Pharmaceutical combinations 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 pharmaceutical combinations comprising two active pharmaceutical compounds as described herein and methods of using the combinations of the invention in the treatment of neoplastic diseases, particularly cancer. [Background technology]

[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. It is marketed under the trade name Paraplatin®. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2015 / 155042 Summary of the Invention [Problem 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 problem]

[0006] In a first aspect, the present invention provides a method for producing a composition comprising the steps of: (a) A compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof; (b) Carboplatin and The present invention provides a pharmaceutical combination comprising:

[0007] The compound of formula (I) is disclosed in WO 2015 / 155042 as Example 17.

[0008] Surprisingly, in addition to TTK inhibitory activity, compounds of formula (I) have been found to also exhibit polo-like kinase 1 (PLK1) inhibition (see examples below). Both kinases cooperate to activate the mitotic spindle assembly checkpoint (SAC) at kinetochores to control chromosome alignment and separation before cells can exit mitosis. Von Schubert et al., Cell Reports 2015,12;66-78 disclose that PLK1 and TTK (also known as MPS1) cooperate to control the spindle assembly checkpoint (SAC) in human cells. This possibility of enhanced effects from the inhibition of both TTK and PLK1 has also been suggested in Dou et al., Plos ONE 2011,6:4;e18793, which shows that some substrates of both kinases share similar consensus motifs.

[0009] In contrast to TTK-specific inhibitors, the compounds of formula (I) have a long-term effect on TTK combined with a transient effect on PLK1 (see Examples below) that results in a more rapid destruction of SAC enhancing aberrant mitotic progression. Thus, the dual TTK / PLK1 inhibitory activity gives the compounds of formula (I) unique properties and makes them different from other molecules that exhibit TTK inhibitory activity without appreciable levels of PLK1 inhibitory activity.

[0010] In a further aspect, the present invention provides a method for treating a neoplastic disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a pharmaceutical combination of the present invention.

[0011] In a further aspect, the present invention provides a method for treating a neoplastic disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, said subject being or will be undergoing treatment with carboplatin.

[0012] In a further aspect, the present invention provides a method for treating a neoplastic disease in a subject in need thereof, comprising administering a therapeutically effective amount of carboplatin to said subject, said subject being or will be undergoing treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0013] In a further aspect, the present invention provides a pharmaceutical combination of the present invention for use in the treatment of a neoplastic disease in a subject.

[0014] In a further aspect, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in combination with carboplatin for the treatment of a neoplastic disease in a subject.

[0015] In a further aspect, the present invention provides carboplatin for use in combination with a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the treatment of a neoplastic disease in a subject.

[0016] In a further aspect, the present invention provides the use of a pharmaceutical combination of the present invention in the preparation of a single medicament or a combination medicament for the treatment of a neoplastic disease in a subject.

[0017] In a further aspect, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the preparation of a single agent medicament for use in combination with carboplatin or in the preparation of a combination medicament with carboplatin, for the treatment of a neoplastic disease in a subject.

[0018] In a further aspect, the present invention provides the use of carboplatin in the preparation of a single agent medicament for use in combination with a compound of formula (I) or a pharma- ceutically acceptable salt thereof, for the treatment of a neoplastic disease in a subject, or in the preparation of a combination medicament with a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0019] Neoplastic diseases for treatment with the combination of the present invention are described below and are particularly envisaged with respect to the treatment of cancer, and particularly with respect to human subjects.

