Combinations of pharmaceuticals for use in the treatment of neoplastic diseases

Abstract

The present invention provides a pharmaceutical combination comprising (a) a TTK / PLK1 inhibitor (i.e., a compound of formula (I) or a pharma- ceutically acceptable salt thereof as covered in the claims) and (b) carboplatin, as well as methods of using the combination of the present invention for the treatment of neoplastic diseases, such as cancer.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical combination comprising two active pharmaceutical compounds described herein, and to methods of using the combination of the present invention in the treatment of neoplastic diseases, particularly cancer.

Background Art

[0002] WO 2015 / 155042 describes a recently discovered class of inhibitors of threonine tyrosine kinase (TTK) for use in the treatment of cancer.

[0003] Carboplatin is a well-known small molecule approved for the treatment of many cancer indications. Carboplatin is commercially available under the trade name Paraplatin®.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] There is a continuing need for new and effective treatment options for cancer patients.

Means for Solving the Problems

[0006] In a first aspect, the present invention provides (a) a compound of formula (I)

Chemical Formula

[0007] The compound of formula (I) is disclosed as Example 17 in International Publication No. 2015 / 155042.

[0008] Surprisingly, in addition to TTK inhibitory activity, the compound of formula (I) was also found to exhibit polo-like kinase 1 (PLK1) inhibition (see examples below). Both kinases work together to activate the spindle formation checkpoint (SAC) of mitosis in the kinetochore, controlling chromosome alignment and segregation before cells can terminate mitosis. Von Schubert et al., Cell Reports 2015, 12; 66-78, disclose that PLK1 and TTK (also known as MPS1) work together to regulate the spindle formation checkpoint (SAC) in human cells. This potential for enhanced effects obtained from the inhibition of both TTK and PLK1 is also suggested by Dou et al., Plos ONE 2011, 6:4; e18793, which shows that several substrates of both kinases share similar consensus motifs.

[0009] In contrast to TTK-specific inhibitors, the compound of formula (I) exhibits a long-lasting effect on TTK, combined with a transient effect on PLK1 (see examples below) that leads to more rapid disruption of SAC, which enhances the progression of abnormal mitosis. Thus, the dual TTK / PLK1 inhibitory activity gives the compound of formula (I) a unique characteristic, distinguishing it from other molecules that exhibit TTK inhibitory activity without a recognizable level of PLK1 inhibitory activity.

[0010] In a further embodiment, the present invention provides a method for treating a neoplastic disease in a subject that requires treatment for the neoplastic disease, the method comprising administering a therapeutically effective amount of a combination of the pharmaceuticals of the present invention to the subject.

[0011] In a further embodiment, the present invention provides a method for treating a neoplastic disease in a subject requiring treatment for the neoplastic disease, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject, wherein the subject has been or will be treated with carboplatin.

[0012] In a further embodiment, the present invention provides a method for treating a neoplastic disease in a subject requiring treatment for the neoplastic disease, comprising administering a therapeutically effective amount of carboplatin to the subject, wherein the subject has been or will be treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0013] In a further embodiment, the present invention provides a combination of pharmaceuticals for use in the treatment of neobiotic diseases in a subject.

[0014] In a further embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with carboplatin for the treatment of neobiotic diseases in subjects.

[0015] In a further embodiment, the present invention provides carboplatin for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of neobiotic diseases in a subject.

[0016] In a further embodiment, the present invention provides the use of combinations of the pharmaceuticals of the present invention in preparation as monopharmaceuticals or combination pharmaceuticals for the treatment of neoplastic diseases in a subject.

[0017] In a further embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a monotherapy drug for use in combination with carboplatin or in the preparation of a combination drug with carboplatin for the treatment of neoplastic diseases in a subject.

[0018] In a further aspect, the present invention provides the use of carboplatin in the preparation of a monotherapy medicament for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of neoplastic diseases in a subject or in the preparation of a combined medicament in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0019] The neoplastic diseases for treatment by the combination of the present invention are described below and are particularly envisaged for the treatment of cancer and particularly for human subjects.

[0020] Further aspects and embodiments of the present invention are described in more detail below. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] [Figure 1] FIG. 1 shows the additivity of the compound of formula (I) in combination with carboplatin in the TNBC PDX model BR1282. Carboplatin (60 mg / kg) was administered intravenously weekly (qw). The compound of formula (I) (7 mg / kg) was administered intravenously twice a week (2qw). (When administered on the same day, 4 or 24 hours after carboplatin). The average tumor volume (A) and the average change in body weight in % (B) are shown. One non-drug-related death occurred on day 15 in the vehicle-treated group. One mouse in the combination group with a dosing interval of 4 hours on day 20 and 24 hours on day 10 had to be euthanized due to a tumor volume exceeding 1500 mm3. In any mouse showing a transient weight loss of more than 10% at any time point, dosing was delayed by one day. The vehicle control group was given the vehicle of carboplatin and the vehicle of the compound of formula (I) using an interval of 4 hours between both administrations (shown as both vehicles). N = 8 mice per group. [Figure 2] FIG. 2 shows the individual tumors of the study presented in FIG. 1 until sacrifice. The vehicle control group was given the vehicle of carboplatin and the vehicle of the compound of formula (I) using an interval of 4 hours between both administrations (shown as both vehicles). [Figure 3]Figure 3 shows the average growth rate (k), suggesting that the combination of carboplatin and the compound of formula (I) has additive efficacy as a single agent in the BR1282 TNBC PDX model. The exponential function calculations of the k means for treatment with both vehicle (vehicle), 7 mg / kg of the compound of formula (I) intravenously 2qw, 60 mg / kg of carboplatin intravenously qw or the combination of both are shown up to the day of sacrificing the mice (the most recent day 31). In the combination group, carboplatin was first administered, and the compound of formula (I) was administered 4 or 24 hours later if administered on the same day. The lines represent mean + / − SD. Statistical analysis was based on one-way analysis of variance (1WA) using the Holm-Sidak post hoc test for group comparison. All groups treated with different compounds were statistically significantly different compared to the vehicle, and both combination groups were statistically different compared to the carboplatin single-agent group (p < 0.05). However, the combination group was not statistically different compared to the compound of formula (I) single-agent group (p = 0.5736). Detailed statistical analysis is shown in Table 2. N = 8 mice per group. [Figure 4] Figure 4 shows the antagonism of the compound of formula (I) combined with carboplatin in the TNBC PDX model BR1282 when the compound of formula (I) was administered first and carboplatin second. The compound of formula (I) (8 mg / kg) and carboplatin (60 mg / kg) were administered intravenously qw. (If administered on the same day, carboplatin was administered 4 hours after the compound of formula (I)). The mean tumor volume (A) and mean body weight change in % (B) are shown. The vehicle control group was given the vehicle of the compound of formula (I) and the vehicle of carboplatin with a 4-hour interval between both administrations (shown as both vehicles). N = 6 mice for the vehicle and both single-agent groups, and N = 7 mice for the combination group. [Figure 5] Figure 5 shows the individual tumors of the study presented in Figure 4. The vehicle control group was given the vehicle of the compound of formula (I) and the vehicle of carboplatin with a 4-hour interval between both administrations (shown as both vehicles). [Figure 6]Figure 6 shows the statistical analysis on day 14, suggesting that the combination of carboplatin and the compound of formula (I) has similar efficacy to monotherapy in the BR1282 TNBC PDX model. The Δtumor volume (tumor volume on day 14 - tumor volume on day 0) on day 14 is shown for treatment with both vehicles (vehicle), 8 mg / kg intravenous qw of the compound of formula (I), 60 mg / kg intravenous qw of carboplatin, or a combination of both. In the combination group, the compound of formula (I) was administered first, followed by carboplatin 4 hours later if administered on the same day. The lines represent mean + / - SD. Statistical analysis is based on one-way ANOVA (1WA) with Holm-Sidak post-hoc tests for group comparisons. All groups treated with different compounds were not statistically significantly different compared to the vehicle, and the combination group was not statistically different compared to the compound of formula (I) monotherapy group (p>0.05). For the vehicle and the monotherapy groups, N=6 mice were used, while for the combination therapy group, N=7 mice were used. [Figure 7] Figure 7 shows the efficacy (A) and tolerability (B) of the carboplatin + compound of formula (I) combination in Balb / c nude mice with subcutaneous xenografts of SKOV-3. Balb-c nude mice with subcutaneous SKOV-3 tumors were treated with monotherapy or combination therapy at the indicated doses and schedules until day 24. Time-dependent changes in tumor volume (efficacy) and body weight (tolerability) are shown as mean ± standard error of the mean until individual mice needed to be euthanized due to tumor sizes exceeding 1500 mm3 (n=8). "CRB" refers to carboplatin. [Figure 8] Figure 8 shows the efficacy (A) and tolerability (B) of the carboplatin + formula (I) compound combination in Balb / c nude mice with subcutaneous SKOV-3 xenografts up to the first euthanasia due to excessive tumor size. Balb-c nude mice with subcutaneous SKOV-3 tumors were treated with monotherapy or combination therapy at the indicated doses and schedules. [Figure 9]Figure 9 shows the endpoint statistical analysis for tumor volume (A) and body weight (B) at day 23 using one-way ANOVA with the Holm-Sidak post-hoc test for multiple comparisons, with *p<0.05, **p<0.01, and ***p<0.001 compared to the vehicle group. [Figure 10] Figure 10 shows the exponential fit to individual SKOV-3 tumors in each treatment group. Since mice had to be regularly euthanized until the end of the study on day 51, alternative representations are shown using the exponential fit (Prism 9.3) for each tumor in each group from day 0 to the last day of measurement. "Combination" refers to a combination treatment using the total dose of both compounds with the compound of formula (I) in a 2qw or qw schedule at intervals of 1, 4, or 24 hours, as shown. [Modes for carrying out the invention]

[0022] definition The specific terms used herein are defined below. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art.

[0023] The terms "combination," "therapeutic combination," or "combination of medications" are interchangeable terms and refer to either a fixed or unfixed combination.

[0024] The term “combination therapy” refers to the administration of two or more therapeutic agents to treat a therapeutic symptom or disorder described herein. Such administrations include the simultaneous administration of these therapeutic agents substantially concurrently, as well as the use of each type of therapeutic agent sequentially and / or separately (e.g., via different routes of administration) at roughly the same or different times, for example, according to different dosing regimens, examples of which are described herein. When therapeutic agents are administered sequentially and / or separately, the dosing schedule is such that therapeutic interactions between the therapeutic agents exist in the patient’s body, and / or, when a second therapeutic agent is administered, a therapeutic effect attributable to the first therapeutic agent exists. For example, when drugs are administered according to a cyclical treatment schedule, the cyclical treatment schedules may overlap, or when one therapeutic agent is administered according to a continuous dosing schedule and a second therapeutic agent is administered according to a cyclical schedule, at least one dose from the drug administered according to the continuous schedule occurs during the treatment cycle of the other therapeutic agent. Typically, when both therapeutic agents are administered according to a cyclical treatment schedule, there is at least one interval of 7 days or less between doses of one therapeutic agent and doses of the other therapeutic agent.

[0025] The term "pharmaceutical composition" is defined herein as a solid or liquid formulation containing at least one therapeutic agent to be administered to a patient, together with one or more pharmaceutically acceptable excipients, to treat a particular disease or condition affecting the patient.

[0026] As used herein, the term “pharmaceutically acceptable” means, within the bounds of sound medical judgment, an item such as a compound, material, composition and / or dosage form that is suitable for contact with human tissue without excessive toxicity or other problems commensurate with a reasonable benefit / risk ratio.

