mean preventing cancer.

[0070] In some embodiments, the cancer can be selected from breast cancer and gynecological cancers.

[0071] “Gynecological cancers” include uterine cancer, ovarian cancer, cervical cancer, vulvar cancer, and vaginal cancer.

[0072] In some embodiments, the cancer can be selected from breast cancer, uterine cancer, ovarian cancer, cervical cancer, vulvar cancer, and vaginal cancer.

[0073] In some embodiments, the cancer can be ER-positive HER2-negative breast cancer.

[0074] “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 determined by methods known in the art, including using commercial kits.

[0075] In some embodiments, the breast cancer can be ER-positive breast cancer.

[0076] In some embodiments, the breast cancer can be HER2-negative breast cancer.

[0077] In some embodiments, the cancer can be ER-positive HER2-negative advanced breast cancer.

[0078] In some embodiments, the breast cancer can be ER-positive advanced breast cancer.

[0079] In some embodiments, the breast cancer can be HER2-negative advanced breast cancer.

[0080] Patient selection

[0081] In some embodiments, AZD9833 can be administered to premenopausal or postmenopausal women.

[0082] In some embodiments, AZD9833 can be administered to premenopausal women.

[0083] In some embodiments, AZD9833 can be administered to postmenopausal women.

[0084] In some embodiments, AZD9833 can be administered to premenopausal or postmenopausal women whose cancer is ER-positive.

[0085] In some embodiments, AZD9833 can be administered to premenopausal or postmenopausal women whose cancer is HER2-negative.

[0086] In some embodiments, AZD9833 can be administered to premenopausal or postmenopausal women whose cancer is ER-positive and HER2-negative.

[0087] In some embodiments, AZD9833 can be administered to premenopausal or postmenopausal women whose cancer has an ESR1 mutation.

[0088] In some embodiments, AZD9833 can be administered to premenopausal or postmenopausal women whose cancer does not have an ESR1 mutation.

[0089] In some embodiments, AZD9833 can be administered to patients whose cancer has previously been treated with 1 to 15 anti-cancer therapies.

[0090] In some embodiments, AZD9833 can be administered to patients whose cancer has previously been treated with 1 to 10 anti-cancer therapies.

[0091] In some embodiments, AZD9833 can be administered to patients whose cancer has previously been treated with 1 to 5 anti-cancer therapies.

[0092] In some embodiments, AZD9833 can be administered to patients whose cancer has previously been treated with 5 to 10 anti-cancer therapies.

[0093] If a patient has been "previously treated", this refers to any treatment administered to the patient prior to administering AZD9833 to the patient. The previous treatment does not mean that the therapy in question was successful or curative, only that the patient received treatment with that therapy (e.g., as a result of the therapy being prescribed by a duly qualified healthcare professional).

[0094] "Anti-cancer therapy" includes drugs, pharmaceuticals, compounds or other medical methods intended to treat cancer (e.g., treatment using the patient's own immune agents). Example anti-cancer therapies are endocrine therapy and chemotherapy.

[0095] "Endocrine therapy" refers to those therapies that act by modulating the hormonal pathways of the patient. Examples include estrogen inhibitors (such as tamoxifen or fulvestrant), aromatase inhibitors (such as letrozole, anastrozole, vorazole or exemestane), progesterins (such as megestrol acetate) and luteinizing hormone blockers (such as leuprolide or goserelin).

[0096] "Chemotherapy" is a cancer therapy that is not an endocrine therapy. They include, for example:

[0097] i. Traditional anti-proliferative / anti-tumor drugs and their combinations, including alkylating agents (such as cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (such as gemcitabine and anti-folates, such as fluoropyrimidines, like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); anti-tumor antibiotics (such as anthracyclines, like doxorubicin, bleomycin, epirubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); anti-mitotic agents (such as vinca alkaloids, like vincristine, vinblastine, deacetylvinblastine amide, and vinorelbine, and taxanes, like paclitaxel and docetaxel, and polo kinase inhibitors); and topoisomerase inhibitors (such as epipodophyllotoxins, like etoposide and teniposide, amsacrine, topotecan, and camptothecin);

[0098] ii. Inhibitors of growth factor functions and their downstream signaling pathways: including any Ab modulators of growth factor or growth factor receptor targets, such as reviewed by Stern et al., Critical Reviews in Oncology / Haematology Critical Reviews in Oncology / Hematology , 2005, 54, pp. 11 - 29; small molecule inhibitors of such targets, such as kinase inhibitors. Specific examples include the anti-erbB2 antibody trastuzumab [Herceptin TM and pertuzumab [Perjeta TM , the HER-2 directed antibody-drug conjugate deruxtecan-trastuzumab [Enhertu TM and trastuzumab emtansine [Kadcyla TM ​, anti-EGFR antibody panitumumab, anti-EGFR antibody cetuximab (Erbitux, C225), and tyrosine kinase inhibitors (which include inhibitors of the erbB receptor family, such as 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 erb1 / 2 inhibitors (such as afatinib). Other example classes of growth factor and its receptor modulators include, for example, inhibitors of the hepatocyte growth factor family or its receptors (including c-met and ron); inhibitors of the insulin and insulin-like growth factor family or its receptors (IGFR, IR), inhibitors of the platelet-derived growth factor (PDGFR) family or its receptors, and inhibitors of signal transduction mediated by other receptor tyrosine kinases such as c-kit, AnLK, and CSF-1R; modulators that target signal transduction proteins in the PI3-kinase signaling pathway, such as inhibitors of PI3-kinase isotypes, such as PI3K-α, PI3K-β, PI3K-γ, and PI3K-δ, and ser / thr kinases, such as AKT (such as capivasertib, afuresertib, miransertib, ARQ751, ipataserib, MK-2206, or perifosine), mTOR (such as AZD2014 or everolimus), PDK, SGK, PI4K, or PIP5K; inhibitors of serine / threonine kinases not listed above, such as raf inhibitors such as vemurafenib, MEK inhibitors such as selumetinib (AZD6244), Abl inhibitors such as imatinib or nilotinib, Btk inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib, Syk inhibitors such as fostamatinib, aurora kinase inhibitors (such as AZD1152), inhibitors of other ser / thr kinases such as JAK, STAT, and IRAK4, and cyclin-dependent kinase inhibitors, such as inhibitors of CDK1, CDK4, CDK6, CDK7, CDK9, and CDK4 / 6 (such as palbociclib, ribociclib, abemaciclib, lerciclib, and trilaciclib);