[0020] Further aspects and embodiments of the 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 every week (qw). The compound of formula (I) (7 mg / kg) was administered intravenously twice a week (2qw). (4 or 24 hours after carboplatin when administered on the same day). The mean tumor volume (A) and mean body weight change in % (B) are shown. One non-drug related death in the vehicle treatment group occurred on day 15. One mouse in the combination group with a 4 hour dosing interval on day 20 and a 24 hour dosing interval on day 10 had to be euthanized due to a tumor volume exceeding 1500 mm3. Dosing was delayed by one day in any mice showing a transient weight loss of 10% or more at any time point. The vehicle control group received the vehicle of carboplatin and the vehicle of the compound of formula (I) (denoted as both vehicles) with a 4 hour interval between both doses. N=8 mice per group. [Diagram 2] Figure 2 shows individual tumors from the study presented in Figure 1 up to sacrifice. A vehicle control group received the vehicle of carboplatin and the vehicle of the compound of formula (I) (both shown as vehicle) with a 4 hour interval between both doses. [Diagram 3]Figure 3 shows the mean proliferation rates (k) suggesting that the combination of carboplatin and compound of formula (I) has additive efficacy as single agents in the BR1282 TNBC PDX model. Exponential calculations of k-means for treatment with both vehicles (Vehicle), compound of formula (I) at 7 mg / kg intravenous 2 qw, carboplatin at 60 mg / kg intravenous qw or a combination of both are shown until the day the mice were sacrificed (the most recent day 31). In the combination groups, carboplatin was administered first, followed by compound of formula (I) 4 or 24 hours later if administered on the same day. Lines represent the mean + / - SD. Statistical analysis was based on one-way analysis of variance (1WA) with Holm-Sidak post-hoc test for group comparison. All groups treated with different compounds were statistically significantly different compared to 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) alone group (p=0.5736). Detailed statistical analysis is shown in Table 2. N=8 mice per group. [Figure 4] Figure 4 shows the antagonistic effect of compound of formula (I) in combination with carboplatin in TNBC PDX model BR1282, where compound of formula (I) was administered first and carboplatin second. Compound of formula (I) (8 mg / kg) and carboplatin (60 mg / kg) were administered qw intravenously. (Carboplatin 4 hours after compound of formula (I) when administered on the same day). Mean tumor volume (A) and mean body weight change in % (B) are shown. Vehicle control groups received vehicle of compound of formula (I) and vehicle of carboplatin (denoted as both vehicles) with a 4 hour interval between both administrations. N=6 mice for vehicle and both single agent groups, N=7 mice for combination group. [Diagram 5] Figure 5 shows individual tumors from the study presented in Figure 4. A vehicle control group received the vehicle of the compound of formula (I) and the vehicle of carboplatin (both shown as vehicles) with a 4 hour interval between both doses. [Figure 6]Figure 6 shows statistical analysis at day 14, suggesting that the combination of carboplatin and compound of formula (I) has similar efficacy as single agents in the BR1282 TNBC PDX model. Delta tumor volume (tumor volume on day 14-tumor volume on day 0) on day 14 of treatment with both vehicles (Vehicle), compound of formula (I) 8 mg / kg intravenous qw, carboplatin 60 mg / kg intravenous qw or a combination of both is shown. In the combination group, compound of formula (I) was administered first, followed by carboplatin 4 hours later if administered on the same day. Lines represent mean + / - SD. Statistical analysis was based on one-way analysis of variance (1WA) with Holm-Sidak post-hoc test for group comparison. All groups treated with different compounds were not statistically significantly different compared to vehicle, and the combination group was not statistically different compared to compound of formula (I) single agent group (p>0.05). N=6 mice for vehicle and both single agent groups, N=7 mice for the combination group. [Figure 7] FIG. 7 shows the efficacy (A) and tolerability (B) of the combination of carboplatin + compound of formula (I) in Balb / c nude mice bearing SKOV-3 subcutaneous xenografts. Balb-c nude mice bearing subcutaneous SKOV-3 tumors were treated with single agents or combinations at the doses and schedules indicated until day 24. Time-dependent changes in tumor volume (efficacy) and body weight (tolerability) are shown as mean ± standard error of the mean (n=8) until individual mice had to be sacrificed due to tumor size exceeding 1500 mm3. "CRB" refers to carboplatin. [Figure 8] Figure 8 shows the efficacy (A) and tolerability (B) of the combination of carboplatin + compound of formula (I) in Balb / c nude mice bearing SKOV-3 subcutaneous xenografts until first sacrifice due to excessive tumor size. Balb-c nude mice bearing subcutaneous SKOV-3 tumors were treated with single agents or combinations at the doses and schedules indicated. [Figure 9]Figure 9 shows the endpoint statistical analysis at day 23 for tumor volume (A) and body weight (B) using one-way ANOVA with Holm-Sidak post-hoc test for multiple comparisons, *p<0.05, **p<0.01, ***p<0.001 compared to the vehicle group. [Figure 10] Figure 10 shows the exponential fits to individual SKOV-3 tumors in each treatment group. Because mice had to be sacrificed periodically until the end of the study on day 51, an alternative display is shown using exponential fits (Prism 9.3) to each tumor in each group from day 0 to the last day of measurement. "Combination" refers to combination treatment using a total dose of both compounds with a compound of formula (I) on a 2qw or qw schedule, with 1, 4 or 24 hour intervals as indicated. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] definition Certain terms used herein are explained below: Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0023] The terms "combination," "therapeutic combination," or "pharmaceutical combination" are interchangeable terms and refer to either a fixed combination or a non-fixed combination.