[0027] As used herein, the terms “fixed combination,” “fixed dose,” “single formulation,” and “combination drug” refer to a single dosage form formulated to deliver to a patient an amount of both therapeutic agents that together are therapeutically effective for the treatment of a neoplastic disease. A single dosage form is designed to deliver an amount of each therapeutic agent together with any pharmaceutically acceptable carrier or excipient.

[0028] The terms “non-fixed combination,” “kit,” “separate formulations,” and “monotherapy” mean that the active ingredients are formulated as separate entities to allow them to be administered to a patient simultaneously, sequentially, or separately, and such administration provides therapeutically effective levels of the two compounds in the patient’s body.

[0029] The term "patient" refers to a person undergoing therapeutic treatment.

[0030] The term "subject" refers to a mammal, preferably a patient.

[0031] As used herein in the context of treating a disease in a subject, the term “treatment” refers to treatments and therapies in general that achieve one or more of several desired therapeutic effects, such as: inhibiting disease progression, slowing the rate of progression, stopping the rate of progression, preventing disease progression, alleviating the symptoms of disease, improving the disease, and curing the disease. For example, treatment may be a reduction in one or more symptoms of a disorder or complete elimination of the disorder. Within the meaning of this disclosure, the term “to treat” also means to stop a disease, delay the onset of a disease (i.e., the period before the onset of clinical symptoms of the disease), and / or reduce the risk of developing or worsening the disease.

[0032] As used herein, the terms “prevent,” “preventing,” or “prevention” include the prevention of at least one symptom associated with or caused by the disease being prevented.

[0033] The terms “pharmaceutically effective dose,” “therapeutically effective dose,” or “clinically effective dose” refer to an amount sufficient to provide an observable or clinically significant improvement in baseline clinically observable signs and symptoms of the treated disease, for example, commensurate with a reasonable benefit / risk ratio, when administered according to the desired treatment regimen. Those skilled in the art will understand that a therapeutically effective dose of an agent for use in combination therapy may be less than the amount required to provide a therapeutic effect when the agent is used as monotherapy.

[0034] The term "approximately" means a variation of 10% or less of the relevant figure. In some embodiments, the term "approximately" means a variation of 5% or less of the relevant figure.

[0035] To avoid misunderstanding, if a range is provided (e.g., 5 mg to 480 mg), that range includes the stated upper limit (480 mg) and lower limit (5 mg) of that range.

[0036] Compound of formula (I) In some embodiments, the compound of formula (I) is used as a free base. In other embodiments, the compound of formula (I) is used as a pharmaceutically acceptable salt.

[0037] A pharmaceutically acceptable salt of the compound of formula (I) may be an acid addition salt. The salt is formed, for example, from the compound of formula (I) using an organic or inorganic acid. A pharmaceutically acceptable salt is within the realm of common sense for those skilled in the art. A pharmaceutically acceptable salt may contain two or more molecules or ions of the corresponding acid.

[0038] Compounds of formula (I) and their pharmaceutically acceptable salts can be solvated, and in particular hydrated. Solvation and / or hydration may occur during the preparation process.

[0039] Compounds of formula (I) and pharmaceutically acceptable salts thereof can be synthesized as described in International Publication No. 2015 / 155042, particularly pages 17-19 incorporated herein by reference, and in Example 17 on page 49 of International Publication No. 2015 / 155042, including the references in Example 9, intermediate H and Example 17 of Example 1, which are also incorporated herein by reference.

[0040] disease The combination of pharmaceuticals of the present invention may be used to treat neoplastic diseases by administration of the combination of the present invention, for example, to inhibit protein kinase TTK (a compound of formula (I) or a pharmaceutically acceptable salt thereof) and to inhibit DNA repair and / or synthesis (carboplatin). Furthermore, given the observation that the compound of formula (I) also has PLK1 inhibitory activity, neoplastic diseases may be treatable by inhibition of PLK1 in addition to treatment with carboplatin and a TTK inhibitor (e.g., a compound of formula (I)).

[0041] Furthermore, the combination of pharmaceuticals of the present invention may be used to treat cancer at any clinical stage or pathological grade (e.g., tumor stage I, tumor stage II, tumor stage III, tumor stage IV) or treatment situation (e.g., therapeutic, including prophylactic, adjuvant, neoadjuvant, and palliative treatments). The combination of pharmaceuticals of the present invention may be used to slow, delay, or halt the progression or growth of cancer, or to increase overall survival or progression-free survival or time to progression of cancer, or to improve or maintain the quality of life or functional status of the subject (e.g., the patient). The combination of pharmaceuticals of the present invention may also be used in post-treatment recovery from cancer. The combination of pharmaceuticals of the present invention may be used in the treatment of metastatic cancer. The cancer being treated may be advanced cancer. Advanced cancer is cancer that is unlikely to be cured or controlled by treatment. Cancer may have spread from where it first started to nearby tissues, lymph nodes, or distant parts of the body. In this case, treatment may be given to help shrink the tumor, slow the growth of cancer cells, or alleviate symptoms.

[0042] For example, combinations of pharmaceuticals of the present invention may be used to (i) reduce the number of cancer cells; (ii) reduce tumor volume; (iii) increase the rate of tumor regression; (iv) reduce or delay cancer cell infiltration into peripheral organs; (v) reduce or delay tumor metastasis; (vi) reduce or inhibit tumor growth; (vii) prevent or delay the onset and / or recurrence of cancer and / or extend disease-free or tumor-free survival; (viii) increase overall survival; (ix) reduce the frequency of treatment; and / or (x) alleviate one or more symptoms associated with cancer.

[0043] As described above, the combination of pharmaceuticals of the present invention can be used for the treatment of neoplastic diseases. Examples of neoplastic diseases include epithelial neoplasms, squamous neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, cutaneous appendage neoplasms, mucoepidermal neoplasms, cystic neoplasms, mucinous and serous neoplasms, glandular, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized gonadal neoplasms, paragangliomas and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms This includes, but is not limited to, neoplasms, synovial neoplasms, mesothelial neoplasms, germ cell neoplasms, chorionic neoplasms, mesonephromas, hemangiomas, lymphangiomomas, ossicular and chondrocytic neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepitheliomatous neoplasms, meningiomas, schwannomas, granulocyte tumors and hydatidiform soft part sarcomas, Hodgkin and non-Hodgkin lymphomas, other lymphoreticular neoplasms, plasma cell neoplasms, mast cell tumors, immunoproliferative disorders, leukemias, various myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.

[0044] In some embodiments, the neoplastic disease is cancer. Examples of cancers relating to affected organs and parts of the body include, but are not limited to, the brain, breast (including triple-negative breast cancer), cervix, ovaries, colon, rectum (including colon and rectum, i.e., colorectal cancer), lungs (including small cell lung cancer, non-small cell lung cancer, large cell lung cancer, and mesothelioma), endocrine system, bone, adrenal gland, thymus, liver, stomach, intestine (including gastric cancer), pancreas, bone marrow, hematological malignancies (such as lymphoma, leukemia, myeloma, or lymphoid malignancies), bile duct, bladder, urinary tract, kidneys, skin, thyroid, head, neck, prostate, and testes.

[0045] In some embodiments, the neoplastic disease is a cancer selected from breast cancer (including triple-negative breast cancer), gastric cancer, colorectal cancer, liver cancer (including hepatocellular carcinoma), endometrial cancer, ovarian cancer, esophageal cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), Kaposi's sarcoma, cervical cancer, pancreatic cancer, melanoma, prostate cancer, testicular cancer, cervical cancer, bladder cancer, head and neck cancer, brain tumors (e.g., glioma, medulloblastoma), neuroblastoma, retinoblastoma, Wilms' tumor, leukemia, e.g., acute myeloid leukemia (AML) (including complex karyotype AML), and malignant mesothelioma.

[0046] In some embodiments, the neoplastic disease is breast cancer.

[0047] In some embodiments, the neoplastic disease is triple-negative breast cancer.

[0048] In some embodiments, the neoplastic disease is ovarian cancer.

[0049] In some embodiments, the neoplastic disease is gastric cancer.

[0050] In some embodiments, the neoplastic disease is colorectal cancer.

[0051] In some embodiments, the neoplastic disease is hepatocellular carcinoma.

[0052] In some embodiments, the neoplastic disease is endometrial cancer (e.g., advanced or recurrent endometrial cancer).

[0053] In some embodiments, the neoplastic disease is acute myeloid leukemia (AML) (including complex karyotype AML).

[0054] In some embodiments, the neoplastic disease is lung cancer (e.g., small cell lung cancer, non-small cell lung cancer).

[0055] In some embodiments, the neoplastic disease is cervical cancer (e.g., metastatic or recurrent cervical cancer).

[0056] In some embodiments, the neoplastic disease is head and neck cancer (e.g., recurrent or metastatic squamous cell carcinoma of the head and neck).

[0057] In some embodiments, the neoplastic disease is Wilms' tumor.

[0058] In some embodiments, the neoplastic disease is a brain tumor (e.g., a glioma such as progressive or recurrent glioma, or a medulloblastoma such as recurrent medulloblastoma).

[0059] In some embodiments, the neoplastic disease is neuroblastoma.

[0060] In some embodiments, the neoplastic disease is testicular cancer (e.g., metastatic non-seminomatous germ cell tumor).

[0061] In some embodiments, the neoplastic disease is bladder cancer (e.g., advanced bladder cancer, including those with abnormal renal function).

[0062] In some embodiments, the neoplastic disease is retinoblastoma (e.g., recurrent or progressive retinoblastoma).

[0063] In some embodiments, the neoplastic disease is cancer treatable with carboplatin. Such cancers include those listed in the carboplatin study, for example, available at www.drugs.com / monograph / carboplatin.html. Such cancers include ovarian cancer (e.g., advanced ovarian epithelial carcinoma, recurrent ovarian cancer, early ovarian cancer), lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), cervical cancer (e.g., metastatic or recurrent cervical cancer), head and neck cancer (e.g., recurrent or metastatic squamous cell carcinoma of the head and neck, Wilms' tumor, brain tumor (e.g., gliomas such as advanced or recurrent glioma, medulloblastoma such as recurrent medulloblastoma), neuroblastoma, testicular cancer, bladder cancer, retinoblastoma, breast cancer (e.g., metastatic breast cancer), endometrial cancer, for example, advanced or recurrent endometrial cancer).

[0064] Cancer can be a primary tumor and / or metastasis. Cancer can originate from a solid or liquid (e.g., blood or intraperitoneal) tumor. In some embodiments, the neoplastic disease being treated (e.g., cancer) is a tumor, e.g., a solid tumor.

[0065] Administration The administration of the combination of pharmaceuticals of the present invention includes the administration of the combination as a single formulation and the administration of the individual agents of the combination as separate formulations. Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are contained in the separate formulations. Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered intravenously to a subject (preferably a human).

[0066] In some embodiments, the combinations of the present invention are used for the treatment of cancer in a subject, comprising administering a combination therapy to the subject comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of carboplatin. When administered in therapeutically effective doses and combined, these compounds provide beneficial effects, as described herein, for example. Those skilled in the art will understand that the therapeutically effective dose for use in combination therapy may be less than the dose required to provide a therapeutic effect when either agent is used as monotherapy.

[0067] The administration of the combination of pharmaceuticals of the present invention may not only yield beneficial effects with respect to alleviating symptoms, delaying the progression of symptoms, or inhibiting symptoms, but may also yield further beneficial effects compared to monotherapy using only one of the pharmaceutical agents used in the combination of the present invention, such as fewer side effects, more sustained therapeutic effects, improved quality of life, and / or reduced morbidity. For example, lower doses of the therapeutic agents in the combination of the present invention may be used so that the dosage may often be lower, and they may be applied less frequently, or they may be used to reduce the frequency of side effects observed with only one of the combination partners.

