WEE1 Compound for Treating Uterine Serous Carcinoma

Abstract

Disclosed herein are methods for treating a subject having uterine serous carcinoma with a WEE1 inhibitor, or a pharma- ceutically acceptable salt thereof.

Description

[Technical field]

[0001] INCORPORATION BY REFERENCE OF PRIORITY APPLICATION This application claims priority to U.S. Provisional Patent Application No. 63 / 174,004, filed April 12, 2021, and U.S. Provisional Patent Application No. 63 / 174,005, filed April 12, 2021, both of which are incorporated by reference in their entireties herein.

[0002] The present application relates generally to methods of treating uterine serous carcinoma (USC) using WEE1 inhibitors. [Background technology]

[0003] DNA is constantly damaged by the environment. Light, chemicals, stress and cell replication result in single or double strand breaks along the DNA backbone. Typically, organisms defend against DNA damage by repair proteins that reconnect or resynthesize damaged DNA. Correct functioning of these proteins is essential for life. Incorrect substitution of nucleotides into DNA can cause mutations (and other genetic alterations, including but not limited to insertions, deletions and frameshifts), genetic diseases and loss of protein function. Complete loss of DNA repair can cause cell death, tumor progression and cancer.

[0004] Cell cycle checkpoints are important for proper DNA repair and ensure that cells do not proceed with cell replication until their genomic integrity is restored. WEE1 is a nuclear kinase involved in arrest at the G2-M cell cycle checkpoint for DNA repair before the start of mitosis. Normal cells repair damaged DNA during G1 arrest. Cancer cells often lack a G1-S checkpoint and rely on a functional G2-M checkpoint for DNA repair. WEE1 is overexpressed in various cancer types, and several inhibitors and / or decomposers of WEE1 are known to those skilled in the art. See, for example, WO 2019 / 173082 and WO 2020 / 069105.

[0005] Uterine serous carcinoma (USC) is a highly aggressive type II endometrial cancer. See, for example, Ferriss JS et al, Uterine serous carcinoma: key advances and novel treatment approaches. International Journal of Gynecologic Cancer 2021;31:1165-1174. A phase II study of adavosertib in recurrent uterine serous carcinoma has been reported. Liu JF et al al.Phase II study of the WEE1 inhibitor adavosertib in recurrent uterine serous See carcinoma.J Clin Oncol 2021;39. However, existing therapeutic approaches remain limited, and therefore additional therapies are urgently needed. Summary of the Invention

[0006] Various embodiments provide a method of treating a subject having uterine serous carcinoma (USC), comprising administering to the subject a therapeutically effective amount of ZN-c3 or a pharma- ceutically acceptable salt thereof according to a dosing regimen.

[0007] These and other embodiments are described in more detail below. [Brief description of the drawings]

[0008] [Figure 1] Illustrated are certain baseline (November 2020) and second stage reassessment (April 2021) peritoneal imaging results for subject #1, demonstrating a confirmed partial response at that follow-up time. [Diagram 2] Illustrate certain baseline (January 2021) and first stage reassessment (March 2021) peritoneal imaging results for subject #2, demonstrating a partial response at that follow-up time. [Diagram 3] Illustrated are certain baseline (April 2021) and fifth stage reassessment (November 2021) peritoneal imaging results for subject #3, demonstrating a complete response at that follow-up point. [Figure 4] Illustrated are certain baseline (April 2021) and fifth stage reassessment (November 2021) peritoneal imaging results for subject #3, demonstrating a complete response at that follow-up point. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] WEE1 is a tyrosine kinase that is a key component of the ATR-mediated G2 cell cycle checkpoint control that prevents the initiation of mitosis in response to cellular DNA damage. ATR phosphorylates and activates CHK1, which in turn activates WEE1, leading to the selective phosphorylation of cyclin-dependent kinase 1 (CDK1) at Tyr15. , thereby stabilizing the CDK1-cyclin B complex and halting cell cycle progression. This process confers a survival advantage by allowing tumor cells time to repair damaged DNA before the onset of mitosis. Suppressing WEE1 inhibits the G2 checkpoint and causes cancer cells with DNA damage to enter unscheduled mitosis and undergo cell death by mitotic apoptosis. Thus, inhibition and / or degradation of WEE1 has the potential to sensitize tumors to DNA damaging agents such as cisplatin and induce tumor cell death.