[0024] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration encompasses the simultaneous administration of these therapeutic agents in a substantially simultaneous manner, as well as the use of each type of therapeutic agent in a sequential and / or separate manner, for example, according to different dosing regimens, at about the same time or at different times (for example, according to different administration routes), examples of which are described herein. When the therapeutic agents are administered sequentially and / or separately, the dosing schedule is such that there is a therapeutic interaction between the therapeutic agents in the patient's body, and / or when a second therapeutic agent is administered, there is a therapeutic effect due to the first therapeutic agent. For example, when the agents 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 agent 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 cyclic treatment schedule, there will be at least one interval of no more than 7 days between the dose of one of the therapeutic agents and the dose of the other therapeutic agent.

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

[0026] As used herein, the term "pharmacologically acceptable" refers to items such as compounds, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, 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 pharmaceutical" refer to a single dosage form formulated to deliver to a patient amounts of both therapeutic agents that together are therapeutically effective for the treatment of a neoplastic disease. The single dosage form is designed to deliver an amount of each of the therapeutic agents, along with any pharma- ceutical acceptable carriers or excipients.

[0028] The terms "non-fixed combination," "kit," "separate formulation," and "monopharmaceutical" mean that the active ingredients are formulated as separate entities to enable them to be administered simultaneously, sequentially, or separately to a patient, such administration providing therapeutically effective levels of the two compounds in the patient's body.

[0029] The term "patient" refers to a human subject to therapeutic treatment.

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

[0031] The term "treatment" used herein in the context of treating disease in a subject relates to treatment and therapy in general, in which some desired therapeutic effect is achieved, such as one or more of the following: inhibiting the progression of disease, slowing the rate of progression, stopping the rate of progression, preventing the progression of disease, alleviating symptoms of disease, improving disease, and curing disease. For example, treatment can be the attenuation of one or some symptoms of disorder or the complete eradication of disorder. Within the meaning of this disclosure, the term "treat" also means stopping disease, delaying the onset of disease (i.e., the period before the clinical manifestation of disease), and / or reducing the risk of developing or worsening disease.

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

[0033] The term "pharmacologically effective amount," "therapeutically effective amount," or "clinically effective amount" is an amount sufficient, when administered in accordance with a desired treatment regimen, to provide an observable or clinically significant improvement over baseline clinically observable signs and symptoms of the disease being treated, e.g., commensurate with a reasonable benefit / risk ratio. One of skill in the art will appreciate that the therapeutically effective amount 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 a monotherapy.

[0034] The term "about" refers to a variation of up to 10% of the associated figure. In some embodiments, the term "about" refers to a variation of up to 5% of the associated figure.

[0035] For the avoidance of doubt, where a range is provided (eg, 5 mg to 480 mg), that range includes the stated upper limit (480 mg) and lower limit (5 mg) of that range.

[0036] Compounds of formula (I) In some embodiments, the compound of formula (I) is / is used as the free base. In other embodiments, the compound of formula (I) is used as a pharma- ceutically acceptable salt.

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

[0038] The compounds of formula (I) and their pharma- ceutically acceptable salts may be solvated, in particular hydrated. Solvation and / or hydration may occur during the preparation process.

[0039] Compounds of formula (I) and pharma- ceutically acceptable salts thereof may be synthesized as described in WO 2015 / 155042, in particular pages 17-19, which are incorporated herein by reference, as well as in Example 17 on page 49 of WO 2015 / 155042, including references in Example 9, Intermediate H and Example 1, which are also incorporated herein by reference.