[0099] iii. Modulators of DNA damage signaling pathways, such as PARP inhibitors (e.g., olaparib, rucaparib, niraparib, and talazoparib), ATR inhibitors (e.g., AZD6738), or ATM inhibitors;

[0100] iv. Modulators of apoptosis and cell death pathways, such as BCl family modulators (e.g., ABT-263 / Navitoclax, ABT-199);

[0101] v. Anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor, e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM ) or VEGF receptor tyrosine kinase inhibitors, such as sorafenib, axitinib, pazopanib, sunitinib, or vandetanib (and compounds that act by other mechanisms (e.g., linomide, inhibitors of integrin function, and angiostatin));

[0102] vi. Vascular disrupting agents, such as combretastatin A4;

[0103] vii. Anti-invasive agents, such as c-Src kinase family inhibitors, like (dasatinib, J.Med.Chem. [Journal of Medicinal Chemistry], 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors, like marimastat, inhibitors of urokinase plasminogen activator receptor function, or antibodies against heparanase);

[0104] viii. Immunotherapies, including, for example, ex vivo and in vivo methods for increasing the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor, methods for reducing T cell anergy, methods using transfected immune cells such as dendritic cells transfected with cytokines, methods using tumor cell lines transfected with cytokines, and methods using anti-idiotypic 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);

[0105] ix. Antisense or RNAi-based therapies, such as those targeting the targets listed in this specification; and

[0106] X. Gene therapy methods, including, for example, methods of replacing abnormal genes (such as abnormal p53 or abnormal BRCA1 or BRCA2); GDEPT (gene-directed enzyme prodrug therapy) methods, such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase; and methods of enhancing a patient's tolerance to chemotherapy or radiotherapy (such as multidrug resistance gene therapy).

[0107] In some embodiments, AZD9833 can be administered to patients whose cancer has previously been treated with ≥1 endocrine therapy and ≤2 chemotherapies.

[0108] In some embodiments, AZD9833 can be administered to patients whose cancer has previously been treated with ≥1 endocrine therapy and ≤2 chemotherapies for ER-positive HER2-negative breast cancer.

[0109] "Chemotherapy for ER-positive HER2-negative breast cancer" can include any one or more anticancer regimens that contain at least one cytotoxic drug and are administered for 21 days or longer.

[0110] In some embodiments, AZD9833 can be administered to patients whose cancer has previously been treated with ≥1 endocrine therapy and ≤2 chemotherapies for ER-positive HER2-negative advanced breast cancer.

[0111] In some embodiments, ≥1 endocrine therapy can be selected from estrogen inhibitors, aromatase inhibitors, progestins, and luteinizing hormone blockers.

[0112] In some embodiments, ≥1 endocrine therapy can be selected from tamoxifen, toremifene, raloxifene, droloxifene, idoxifene, fulvestrant, letrozole, anastrozole, vorozole, exemestane, megestrol acetate, leuprorelin, and goserelin.

[0113] In some embodiments, ≤2 chemotherapies can be selected from CDK inhibitors (such as CDK4, CDK6, or CDK4 / CDK6 dual inhibitors) and mTOR inhibitors.

[0114] In some embodiments, ≤2 chemotherapeutic drugs can be selected from palbociclib, ribociclib, abemaciclib, trilaciclib, leroiciclib, and everolimus.

[0115] In some embodiments, AZD9833 can be administered to patients whose cancer is resistant to aromatase inhibitors.

[0116] In some embodiments, AZD9833 can be administered to patients whose cancer is resistant to non-steroidal aromatase inhibitors.

[0117] In some embodiments, AZD9833 can be administered to patients whose cancer is resistant to aromatase inhibitors selected from letrozole and anastrozole.

[0118] When a patient's cancer is "resistant" (or refractory) to a particular drug or therapy, the cancer no longer responds adequately to a treatment that would otherwise be considered a suitable medical option for that patient, and thus the attending physician recommends a different treatment.

[0119] In some embodiments, AZD9833 can be administered to patients whose cancer is resistant to tamoxifen.

[0120] In some embodiments, AZD9833 can be administered to patients whose cancer is resistant to fulvestrant.

[0121] In some embodiments, AZD9833 can be administered to patients whose cancer is resistant to CDK inhibitors.

[0122] Pharmacokinetics and pharmacodynamics properties

[0123] In one embodiment, there is provided AZD9833 for use in the treatment of cancer, wherein AZD9833 is administered orally once daily at a dose of 25 mg to 450 mg and achieves an average peak plasma concentration of 10 to 1000 ng / mL in cancer patients.

[0124] "Peak average plasma concentration" refers to the maximum amount of AZD9833 achieved in a patient's plasma after treatment.

[0125] In one embodiment, there is provided AZD9833 for use in the treatment of cancer, wherein AZD9833 is administered orally once daily at a dose of 25 mg to 450 mg and achieves a median terminal half-life of 8 h to 14 h in cancer patients.

[0126] In one embodiment, there is provided AZD9833 for use in the treatment of cancer, wherein AZD9833 is administered orally once daily at a dose of 25 mg to 450 mg and achieves a median terminal half-life of 12 h in cancer patients.

[0127] "Median terminal half-life" is the median time for the drug plasma concentration in a patient to be halved after reaching pseudo-equilibrium.

[0128] Clinical properties

[0129] In one embodiment, there is provided AZD9833 for use in the treatment of cancer, wherein AZD9833 is administered orally once daily at a dose of 25 mg to 450 mg and achieves an objective response rate of 10% to 20%.

[0130] "Objective response rate" refers to the percentage of patients with measurable disease at baseline and a first dose date ≥ 17 weeks or a post-treatment scan date ≥ 15 weeks (which indicates a confirmed response as measured according to RECIST criteria).

[0131] In one embodiment, AZD9833 is provided for use in treating cancer, wherein AZD9833 is administered orally once daily at a dose of 25 mg to 450 mg and achieves a clinical benefit rate of 25% to 100%.

[0132] "Clinical benefit rate" is the percentage of patients with a first dose date ≥ 25 weeks or a post-treatment scan date ≥ 23 weeks (which indicates a confirmed response or stable disease as measured according to RECIST criteria for > 23 weeks post-treatment).