[0068] The combination of the present invention can be used as adjunct therapy in long-term therapy or in the context of other treatment strategies, as described above. Other possible treatments include therapies to maintain the condition of the subject (e.g., a patient) after tumor regression, or even prophylactic treatment in subjects at risk (e.g., a patient).

[0069] The methods according to the present invention may include (i) administration of a compound of formula (I) in free or pharmaceutically acceptable salt form, and (ii) administration of carboplatin in any order, simultaneously, sequentially, or separately, in a combined therapeutically effective amount, for example, a synergistically effective amount, in a continuous or cyclical dosing schedule corresponding to the amounts described herein. The individual combination partners of the combination of the present invention may be administered separately or simultaneously at different times during the course of treatment. Accordingly, the present invention should be understood to encompass all such treatment regimens, and the term “administer” should be interpreted in that way. Examples of treatment regimens for use in the present invention are described in detail below.

[0070] The compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin may be administered according to the same treatment schedule or according to an independent treatment schedule. The treatment schedule may be cyclical or continuous.

[0071] A periodic treatment schedule is defined by a recurring medication schedule in which repeated elements (cycles) have a specific duration, and doses are administered on specific days within the cycle. Cycles may typically incorporate periods of no administration at the end of the cycle ("drug-free periods") to allow for periods of recovery, for example. Treatment cycles may be, for example, 7, 14, 21, 28 days, or longer. A continuous treatment schedule is a regular medication schedule that does not incorporate drug-free periods (i.e., periods longer than the regular intervals between doses). For example, doses may be administered once daily, twice daily, every two days, every three days, etc. A treatment schedule, whether periodic or continuous, may continue for as long as necessary ("indefinite treatment"), for example, as long as the subject (e.g., patient) is receiving the benefit as determined by the physician supervising the treatment.

[0072] When a compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered according to independent treatment schedules, both treatment schedules may be periodic, or one may be periodic and the other continuous. If both treatment schedules are periodic, the cycles of the two treatment schedules may be of the same duration or different durations, and may begin on the same day or on different days. If the cycles are of the same duration, the treatment cycles of both drugs usually begin on the same day.

[0073] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered according to a cyclical treatment schedule which may be of the same duration, e.g., 3 weeks / 21 days, with each treatment cycle typically starting on the same day (i.e., the same treatment cycle).

[0074] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered (e.g., intravenously) according to a 3-week treatment cycle, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the first week of the treatment cycle, for example on day 1, followed by a 2-week rest period, and carboplatin is administered in the first week of the treatment cycle, for example on day 1, followed by a 2-week rest period. Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered to the subject according to the same 3-week treatment cycle (i.e., the treatment cycles begin on the same day).

[0075] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered (e.g., intravenously) according to a 3-week treatment cycle, where the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the first and second weeks of the treatment cycle, for example on days 1 and 8, the third week being a rest week, and carboplatin is administered in the first week of the treatment cycle, for example on day 1, followed by a 2-week rest week. Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered to the subject according to the same 3-week treatment cycle (i.e., the treatment cycles begin on the same day).

[0076] The effective dose of each combination partner used in the combination of the present invention may vary depending on the pharmaceutical composition used, the mode of administration, the symptoms being treated, and the severity of the symptoms being treated. Therefore, the drug regimen of the combination of the present invention is selected according to various factors, including the route of administration and the renal and hepatic function of the subject (e.g., the patient).

[0077] The optimal ratio of combination partners, individual and combined doses, and concentrations of the pharmaceutical combinations of the present invention that provide efficacy without toxicity are based on the dynamics of the availability of the therapeutic agent to the target site. They can be established using routine clinical trials and procedures well known in the art and depend on various factors such as the mode of administration, the symptom being treated and its severity, as well as the individual's age, weight, overall health, sex, diet, and other medications the individual is taking. Similarly, the frequency of administration may vary depending on the compound used and the specific symptom to be treated. Subjects (e.g., patients) can generally be monitored for the efficacy of the treatment using assays appropriate to the symptom being treated, and such assays are well known to those skilled in the art.

[0078] In some embodiments, the molar ratio of the carboplatin pair compound (I) or its pharmaceutically acceptable salt per weekly dose in the combination of the present invention is, for example, about 0.6:1 to about 250:1, for example, about 0.6:1 to about 210:1, for example, about 0.9:1 to about 250:1, for example, about 0.9:1 to about 210:1, for example, about 1.2:1 to about 10:1, for example, about 1.2:1 to about 8:1, for example, about 1.3:1 to about 8:1, for example, about 1.3:1 to about 7:1, for example, about 1.4:1 to about 32:1, for example, about 1.4:1 to about 26:1, for example, about 1.4:1 to about 7:1, for example, about 1.4:1 to about 6: 1. For example, it could be approximately 1.8:1 to 16:1, approximately 1.8:1 to 13:1, approximately 1.8:1 to 9:1, approximately 1.8:1 to 8:1, approximately 1.9:1 to 8:1, approximately 1.9:1 to 7:1, approximately 2.1:1 to 32:1, approximately 2.1:1 to 26:1, approximately 2.2:1 to 14:1, approximately 2.2:1 to 12:1, approximately 2.1:1 to 7:1, approximately 2.1:1 to 6:1, approximately 2.6:1 to 16:1, approximately 2.6:1 to 13:1, approximately 3.3:1 to 14:1, or approximately 3.3:1 to 12:1. In some embodiments, the molar ratio of the carboplatin pair compound (I) or a pharmaceutically acceptable salt thereof per weekly dose is, for example, about 2.1:1 to about 32:1.

[0079] In some embodiments, the molar ratio of the carboplatin pair (I) compound or a pharmaceutically acceptable salt per weekly dose may be, for example, up to about 250:1, up to about 210:1, up to about 32:1, up to about 26:1, up to about 16:1, up to about 14:1, up to about 13:1, up to about 12:1, up to about 9:1, up to about 8:1, up to about 7:1, or up to about 6:1. In some embodiments, the molar ratio of the carboplatin pair (I) compound or a pharmaceutically acceptable salt per weekly dose is up to about 32:1.

[0080] In some embodiments, the molar ratio of the carboplatin pair (I) compound or a pharmaceutically acceptable salt per weekly dose may be, for example, at least about 0.6:1, for example at least about 0.9:1, for example at least about 1.2:1, for example at least about 1.3:1, for example at least about 1.4:1, for example at least about 1.8:1, for example at least about 1.9:1, for example at least about 2.1:1, for example at least about 2.2:1, for example at least about 2.6:1, for example at least about 3.3:1. In some embodiments, the molar ratio of the carboplatin pair (I) compound or a pharmaceutically acceptable salt per weekly dose is at least about 2.1:1.

[0081] The following dosage examples are for humans. The dosage of the compound of formula (I) is given as mg per person, independent of body weight or body surface area (BSA). The dosages of the compound of formula (I) given below, including in Tables A, B, and C, refer to the dosage of the free base. The dosage also applies to the pharmaceutically acceptable salt of the compound of formula (I) when a pharmaceutically acceptable salt of the compound of formula (I) is used, except that the stated mg dosage should be adjusted (i.e., increased) so that the molar amount of the pharmaceutically acceptable salt of the compound of formula (I) administered is the same as the molar amount of the free base given below. For example, a statement that the (human) weekly dose of the compound of formula (I) is approximately 5 mg to approximately 480 mg per week means that the compound of formula (I) or a pharmaceutically acceptable salt of it is administered to the patient in a dose equivalent to approximately 5 mg to approximately 480 mg of the free base of the compound of formula (I) per week during the week of administration. Unlike the average weekly dose, which may be lower than the actual weekly dose when considering weeks of drug-free periods, the weekly dose in a given week is the actual dose given to the patient in that week.

[0082] In some embodiments, the (human) weekly dose of the compound of formula (I) is approximately 5 mg to approximately 480 mg per week of administration. In some embodiments, the (human) weekly dose of the compound of formula (I) is approximately 40 mg to approximately 200 mg per week of administration. In some embodiments, the (human) weekly dose of the compound of formula (I) is approximately 80 mg to approximately 160 mg per week of administration. In some embodiments, the (human) weekly dose of the compound of formula (I) is approximately 90 mg to approximately 130 mg per week of administration.

[0083] In some embodiments, the (human) weekly dose of the compound of formula (I) is approximately 140 mg to approximately 240 mg per week of administration. In some embodiments, the (human) weekly dose of the compound of formula (I) is approximately 160 mg to approximately 220 mg per week of administration. In some embodiments, the (human) weekly dose of the compound of formula (I) is approximately 180 mg to approximately 200 mg per week of administration.

[0084] Examples of weekly (human) doses of the compound of formula (I) during the week of administration include approximately 10 mg to 20 mg, 20 mg to 30 mg, 30 mg to 40 mg, 40 mg to 50 mg, 50 mg to 60 mg, 60 mg to 70 mg, 70 mg to 80 mg, 80 mg to 90 mg, 90 mg to 100 mg, 100 mg to 110 mg, and 110 mg to 120 mg. , about 120mg to about 130mg, about 130mg to about 140mg, about 140mg to about 150mg, about 150mg to about 160mg, about 160mg to about 170mg, about 170mg to about 180mg, Approximately 180mg to approximately 190mg, approximately 190mg to approximately 200mg, approximately 200mg to approximately 210mg, approximately 210mg to approximately 220mg, approximately 220mg to approximately 230mg, approximately 230mg to approximately 240mg, approximately 2 40mg to about 250mg, about 250mg to about 260mg, about 260mg to about 270mg, about 270mg to about 280mg, about 280mg to about 290mg, about 290mg to about 300mg, about 30 0mg to about 310mg, about 310mg to about 320mg, about 320mg to about 330mg, about 330mg to about 340mg, about 340mg to about 350mg, about 350mg to about 360mg, about 360m Examples include approximately 370mg, 370mg to 380mg, 380mg to 390mg, 390mg to 400mg, 400mg to 410mg, 410mg to 420mg, 420mg to 430mg, 430mg to 440mg, 440mg to 450mg, 450mg to 460mg, 460mg to 470mg, and 470mg to 480mg.

[0085] Examples of specific (human) weekly doses of the compound of formula (I) in the week of administration include approximately 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, and 110 mg. 5mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg , about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 2 40mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300m g, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about Examples include 365 mg, approximately 370 mg, approximately 375 mg, approximately 380 mg, approximately 385 mg, approximately 390 mg, approximately 395 mg, approximately 400 mg, approximately 405 mg, approximately 410 mg, approximately 415 mg, approximately 420 mg, approximately 425 mg, approximately 430 mg, approximately 435 mg, approximately 440 mg, approximately 445 mg, approximately 450 mg, approximately 455 mg, approximately 460 mg, approximately 465 mg, approximately 470 mg, approximately 475 mg, and approximately 480 mg.

[0086] The weekly dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered as a single dose, for example, intravenously, with virtually no interruption. Alternatively, the weekly dose may be administered in multiple doses, for example, in two or three doses with interruptions between doses, for example, at least 30 minutes, e.g., at least 1 hour, e.g., at least 2 hours, e.g., at least 4 hours, e.g., 30 minutes to 12 hours, e.g., 30 minutes to 6 hours, when administered intravenously. Such multiple doses may be administered on the same day or on separate days, for example, on consecutive days or, for example, three days after the day of the first dose. Typically, the weekly dose is administered within a 24-hour period and is usually administered with virtually no interruption.

[0087] The compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably administered intravenously. The duration of the infusion is typically at least 30 minutes and may be up to 24 hours. In some embodiments, the duration of the infusion is 30 minutes to 12 hours, for example 30 minutes to 6 hours, for example 30 minutes to 3 hours, for example 1 to 2 hours, for example about 1 hour.