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

[0041] Furthermore, the pharmaceutical combination of the present invention can 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 setting (e.g., therapeutic, including preventive, adjuvant, neoadjuvant, palliative treatment). The pharmaceutical combination of the present invention can be for use in delaying, delaying or stopping cancer progression or cancer growth, or increasing overall cancer survival time or cancer progression-free survival time or time to progression, or improving or maintaining a subject's (e.g., patient's) quality of life or functional status. The pharmaceutical combination of the present invention can also be used in post-treatment recovery from cancer. The pharmaceutical combination of the present invention can be used in the treatment of metastatic cancer. The cancer to be treated can be advanced cancer. Advanced cancer is cancer that is unlikely to be cured or controlled by treatment. Cancer can 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, the pharmaceutical combinations 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 invasion 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 prolong disease- or tumor-free survival; (viii) increase overall survival; (ix) reduce the frequency of treatments; and / or (x) alleviate one or more symptoms associated with cancer.

[0043] As mentioned above, the pharmaceutical combination of the present invention can be used for the treatment of neoplastic diseases.Examples of neoplastic diseases include epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papilloma and carcinoma, adenoma and adenocarcinoma, skin adnexal neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized glandular neoplasms, paraganglioma and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, fibromatous neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms, fibromatous ... These include, but are not limited to, myeloma, synovial neoplasms, mesothelial neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesonephromas, vascular tumors, lymphatic tumors, osseous and cartilaginous neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepithelioma neoplasms, meningiomas, neurilemmomas, granular cell tumors and alveolar soft part sarcomas, Hodgkin's and non-Hodgkin's 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, neoplastic disease is cancer.Examples of cancers of affected organs and body parts include, but are not limited to, brain, breast (including triple negative breast cancer), cervix, ovary, 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 lymphatic malignancies), bile duct, bladder, urinary tract, kidney, skin, thyroid, head, neck, prostate and testis.

[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, 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 (eg, 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 (eg, small cell lung cancer, non-small cell lung cancer).

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

[0056] In some embodiments, the neoplastic disease is head and neck cancer (eg, 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 (eg, a glioma, such as a progressive or recurrent glioma, a medulloblastoma, such as a recurrent medulloblastoma).

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

[0060] In some embodiments, the neoplastic disease is testicular cancer (eg, metastatic nonseminomatous germ cell tumors).

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

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

[0063] In some embodiments, the neoplastic disease is a cancer treatable with carboplatin. Such cancers include those listed in the Carboplatin monograph, for example, available at www.drugs.com / monograph / carboplatin.html. Such cancers include ovarian cancer (e.g., advanced ovarian epithelial cancer, 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), endometrial cancer, for example, advanced or recurrent endometrial cancer).

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

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

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

[0067] The administration of the pharmaceutical combination of the present invention may not only bring about beneficial effects, such as alleviating symptoms, delaying the progression of symptoms or inhibiting symptoms, but may also bring about further beneficial effects, such as fewer side effects, more sustained therapeutic effect, improved quality of life and / or reduced morbidity, compared to a monotherapy applying only one of the pharmaceutical therapeutic agents used in the combination of the present invention.For example, it may be possible to use lower doses of the therapeutic agents of the combination of the present invention, such that not only the dosage may often be smaller, but also may be applied less frequently or may be used to reduce the incidence of side effects observed with only one of the combination partners.

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

[0069] The method according to the present invention may include (i) administration of a compound of formula (I) in free or pharma- ceutically acceptable salt form, and (ii) administration of carboplatin in any order, simultaneously, sequentially, or separately, in a jointly therapeutically effective amount, e.g., in a synergistically effective amount, e.g., in a continuous or periodic dosing schedule corresponding to the amounts described herein. The individual combination partners of the combination of the present invention may be administered separately at different times during the course of treatment, or may be administered simultaneously. Thus, the present invention should be understood to encompass all such treatment regimes, and the term "administering" should be interpreted accordingly. Examples of treatment regimes for use in the present invention are described in detail below.

[0070] The compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin may be administered according to the same treatment schedule or according to independent treatment schedules, which may be cyclic or continuous.

[0071] A cyclic treatment schedule is defined by a repeated dosing schedule in which the repeated element (cycle) has a specific duration and the dose is administered on a specific day within the cycle. The cycle may incorporate a period of no administration ("day off"), usually at the end of the cycle, for example, to allow a period for recovery. The treatment cycle may be, for example, 7 days, 14 days, 21 days, 28 days or longer. A continuous treatment schedule is a regular dosing schedule that does not incorporate a day off (i.e., a period longer than the regular interval between doses). For example, doses may be administered once a day, twice a day, once every 2 days, once every 3 days, etc. The treatment schedule, whether cyclic or continuous, may be continued as long as needed ("indefinite treatment"), for example, as long as the subject (e.g., patient) is receiving benefit as determined by the physician supervising the treatment.