[0010] definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless otherwise stated. In the event that there are a plurality of definitions for a term herein, the definition in this section prevails unless otherwise stated.

[0011] As used herein, the terms "WEE1 inhibition," "WEE1 inhibitor," and similar terms refer to inhibiting the activity or function of WEE1 tyrosine kinase, for example, by degrading WEE1 tyrosine kinase and / or by reducing the activity of WEE1 tyrosine kinase in mediating the phosphorylation of CDK1. WEE1 inhibitors that function by degrading WEE1 tyrosine kinase may be referred to herein as WEE1 degraders.

[0012] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. The subject animal may be a mammal, such as, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates (such as monkeys, chimpanzees, and apes), and, in particular, humans. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and / or infant. In other embodiments, the subject may be an adult.

[0013] As used herein, "treat," "treating," "treatment," and "therapeutic" And the term "therapy" does not necessarily mean a complete cure or elimination of a disease or condition. Any alleviation, to any extent, of any undesirable signs or symptoms of a disease or condition may be considered treatment and / or therapy. Moreover, treatment may include actions that may worsen a subject's overall feeling of health or appearance.

[0014] The terms "therapeutically effective amount" and "effective amount" are used to indicate an amount of an active compound (e.g., ZN-c3 or a pharma- ceutically acceptable salt thereof) that induces the indicated biological or medical response. For example, a therapeutically effective amount of such a ZN-c3 compound, salt, or composition may be an amount necessary to prevent, alleviate, or ameliorate symptoms of a disease or condition, or to prolong the survival of a subject being treated. This response may occur in a tissue, system, animal, or human, and includes alleviation of signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capabilities of a person skilled in the art in view of the present disclosure provided herein. The therapeutically effective amount of a ZN-c3 compound, salt, or composition required as a dose will depend on the route of administration, the type of animal being treated, including humans, and the physical characteristics of the particular animal under consideration. Dosage may be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concurrent medications, and other factors that a person skilled in the medical field would recognize.

[0015] For example, an effective amount of a ZN-c3 compound, salt or composition may be an amount that results in (a) reduction, alleviation or elimination of one or more symptoms caused by USC, (b) reduction in tumor size, (c) tumor elimination, and / or (d) long-term disease stabilization (proliferation arrest) of tumors. For example, an effective amount of a ZN-c3 compound, salt or composition may be an amount that results in reduction of WEE1 activity and / or phosphorylation (such as phosphorylation of CDC2). Reduction of WEE1 activity is known to those skilled in the art and can be determined by analysis of WEE1 intrinsic kinase activity and phosphorylation of downstream substrates.

[0016] As used herein, the term "dosing regimen" refers to the manner in which a ZN-c3 compound is administered to a subject, including route of administration, dose, and dosing interval. A dosing regimen may include a "periodic" dosing phase in which a specific dosage (e.g., 300 mg) is administered at regular intervals (e.g., once a day) over a specific period (e.g., 3 days). A dosing regimen may further include an "intermittent" dosing phase in which one or more dosing parameters, such as dosage and / or dosing interval, are varied or altered. For example, an intermittent dosing phase may include a "holiday" phase in which the ZN-c3 compound is not administered or is administered at a reduced dosage and / or less frequently.

[0017] It is understood that the compounds described herein may be isotopically labeled. Substitution with an isotope such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced required dosage. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be expressly disclosed or understood as being present in the compound. At any position of a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

[0018] When a range of values ​​is provided, it is understood that the upper and lower limits, as well as every intervening value between the upper and lower limits of that range, are encompassed within an embodiment.

[0019] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open ended rather than limiting, unless expressly stated otherwise. For example, the word "including" above should be construed to mean "including without limitation," "including but not limited to," and the like. As used herein, the term "comprising" is synonymous with "including," "containing," or "featuring," is inclusive or open-ended, and does not exclude additional unrecited elements or method steps. The term "having" should be interpreted as "having at least." The term "including" should be interpreted as "including, but not limited to." The term "example" is used to provide illustrative examples rather than an exhaustive or exclusive list of the items under discussion. The use of terms such as "preferably," "preferred," "desired," or "desirable," as well as words of similar import, should not be understood as implying that a particular feature is critical, essential, or even important to the structure or function, but rather is intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term "comprising" should be interpreted as synonymous with the phrases "having at least" or "including at least." When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0020] With respect to the use of substantially any plural and / or singular term herein, a person skilled in the art may convert from plural to singular and / or from singular to plural as appropriate depending on the context and / or application. Various singular / plural permutations may be expressly set forth herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain means are recited in mutually different dependent claims does not indicate that a combination of these means cannot be used to advantage. Any reference signs in the claims should not be interpreted as limiting the scope thereof.