[0088] The human dose of carboplatin is typically calculated according to the Calvert formula (Calvert et al., J. Clin. Oncol. 1989; 7(11): 1748-56). The Calvert formula incorporates glomerular filtration rate as an important variable. The most common method for estimating glomerular filtration rate for the Calvert formula is by creatine clearance calculated according to the Cockcroft-Gault formula (Cockcroft, Gault, Nephron 1976, 16: 31-41; Ainsworth et al. Annals of Oncology 2012, 23: 1845-1853; Bjornsson, Clin Pharmacokinet. 1979, 4(3): 200-222). Therefore, in this invention, the carboplatin dose is calculated according to the following formula. Carboplatin dose [mg] = Target AUC [mg / mL × min] × (CLCR [mL / min] + 25)

[0089] In the formula, CL CR This is the creatine clearance calculated according to the Cockcroft-Gault formula.

[0090] For example, the AUC5 dose is calculated as follows: Carboplatin dose [mg] = 5 × (CL CR [mL / min]+25)

[0091] The maximum dose of carboplatin (this dose should not be exceeded) is the target AUC. (mg / mL / min) × (150): • For a target AUC of 6, the maximum dose is 6 × 150 = 900 mg. • For a target AUC of 5, the maximum dose is 5 × 150 = 750 mg. • For a target AUC of 4, the maximum dose is 4 × 150 = 600 mg.

[0092] In some embodiments, carboplatin is administered according to AU4 per week during the week in which it is administered. In some embodiments, carboplatin is administered according to AU5 per week during the week in which it is administered. In some embodiments, carboplatin is administered according to AU6 per week during the week in which it is administered.

[0093] The weekly dose of carboplatin may be administered as a single dose, for example, without interruption when administered intravenously. Alternatively, the weekly dose may be administered in multiple doses, for example, in two or three doses with interruptions between doses, for example, at least about 30 minutes, for example at least about 1 hour, for example at least about 2 hours, for example at least about 4 hours, for example about 30 minutes to about 12 hours, for example about 30 minutes to about 6 hours, when administered intravenously. Such multiple doses may be administered on the same day or on separate days, for example on consecutive days or 3 days after the first dose. Typically, the weekly dose is administered within a 24-hour period and is usually administered substantially without interruption.

[0094] Carboplatin is preferably administered intravenously. The duration of the infusion is typically at least about 30 minutes and may be up to about 24 hours. In some embodiments, the duration of the infusion is about 30 minutes to about 12 hours, for example, about 30 minutes to about 6 hours, for example, about 30 minutes to about 3 hours, for example, about 1 to about 2 hours, for example, about 30 minutes.

[0095] In some embodiments, the (human) weekly dose of the compound of formula (I) and the (human) weekly dose of carboplatin in the week of administration are as shown in any one of Embodiments 1A to 21A in Table A. [Table 1]

[0096] As described above, Embodiment 1A refers to a situation in which carboplatin is administered to the patient at an AUC4 per week during the week of administration, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose corresponding to the molar equivalent of the free base of the compound of formula (I) at a dose of approximately 5 mg to approximately 480 mg per week during the week of administration. The same applies to Embodiments 2A to 21A.

[0097] In some embodiments, the (human) weekly dose of the compound of formula (I) and the (human) weekly dose of carboplatin in the week of administration are as shown in any one of Embodiments 1B to 144B in Table B. [Table 2-1] [Table 2-2]

[0098] As described above, Embodiment 1B refers to a situation in which carboplatin is administered to the patient at an AUC4 per week during the week of administration, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose equivalent to approximately 5 mg to approximately 10 mg of the free base of the compound of formula (I) per week during the week of administration. The same applies to Embodiments 2B to 144B.

[0099] In some embodiments, the duration of the treatment cycle for the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin is 3 weeks, and the (human) weekly dose of the compound of formula (I) and carboplatin in the week of administration and the week of administration within the cycle are as shown in any one of Embodiments 1C to 42C in Table C, and the compound of formula (I) and carboplatin are administered according to the same treatment cycle (i.e., starting on the same day). [Table 3]

[0100] As described above, Embodiment 1C refers to a situation in which the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered to the patient (e.g., intravenously) according to the same 3-week treatment cycle, with the compound of formula (I) or a pharmaceutically acceptable salt thereof being administered in the first week of the treatment cycle followed by a 2-week rest period, the carboplatin being administered in the first week of the treatment cycle followed by a 2-week rest period, the carboplatin being administered to the patient at an AUC4 per week during the week of administration, and the compound of formula (I) or a pharmaceutically acceptable salt thereof being administered to the patient at a dose corresponding to the molar equivalent of the free base of the compound of formula (I) at approximately 5 mg to approximately 480 mg per week during the week of administration. The same applies to Embodiments 2C to 42C.

[0101] In some embodiments, the duration of the treatment cycle for the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin is 21 days, and the (human) weekly dose of the compound of formula (I) and carboplatin in the week of administration and the days of administration within the cycle are as shown in any one of Embodiments 1D to 42D in Table D, and the compound of formula (I) and carboplatin are administered according to the same treatment cycle (i.e., starting on the same day). [Table 4]

[0102] As described above, Embodiment 1D refers to a situation in which the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered to a patient (e.g., intravenously) according to the same 21-day treatment cycle, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on day 1 of the treatment cycle, carboplatin is administered on day 1 of the treatment cycle, carboplatin is administered to the patient at an AUC4 per week during the week of administration, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose corresponding to the molar equivalent of the free base of the compound of formula (I) at a dose of approximately 5 mg to approximately 480 mg per week during the week of administration. The same applies to Embodiments 2D to 42D.

[0103] In some embodiments, the compound of formula (I) may be administered twice per week during the week in which it is administered.

[0104] As shown in the following examples, it may be advantageous to administer the dose of carboplatin before the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, especially when carboplatin and a compound of formula (I) or a pharmaceutically acceptable salt thereof are administered simultaneously, for example, on the same day.

[0105] Therefore, in some embodiments, carboplatin is administered to the subject before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, when both carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to the subject within a period of 48 hours, carboplatin is administered to the subject before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, when both carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to the subject within a period of 24 hours, carboplatin is administered to the subject before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

[0106] Between the administration of carboplatin (1) and a compound of formula (I) or a pharmaceutically acceptable salt thereof (2), there may be a pause of, for example, at least about 30 minutes, for example at least about 1 hour, for example at least about 2 hours, for example at least about 4 hours, for example at least about 24 hours, for example up to about 4 hours, for example up to about 6 hours, for example up to about 12 hours, for example up to about 24 hours, for example from about 30 minutes to about 24 hours, for example from about 30 minutes to about 12 hours, for example from about 30 minutes to about 6 hours, for example from about 2 to about 4 hours, for example from about 4 to about 6 hours.

[0107] Therefore, in some embodiments, carboplatin is administered to the subject at least about 30 minutes before the subject is administered the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, carboplatin is administered to the subject at least about 1 hour before the subject is administered the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, carboplatin is administered to the subject at least about 4 hours before the subject is administered the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, carboplatin is administered to the subject at least about 24 hours before the subject is administered the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject within a 24-hour period, carboplatin is administered to the subject at least about 30 minutes before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject within a 24-hour period, carboplatin is administered to the subject at least about 1 hour before the compound of formula (I) or a pharmaceutically acceptable salt thereof (in the planned dose) is administered to the subject. In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject within a 24-hour period, carboplatin is administered to the subject at least 4 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to the subject within a 48-hour period, carboplatin is administered to the subject at least about 24 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

[0109] In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject within a 48-hour period, carboplatin is administered to the subject up to 24 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject within a 24-hour period, carboplatin is administered to the subject up to 12 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject within a 24-hour period, carboplatin is administered to the subject up to 6 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject within a 24-hour period, carboplatin is administered to the subject up to 4 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject within a 24-hour period, carboplatin is administered to the subject up to 1 hour before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

[0110] In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject within a 48-hour period, carboplatin is administered to the subject approximately 30 minutes to 24 hours before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject within a 24-hour period, carboplatin is administered to the subject approximately 30 minutes to 12 hours before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject within a 24-hour period, carboplatin is administered to the subject approximately 30 minutes to 6 hours before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject within a 24-hour period, carboplatin is administered to the subject about 2 to 4 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to a subject within a 24-hour period, carboplatin is administered to the subject about 4 to 6 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

[0111] In some embodiments, carboplatin is administered to a subject before a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject, and the neoplasm to be treated is breast cancer, for example, triple-negative breast cancer, or ovarian cancer.

[0112] In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to the subject within a 48-hour period, carboplatin is administered to the subject up to 24 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject, and the neoplasm to be treated is breast cancer, e.g., triple-negative breast cancer or ovarian cancer.

[0113] In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to the subject within a 24-hour period, carboplatin is administered to the subject up to 6 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject, and the neoplasm to be treated is breast cancer, e.g., triple-negative breast cancer or ovarian cancer.

[0114] In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to the subject within a 24-hour period, carboplatin is administered to the subject up to 4 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject, and the neoplasm to be treated is breast cancer, e.g., triple-negative breast cancer or ovarian cancer.

[0115] In some embodiments, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to the subject within a 48-hour period, carboplatin is administered to the subject approximately 30 minutes to approximately 24 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject, and the neoplasm to be treated is breast cancer, e.g., triple-negative breast cancer or ovarian cancer.

[0116] As described above, the possibility of administering carboplatin before the compound of formula (I) or a pharmaceutically acceptable salt thereof applies particularly to the embodiments described in Tables A, B, C, and D.

[0117] In general, compounds of formula (I) or their pharmaceutically acceptable salts and carboplatin are administered in doses not exceeding the maximum tolerated dose (MTD) for a particular mode of administration and indication, as determined by clinical dose escalation studies.

[0118] formulation Compounds of formula (I) or their pharmaceutically acceptable salts and carboplatin may be provided as a combination drug, although each is usually provided as a monotherapy drug. Separate pharmaceutical compositions have many advantages, for example, to allow different dosing schedules, different dosages and / or different routes of administration for each compound. When provided as monotherapy drugs, the combination may be for separate, simultaneous, or sequential administration.

[0119] The compounds of the present invention can be formulated as pharmaceutical compositions for non-parenteral administration, such as nasal, buccal, rectal, lung, vaginal, sublingual, topical, transdermal, ocular, or ocular or ocular administration, or particularly for oral administration, such as in the form of oral solid dosage forms, e.g., granules, pellets, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, coated hard and soft gelatin or HPMC capsules where applicable, or orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or as pharmaceutical compositions for parenteral administration to mammals, particularly humans, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration, such as in the form of solutions, lipid emulsions or suspensions containing, for example, microparticles or nanoparticles. Liposome formulations provide a convenient method for co-formulating compounds with different solubility (see, for example, Bulbake et al. Pharmaceutics 2017, 9(2):12). The compositions may contain (one or more) active ingredients alone or preferably together with a pharmaceutically acceptable carrier.

[0120] Pharmaceutical compositions may be treated with pharmaceutically inert inorganic or organic excipients for the manufacture of oral solid dosage forms, such as granules, pellets, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard gelatin or HPMC capsules, or orally disintegrating tablets. Fillers, such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch, or derivatives thereof; binders, such as cellulose, starch, polyvinylpyrrolidone, or derivatives thereof; flow enhancers, such as talc, stearic acid or its salts; and flowing agents, such as fumed silica, may be used as such excipients for the formulation and manufacture of oral solid dosage forms such as granules, pellets, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard gelatin or HPMC capsules, or orally disintegrating tablets. Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols.

[0121] Suitable excipients for the preparation of oral solutions, lipid emulsions, or suspensions include, for example, water, alcohol, polyol, sucrose, invert sugar, and glucose. Suitable excipients for parenteral formulations include, for example, water, alcohol, polyol, glycerol, vegetable oil, lecithin, and surfactants. Furthermore, pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts to alter osmotic pressure, buffers, masking agents, or antioxidants. Pharmaceutical preparations may also contain other therapeutically valuable substances.