[0072] When the compound of formula (I) or its pharmaceutically acceptable salt and carboplatin are administered according to independent treatment schedules, both treatment schedules can be cyclic, or one can be cyclic and the other can be continuous.When both treatment schedules are cyclic, the cycles of the two treatment schedules can be the same duration or different duration, and can start on the same day or different days.When the cycles are the same duration, the treatment cycles of both drugs usually start on the same day.

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

[0074] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin are administered (e.g., intravenously) according to a three-week treatment cycle, where the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on week 1, e.g., day 1, of the treatment cycle, followed by a two-week rest week, and the carboplatin is administered on week 1, e.g., day 1, of the treatment cycle, followed by a two-week rest week. Preferably, the compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin are administered to the subject according to the same three-week treatment cycle (i.e., the treatment cycles start on the same day).

[0075] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin are administered (e.g., intravenously) according to a three-week treatment cycle, where the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on weeks 1 and 2, e.g., days 1 and 8, of the treatment cycle, with week 3 being a rest week, and carboplatin is administered on week 1, e.g., day 1, of the treatment cycle, followed by a two-week rest week. Preferably, the compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin are administered to the subject according to the same three-week treatment cycle (i.e., the treatment cycles start on the same day).

[0076] The effective dosage of each of the combination partners used in the combination of the present invention may vary depending on the pharmaceutical composition used, the mode of administration, the condition being treated and the severity of the condition being treated.Therefore, the dosage 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., patient).

[0077] The optimal ratio, individual and combined dosages, and concentrations of the combination partners of the pharmaceutical combination of the present invention that bring about efficacy without toxicity are based on the kinetics of the availability of therapeutic agents to target sites. 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 condition being treated and the severity of the condition being treated, as well as the individual's age, weight, overall health, sex and diet, and other drugs that the individual is taking. Similarly, the frequency of dosing can vary depending on the compound used and the specific condition to be treated. Subjects (e.g., patients) can generally be monitored for the effectiveness of treatment using an assay suitable for the condition being treated, and such assays are well known to those skilled in the art.

[0078] In some embodiments, the molar ratio of carboplatin to the compound of formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose in the combination of the present invention is, for example, about 0.6:1 to about 250:1, such as 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, about 1.8:1 to about 16:1, for example, about 1.8:1 to about 13:1, for example, about 1.8:1 to about 9:1, for example, about 1.8:1 to about 8:1, for example, about 1.9:1 to about 8:1, for example, about 1.9:1 to about 7:1, for example, about 2.1:1 to about 32:1, for example, about 2.1:1 to about 26:1, for example, about 2.2:1 to about 14:1, for example, about 2.2:1 to about 12:1, for example, about 2.1:1 to about 7:1, for example, about 2.1:1 to about 6:1, for example, about 2.6:1 to about 16:1, for example, about 2.6:1 to about 13:1, for example, about 3.3:1 to about 14:1, for example, about 3.3:1 to about 12:1. In some embodiments, the molar ratio of carboplatin to the compound of Formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose is, for example, from about 2.1:1 to about 32:1.

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

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

[0081] The following examples of dosages are for humans. Doses of the compound of formula (I) are given in mg per person, regardless of body weight or body surface area (BSA). The dosages of the compound of formula (I) given below, including Tables A, B and C, refer to the dosage of the free base. The dosages also apply to the pharma- ceutically acceptable salt of the compound of formula (I), except that if a pharma- ceutically acceptable salt of the compound of formula (I) is used, the mg dosages given should be adjusted (i.e., increased) so that the molar amount of the pharma- ceutically 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 dosage of the compound of formula (I) is about 5 mg to about 480 mg in the week administered means that the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 5 mg to about 480 mg per week in the week administered. Unlike the average weekly dose, which may be less than the actual weekly dose when taking into account weeks of drug holiday, the weekly dose in the administered week is the actual dose given to the patient in a given week.