[0021] WEE1 compound ZN-c3 is a selective, orally bioavailable, small molecule inhibitor of WEE1, a key component of the G2 / M cell cycle checkpoint that prevents cells from entering mitosis and allows the repair of DNA damage. ZN-c3 has demonstrated significant in vitro antitumor activity in multiple cell lines and xenograft models.

[0022] [Table 1]

[0023] ZN-c3 can be prepared as described in WO 2019 / 173082 (see, e.g., Example 9B therein), which is incorporated by reference herein, particularly for the purposes of describing methods for making ZN-c3, as well as methods for making salts and pharmaceutical compositions thereof.

[0024] Pharmaceutical Compositions Some embodiments described herein relate to pharmaceutical compositions that may include an effective amount of a ZN-c3 compound or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, diluent, excipient, or combination thereof.

[0025] The term "pharmaceutical composition" refers to a mixture of ZN-c3 and / or its pharma- ceutically acceptable salts with other chemical components, such as diluents or carriers. Pharmaceutical compositions facilitate the administration of a compound to an organism. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions are generally tailored to the specific intended route of administration.

[0026] The term "physiologically acceptable" defines a carrier, diluent or excipient that does not inhibit the biological activity and properties of the ZN-c3 compound or cause obvious damage or injury to the animal to which the composition is intended to be delivered.

[0027] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, and without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the incorporation of many organic compounds into cells or tissues of a subject.

[0028] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that has no apparent pharmacological activity, but may be medicamentally necessary or desirable. For example, a diluent may be used to bulk a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, without limitation, phosphate buffered saline, which mimics the pH and isotonicity of human blood.

[0029] As used herein, "excipient" refers to an essentially inert substance added to a pharmaceutical composition to provide the composition with, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegration ability, and the like. For example, stabilizers such as antioxidants and metal chelators are excipients. In one embodiment, the pharmaceutical composition includes an antioxidant and / or a metal chelator. A "diluent" is a type of excipient.

[0030] The pharmaceutical compositions described herein can be administered to human patients by themselves or in pharmaceutical compositions in which they are mixed with other active ingredients, such as in combination therapy, or with carriers, diluents, excipients, or combinations thereof.The appropriate formulation depends on the route of administration selected.Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0031] The pharmaceutical compositions disclosed herein can be prepared in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee making, elutriating, emulsifying, encapsulating, entrapping or tabletting processes. Additionally, the ZN-c3 active ingredient is typically contained in an amount effective to achieve its intended purpose, and can be provided as a salt with a pharma-ceutically compatible counterion.

[0032] Any of a number of art-recognized techniques for administering ZN-c3 compounds, salts and / or compositions may be used, including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injection. In some embodiments, ZN-c3 or a pharma- ceutically acceptable salt thereof may be administered orally.

[0033] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may include a storage compartment for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a format prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the drug form for human or animal administration. Such notice may be, for example, a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. Compositions comprising ZN-c3 and / or salts formulated in a suitable pharmaceutical carrier as described herein may also be prepared, placed in a suitable container, and labeled for the treatment of an indicated condition.

[0034] Methods of Use and Treatment Some embodiments described herein relate to a method of treating a subject having USC, comprising administering to the subject a therapeutically effective amount of ZN-c3 or a pharma- ceutically acceptable salt thereof according to a dosing regimen.

[0035] Some embodiments described herein relate to the use of a therapeutically effective amount of ZN-c3 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a subject with USC according to a dosing regimen. Other embodiments relate to ZN-c3 for use in treating a subject with USC, the treatment comprising administering a therapeutically effective amount of ZN-c3 or a pharma-ceutically acceptable salt thereof to the subject according to a dosing regimen. In various embodiments, the dosing regimen comprises oral administration of ZN-c3 to the subject.