[0133] In one embodiment, AZD9833 is provided for use in treating cancer, wherein AZD9833 is administered orally once daily at a dose of 25 mg to 450 mg and achieves a clinical benefit rate of greater than 25%.

[0134] In one embodiment, AZD9833 is provided for use in treating cancer, wherein AZD9833 is administered orally once daily at a dose of 25 mg to 450 mg and achieves a clinical benefit rate of 25% to 90%.

[0135] In one embodiment, AZD9833 is provided for use in treating cancer, wherein AZD9833 is administered orally once daily at a dose of 25 mg to 450 mg and achieves a clinical benefit rate of 25% to 80%.

[0136] In one embodiment, AZD9833 is provided for use in treating cancer, wherein AZD9833 is administered orally once daily at a dose of 25 mg to 450 mg and achieves a clinical benefit rate of 25% to 75%.

[0137] In one embodiment, AZD9833 is provided for use in treating cancer, wherein AZD9833 is administered orally once daily at a dose of 25 mg to 450 mg and does not cause any serious side effects in cancer patients.

[0138] In some embodiments, serious side effects can be defined as grade 4 or 5 adverse events.

[0139] "Grade 4 or 5 adverse events" can be classified according to the Common Terminology Criteria for Adverse Events (CTCAE).

[0140] Combination therapy

[0141] In one embodiment, AZD9833 is provided for use in treating cancer, wherein AZD9833 is administered orally once daily at a dose of 25 mg to 450 mg, in combination with an additional anti-cancer therapy.

[0142] When a drug is administered "in combination" with AZD9833, the combination may include separate, sequential, or simultaneous administration of the drug. If the treatments are separate and / or sequential, the interval between the AZD9833 dose and the additional anti-cancer therapy dose can be selected to ensure a combined therapeutic effect.

[0143] In some embodiments, the administration of AZD9833 and the additional anti-cancer therapy are separate.

[0144] In some embodiments, the administration of AZD9833 and the additional anti-cancer therapy are sequential.

[0145] In some embodiments, the administration of AZD9833 and the additional anti-cancer therapy are separate and sequential.

[0146] In some embodiments, the additional anti-cancer therapy can be a CDK inhibitor.

[0147] In some embodiments, the additional anti-cancer therapy can be a CDK4 inhibitor.

[0148] In some embodiments, the additional anti-cancer therapy can be a CDK6 inhibitor.

[0149] In some embodiments, the additional anti-cancer therapy can be a dual CDK4 / CDK6 inhibitor.

[0150] In some embodiments, the additional anti-cancer therapy can be a CDK inhibitor selected from palbociclib, ribociclib, abemaciclib, lero ciclib, or trilaciclib.

[0151] In some embodiments, the additional anti-cancer therapy can be palbociclib.

[0152] In some embodiments, the additional anti-cancer therapy can be an mTOR inhibitor.

[0153] In some embodiments, the additional anti-cancer therapy can be an mTOR inhibitor selected from sirolimus, deforolimus, everolimus, and temsirolimus.

[0154] In some embodiments, the additional anti-cancer therapy can be everolimus.

[0155] In some embodiments, the additional anti-cancer therapy can be everolimus, which is administered orally once daily at a dose of up to 10 mg.

[0156] In some embodiments, the additional anti-cancer therapy may be selected from palbociclib, ribociclib, abemaciclib, leroiciclib, trilaciclib, and everolimus.

[0157] In some embodiments, the additional anti-cancer therapy may be selected from palbociclib, ribociclib, abemaciclib, leroiciclib, and trilaciclib.

[0158] In some embodiments, the additional anti-cancer therapy may be an AKT inhibitor.

[0159] In some embodiments, the additional anti-cancer therapy may be selected from capmatinib, afatinib, masitinib, ARQ751, epratuzumab, MK-2206, or perifosine.

[0160] Composition

[0161] In one embodiment, there is provided a composition for once-daily oral administration, the composition comprising 25 mg to 450 mg of AZD9833 and a pharmaceutically acceptable excipient.

[0162] In some embodiments, the pharmaceutically acceptable excipient may be selected from inert diluents (such as microcrystalline cellulose or anhydrous calcium phosphate), granulating agents, disintegrants (such as sodium starch glycolate), binders, lubricants (such as magnesium stearate), preservatives, antioxidants, and chelating agents.

[0163] 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), anhydrous calcium phosphate (DCPA), mannitol, lactose, calcium phosphate, calcium sulfate dihydrate, tribasic calcium phosphate, dibasic calcium phosphate dihydrate, siliconized microcrystalline cellulose, co-processed combinations thereof, polydextrose, trehalose, sucrose, glucose, cyclodextrin, and hydroxypropyl cellulose.

[0164] The composition for once-daily oral administration may further comprise at least one disintegrant selected from sodium croscarmellose, crospovidone, sodium starch glycolate (SSG), and low-substituted hydroxypropyl cellulose (L-HPC).

[0165] 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.

[0166] Dosage form

[0167] In one embodiment, a pharmaceutical composition is provided, which comprises 25 mg to 450 mg of AZD9833 and a pharmaceutically acceptable excipient. The pharmaceutical composition is in the form of a tablet or a capsule and is administered orally once a day.

[0168] Tablet formulations may be uncoated or coated to alter their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and / or appearance, in either case using conventional coating agents and methods known in the art. For example, tablet formulations can be processed to provide immediate release of the active ingredient.

[0169] In one embodiment, a pharmaceutical composition is provided, which comprises 25 mg to 450 mg of AZD9833 (such as 25 mg to 100 mg of AZD9833) and a pharmaceutically acceptable excipient, and the composition is an immediate release composition.

[0170] In one embodiment, a pharmaceutical composition is provided, which comprises 25 mg to 450 mg of AZD9833 (such as 25 mg to 100 mg of AZD9833) and a pharmaceutically acceptable excipient. The pharmaceutical composition is in the form of a single tablet and is administered orally once a day.

[0171] In addition to tablets, the compositions 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 in the form of soft gelatin capsules, in which the active ingredient is mixed with water or an oil.