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

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

[0084] Examples of weekly (human) doses of the compound of formula (I) during the week of administration include about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, about 90 mg to about 100 mg, about 100 mg to about 110 mg, and about 110 mg to about 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 of the active ingredient include about 370 mg to about 370 mg, about 370 mg to about 380 mg, about 380 mg to about 390 mg, about 390 mg to about 400 mg, about 400 mg to about 410 mg, about 410 mg to about 420 mg, about 420 mg to about 430 mg, about 430 mg to about 440 mg, about 440 mg to about 450 mg, about 450 mg to about 460 mg, about 460 mg to about 470 mg, and about 470 mg to about 480 mg.

[0085] Examples of specific (human) weekly doses of a compound of formula (I) during the week in which it is administered include about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 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 about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, and about 480 mg.

[0086] The weekly dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof may be administered in a single dose, e.g., substantially without pause when administered intravenously. Alternatively, the weekly dose may be administered in multiple doses, e.g., two or three doses, with a break between doses of 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, between doses, when administered intravenously. Such multiple doses may be administered on the same day or on separate days, e.g., on consecutive days or, e.g., three days after the day of the first administration. Usually, the weekly dose is administered within a 24-hour period, usually substantially without pause.

[0087] The compound of formula (I) or a pharma- ceutically acceptable salt thereof is preferably administered intravenously. The duration of the infusion is usually at least 30 minutes and can be up to 24 hours. In some embodiments, the duration of the infusion is 30 minutes to 12 hours, such as 30 minutes to 6 hours, such as 30 minutes to 3 hours, such as 1 to 2 hours, such as about 1 hour.

[0088] The human dose of carboplatin is usually calculated according to the Calvert formula (Calvert et al., J. Clin. Oncol. 1989; 7(11): 1748-56). The Calvert formula incorporates the glomerular filtration rate as its key variable. The most common way to estimate the glomerular filtration rate for the Calvert formula is by creatine clearance calculated according to the Cockroft-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). Thus, in the present 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 is the creatine clearance calculated according to the Cockroft-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, which should not be exceeded, is the target AUC (mg / mL / min) × (150): For a target AUC of 6, the maximum dose is 6 x 150 = 900 mg. For a target AUC5, the maximum dose is 5 x 150 = 750 mg. For a target AUC4, the maximum dose is 4 x 150 = 600 mg.

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

[0093] The weekly dose of carboplatin may be administered in a single dose, e.g., without a break when administered intravenously. Alternatively, the weekly dose may be administered in multiple doses, e.g., 2 or 3 doses, with a break of at least about 30 minutes, e.g., at least about 1 hour, e.g., at least about 2 hours, e.g., at least about 4 hours, e.g., about 30 minutes to about 12 hours, e.g., about 30 minutes to about 6 hours, between doses when administered intravenously. Such multiple doses may be administered on the same day or on separate days, e.g., on consecutive days or 3 days after the first dose. Typically, the weekly dose is administered within a 24 hour period, typically without a break.

[0094] Carboplatin is preferably administered intravenously. The duration of the infusion is usually 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, such as about 30 minutes to about 6 hours, such as about 30 minutes to about 3 hours, such as about 1 to about 2 hours, such as about 30 minutes.

[0095] In some embodiments, the weekly (human) dose of the compound of formula (I) in the week it is administered and the weekly (human) dose of carboplatin in the week it is administered are as set forth in any one of embodiments 1A to 21A in Table A. [Table 1]

[0096] As described above, embodiment 1A refers to the situation where carboplatin is administered to a patient at AUC4 per week during the week of administration, and the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 5 mg to about 480 mg per week during the week of administration.The same applies to embodiments 2A to 21A.

[0097] In some embodiments, the weekly (human) dose of the compound of formula (I) in the week it is administered and the weekly (human) dose of carboplatin in the week it is administered are as set forth 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 the situation where carboplatin is administered to a patient at AUC4 per week during the week of administration, and the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to about 5 mg to about 10 mg of the molar equivalent 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 treatment cycle duration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin is 3 weeks, the (human) weekly doses of the compound of formula (I) and carboplatin in the weeks they are administered and the weeks of administration within the cycle are as set forth in any one of embodiments 1C-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 the situation where the compound of formula (I) or its pharmaceutically acceptable salt and carboplatin are administered to the patient (e.g., intravenously) according to the same 3-week treatment cycle, the compound of formula (I) or its pharmaceutically acceptable salt is administered in the first week of the treatment cycle followed by a two-week rest week, the carboplatin is administered in the first week of the treatment cycle followed by a two-week rest week, the carboplatin is administered to the patient at AUC4 per week during the week in which it is administered, and the compound of formula (I) or its pharmaceutically acceptable salt is administered to the patient at a dose equivalent to about 5mg to about 480mg of the molar equivalent of the free base of the compound of formula (I) per week during the week in which it is administered.The same applies to embodiments 2C to 42C.