[0122] Suitable pharmaceutical compositions for injection include sterile aqueous solutions (if water-soluble) or dispersions, and sterile powders for the immediate preparation of sterile injection solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor® EL, or phosphate-buffered saline (PBS). The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol) and suitable mixtures thereof. For intravenous injection of strongly lipophilic molecules, it may be advantageous to include solubilizers in the formulation, such as surfactants, polymeric surfactants, polymers, complexing agents, and / or co-solvents, which can significantly increase the solubility of the compound in water. Examples of solubilizers include polyethylene glycol, propylene glycol, ethanol, glycerol, and cyclodextrin (e.g., sulfobutyl ether-β-cyclodextrin).

[0123] In some embodiments, the compound of formula (I) as a free base is provided as a pharmaceutical composition containing β-cyclodextrin, for example, for intravenous administration. The β-cyclodextrin may be sulfobutyl ether-β-cyclodextrin, for example CAS 182410-00-0, for example Captisol® (Ligand) or Dexolve® (Cyclolab).

[0124] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in a suitable solvent, along with one or a combination of the components listed above, as needed, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a dispersion medium and other required components from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation method is vacuum drying and freeze-drying, resulting in powders of the active ingredient plus any further desired components from their pre-sterilized filtered solutions.

[0125] Furthermore, the pharmaceutical composition used in the present invention optionally includes buffering agents such as phosphates, citrates, or other organic acids; antioxidants including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN®, PLURONICS®, or PEG.

[0126] Optionally, the pharmaceutical composition contains a pharmaceutically acceptable preservative. In some embodiments, the preservative concentration is in the range of 0.1–2.0%, typically v / v. Suitable preservatives include those known in the pharmaceutical field, such as benzyl alcohol, phenol, m-cresol, methylparaben, and propylparaben.

[0127] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is formulated with a suitable acceptable carrier for intravenous administration. In some embodiments, carboplatin is formulated with a suitable acceptable carrier for intravenous administration.

[0128] kit The present invention also provides pharmaceuticals such as kits that may include containers having a compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin, which can be provided in an amount sufficient for administration, for example, a pharmaceutically acceptable amount. Thus, a kit may include a plurality of containers, each containing a pharmaceutically effective amount of the active ingredient. Optionally, the kit may also include instruments and / or devices necessary for administering (one or more) pharmaceutical compositions. Furthermore, the kit may include further components such as instructions or administration schedules for treating patients with neoplastic diseases with the combination of the present invention.

[0129] Accordingly, in further embodiments, the present invention provides pharmaceuticals such as kits for use in treating neoplastic diseases, for example, as described herein, in which a compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are provided as monopharmaceuticals. In some embodiments, the kits further include instructions for simultaneous, separate, or sequential administration thereof for use in treating neoplastic diseases.

[0130] paragraph The following numbered paragraphs describe specific embodiments of the present invention.

[0131] Paragraph 1. A combination of a pharmaceutical product comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) carboplatin.

[0132] Paragraph 2. A combination of the pharmaceuticals described in Paragraph 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are contained in separate formulations, each formulation preferably for intravenous administration.

[0133] A combination of medicines described in paragraph 1 or paragraph 2, wherein the molar ratio of the carboplatin pair compound (I) or a pharmaceutically acceptable salt thereof per weekly dose is approximately 0.6:1 to approximately 250:1.

[0134] Paragraph 4.1 A combination of medicines described in Paragraph 1 or Paragraph 2, wherein the molar ratio of the carboplatin pair compound (I) or a pharmaceutically acceptable salt thereof per weekly dose is approximately 1.4:1 to approximately 32:1.

[0135] Paragraph 5.1 A combination of medicines described in Paragraph 1 or Paragraph 2, wherein the molar ratio of the carboplatin pair compound (I) or a pharmaceutically acceptable salt thereof per weekly dose is approximately 3.3:1 to approximately 14:1.

[0136] Paragraph 6. A method for treating a neoplastic disease in a subject requiring treatment, particularly in a human, comprising administering a therapeutically effective amount of a combination of pharmaceuticals described in any one of Paragraphs 1 to 5 to the subject.

[0137] Paragraph 7. The method according to Paragraph 6, wherein carboplatin is administered to the subject before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

[0138] Paragraph 8. The method according to Paragraph 6, wherein carboplatin is administered to the subject at least about 30 minutes before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

[0139] Paragraph 9. The method according to Paragraph 6, wherein carboplatin is administered to the subject at least about one hour before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0140] Paragraph 10. The method according to Paragraph 6, wherein carboplatin is administered to the subject at least about 4 hours before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0141] Paragraph 11. The method according to Paragraph 6, wherein carboplatin is administered to the subject approximately 30 minutes to approximately 24 hours before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, when both carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are administered to the subject within a 48-hour period.

[0142] Paragraph 12. The method according to any one of paragraphs 6 to 11, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered intravenously to the subject.

[0143] Paragraph 13. The method according to any one of paragraphs 6 to 12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered to the subject according to a 3-week treatment cycle (preferably the same 3-week treatment cycle), wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the first week of the treatment cycle, followed by a 2-week rest period, and carboplatin is administered in the first week of the treatment cycle, followed by a 2-week rest period.

[0144] Paragraph 14. The method according to Paragraph 13, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on day 1 of the treatment cycle, and carboplatin is administered on day 1 of the treatment cycle.

[0145] Paragraph 15. The method according to any one of paragraphs 6 to 12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered to the subject according to a 3-week treatment cycle (preferably the same 3-week treatment cycle), the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the first and second weeks of the treatment cycle, the third week is a rest week, and carboplatin is administered in the first week of the treatment cycle, followed by a 2-week rest week.

[0146] Paragraph 16. The method according to Paragraph 15, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on day 1 of the treatment cycle, and carboplatin is administered on days 1 and 8 of the treatment cycle.

[0147] Paragraph 17. The method according to any one of paragraphs 6 to 16, wherein the molar ratio of the carboplatin pair compound (I) or a pharmaceutically acceptable salt thereof per weekly dose is approximately 0.6:1 to approximately 250:1.

[0148] Paragraph 18. The method according to any one of paragraphs 6 to 16, wherein the molar ratio of the carboplatin pair compound (I) or a pharmaceutically acceptable salt thereof per weekly dose is approximately 3.3:1 to approximately 14:1.

[0149] Paragraph 19. The method according to any one of paragraphs 6 to 16, wherein the molar ratio of the carboplatin pair compound (I) or a pharmaceutically acceptable salt thereof per weekly dose is approximately 3.3:1 to approximately 14:1.

[0150] Paragraph 20. The method according to any one of paragraphs 6 to 16, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in a dose equivalent to approximately 5 mg to approximately 480 mg of the free base of the compound of formula (I) per week during the week of administration.

[0151] Paragraph 21. The method according to any one of paragraphs 6 to 16, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in a dose equivalent to approximately 40 mg to approximately 200 mg of the free base of the compound of formula (I) per week during the week of administration.

[0152] Paragraph 22. The method according to any one of paragraphs 6 to 16, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in a dose equivalent to approximately 80 mg to approximately 160 mg of the free base of the compound of formula (I) per week during the week of administration.

[0153] Paragraph 23. The method according to any one of paragraphs 6 to 16, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in a dose equivalent to approximately 90 mg to approximately 130 mg of the free base of the compound of formula (I) per week during the week of administration.

[0154] Paragraph 24. The method according to any one of paragraphs 6 to 16, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in a dose equivalent to approximately 140 mg to approximately 240 mg of the free base of the compound of formula (I) per week during the week of administration.

[0155] Paragraph 25. The method according to any one of paragraphs 6 to 16, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in a dose equivalent to approximately 160 mg to approximately 220 mg of the free base of the compound of formula (I) per week during the week of administration.

[0156] Paragraph 26. The method according to any one of paragraphs 6 to 16, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in a dose equivalent to approximately 180 mg to approximately 200 mg of the free base of the compound of formula (I) per week during the week of administration.

[0157] Paragraph 27. The method according to any one of paragraphs 17-26, wherein carboplatin is administered to the patient according to the AUC4 per week during the week in which it is administered.

[0158] Paragraph 28. The method according to any one of paragraphs 17-26, wherein carboplatin is administered to the patient according to the AUC5 per week during the week in which it is administered.

[0159] Paragraph 29. The method according to any one of paragraphs 17-26, wherein carboplatin is administered to the patient in accordance with the AUC6 per week during the week in which it is administered.

[0160] Paragraph 30. The method according to any one of paragraphs 6 to 29, wherein the neoplastic disease is a solid tumor.

[0161] Paragraph 31. The neoplastic diseases include epithelial neoplasms, squamous neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, cutaneous appendage neoplasms, mucoepidermal neoplasms, cystic neoplasms, myxoid and serous neoplasms, glandular, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized gonadal neoplasms, paragangliomas and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms, synovial neoplasms. The method according to any one of paragraphs 6 to 30, selected from the group consisting of neoplasms, mesothelial neoplasms, germ cell neoplasms, chorionic neoplasms, mesonephromas, hemangiomas, lymphangiomas, ossicular and chondrocytic neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepitheliomatous neoplasms, meningiomas, schwannomas, granulocyte tumors and hydatidiform soft part sarcomas, Hodgkin and non-Hodgkin lymphomas, other lymphoreticular neoplasms, plasma cell tumors, mast cell tumors, immunoproliferative disorders, leukemias, various myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.

[0162] Paragraph 32. The method according to any one of paragraphs 6 to 31, wherein the neoplastic disease is a neoplastic disease treatable by inhibition of PLK1 in addition to treatment with carboplatin and a TTK inhibitor (e.g., a compound of formula (I)).

[0163] Paragraph 33. The method according to any one of paragraphs 6 to 32, wherein the neoplastic disease is cancer.

[0164] Paragraph 34. The method according to Paragraph 33, wherein the cancer of the affected organ and part of the body is selected from the brain, breast (including triple-negative breast cancer), cervix, ovaries, colon, rectum (including colon and rectum, i.e., colorectal cancer), lung (including small cell lung cancer, non-small cell lung cancer, large cell lung cancer, and mesothelioma), endocrine system, bone, adrenal gland, thymus, liver, stomach, intestine (including gastric cancer), pancreas, bone marrow, hematological malignancies (such as lymphoma, leukemia, myeloma, or lymphoid malignancy), bile duct, bladder, urinary tract, kidney, skin, thyroid, head, neck, prostate, and testes.

[0165] Paragraph 35. The method according to Paragraph 33, wherein the cancer is selected from breast cancer (including triple-negative breast cancer), gastric cancer, colorectal cancer, liver cancer (including hepatocellular carcinoma), endometrial cancer, ovarian cancer, esophageal cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), Kaposi's sarcoma, cervical cancer, pancreatic cancer, melanoma, prostate cancer, testicular cancer, cervical cancer, bladder cancer, head and neck cancer, brain tumors (e.g., glioma, medulloblastoma), neuroblastoma, retinoblastoma, Wilms' tumor, leukemia, e.g., acute myeloid leukemia (AML) (including complex karyotype AML), and malignant mesothelioma.

[0166] Paragraph 36. The method according to Paragraph 33, wherein the cancer is breast cancer, for example, triple-negative breast cancer.

[0167] Paragraph 37. The method according to Paragraph 33, wherein the cancer is ovarian cancer.

[0168] Paragraph 38. A method for treating a neoplastic disease in a subject requiring treatment for a neoplastic disease, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the subject has been or will be treated with carboplatin.