[0172] In one embodiment, a pharmaceutical composition is provided, which comprises 25 mg to 450 mg of AZD9833 (such as 25 mg to 100 mg of AZD9833) and a pharmaceutically acceptable excipient. The pharmaceutical composition is in the form of a single capsule and is administered orally once a day.

[0173] In one embodiment, the use of a pharmaceutical composition comprising 25 mg to 450 mg of AZD9833 (such as 25 mg to 100 mg of AZD9833) and a pharmaceutically acceptable excipient in the treatment of cancer is provided, wherein the pharmaceutical composition is administered once a day.

[0174] Kit

[0175] In one embodiment, a kit is provided, which comprises a pharmaceutical composition containing AZD9833 and at least one pharmaceutically acceptable excipient, and instructions for the use of the pharmaceutical composition in the treatment of cancer, wherein AZD9833 is administered once a day at a dose of 25 mg to 450 mg.

[0176] In one embodiment, a kit is provided, which comprises:

[0177] - A pharmaceutical composition comprising AZD9833 and at least one pharmaceutically acceptable excipient;

[0178] - Another anti-cancer agent to be administered in combination with AZD9833; and

[0179] - Instructions for the use of the pharmaceutical composition in the treatment of cancer, wherein AZD9833 is administered once a day at a dose of 25 mg to 450 mg.

[0180] In one embodiment, a kit is provided, which comprises:

[0181] - A pharmaceutical composition comprising AZD9833 and at least one pharmaceutically acceptable excipient;

[0182] - Another anti-cancer agent to be administered in combination with AZD9833; and

[0183] - Instructions for the use of the pharmaceutical composition in the treatment of cancer, wherein AZD9833 is administered once a day at a dose of 25 mg to 450 mg.

[0184] In one embodiment, a kit is provided, which comprises:

[0185] - A pharmaceutical composition comprising AZD9833 and at least one pharmaceutically acceptable excipient;

[0186] - Another anti-cancer agent selected from palbociclib, ribociclib, abemaciclib or trilaciclib to be administered in combination with AZD9833; and

[0187] - Instructions for the use of the pharmaceutical composition in the treatment of cancer, wherein AZD9833 is administered once a day at a dose of 25 mg to 450 mg.

[0188] Examples

[0189] Clinical trial protocol

[0190] Introduction: To determine the optimal dosing regimen for the phase 1 dose escalation and expansion of AZD9833 in ER-positive patients, HER2-negative advanced breast cancer patients were treated according to the following basic protocol.

[0191] Basic principle: In estrogen receptor-positive (ER+) breast cancer patients, AZD9833 has the potential to provide superior clinical benefits to existing endocrine therapies through enhanced bioavailability (compared to intramuscularly administered fulvestrant) and target (estrogen receptor) engagement and modulation. 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. In addition, the pharmacokinetics and preliminary anti-tumor activity of AZD9833 will also be investigated.

[0192] Primary objectives and endpoints:

[0193] Table 1

[0194]

[0195]

[0196] Secondary objectives and endpoints:

[0197] Table 2

[0198]

[0199] Exploratory objectives and endpoints:

[0200] Table 3

[0201]

[0202]

[0203] Overall design: This is a multi-center, first-in-human, dose-escalation and expansion study designed to evaluate the safety and tolerability of AZD9833 alone in women with endocrine-resistant ER+HER2- breast cancer (which is not suitable for curative-intent treatment) (Parts A and B).

[0204] Part A of the study allows dose escalation of AZD9833 alone. For these parts, a "cohort" will consist of all patients dosed at a specific dose level in the dose-escalation scheme, as Figure 1 shown. In Part B (expansion) of the study, eligible subjects will be randomly assigned to receive a selected dose of AZD9833 based on the findings from Part A.

[0205] Throughout the study, premenopausal subjects will receive AZD9833 with a background of LHRH agonist (see background drug).

[0206] Part A: Eligible pre- and post-menopausal subjects will receive AZD9833. For the initial dose, the first patient in each cohort will be followed up to Day 8, and then more patients will be assigned to the cohort at that dose level; see Section 6.1.5.5. When there are sufficient evaluable subjects for the decision on dose escalation (3 to 6 subjects), the cohort may optionally be expanded to include additional subjects (up to 12 evaluable subjects in the cohort) and / or the cohort may be opened at the next dose level. Part A of the study is expected to have up to 8 dose level cohorts. Escalation will stop at the MTD / MFD. Part A will include at least 2 subjects, with paired tumor biopsies performed at each dose level.

[0207] The dose escalation phase of the study will determine the MTD or MFD of AZD9833 based on the evaluation of safety, tolerability, and PK data collected during the first 28 days of dosing. The dose escalation and de-escalation plan for evaluating AZD9833 will follow a Bayesian adaptive design scheme (Neuenschwander et al., StatMed . Statistical Medicine 2008, 15 :2420), which incorporates prior expectations of the dose-toxicity relationship and applies data at the end of each cohort to recommend the dose for the next cohort. After the first subject in each dose level cohort has been treated for at least 7 days, once safety and tolerability have been established, up to 3 additional subjects will be added to ensure at least 3 evaluable subjects at Day 28.

[0208] The dose escalation during the AZD9833 dosing includes an optional expansion, where these doses have a preclinical predicted pharmacodynamic effect on ER greater than or equal to fulvestrant (which is the standard of care in this disease setting). This will provide subjects with an early opportunity to receive the drug at potentially therapeutic doses and allow further investigation of the safety, tolerability, and pharmacological and biological activity profiles of AZD9833. The dose levels to be expanded will be based on emerging data and will be approved by the Safety Review Committee (SRC).

[0209] The expansion of Part A of the study also provides for the recruitment of at least 2 subjects suitable for paired tumor biopsies in the study, enabling a preliminary assessment of tumor pharmacodynamics over a wider dose range than that examined in Part B.

[0210] Part B: Eligible pre-menopausal (n = 12) subjects will receive AZD9833 300 mg (the highest of the three selected dose levels in Part A), while post-menopausal (n = 36) subjects will be randomized to receive AZD9833 300 mg, AZD9833 150 mg or AZD9833 75 mg in a 1:1:1 ratio. Part B will include at least 5 evaluable paired biopsy subjects in each of the 4 treatment groups (pre-menopausal dose 300 mg, post-menopausal dose 300 mg, post-menopausal dose 150 mg, post-menopausal dose 75 mg).