[0101] In some embodiments, the treatment cycle duration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin is 21 days, the (human) weekly doses of the compound of formula (I) and carboplatin in the week they are administered and the days of administration within the cycle are as set forth in any one of embodiments 1D-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 where the compound of formula (I) or its pharmaceutically acceptable salt and carboplatin are administered to a patient (e.g., intravenously) according to the same 21-day treatment cycle, the compound of formula (I) or its pharmaceutically acceptable salt is administered on day 1 of the treatment cycle, the carboplatin is administered on day 1 of the treatment cycle, the carboplatin is administered to the patient at AUC4 per week during the week in which it is administered, and the compound of formula (I) or its pharmaceutically acceptable salt is administered to the patient at a dose equivalent to about 5 mg to about 480 mg of the molar equivalent of the free base of the compound of formula (I) per week during the week in which it is administered. 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 Examples below, it may be advantageous to administer a dose of carboplatin prior to a dose of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof, particularly when carboplatin and the compound of Formula (I) or a pharma- ceutically acceptable salt thereof are administered simultaneously, e.g., on the same day.

[0105] Thus, in some embodiments, carboplatin is administered to the subject before the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject. In some embodiments, carboplatin is administered to the subject before the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject, if both carboplatin and the compound of formula (I) or a pharma- ceutically acceptable salt thereof are administered to the subject within a 48-hour period. In some embodiments, carboplatin is administered to the subject before the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject, if both carboplatin and the compound of formula (I) or a pharma- ceutically acceptable salt thereof are administered to the subject within a 24-hour period.

[0106] Between the administration of carboplatin (first) and the compound of formula (I) or a pharma- ceutically acceptable salt thereof (second), there may be, for example, a pause of at least about 30 minutes, such as at least about 1 hour, for example at least about 2 hours, such as at least about 4 hours, for example at least about 24 hours, such as up to about 4 hours, for example up to about 6 hours, for example up to about 12 hours, such as 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] Thus, in some embodiments, carboplatin is administered to the subject at least about 30 minutes before the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject. In some embodiments, carboplatin is administered to the subject at least about 1 hour before the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject. In some embodiments, carboplatin is administered to the subject at least about 4 hours before the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject. In some embodiments, carboplatin is administered to the subject at least about 24 hours before the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject.

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

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

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

[0111] In some embodiments, carboplatin is administered to the subject before the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject, and the neoplastic disease to be treated is breast cancer, e.g., triple-negative breast cancer, or ovarian cancer.

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

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

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

[0115] In some embodiments, carboplatin is administered to the subject about 30 minutes to about 24 hours before the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject, where both carboplatin and the compound of Formula (I) or a pharma- ceutically acceptable salt thereof are administered to the subject within a 48 hour period, and the neoplastic disease to be treated is breast cancer, e.g., triple-negative breast cancer, or ovarian cancer.

[0116] The possibility of administering carboplatin prior to the compound of formula (I) or a pharma- ceutically acceptable salt thereof, as described above, applies particularly to the embodiments described in Tables A, B, C and D.

[0117] Generally, the compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin are administered at doses that do not exceed the maximum tolerated dose (MTD) for the particular mode of administration and indication, as determined in a clinical dose escalation study.

[0118] formulation The compound of formula (I) or its pharmaceutically acceptable salt and carboplatin can be provided as a combined pharmaceutical, but each is usually provided as a single pharmaceutical.Separate pharmaceutical compositions have many advantages, for example, to allow different dosing schedules, different dosages and / or different administration routes for each compound.When provided as a single pharmaceutical, the combination can be for separate, simultaneous or sequential administration.