[0169] Paragraph 39. The method according to Paragraph 38, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject as defined in any one of Paragraphs 7 to 29.

[0170] Paragraph 40. The method according to paragraph 38 or paragraph 39, wherein the neoplastic disease is as defined in any one of paragraphs 30 to 37.

[0171] Paragraph 41. A method for treating a neoplastic disease in a subject requiring treatment for a neoplastic disease, comprising administering a therapeutically effective amount of carboplatin to the subject, wherein the subject has been or will be treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0172] Paragraph 42. The method according to paragraph 41, wherein carboplatin is administered to the subject as defined in any one of paragraphs 7 to 29.

[0173] Paragraph 43. The method according to paragraph 41 or paragraph 42, wherein the neoplastic disease is as defined in any one of paragraphs 30 to 37.

[0174] Paragraph 44. A combination of the drugs described in any one of paragraphs 1-5 for use in the treatment of neoplastic diseases, particularly in humans.

[0175] Paragraph 45. A combination of pharmacopoeias for use as described in Paragraph 44, wherein carboplatin is administered to the subject before a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

[0176] Paragraph 46. The combination of pharmacopoeias for use described in Paragraph 44, wherein carboplatin is administered to the subject at least about 30 minutes before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0177] Paragraph 47. The combination of pharmacopoeias for use according to Paragraph 44, wherein carboplatin is administered to the subject at least about one hour before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0178] Paragraph 48. The combination of pharmacopoeias for use according to Paragraph 44, wherein carboplatin is administered to the subject at least about 4 hours before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0179] Paragraph 49. The combination of pharmacopoeias for use as described in Paragraph 44, wherein carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to the subject within a period of 48 hours, and carboplatin is administered to the subject approximately 30 minutes to approximately 24 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

[0180] Paragraph 50. A combination of pharmacopoeias for use as described in any one of paragraphs 44-49, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered intravenously to the subject.

[0181] Paragraph 51. A combination of pharmaceuticals for use as described in any one of paragraphs 44-50, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered to the subject according to a 3-week treatment cycle (preferably the same 3-week treatment cycle), wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the first week of the treatment cycle, followed by a 2-week rest period, and carboplatin is administered in the first week of the treatment cycle, followed by a 2-week rest period.

[0182] Paragraph 52. The combination of the pharmacopoeia for use described in Paragraph 51, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on day 1 of the treatment cycle, and carboplatin is administered on day 1 of the treatment cycle.

[0183] Paragraph 53. A combination of pharmaceuticals for use as described in any one of paragraphs 44-50, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered to the subject according to a 3-week treatment cycle (preferably the same 3-week treatment cycle), the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the first and second weeks of the treatment cycle, the third week is a rest week, and carboplatin is administered in the first week of the treatment cycle, followed by a 2-week rest week.

[0184] Paragraph 54. The combination of pharmacopoeias for use as described in Paragraph 53, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on day 1 of the treatment cycle, and carboplatin is administered on days 1 and 8 of the treatment cycle.

[0185] Paragraph 55. A combination of pharmaceuticals for use as described in any one of paragraphs 44 to 54, wherein the molar ratio of the carboplatin pair compound (I) or a pharmaceutically acceptable salt thereof per weekly dose is approximately 0.6:1 to approximately 250:1.

[0186] Paragraph 56.1 A combination of pharmaceuticals for use as described in any one of paragraphs 44 to 54, wherein the molar ratio of the carboplatin pair compound (I) or a pharmaceutically acceptable salt thereof per weekly dose is approximately 3.3:1 to approximately 14:1.

[0187] Paragraph 57.1 A combination of pharmaceuticals for use as described in any one of paragraphs 44 to 54, wherein the molar ratio of the carboplatin pair compound (I) or a pharmaceutically acceptable salt thereof per weekly dose is approximately 3.3:1 to approximately 14:1.

[0188] Paragraph 58. A combination of pharmacologics for use as described in any one of paragraphs 44-54, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in doses corresponding to the molar equivalent of the free base of the compound of formula (I) at a rate of approximately 5 mg to approximately 480 mg per week during the week of administration.

[0189] Paragraph 59. A combination of pharmacopoeias for use as described in any one of paragraphs 44-54, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in doses corresponding to approximately 40 mg to approximately 200 mg per week of the free base of the compound of formula (I) during the week of administration.

[0190] Paragraph 60. A combination of pharmacopoeias for use as described in any one of paragraphs 44-54, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in doses corresponding to approximately 80 mg to approximately 160 mg per week of the free base of the compound of formula (I) during the week of administration.

[0191] Paragraph 61. A combination of pharmacologics for use as described in any one of paragraphs 44-54, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in doses corresponding to approximately 90 mg to approximately 130 mg per week of the free base of the compound of formula (I) during the week of administration.

[0192] Paragraph 62. A combination of pharmacopoeias for use as described in any one of paragraphs 44-54, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in doses corresponding to approximately 140 mg to approximately 240 mg per week of the free base of the compound of formula (I) during the week of administration.

[0193] Paragraph 63. A combination of pharmacopoeias for use as described in any one of paragraphs 44-54, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in doses equivalent to approximately 160 mg to approximately 220 mg of the free base of the compound of formula (I) per week during the week of administration.

[0194] Paragraph 64. A combination of pharmacologics for use as described in any one of paragraphs 44-54, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in a dose equivalent to approximately 180 mg to approximately 200 mg of the free base of the compound of formula (I) per week during the week of administration.

[0195] Paragraph 65. A combination of pharmacologics for use described in any one of paragraphs 58-64, wherein carboplatin is administered to the patient in accordance with AUC4 per week during the week in which it is administered.

[0196] Paragraph 66. A combination of pharmacologics for use described in any one of paragraphs 58-64, wherein carboplatin is administered to the patient in accordance with AUC5 per week during the week in which it is administered.

[0197] Paragraph 67. A combination of pharmacologics for use described in any one of paragraphs 58-64, wherein carboplatin is administered to the patient in accordance with a weekly AUC6 during the week in which it is administered.

[0198] Paragraph 68. A combination of pharmaceuticals for use described in any one of paragraphs 44-67, wherein the neoplastic disease is a solid tumor.

[0199] Paragraph 69. The neoplastic diseases include epithelial neoplasms, squamous neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, cutaneous appendage neoplasms, mucoepidermal neoplasms, cystic neoplasms, myxoid and serous neoplasms, glandular, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized gonadal neoplasms, paragangliomas and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms, synovial neoplasms, and A combination of pharmaceuticals for use as described in any one of paragraphs 44-68, selected from the group consisting of cutaneous neoplasms, germ cell neoplasms, chorionic neoplasms, mesonephroma, hemangiomas, lymphangiomas, ossicular and chondrocytic neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepitheliomatous neoplasms, meningiomas, schwannomas, granular cell tumors and hydatidiform soft part sarcomas, Hodgkin and non-Hodgkin lymphomas, other lymphoreticular neoplasms, plasma cell tumors, mast cell tumors, immunoproliferative disorders, leukemias, various myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.

[0200] Paragraph 70. A combination of pharmaceuticals for use according to any one of paragraphs 44-69, wherein the neoplastic disease is a neoplastic disease treatable by inhibition of PLK1 in addition to treatment with carboplatin and a TTK inhibitor (e.g., a compound of formula (I)).

[0201] Paragraph 71. A combination of pharmaceuticals for use as described in any one of paragraphs 44-70, wherein the neoplastic disease is cancer.

[0202] Paragraph 72. A combination of the pharmacologics for use as described in Paragraph 71, wherein the cancer relating to the affected organ and part of the body is selected from the brain, breast (including triple-negative breast cancer), cervix, ovaries, colon, rectum (including colon and rectum, i.e., colorectal cancer), lung (including small cell lung cancer, non-small cell lung cancer, large cell lung cancer, and mesothelioma), endocrine system, bone, adrenal gland, thymus, liver, stomach, intestine (including gastric cancer), pancreas, bone marrow, hematological malignancies (such as lymphoma, leukemia, myeloma, or lymphoid malignancies), bile duct, bladder, urinary tract, kidney, skin, thyroid, head, neck, prostate, and testes.

[0203] Paragraph 73. A combination of the pharmaceuticals for use described in Paragraph 71, wherein the cancer is selected from breast cancer (including triple-negative breast cancer), gastric cancer, colorectal cancer, liver cancer (including hepatocellular carcinoma), endometrial cancer, ovarian cancer, esophageal cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), Kaposi's sarcoma, cervical cancer, pancreatic cancer, melanoma, prostate cancer, testicular cancer, cervical cancer, bladder cancer, head and neck cancer, brain tumors (e.g., glioma, medulloblastoma), neuroblastoma, retinoblastoma, Wilms' tumor, leukemia, e.g., acute myeloid leukemia (AML) (including complex karyotype AML) and malignant mesothelioma.

[0204] Paragraph 74. The combination of pharmaceuticals for use described in Paragraph 71, wherein the cancer is breast cancer, for example, triple-negative breast cancer.

[0205] Paragraph 75. The combination of pharmaceuticals for use described in Paragraph 71, wherein the cancer is ovarian cancer.

[0206] Paragraph 76. Compounds of formula (I) or pharmaceutically acceptable salts thereof for use in combination with carboplatin for the treatment of neobiotic diseases, particularly in humans.

[0207] Paragraph 77. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use as described in Paragraph 76, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject as defined in any one of Paragraphs 45-67.

[0208] Paragraph 78. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use as described in Paragraph 76 or Paragraph 77, wherein the neoplastic disease is as defined in any one of Paragraphs 68-75.

[0209] Paragraph 79. Carboplatin for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, particularly for the treatment of neobiotic diseases in humans.

[0210] Paragraph 80. Carboplatin for use as described in Paragraph 79, administered to the subject as defined in any one of Paragraphs 45-67.

[0211] Paragraph 81. Carboplatin for use as described in Paragraph 80 or Paragraph 81, wherein the neoplastic disease is as defined in any one of Paragraphs 68-75.

[0212] Paragraph 82. Use of any combination of the pharmaceuticals described in any one of paragraphs 1 to 5 in preparation as monopharmaceuticals or combination pharmaceuticals for the treatment of neoplastic diseases in humans.

[0213] Paragraph 83. The use according to paragraph 82, wherein the pharmaceutical composition is administered to the subject as defined in any one of paragraphs 45 to 67.

[0214] Paragraph 84. The use described in paragraph 82 or paragraph 83, wherein the neoplastic disease is as defined in any one of paragraphs 68-75.

[0215] Paragraph 85. Use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of monotherapy drugs for use in combination with carboplatin, or in the preparation of combination drugs with carboplatin, for the treatment of neoplastic diseases in humans.

[0216] Paragraph 86. The use according to paragraph 85, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject as defined in any one of paragraphs 45-67.

[0217] Paragraph 87. The use described in paragraph 85 or paragraph 86, wherein the neoplastic disease is as defined in any one of paragraphs 68-75.

[0218] Paragraph 88. Use of carboplatin in the preparation of monotherapy drugs for use in combination with the compound of formula (I) or a pharmaceutically acceptable salt thereof, or in the preparation of combination drugs with the compound of formula (I) or a pharmaceutically acceptable salt thereof, for the treatment of neoplastic diseases in subjects, particularly in humans.

[0219] Paragraph 89. The use described in Paragraph 88, wherein carboplatin is administered to the subject as defined in any one of Paragraphs 45-67.

[0220] Paragraph 90. The use described in paragraph 88 or paragraph 89, wherein the neoplastic disease is as defined in any one of paragraphs 68-75.

[0221] Paragraph 91. A kit comprising a combination of pharmaceuticals described in any one of paragraphs 1 to 5, wherein component (a) and component (b) are provided as monopharmaceuticals.