[0036] In various embodiments, the therapeutically effective amount of ZN-c3 administered to the subject is 300 mg or more per day. For example, in some embodiments, the therapeutically effective amount of ZN-c3 administered to the subject is about 300 mg per day. In other embodiments, the therapeutically effective amount of ZN-c3 administered to the subject is about 350 mg per day. In other embodiments, the therapeutically effective amount of ZN-c3 administered to the subject is about 200 mg per day. In some embodiments, the therapeutically effective amount of ZN-c3 administered to the subject is 300 mg or more once per day (QD). In one embodiment, the therapeutically effective amount of ZN-c3 administered to the subject is about 300 mg once per day (QD). In another embodiment, the therapeutically effective amount of ZN-c3 administered to the subject is about 350 mg once per day (QD). In yet another embodiment, the therapeutically effective amount of ZN-c3 administered to the subject is about 200 mg once per day (QD). In some embodiments, the therapeutically effective amount of ZN-c3 administered to the subject is 150 mg or more twice a day (BID). In one embodiment, the therapeutically effective amount of ZN-c3 administered to the subject is about 150 mg twice a day (BID). In another embodiment, the therapeutically effective amount of ZN-c3 administered to the subject is about 175 mg twice a day (BID). In yet another embodiment, the therapeutically effective amount of ZN-c3 administered to the subject is about 100 mg twice a day (BID).

[0037] In various embodiments, the dosing regimen includes a cyclical dosing phase in which the dose and frequency of administration of ZN-c3 to the subject is fixed for a period of time, for example, 3 or more consecutive days. For example, in one embodiment, the cyclical dosing phase includes a daily dose in the range of about 200 mg per day to about 350 mg per day, which is fixed for a period of at least 3 consecutive days. In one embodiment, the daily dose is administered once daily (QD). In another embodiment, the daily dose is administered in split doses provided 2, 3 or 4 times daily. In one embodiment, the cyclical dosing phase includes once daily dosing for a period of at least 3 consecutive days.

[0038] In various embodiments, the dosing regimen includes an intermittent dosing phase, in which the dose and frequency of administration of ZN-c3 to the subject is altered. In one embodiment, the intermittent dosing phase includes at least one change in the amount of ZN-c3 administered to the subject daily. In one embodiment, the intermittent dosing phase includes at least one drug-free day, e.g., 1, 2, 3, 4, 5, 6, or 7 drug-free days. For example, in one embodiment, the dosing regimen includes a cyclic phase in which ZN-c3 is orally administered to the subject once a day for 5 days, followed by an intermittent or drug-free phase in which ZN-c3 is not administered for 2 days. Such a dosing regimen, which may be referred to as one day on / two days off, may be repeated or cycled as often as necessary, depending on the particular case.

[0039] In various embodiments, the subject is a human. In some embodiments, the subject has USC that is advanced USC. In some embodiments, the subject has USC that is recurrent USC.

[0040] In various embodiments, the subject has been previously treated for USC by a previous treatment regimen. Various treatment regimens are known to those skilled in the art or are under development. In one embodiment, the previous treatment regimen can include administering a previous USC therapy to the subject. For example, in various embodiments, the previous USC therapy can include at least one selected from carboplatin, paclitaxel, bevacizumab, trastuzumab, pembrolizumab, lenvatinib and doxorubicin.

[0041] The amount of ZN-c3 compound or its pharma- ceutically acceptable salt that is effective in treating a particular case of USC will vary depending on the particular compound or salt selected, as well as the route of administration, the nature and / or symptoms of the disease or condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician. In the case of administration of a pharma-ceutically acceptable salt, the dosage may be calculated as a free base. As will be understood by those skilled in the art, in certain circumstances, it may be necessary to administer ZN-c3 compound, salt or composition in amounts that exceed or even far exceed the dosage ranges described herein in order to effectively and aggressively treat, particularly aggressive cases of USC.

[0042] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more partial doses per day. The partial dose itself may be further divided, for example, into several discrete loosely spaced administrations.

[0043] As will be readily apparent to those skilled in the art, the useful in vivo dosage and the specific mode of administration will vary depending on the age, weight, severity of the affliction, the mammalian species being treated, the specific ZN-c3 compound, salt or composition being used, and the specific application for which these therapies are being used. Determination of effective dosage levels, i.e., the dosage levels required to achieve the desired results, can be accomplished by those skilled in the art using routine methods, such as human clinical trials, in vivo studies, and in vitro studies. For example, useful dosages of ZN-c3 or its pharma-ceutically acceptable salts can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparisons can be made by comparison with established drugs such as carboplatin and / or paclitaxel.