[0211] Part B will allow for further evaluation of the safety profile of AZD9833 at 3 different dose levels in a larger post-menopausal subject population. The goal of examining the 3 dose levels is to robustly select a recommended dose for further clinical studies in future AZD9833 studies, whether in the advanced breast cancer patient setting or the potential early disease / adjuvant setting. A randomized design is applied to assign 1 of the 3 tolerated dose levels in Part A to 36 subjects to facilitate a robust comparison of the safety profiles by avoiding assignment or any other potential experimental bias. Part B will also allow up to 12 pre-menopausal subjects to be assigned to the highest of the 3 doses (300 mg) in Part A that are considered safe and well-tolerated.

[0212] Part B also includes providing for the recruitment of a subset of subjects suitable for tumor biopsies in paired studies (n = 15 post-menopausal, i.e., 5 at each dose level, and n = 5 pre-menopausal, 300 mg dose level) to further evaluate tumor pharmacodynamics.

[0213] Study Population: Prospective approval of protocol deviations (also known as protocol waivers or exemptions) to the inclusion and exclusion criteria is not allowed. For this study, each subject should meet all inclusion criteria and not meet any exclusion criteria in order to be assigned / randomized to AZD9833. This rule cannot have any exceptions under any circumstances. Subjects who do not meet the entry requirements are screening failures.

[0214] Included subjects are defined as those who have signed the informed consent form. Treated subjects are those who have received at least 1 dose of AZD9833. In Parts B and D, the included subjects are randomized into treatment groups. Randomized subjects are those who have undergone randomization and received a randomization number.

[0215] Inclusion Criteria: Patients are eligible to be included in the study only if all of the following inclusion criteria apply and none of the exclusion criteria apply:

[0216] 1. Provide a signed and dated written informed consent form prior to any mandatory study-specific procedures, sampling, and analysis. If the subject refuses to participate in any voluntary exploratory research and / or the genetic portion of the study, there will be no penalty or loss of benefits for the subject, and she will not be excluded from other aspects of the study.

[0217] 2. Be at least 18 years of age.

[0218] 3. Menopausal status is as follows:

[0219] (a) Premenopausal women must initiate luteinizing hormone-releasing hormone (LHRH) agonist therapy at least 4 weeks prior to starting AZD9833 and must be willing to continue LHRH agonist therapy during the study.

[0220] (b) Postmenopausal is defined as meeting at least 1 of the following criteria:

[0221] (i) Have had bilateral oophorectomy.

[0222] (ii) Be ≥60 years of age.

[0223] (iii) Be ≥50 years of age, have had normal menses cease ≥12 months, and have an intact uterus without oral contraceptive or hormone replacement therapy prior to breast cancer diagnosis.

[0224] (iv) Be <60 years of age, have had normal menses cease ≥12 months, and have follicle-stimulating hormone (FSH) and estradiol levels in the postmenopausal range (range used by local laboratory facilities).

[0225] (c) Those who do not meet the definition of postmenopausal are considered premenopausal.

[0226] 4. Histological or cytological confirmation of breast adenocarcinoma.

[0227] 5. Estrogen receptor-positive status of primary or metastatic tumor tissue based on local laboratory parameters and recorded when those laboratory parameters conform to recognized diagnostic guidelines (e.g., American Society of Clinical Oncology / College of American Pathologists guidelines for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (Hammond et al. 2010)). HER2 is defined as immunohistochemistry (IHC) score 0 or 1+ or negative by in situ hybridization (ISH; FISH / CISH / SISH); if IHC is 2+, then ISH negative is required. Where feasible, the status of ER and HER2 should be evaluated based on the most recent tumor biopsy sample.

[0228] 6. Metastatic disease or locally recurrent disease refractory or intolerant to one or more existing therapies known to provide clinical benefit.

[0229] 7. Prior chemotherapy, endocrine therapy, and other therapies are as follows:

[0230] (a) Chemotherapy for advanced disease is no more than 2 lines.

[0231] (b) Recurrence or progression of at least one line of endocrine therapy in advanced / metastatic disease.

[0232] (c) There is no limit to the number of lines of prior endocrine therapy.

[0233] (d) Prior treatment with CDK4 / 6 inhibitors is permitted.

[0234] The chemotherapy line in advanced disease is one or more anticancer regimens that contain at least one cytotoxic chemotherapeutic agent and are administered for 21 days or longer. If the cytotoxic chemotherapy regimen is discontinued for reasons other than disease progression and the duration is less than 21 days, the regimen does not count as a prior chemotherapy line. Repeated administration of the same anticancer regimen on separate occasions does not count as a new chemotherapy line.

[0235] 8. Metastatic disease or locally recurrent disease that is refractory or intolerant to one or more existing therapies known to provide clinical benefit.

[0236] 9. Women of childbearing potential must consent to use an effective contraceptive measure (as defined in Section 5.3.1, "Contraceptive Measures") from the time of screening until 4 weeks after stopping AZD9833, must not breastfeed, and must have a negative pregnancy test before starting dosing.

[0237] 10. At least one lesion (measurable and / or non-measurable according to Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]) that can be accurately evaluated at baseline and is suitable for repeated evaluation by computed tomography (CT), magnetic resonance imaging (MRI), or plain X-ray; or clinical examination. Lesions that are only osteoblastic in bone are not considered evaluable.

[0238] 11. Eastern Cooperative Oncology Group (ECOG) / World Health Organization (WHO) performance status of 0 to 1, with no worsening in the past 2 weeks and a minimum life expectancy of 12 weeks.

[0239] Exclusion criteria: If any of the following exclusion criteria are met, then the patient must not be enrolled in the study:

[0240] 1. Intervention in any of the following situations:

[0241] (a) Any cytotoxic chemotherapy, investigational drug, or other anti-cancer drug used to treat advanced breast cancer within 14 days after the first dose of AZD9833, according to the previous treatment regimen or clinical study.

[0242] (b) Drugs or herbal supplements that are known to be strong inhibitors / inducers of cytochrome P450 3A4 / 5 (CYP3A4 / 5) and sensitive cytochrome P450 2B6 (CYP2B6) substrates (common prescription drugs are listed in Appendix B), or that could not be discontinued within the washout period specified in Appendix B before receiving the first dose of AZD9833.

[0243] (c) Drugs known to prolong QT and with a known risk of torsades de pointes ventricular tachycardia.