[0222] Paragraph 92. The kit described in Paragraph 91, which is intended for use in treating any one of the neoplastic diseases defined in Paragraphs 68-75.

[0223] Paragraph 93. The kit described in paragraph 91 or paragraph 92, further including instructions for simultaneous, separate, or sequential administration thereof for use in the treatment of neobiotic diseases, particularly cancer, in humans.

[0224] Several publications are referenced herein to better describe and disclose the state of the present invention and the art to which it pertains. Each of these references is incorporated into this disclosure by reference to the same extent as each individual reference is incorporated by reference specifically and individually.

[0225] Specific embodiments of the present invention are described in the following examples, which serve to further illustrate the present invention, and should not be construed as limiting the invention.

[0226] Examples method Kinase assay To measure the kinase activity of TTK and PLK1, a radiometric protein kinase assay (33PanQinase® Activity Assay) was used. TTK and PLK1 protein kinases were expressed as recombinant full-length GST fusion proteins. The reaction cocktail contained 25 μL of assay buffer (standard buffer / [γ-33P]-ATP), 10 μL of ATP solution (in water), 5 μL of the test compound, and 10 μL of the enzyme / substrate mixture. The protein kinase assays included 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3 mM MnCl2, 3 μM sodium orthovanadate, 1.2 mM DTT, 50 μg / ml PEG20000, ATP (0.3 μM for TTK and 1 μM for PLK1), [γ-33P]-ATP (approximately 8 × 10⁵ cpm per well), protein kinase (15.8 nM for TTK and 5 nM for PLK1), and substrate (1 μg / 50 μL for TTK and 2 μg / 50 μL for PLK1). All assays were performed using the BeckmanCoulter / SAGIAN® Core System. The fitting model for IC50 determination was a "sigmoid response (variable gradient)," with the "highest" parameter fixed at 100% and the "lowest" parameter fixed at 0%. The fitting method used was least squares fitting.

[0227] Targeted Residence Time Assay Using recombinantly expressed TTK kinase domains (amino acids 519-808) or biotinylated PLK1, the affinity of the compound of formula (I) to TTK and PLK1, i.e., the equilibrium dissociation constant (KD) (also called residence time), was determined using a Biacore T200™ surface plasmon resonance spectrometer. Immobilization of TTK was performed as described in Maia et al. Annals of Oncology, 2015;26:2180-2192. Immobilization of biotinylated PLK1 was performed as described in Willemsen-Seegers et al. Journal of Molecular Biology, 2017;429:574-586. For TTK, compound concentration gradients of 1, 3.6, 10, 31.6, and 100 nM were used, and for PLK1, gradients of 10, 31.6, 100, 316, and 1000 nM were used. A contact time of 100 seconds and a flow rate of 30 μL / min were used, followed by a single-cycle kinetic assay at 22°C. Dissociation times ranged from 1200 to 1800 seconds, and a blank run using buffer was used to correct for unstable surfaces. Binding kinetics were calculated based on the binding curves, demonstrating a good signal-to-noise ratio for all tested compounds (data not shown).

[0228] PDX research In the initial PDX study, tumor fragments (3×3×3 mm) from BR1282, a stock mouse with patient-derived xenograft (PDX) triple-negative mammary cancer (TNBC) tumors, were subcutaneously (sc) inoculated into the right flank of female BALB / c nude mice (CrownBio) weighing at least 20 g. When the mean tumor size reached 150–200 mm3, the mice were randomly assigned to five different treatment groups (8 mice per group). Mice were administered intravenously (iv) either the compound of formula (I) (7 mg / kg, iv, 5 mL / kg) twice weekly (2 qw) or carboplatin (60 mg / kg, iv, 10 mL / kg) once weekly (qw), or a combination of these doses. When both compounds were administered on the same day / consecutive days, the compound of formula (I) was administered after carboplatin using either a 4-hour or 24-hour interval. Group 5 received both vehicles with a 4-hour time interval, and all groups received two doses via the tail vein. In any mouse that showed a transient weight loss of 10% or more at any point in time, drug administration was delayed by one day.

[0229] In the second PDX study, the same model as the first study (TNBC BR1282 PDX model) was used, but this time a 4-hour interval was used between the two doses. Compound (I) (8 mg / kg, iv, qw, 5 mL / kg) was administered first, followed by carboplatin (60 mg / kg, iv, qw, 6 mL / kg), with compound (I) given qw. As a result, the mice were given both compounds on the same day (with a 4-hour interval).

[0230] Carboplatin was purchased from Qilu Pharmaceutical Co. Ltd. as a solution (10 mg / mL in 5% (w / v) glucose in pure water). The compound of formula (I) was supplied as a powder by Basilea Pharmaceutica International Ltd. and was prepared immediately before use as a solution in ethanol:PEG400:20 mM citrate in a ratio of 1:1:8 and a final pH of 3.7 for immediate administration.

[0231] Body weight and tumor volume were determined at least twice a week. The latter was determined by measuring two dimensions with calipers and applying the formula "V = (L × W²) / 2" (where V is tumor volume, and L and W are tumor length and width, respectively). Individual mice were euthanized when the tumor reached 1500 mm³ or more, or when body weight loss (BWL) exceeded 20%. Mice were also euthanized if BWL was determined to be >15% for three consecutive days. Any mouse with BWL >10% was automatically administered medication on one of the following days as soon as BWL returned to <10%. All animal protocols were reviewed and approved by the relevant local committee in China where this study was conducted.

[0232] The statistical significance of efficacy was determined in two different ways, using a) the 10-day or 14-day endpoint, depending on the study, when the vehicle group needed to be removed due to tumor volume exceeding 1500 mm3, and b) the 31-day endpoint in the first trial, when exponential curve fitting was applied to estimate tumor growth rates in different groups. The degree of the effect was quantified by the delta (Δ) treatment / control ratio (ΔT / C), and the statistical significance of the effect was determined by one-way analysis of variance (1W-ANOVA) with Holms-Sidak applied post-hoc for multiple determinations, with a p-value <0.05 considered statistically significant. Furthermore, the evaluation of the combined effect is based on the Clarks Combination Index (CCI), where CCI = ΔT / CAB - (ΔT / CA * ΔT / CB), where A and B are two different compounds and AB is their combination, and CCI < -0.1 indicates a synergistic effect (or positive interaction), +0.1 indicates antagonism or negative interaction, and -0.1 to +0.1 indicates additiveity (no interaction). See O'Reilly et al. Anti Cancer Drugs 2011;22:58-78.

[0233] result TTK and PLK1 are kinases that play essential roles in regulating the spindle formation checkpoint (SAC), a cell cycle monitoring mechanism that ensures optimal cell division through proper chromosome alignment. Since TTK and PLK1 work together to recruit SAC components to the SAC protein complex at the chromosomal kinetochore, inhibition of both enzymes should maximize mitotic progression through more rapid cleavage of SAC (Von Schubert et al., Cell Reports 2015, 12; 66-78). This has been proven valid in tumor cell lines when comparing the compound of formula (I) with a TKK inhibitor that does not exhibit significant PLK1 inhibitory activity (data not shown).

[0234] Generally, compounds of formula (I) exhibit strong specificity for TTK, and the IC50 of other kinases is at least 10 times higher than the IC50 for TTK. The above TTK kinase assay confirmed that compounds of formula (I) are very potent for TTK, giving an IC50 of 7 nM (0.4 nM when measured as described in International Publication No. 2015 / 155042).

[0235] The PLK1 kinase assay described above also showed that the compound of formula (I) targets PLK1. The compound of formula (I) was found to inhibit PLK1 with an IC50 of 72 nM. When measured as described in International Publication 2015 / 155042, the compound of formula (I) inhibited PLK1 with an IC50 of 46 nM. Other TTK inhibitors reported in the literature have similar or slightly better overall specificity for TTK, but conversely, have little to no activity against PLK1 compared to their activity against TTK (data not shown). Importantly, the compound of formula (I) has an extremely long target retention period of over 12 hours against TTK, while its target retention period against PLK1 is only a few minutes. This long-term inhibition of TTK, coupled with a transient effect on PLK1, resulted in rapid disruption of SAC, leaving cells without sufficient time for proper chromosome segregation.

[0236] Long-term TTK target occupation was also measured in tumors derived from MDA-MB-231 xenograft-bearing mice treated with an intermittent intravenous administration regimen of the compound of formula (I). To determine the tumor TTK target occupation time of the compound of formula (I), model MDA-MB-231 mice, which are mice with TNBC xenografts, were intravenously treated twice a week with the compound of formula (I) at MTD doses and doses below the MTD. Analysis of vehicle-treated tumors and compound of formula (I)-treated tumors for TTK target occupation showed that the compound of formula (I) occupied tumor-derived TTK in a concentration-dependent manner, and the TTK was completely occupied by the compound of formula (I) for at least 72 hours after the last MTD dose. Repeated experiments using weekly MTD intravenous administration showed that tumor-derived TTK was completely occupied by the drug for up to 6 days after the last dose.

[0237] In cell lines, the compound of formula (I) exhibits high efficacy against sensitive cells. In a 5-day antiproliferative screening of 18 different triple-negative breast cancer cell lines, the compound of formula (I) had a median GI50 of 35 nM. In mice, the compound of formula (I) showed significant activity against patient-derived tumor xenografts, including TNBC and hepatocellular carcinoma (HCC) models, with effects ranging from minimal to very strong, including substantial regression (data not shown).

[0238] Carboplatin is the standard treatment for numerous tumor indications. To determine the combined efficacy of the compound of formula (I) and carboplatin, the maximum tolerated dose (MTD) of the compound of formula (I) in combination with the optimal dose of carboplatin was first defined in non-tumor-bearing BALB / c nude mice. Carboplatin (60 mg / kg, qw, iv) was administered first, followed by the compound of formula (I) 24 hours later (sequential approach) or 4 hours later (near-simultaneous approach). The maximum tolerated dose of the compound of formula (I) administered intravenously for 2 qw in combination with the optimal dose of carboplatin was 6–7 mg / kg using the above schedule. In contrast, when the compound of formula (I) was applied first, followed by carboplatin (60 mg / kg, iv, qw) 4 or 24 hours later, non-tumor-bearing mice tolerated weekly administration of the compound of formula (I) at 8 mg / kg, using a 4-hour interval between the compound of formula (I) and carboplatin. Therefore, mice were always treated with the compound of formula (I) and carboplatin on the same day. When the compound of formula (I) was applied first, a 24-hour interval between the two doses or a 2qw schedule of the compound of formula (I) was not tolerated when using 6-8 mg / kg of the compound of formula (I). Importantly, these doses of the compound of formula (I) are known to be effective as monotherapy in tumor-bearing mice.

[0239] In the first combination experiment, mice with BR1282 PDX TNBC tumors were treated with 60 mg / kg qw iv of carboplatin and 7 mg / kg 2 qw iv of the compound of formula (I) (4 or 24 hours apart, if administered on the same day or consecutive days). This model was selected because it was known to have an intermediate response to the compound of formula (I) and a minimal response to carboplatin. As previously shown, monotherapy with either compound was well tolerated with or without slight weight loss (Figure 1B). Furthermore, both combination regimens were well tolerated, although some individual mice experienced transient weight loss. To allow for recovery, individual mice with weight loss greater than 10% were treated one day later than planned. The 24-hour interval group tolerated this combination slightly better than the 4-hour interval group, and the latter showed greater weight loss within one week of the start of treatment.