[0044] Dosage amounts and intervals are individually tailored to provide a plasma level of the active moiety sufficient to maintain a modulating effect, i.e., a minimal effective concentration (MEC). The MEC may be adjusted. The MEC varies for each compound but can be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably 30-90% and most preferably 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0045] The method and timing of termination, interruption, or adjustment of treatment due to toxicity or organ dysfunction should be determined by the primary It should be noted that the attending physician would know. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response is not adequate (precluding toxicity). The magnitude of the dose administered in the management of the disease of interest will vary with the severity of the disease or condition to be treated and with the route of administration. The severity of the disease or condition can, for example, be assessed, in part, by standard prognostic evaluation methods. Furthermore, the dose and perhaps the frequency of administration will also vary with the age, weight and response of the individual patient. Programs comparable to those discussed above can be used in veterinary medicine.

[0046] The ZN-c3 compounds, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of ZN-c3 can be established by determining in vitro toxicity on cell lines, such as mammalian cell lines, and preferably human cell lines. The results of such studies often predict toxicity in animals, such as mammals, or especially humans. Alternatively, the toxicity of a particular compound in an animal model, such as mice, rats, rabbits, dogs or monkeys, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model for determining efficacy, the skilled artisan can be guided by the state of the art in selecting the appropriate model, dose, route of administration and / or regimen. EXAMPLES

[0047] Examples 1 to 3 method ZN-c3-001 (NCT04158336) is an open-label, multicenter, Phase I dose escalation and expansion study evaluating the safety and clinical activity of ZN-c3 in subjects with advanced or metastatic solid tumors, subjects refractory to standard therapy, or subjects for whom standard therapy is not available. Daily oral ZN-c3 dosing was escalated from 25 mg to 450 mg once daily (QD), with the recommended Phase 2 dose being 300 mg QD. Here, we report preliminary safety and efficacy results for subjects with USC who received ZN-c3 at doses of 300 mg QD or greater.

[0048] result As of January 21, 2022, a total of 80 subjects across all tumor types have been enrolled. For uterine serous carcinoma (USC), 14 subjects received ZN-c3 at doses ≥ 300 mg QD and were evaluated for safety. Median treatment duration was 12.4 weeks (range 2-36 weeks). The safety profile of this subgroup was comparable to the overall patient population, with 12 of 14 subjects reporting at least one treatment-related adverse event (TRAE). TRAE grades 1-4 were ≥ 3. Occurring in ≥ 10 subjects, in descending order of frequency, included nausea, vomiting, diarrhea, fatigue, decreased appetite, dehydration, and anemia. Grade ≥ 3 TRAEs occurring in ≥ 2 subjects included anemia and thrombocytopenia. These hematological events were limited to 2 subjects each. Eleven of 14 subjects had measurable disease and at least one post-baseline tumor assessment, with 3 subjects (27.3%) having a confirmed partial response as the best overall response for these subjects (one of these subjects achieved a complete response at the last tumor assessment), 7 (63.6%) had stable disease, and 1 (9.1%) had progressive disease. The disease control rate, defined as those with complete response, partial response, and stable disease, was 90.9%.

[0049] USC Confirmed Partial Response No. 1 - Summary 72-year-old Caucasian female, stage IV USC, peritoneal and lymph node metastases, ECOG PS 1 Two prior therapies in the advanced / metastatic setting ●ZN-c3 starting dose: 350mg QD in December 2020 Tumor marker CA-125 decreased from 36 U / mL at baseline to a minimum of 12 U / mL after approximately 3 months of treatment. Partial response was confirmed, with an overall reduction of 49% Subjects continued to receive study drug for 199 days until radiological disease progression.

[0050] [Table 2]

[0051] [Table 3]

[0052] [Table 4]

[0053] Figure 1 illustrates certain baseline (November 2020) and second stage reassessment (April 2021) peritoneal imaging results for subject number 1, demonstrating the confirmed partial response at that follow-up time point.

[0054] USC Partial Response No. 2 - Summary 69-year-old African-American female, stage IV USC, lymph node and lung metastases, ECOG PS 0 - Four prior therapies in the advanced / metastatic setting, including prior use of pembrolizumab and lenvatinib Starting dose of ZN-c3: 300mg QD in January 2021 Tumor marker CA-125 increased from 440 U / mL at baseline to 440 U / mL at 2 months of treatment. Later decreased to <50 U / mL Partial response was confirmed, with an overall reduction of 43% Subjects continued to receive study medication for 230 days until radiological disease progression.