[0244] (d) Radiotherapy within a limited radiation field for pain relief within 1 week after the first dose of AZD9833, except for patients who received radiation to more than 30% of the bone marrow or wide-field radiation within 4 weeks of the first dose of AZD9833.

[0245] (e) Major surgery or significant trauma within 4 weeks after the first dose of AZD9833, as judged by the investigator, or any surgery during the study period that is expected to require major surgery and / or general anesthesia.

[0246] 2. Any unresolved toxicity greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 from previous therapies at the start of AZD9833, except for alopecia.

[0247] 3. The presence of life-threatening metastatic visceral disease, such as uncontrolled central nervous system (CNS) metastatic disease, as judged by the investigator. Patients with spinal cord compression and / or brain metastases may be enrolled if definitive treatment (e.g., surgery or radiotherapy) has been performed and the patient has been stable off steroids for at least 4 weeks before starting AZD9833.

[0248] 4. Any evidence of severe or uncontrolled systemic disease, including uncontrolled hypertension and active bleeding diathesis, or an infection such as one requiring intravenous antibiotic treatment (which the investigator deems to be unfavorable for the patient's participation in the study or compromising compliance with the protocol), or active infections including hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) (requiring antiviral treatment).

[0249] 5. Any of the following cardiac criteria:

[0250] (a) Corrected mean resting QT interval (QTcF) > 470 msec obtained from three electrocardiograms (ECGs) by the Fridericia formula.

[0251] (b) Any clinically significant abnormality in the rhythm, conduction, or morphology of the resting ECG (e.g., complete left bundle branch block, second-degree and third-degree heart block), or clinically significant sinus pauses. Patients with controlled atrial fibrillation may be enrolled.

[0252] (c) Any factor that increases the risk of QTc prolongation or arrhythmic events, such as symptomatic heart failure, hypokalemia, congenital long QT syndrome, a family history of long QT syndrome in first-degree relatives, or unexplained sudden death <40 years of age. Hypertrophic cardiomyopathy and clinically significant stenotic valvular disease.

[0253] (d) Having experienced any of the following procedures or conditions within the past 6 months: coronary artery bypass grafting, angioplasty, vascular stenting, myocardial infarction, unstable angina, congestive heart failure New York Heart Association (NYHA) class ≥ 2, cerebrovascular accident, or transient ischemic attack.

[0254] (e) Uncontrolled hypertension. Patients with hypertension may be eligible, but blood pressure must be well controlled at baseline. Patients may be rescreened for blood pressure requirements.

[0255] 6. Insufficient bone marrow reserve or organ function, as indicated by any of the following laboratory values:

[0256] (a) Absolute neutrophil count (ANC) < 1.5 × 109 / L.

[0257] (b) Platelet count < 100 × 109 / L.

[0258] (c) Hemoglobin < 90 g / L.

[0259] (d) Alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN).

[0260] (e) Aspartate aminotransferase (AST) > 2.5 × ULN.

[0261] (f) Total bilirubin (TBL) > 1.5 × ULN or > 3 × ULN in the presence of documented Gilbert syndrome (unconjugated hyperbilirubinemia).

[0262] (g) Glomerular filtration rate (GFR) < 50 mL / min.

[0263] 7. Having participated in the planning and conduct of the study.

[0264] 8. Refractory nausea and vomiting, uncontrolled chronic gastrointestinal (GI) diseases, inability to swallow the formulated product, or previous large bowel resection precluding adequate absorption of AZD9833. History of allergy to the active or inactive excipients of AZD9833 or to drugs with a chemical structure or class similar to AZD9833.

[0265] 9. If a patient is unlikely to comply with the study procedures, restrictions, and requirements, the investigator determines that the patient should not participate in the study.

[0266] 10. Male subjects are excluded from this study.

[0267] Study treatment: AZD9833, administered as 25 mg and 100 mg tablets. AZD9833 will be administered at an oral dose, initially once daily. It should be taken in the morning, with or without food, at approximately the same time of day. Based on emerging study data, the SRC may decide to require fed or fasted dosing of AZD9833 (i.e., no food for at least 2 hours before and at least 1 hour after each AZD9833 dose). An alternative dosing frequency or intermittent schedule for AZD9833 may be initiated based on the SRC's recommendations in response to emerging safety, tolerability, and PK data.

[0268] The dose will start at 75 mg once daily. At each dose level, 1 subject will be exposed and monitored up to Day 8; see details. After each dose level during the dose escalation phase of the study, the SRC will evaluate all available safety information. The decision on the dose for subsequent cohorts or to stop recruitment will be agreed upon by the SRC after reviewing the data for each cohort. The escalation and de-escalation of the dose will be determined by the SRC. The proposed dose escalation protocol will, in principle, allow the dose to be doubled for each cohort, e.g., 75 mg, 150 mg, 300 mg, etc. However, alternative or intermediate dose levels may be tested after the SRC reviews the safety data.

[0269] At least 2 subjects in each dose level in Part A and at least 5 subjects in each cohort in Part B will be selected such that they are eligible and agree to provide one pre-treatment and one on-treatment paired tumor biopsy sample. If subjects are selected to provide paired biopsies and this becomes clinically infeasible during their care, individual cohorts may be expanded by recruiting additional biopsy-eligible subjects until the required number of evaluable biopsy pairs are collected in each cohort.

[0270] There is no maximum treatment duration, and subjects may continue to receive AZD9833 as long as they continue to show clinical benefit, as judged by the investigator. If AZD9833 is discontinued for reasons other than disease progression, the subject must continue tumor evaluations until disease progression or until another line of anti-cancer therapy is administered.

[0271] Dose-limiting toxicity (DLT): DLT is defined as an AE or abnormal laboratory value occurring from the first dose of AZD9833 through and including Day 28 of Cycle 1 (DLT Cycle), which is evaluated to be unrelated to disease progression, concurrent illness, or concomitant medications and meets any of the following criteria despite optimal therapeutic intervention:

[0272] (a) Any death not clearly due to underlying disease or external cause

[0273] (b) The following hematologic toxicities (CTCAE):

[0274] (i) The presence of any ≥ Grade 4 hematologic toxicity lasting more than 4 consecutive days or requiring transfusion, G-CSF, or erythropoietin.