[0240] Both combination regimens resulted in reduced tumor growth similar to that observed with the compound of formula (I) alone, whereas carboplatin alone had little effect on tumor growth (Figures 1A and 2). The Clarks combination index (CCI) of approximately 0.1 at day 10 of treatment in this study demonstrated an additive trend in both combination groups. At that point, using ΔT / C, neither comparison differed significantly from the other (Table 1). Furthermore, since the weight change at day 10 in the compound treatment groups did not differ statistically between groups (p>0.05; Table 1), this treatment is well tolerated. Due to tail vein damage resulting from repeated intravenous administration, the treatment in the combination groups could not be extended beyond 31 days. Exponential curve fitting from day 0 to the euthanasia date (most recent day 31) for each group provided greater statistical power and showed a much stronger effect. Both combination groups were significantly different from carboplatin monotherapy, but not significantly different from monotherapy of the compound of formula (I) (Figure 3 and Tables 1 and 2). The CCI showed additiveity for the 4-hour combination group (CCI=0.02) and antagonistic effect for the 24-hour combination group (CCI=0.16).

[0241] Based on favorable tolerability and a trend towards additive effects on tumor growth, these data support further evaluation of the compound of formula (I) in combination with carboplatin.

[0242] [Table 5]

[0243] Table 2 outlines the statistical analysis of the mean growth rate (k) in Figure 3 for each individual comparison based on one-way analysis of variance (1WA) using the Holm-Sidak post-hoc test for group comparison. [Table 6]

[0244] In a second combination study of the same model, the compound of formula (I) (8 mg / kg, qw, iv, 5 mL / kg) was administered first, followed 4 hours later by carboplatin (60 mg / kg, qw, iv, 6 mL / kg). All groups, namely the vehicle control group and the compound treatment group, reached the ethical endpoint on day 14. At that point, only the compound of formula (I) group demonstrated a certain level of efficacy (Figures 4A, 5, and 6, Table 3), although this was not statistically significant (p > 0.05 for all comparisons). After exponential growth, the difference between groups remained statistically insignificant (Table 3). The CCI showed a negative interaction, also known as antagonism, with a value of 0.42. Overall, there was no significant difference in weight change between the treatment group and the vehicle group on day 14, and the treatment was well tolerated (Figure 4B and Table 3). In conclusion, when mice are first administered the compound of formula (I) and then carboplatin 4 hours later, an antagonistic effect occurs, in contrast to the additive effect observed in the first study where carboplatin was administered 4 hours before the compound of formula (I). Therefore, it is crucial to treat the mice with carboplatin first and then the compound of formula (I) to achieve at least an additive effect.

[0245] [Table 7]

[0246] Table 4 summarizes the statistical analysis of Δtumor volume and mean growth rate (k) at day 14 in Figure 6 for each individual comparison based on one-way analysis of variance (1WA) using the Holm-Sidak post-hoc test for group comparison. [Table 8]

[0247] The antitumor activity of the compound of formula (I) in combination with carboplatin was evaluated in an ovarian cancer model using human SKOV-3 cells grown subcutaneously (sc) as solid tumor xenografts in nude mice.

[0248] In the experiments described above, the maximum tolerated dose (MTD) of the compound of formula (I) in combination with the optimal dose of carboplatin was defined in non-tumor-bearing BALB / c nude mice. These studies identified the most effective and well-tolerated schedule as the compound of formula (I) (7 mg / kg, iv, 2 qw) administered 4 hours after carboplatin (60 mg / kg, iv, qw). Therefore, in this study, this schedule was applied using a human ovarian cell line-derived xenograft (CDX) model and directly compared to the same administration sequence with 1-hour or 24-hour intervals between compounds. Furthermore, using a 4-hour interval, the twice-weekly schedule was compared to the once-weekly schedule of 7 mg / kg BAL0891 (a weekly dose well below the MTD of compound of formula (I) monotherapy). Treatment was continued until day 24, and tumor volume and body weight were monitored until day 51.

[0249] Figure 7 shows the mean ± SEM (n=8) for efficacy (TVol) and tolerability (BW), and the complete experiment in which mice were euthanized from day 23 when individual tumors reached at least 1500 mm3. Therefore, 23 days was the selected endpoint for comparing efficacy T / C (Figures 8, 9, Table 5). Individual plots for each tumor, along with exponential fits for tumor growth, are also shown in Figure 10. [Table 9]

[0250] ΔT / C showed only slight anticancer effects for the three different monotherapies, but each was significantly different from the vehicle group at day 23 (p<0.05). However, the combination of carboplatin and the compound of formula (I) administered once weekly was clearly the least effective (ΔT / C=0.46), although all combinations showed a very significant difference compared to the vehicle (p<0.001). Nevertheless, multiple comparisons (one-way ANOVA) did not show significant differences between the combinations at this point. Based on ΔT / C at day 23, the most effective combination was carboplatin (carboplatin always first) combined with the compound of formula (I) (2qw) using a 1-hour or 4-hour interval between treatments, and indeed, each of these two groups had one tumor that had completely regressed. This was confirmed at day 51 by immunohistochemistry (IHC), in which tumor cells could not be seen. Synergistic effects were evaluated using the Clark Combination Index (CCI) for three combinations of BAL0891 administered twice weekly (at intervals of 1, 4, or 24 hours), while the once-weekly BAL0891 schedule only provided additive effects (Table 5).

[0251] All treatments were relatively well tolerated, except for the combination group with a 24-hour interval between carboplatin and compound (I) treatment, during the first two weeks, in which some significant but transient weight loss was observed. Overall, these data suggest a significant synergistic effect between the two compounds when shorter intervals (1–4 hours) were used, as shorter intervals (1–4 hours) provided the highest efficacy and best tolerability.

[0252] In conclusion, in nude mice carrying subcutaneous human ovarian tumors SKOV-3, the combination of carboplatin (60 mg / kg, IV, qw) followed by the compound of formula (I) (7 mg / kg, intravenous, 2qw) was well tolerated and demonstrated synergistic efficacy. The most effective combination was carboplatin combined with the compound of formula (I) (2qw) using a 1-hour or 4-hour interval between treatments. Indeed, each of these two groups had one tumor that had completely regressed. Evaluation of synergistic effects using the Clark Combination Index (CCI) showed synergistic effects for three combinations (1, 4, or 24-hour intervals) using the compound of formula (I) administered twice weekly. However, the low-dose, once-weekly schedule of the compound of formula (I) only provided additiveity.

Claims

1. (a) Compound of formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, (b) Carboplatin and A combination of pharmaceuticals including, for use in the treatment of neoplastic diseases in humans, A pharmaceutical combination in which carboplatin is administered to the subject before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

2. The pharmaceutical combination according to claim 1, wherein the molar ratio of carboplatin to the compound of formula (I) or a pharmaceutically acceptable salt thereof per weekly dose is about 2.1:1 to about 32:

1.

3. The pharmaceutical combination for use according to claim 1, wherein, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to the subject within a period of 48 hours, carboplatin is administered to the subject up to 24 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

4. The pharmaceutical combination for use according to claim 1, wherein, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to the subject within a period of 24 hours, carboplatin is administered to the subject up to 6 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

5. The pharmaceutical combination for use according to claim 1, wherein, when carboplatin and the compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to the subject within a period of 48 hours, carboplatin is administered to the subject about 30 minutes to about 24 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered to the subject according to a 3-week treatment cycle. The compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the first week of the treatment cycle, followed by a two-week rest period, and carboplatin is administered in the first week of the treatment cycle, followed by a two-week rest period, or The compound of formula (I) or a pharmaceutically acceptable salt thereof is administered during weeks 1 and 2 of the treatment cycle, with week 3 being a rest week, and carboplatin is administered during week 1 of the treatment cycle, followed by a two-week rest week. Preferably, in each case, the compound of formula (I) or a pharmaceutically acceptable salt thereof and carboplatin are administered to the subject according to the same three-week treatment cycle. A pharmaceutical combination for use according to any one of claims 1 to 5.

7. A pharmaceutical combination for use according to any one of claims 1 to 6, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in a dose corresponding to about 40 mg to about 200 mg per week of free base equivalent of the compound of formula (I) during the week of administration.

8. A pharmaceutical combination for use according to any one of claims 1 to 6, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient in a dose corresponding to about 80 mg to about 160 mg per week of free base equivalent of the compound of formula (I) during the week of administration.

9. A pharmaceutical combination for use according to any one of claims 1 to 6, wherein carboplatin is administered to the patient in a dose according to AUC 5 per week during the week in which it is administered, or carboplatin is administered to the patient in a dose according to AUC 6 per week during the week in which it is administered.

10. The neoplastic diseases include epithelial neoplasms, squamous neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, cutaneous appendage neoplasms, mucoepidermal neoplasms, cystic neoplasms, myxoid and serous neoplasms, glandular, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized gonadal neoplasms, paragangliomas and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms, synovial neoplasms, mesothelial neoplasms A pharmaceutical combination for use according to any one of claims 1 to 9, selected from the group consisting of organisms, germ cell neoplasms, chorionic neoplasms, mesonephromas, hemangiomas, lymphangiomas, ossicular and chondrocytic neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepitheliomatous neoplasms, meningiomas, schwannomas, granulocyte tumors and hydatidiform soft part sarcomas, Hodgkin and non-Hodgkin lymphomas, other lymphoreticular neoplasms, plasma cell tumors, mast cell tumors, immunoproliferative disorders, leukemias, myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.

11. The pharmaceutical combination for use according to any one of claims 1 to 10, wherein the neoplastic disease is a neoplastic disease that can be treated by inhibition of PLK1 in addition to treatment with carboplatin and a TTK inhibitor.

12. A pharmaceutical combination for use according to any one of claims 1 to 11, wherein the neoplastic disease is cancer, in particular, selected from breast cancer (including triple-negative breast cancer), gastric cancer, colorectal cancer, liver cancer (including hepatocellular carcinoma), endometrial cancer, ovarian cancer, esophageal cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), Kaposi's sarcoma, cervical cancer, pancreatic cancer, melanoma, prostate cancer, testicular cancer, cervical cancer, bladder cancer, head and neck cancer, brain tumors (e.g., glioma, medulloblastoma), neuroblastoma, retinoblastoma, Wilms' tumor, leukemia, for example, acute myeloid leukemia (AML) (including complex karyotype AML) and malignant mesothelioma.

13. A pharmaceutical combination for use according to any one of claims 1 to 11, wherein the neoplastic disease is breast cancer.

14. A pharmaceutical combination for use according to any one of claims 1 to 11, wherein the neoplastic disease is triple-negative breast cancer.

15. The pharmaceutical combination for use according to any one of claims 1 to 11, wherein the neoplastic disease is a carboplatin-treated cancer.

16. A pharmaceutical combination for use according to any one of claims 1 to 11, wherein the neoplastic disease is ovarian cancer (e.g., advanced ovarian epithelial carcinoma, recurrent ovarian cancer, early ovarian cancer), lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), cervical cancer (e.g., metastatic or recurrent cervical cancer), head and neck cancer (e.g., recurrent or metastatic squamous cell carcinoma of the head and neck), Wilms' tumor, brain tumor (e.g., glioma such as advanced or recurrent glioma, medulloblastoma such as recurrent medulloblastoma), neuroblastoma, testicular cancer, bladder cancer, retinoblastoma, breast cancer (e.g., metastatic breast cancer), or endometrial cancer (e.g., advanced or recurrent endometrial cancer).

17. A pharmaceutical combination for use according to any one of claims 1 to 11, wherein the neoplastic disease is ovarian cancer.

18. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, for use in combination with carboplatin for the treatment of neobiotic diseases in subjects, particularly in humans, A pharmaceutical composition in which carboplatin is administered to the subject before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

19. A pharmaceutical composition comprising carboplatin for use in combination with a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, for the treatment of a target, particularly a neobiotic disease in humans, A pharmaceutical composition in which carboplatin is administered to the subject before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

20. The pharmaceutical combination according to any one of claims 2, 5, 7, or 8, wherein the term "approximately" means a variation of 5% or less of the relevant figures.

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