[0055] [Table 5]

[0056] [Table 6]

[0057] Figure 2 illustrates certain baseline (January 2021) and first restaging (March 2021) peritoneal imaging results for subject #2, demonstrating the partial response at follow-up. Subsequent tumor evaluations confirmed the partial response.

[0058] USC Partial Response No. 3 - Summary 60-year-old Caucasian female, stage IV USC, peritoneal metastasis, ECOG PS 1 - Two prior therapies in the advanced / metastatic setting, including prior use of pembrolizumab and lenvatinib Starting dose of ZN-c3: 300mg QD in April 2021 Tumor marker CA-125 was not collected at baseline Unconfirmed complete response with 100% reduction overall Subjects continued to receive study medication for 252 days until clinical disease progression.

[0059] [Table 7]

[0060] [Table 8]

[0061] Figures 3 and 4 illustrate certain baseline (April 2021) and fifth stage reassessment (November 2021) peritoneal imaging results for subject number 3, demonstrating a complete response at that follow-up point.

[0062] conclusion ZN-c3 appears to be safe and well tolerated as a single agent at oral doses of 300 mg or more QD, as exemplified in Examples 1-3, and has demonstrated clinical activity in subjects with recurrent or advanced USC. Safety results in these subjects were consistent with those of the full study population. An ongoing dose expansion study is enrolling USC patients. Preliminary efficacy signals will be confirmed in a dedicated Phase 2 study (ZN-c3-004, NCT04814108).

[0063] Moreover, although the above has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made without departing from the spirit of the present disclosure. It should therefore be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather encompass all modifications and alternative forms consistent with the true scope and spirit of the present invention.

Claims

1. A pharmaceutical composition for treating a subject with uterine serous carcinoma (USC) according to a dosing regimen, comprising a therapeutically effective amount of ZN-c3 or a pharma- ceutical acceptable salt thereof.

2. The pharmaceutical composition of claim 1 , wherein the USC is advanced or recurrent USC.

3. 10. The pharmaceutical composition of claim 1, wherein the dosing regimen comprises a cyclical dosing phase comprising a daily dose in the range of about 200 mg per day to about 350 mg per day, the daily dose being fixed for a period of at least three consecutive days.

4. 4. The pharmaceutical composition of claim 3, wherein the cyclical dosing phase comprises once-daily dosing for a period of at least three consecutive days.

5. The pharmaceutical composition of claim 1 , wherein the dosing regimen includes an intermittent dosing phase.

6. 6. The pharmaceutical composition of claim 5, wherein the intermittent dosing phase includes at least one drug holiday.

7. 2. The pharmaceutical composition of claim 1, wherein the dosing regimen comprises 5 days of dosing with ZN-c3 and 2 days of rest.

8. 2. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of ZN-c3 administered to the subject is about 200 mg per day.

9. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of ZN-c3 administered to the subject is 300 mg or more per day.

10. 10. The pharmaceutical composition of claim 9, wherein the therapeutically effective amount of ZN-c3 administered to the subject is about 350 mg per day.

11. 10. The pharmaceutical composition of claim 9, wherein the therapeutically effective amount of ZN-c3 administered to the subject is about 300 mg per day.

12. 2. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of ZN-c3 administered to the subject is about 200 mg once daily (QD).

13. 2. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of ZN-c3 administered to the subject is 300 mg or more once daily (QD).

14. 14. The pharmaceutical composition of claim 13, wherein the therapeutically effective amount of ZN-c3 administered to the subject is about 350 mg once daily (QD).

15. 14. The pharmaceutical composition of claim 13, wherein the therapeutically effective amount of ZN-c3 administered to the subject is about 300 mg once daily (QD).

16. The method of claim 1 , wherein the subject has been previously treated for the USC with a previous treatment regimen.

17. The method of claim 16, wherein the previous treatment regimen comprises administering a previous USC therapy to the subject.

18. 18. The pharmaceutical composition of claim 17, wherein the prior USC therapy comprises at least one selected from carboplatin, paclitaxel, bevacizumab, trastuzumab, pembrolizumab, lenvatinib, and doxorubicin.

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