[0275] (ii) ≥ Grade 3 neutropenia with fever ≥ 38.5°C and / or systemic infection for any duration.

[0276] (iii) ≥ Grade 3 thrombocytopenia with bleeding for any duration.

[0277] (iv) Grade 4 thrombocytopenia (regardless of duration or bleeding)

[0278] (c) Any non-hematologic CTCAE ≥ Grade 3, provided the following conditions are met:

[0279] (i) Nausea ≥ CTCAE Grade 3 for more than 3 consecutive days despite administration of maximum antiemetic therapy.

[0280] (ii) Vomiting ≥ CTCAE Grade 3 for more than 3 consecutive days despite administration of maximum antiemetic therapy.

[0281] (iii) Vomiting ≥ CTCAE Grade 4 (regardless of duration)

[0282] (iv) Diarrhea ≥ CTCAE Grade 3 for more than 3 consecutive days despite administration of maximum antidiarrheal therapy.

[0283] (v) Diarrhea ≥ CTCAE Grade 4 (regardless of duration)

[0284] (vi) Fatigue ≥ CTCAE Grade 3 lasting more than 4 days.

[0285] (vii) Creatinine elevation ≥ CTCAE Grade 3.

[0286] (d) Other toxicities:

[0287] (i) The QTcF value is greater than 500 ms or the QTcF is prolonged by 60 ms from baseline and > 480 ms, confirmed on at least 2 separate ECGs.

[0288] (ii) ≥ CTCAE Grade 4 prolongation of the corrected QT interval on electrocardiogram.

[0289] (iii) Serum / plasma AST or ALT elevation ≥ 3 × ULN and concurrently TBL ≥ 2 ULN.

[0290] (e) Any other toxicity that:

[0291] (i) Is greater than baseline, clinically significant and / or unacceptable despite optimal therapeutic intervention and is judged by the SRC to be a DLT, or

[0292] (ii) Results in an interruption of the dosing schedule for more than 14 days despite optimal therapeutic intervention.

[0293] Background medication: Premenopausal women must initiate LHRH agonist therapy at least 4 weeks prior to the start of AZD9833 and continue LHRH agonist therapy throughout the study period.

[0294] Efficacy assessment: Antitumor activity will be evaluated by the investigator using RECIST 1.1. Baseline tumor assessment should cover all known regions of known sites of predilection for metastases in the disease being evaluated and should additionally investigate regions that may be involved based on the signs and symptoms of the individual subject. Baseline assessment should be performed no more than 28 days prior to the start of AZD9833 and, ideally, as close as possible to the start of AZD9833. The assessment method used at baseline should be used at each subsequent assessment during treatment and the study follow-up period. Any other locations where other new diseases are suspected should also be appropriately imaged.

[0295] If an unscheduled assessment is performed and the subject does not progress, every effort should be made to perform the follow-up assessment at the planned visit while the subject remains on AZD9833 or until she progresses. The classification of objective tumor response assessment will be based on the RECIST 1.1 efficacy guidelines: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD). For subjects with only non-measurable disease at baseline, the classification of objective tumor response assessment will be based on the RECIST 1.1 efficacy guidelines for non-target lesions (NTL): CR, PD, and non-CR / non-PD. If the investigator is unsure whether progression has occurred, particularly in response to NTL or the appearance of new lesions, it is recommended to continue AZD9833 and re-evaluate the subject's status at the next planned assessment, or earlier (if there are clinical indications). To achieve 'definite progression' based on non-target disease, the overall level of non-target disease must have deteriorated severely such that even in the presence of SD or PR in the target disease, the overall tumor burden has increased sufficiently to warrant discontinuation of therapy. A moderate 'increase' in the size of one or more NTLs is usually not sufficient to demonstrate a definite disease progression status.

[0296] Safety and clinical assessment: 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.

[0297] Clinical safety laboratory assessment: Clinical chemistry, hematology, urine analysis, and coagulation will be performed at a local laboratory at or near the investigator's study site. The sample tubes and sample volumes may vary depending on the laboratory methods used and the routine practices at the study site.

[0298] Pharmacokinetics: The pharmacokinetic profiles of single-dose and multi-dose AZD9833 are secondary objectives of this study. Any residual samples remaining after PK analysis can be used to identify, characterize, and determine the concentrations of AZD9833 metabolites and drug-related products in plasma, and / or for exploratory biomarker studies. AZD9833 in plasma and urine will be analyzed using appropriate bioanalytical methods. All details of the analytical methods used will be described in a separate bioanalytical report.

[0299] All samples within the known stability range of the analyte of interest will be analyzed upon receipt at the bioanalytical laboratory. In addition, PK samples may be further analyzed to identify, characterize, and determine the concentrations of metabolites in plasma. Any results from such analyses will be reported separately from the clinical study report. Any sample reproducibility analyses that occur (if any) will be performed along with the bioanalysis of the study samples. The results of the assessment will not be reported in the clinical study report but separately in the bioanalytical report.

[0300] Pharmacodynamics: Pharmacodynamic measurements will be made on a number of biomarkers (e.g., optional tumor biopsies, plasma ctDNA, CTCs, and archival tumor tissue). Biological samples (archival tumor tissue, necessary and optional biopsies as applicable) will be collected to analyze tumor DNA as an exploratory objective of this study. Prior to administration of the first dose of AZD9833, 2 mL of blood samples will be collected from subjects who have consented to participate in the genetic analysis portion of this study for DNA isolation. If samples are not drawn prior to dosing for any reason, they may be taken at any visit prior to the last study visit. Only one sample for genetic studies should be collected per subject during the study. Participation is optional. Subjects who do not wish to participate in the genetic study may still participate in the study.

[0301] Biomarkers: The following samples for exploratory biomarker studies are optional or required as indicated and will be collected from appropriate subjects.

[0302] In Part A, paired tumor biopsy samples will be obtained from at least 2 subjects at each dose level. In Part B, these biopsies will be obtained from at least 5 postmenopausal subjects at each AZD9833 dose level (300 mg, 150 mg, and 75 mg) and from at least 5 premenopausal subjects at 300 mg. If subjects wish to participate in this portion of the study, they will sign a biopsy-specific written informed consent form. Paired tumor biopsies will be obtained from subjects with accessible tumors who have consented to biopsy. Accessible lesions are defined as tumor lesions that are biopsiable and amenable to repeat biopsy.

[0303] Pre-treatment biopsies will be performed as close as possible to the start of treatment during the screening process. Samples during treatment should be collected on Day 1 (±7 days) of Cycle 2, but may be collected outside of this time window if agreed upon with AstraZeneca. Further (optional) tumor biopsies should also be collected at the time of disease progression or at the end of treatment. Biomarkers studied using tumor samples may include but are not limited to: ER, PgR, Ki67, genomic / genetic alterations, and other ER-regulated gene expression. Where feasible, tumor biopsies are encouraged to be collected at the time of disease progression. This sample will be used to study alterations in pathway signaling and potential resistance mechanisms (i.e., evidence of genetic alterations or alternative pathway activation).

[0304] For all subjects, formalin-fixed archived tumor tissue embedded in paraffin blocks, if available, should be retrieved. If baseline biopsy samples can also be collected, archived diagnostic tumor material still needs to be retrieved to provide data on how the tumor has evolved since diagnosis. Archived samples can be obtained from the primary tumor and / or metastatic sites, and whenever possible, the most recently obtained archived samples are required. If tumor blocks cannot be submitted, unstained slides freshly prepared from the archived tumor blocks are accepted. From the submitted archived tumor blocks, cores can be removed to construct tissue microarrays for subsequent biomarker analysis. The remaining portion of the tumor blocks can be returned to the institution.

[0305] A 2 mL blood sample will be collected at each time point for the assessment of cancer antigen CA15.

[0306] Blood samples will be obtained at each time point. These samples are obtained to provide a preliminary assessment of AZD9833 activity in the tumor by evaluating changes in pharmacodynamic biomarkers, which may include but are not limited to total counts and the expression levels of ER, Ki67 protein, and ER-regulated genes.

[0307] A 10 mL blood sample will be obtained at the following time points to provide 2 plasma samples and 1 serum sample at each time point. Samples will be collected and stored for retrospective exploratory biomarker analysis and will be analyzed for a panel of tumor biomarkers that may be associated with drug response.

[0308] Two 2.5 mL whole blood samples will be collected in PAXgene tubes for the preparation of RNA and microRNA / RNA samples. RNA analysis can be performed to generate hypotheses related to the mechanism of action of the molecules evaluated in the study and potentially identify changes in gene expression associated with treatment response.

[0309] A 20 mL blood sample will be obtained at screening and 10 mL blood samples will be obtained at all other time points to provide plasma. It will be used for the extraction and analysis of ctDNA for the analysis of predictive and pharmacodynamic biomarkers to interrogate changes in genetic alterations and potential resistance mechanisms.

[0310] Clinical trial results

[0311] A clinical trial was conducted using 60 patients according to the above protocol. The results can be summarized as follows.

[0312] Sixty patients (median age 61 years (39 - 79 years)) were treated across five doses; 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. AZD9833 exposure was proportional to dose after multiple doses, with a median terminal t1 / 2 of 12 h.

[0313] Treatment-related AEs experienced by ≥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: G3 QTcF prolongation (300 mg); G3 vomiting (450 mg); and a combination of G2 visual impairment, G2 headache, and G2 gait disorder (450 mg). DLT cases were managed by dose reduction. No G4 or G5 AEs were reported. None of the observed AEs were considered clinically relevant.

[0314] Efficacy data are shown in the table below; objective response rate (ORR) and clinical benefit rate (CBR) at 24 weeks:

[0315] Table 5

[0316]

[0317] Modulation of the ER signaling pathway was observed in all dose cohorts. In patients who achieved a clinical response and had paired biopsies, a 98% reduction in Ki67 was measured.

[0318] These data suggest that AZD9833 has encouraging efficacy and dose-dependent safety. Evidence of clinical benefit and target engagement was observed at all dose levels in ER+ ABC women, including patients treated with CDK4 / 6 inhibitors and fulvestrant, and those with ESR1 mutations.

Claims

Use 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) in an amount of 1.75 mg in the preparation of a medicament for the treatment of ER-positive HER2-negative advanced breast cancer, wherein the AZD9833 is administered orally once daily at a dose of 75 mg.

2. The use according to claim 1, wherein the AZD9833 is administered as a single dosage unit.

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

4. The use according to any one of the preceding claims, wherein the AZD9833 is administered in combination with another anticancer therapy.

5. The use according to any one of the preceding claims, wherein the AZD9833 is administered in combination with palbociclib.

6. The use according to any one of claims 1 to 4, wherein the AZD9833 is administered in combination with an mTOR inhibitor.

7. The use according to claim 6, wherein the AZD9833 is administered in combination with everolimus.

8. The use according to any one of the preceding claims, wherein the AZD9833 is administered to premenopausal or postmenopausal women.

9. The use according to any one of the preceding claims, wherein for ER-positive HER2-negative advanced breast cancer, the cancer has previously been treated with ≥1 endocrine therapy and ≤2 prior chemotherapy regimens.

10. The use according to any one of the preceding claims, wherein the AZD9833 is administered to patients whose cancer is resistant to non-steroidal aromatase inhibitors.

11. The use according to any one of the preceding claims, wherein the dose of the AZD9833 i) achieves an average peak plasma concentration of 10 ng / mL to 1000 ng / mL in cancer patients; and / or ii) achieves a median terminal half-life of 8 h to 14 h in cancer patients; and / or iii) achieves a median terminal half-life of 12 h in cancer patients.

12. The use according to any one of the preceding claims, wherein the dose of the AZD9833 achieves an objective response rate of at least 10%.

13. The use according to any one of the preceding claims, wherein the dose of the AZD9833 does not cause any serious side effects in cancer patients.

14. A pharmaceutical composition, which is administered orally once daily and comprises 75 mg of AZD9833 and a pharmaceutically acceptable excipient.

15. The pharmaceutical composition according to claim 14, which is in the form of a single tablet.

16. Use of the pharmaceutical composition according to any one of claims 14 to 15 in the preparation of a medicament for the treatment of ER-positive HER2-negative advanced breast cancer.

17. A kit, the kit comprising a pharmaceutical composition containing 75 mg of 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 administered once daily at a dose of 75 mg.

18. The kit according to claim 17, the kit further comprising an additional anti-cancer agent to be administered in combination with AZD9833.

Images