[0119] The compounds of the present invention may be formulated as pharmaceutical compositions for non-parenteral administration, such as nasal, buccal, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ocular, aural, or in particular for oral administration, e.g. in the form of oral solid dosage forms, e.g. granules, pellets, powders, tablets, film-coated or dragees, effervescent tablets, hard and soft gelatin or HPMC capsules, orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or in the form of solutions, lipid emulsions or suspensions, e.g. containing microparticles or nanoparticles, for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural, to mammals, in particular humans. Liposomal formulations provide a convenient way to co-formulate compounds with different solubilities (see, e.g., Bulbake et al.Pharmaceutics 2017,9(2):12). The composition may comprise the active ingredient(s) alone or, preferably, together with a pharmaceutically acceptable carrier.

[0120] Pharmaceutical compositions can be processed with pharma- ceutical inert inorganic or organic excipients for the preparation 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, glidants, such as talc, stearic acid or its salts, flowing agents, such as fumed silica, can be used as such excipients for the formulation and preparation 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 are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.

[0121] Suitable excipients for the preparation of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, saccharose, invert sugar, glucose, etc. Suitable excipients for parenteral preparations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants, etc. In addition, pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for changing osmotic pressure, buffers, masking agents or antioxidants. Pharmaceutical preparations can also contain other therapeutically valuable substances.

[0122] Pharmaceutical compositions suitable for injection use include sterile aqueous solutions (if water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor® EL, or phosphate buffered saline (PBS). The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof. For intravenous injection of strongly lipophilic molecules, it can be advantageous to include in the formulation a solubilizing agent, such as a surfactant, a polymeric surfactant, a polymer, a complexing agent, and / or a cosolvent, which can significantly increase the solubility of the compound in water. Examples of solubilizing agents include polyethylene glycol, propylene glycol, ethanol, glycerol, and cyclodextrin (e.g., sulfobutylether-β-cyclodextrin).

[0123] In some embodiments, the compound of formula (I) as a free base is provided in a pharmaceutical composition comprising β-cyclodextrin, e.g., for intravenous administration. The β-cyclodextrin can be sulfobutylether-β-cyclodextrin, e.g., CAS 182410-00-0, e.g., Captisol™ (Ligand) or Dexolve™ (Cyclolab).

[0124] Sterile injectable solution can be prepared by incorporating active compound in the required amount in suitable solvent with one or combination of above-listed components as required, followed by filtration sterilization.Generally, dispersion is prepared by incorporating active compound in sterile vehicle that contains dispersion medium and other components required from above-listed.In the case of sterile powder for preparing sterile injectable solution, the method of preparation is vacuum drying and freeze-drying, which produces powder of active ingredient plus any additional desired components from their solution that has been previously sterilized and filtered.

[0125] Additionally, the pharmaceutical compositions used in the present invention optionally include buffers such as phosphate, citrate or other organic acids; antioxidants including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), 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 dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt forming counterions such as sodium; and / or non-ionic surfactants such as TWEEN®, PLURONICS® or PEG.

[0126] Optionally, the pharmaceutical composition contains a pharma- ceutically 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 art, such as benzyl alcohol, phenol, m-cresol, methylparaben, and propylparaben.

[0127] In some embodiments, the compound of formula (I) or a pharma- ceutically 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 pharmaceutical products, such as kits, which may include a container with a compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin, which may be provided in sufficient amounts for administration, e.g., in pharma- ceutically acceptable amounts.Thus, the kit may include multiple containers, each of which contains a pharma- ceutical effective amount of the active ingredient.Optionally, the kit may also include tools and / or devices required for administering the pharmaceutical composition(s).In addition, the kit may include additional components, such as instructions or administration schedules, for treating patients with neoplastic disease with the combination of the present invention.

[0129] Thus, in a further aspect, the present invention provides pharmaceutical products, such as kits for use in treating neoplastic disease, e.g., as described herein, in which a compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin are provided as single agent pharmaceuticals. In some embodiments, the kits further comprise instructions for their simultaneous, separate or sequential administration for use in treating neoplastic disease.

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

[0131] Paragraph 1. A pharmaceutical combination comprising: (a) a compound of formula (I) or a pharma- ceutically acceptable salt thereof; and (b) carboplatin.

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

[0133] Paragraph 3. A pharmaceutical combination according to Paragraph 1 or Paragraph 2, wherein the molar ratio of carboplatin to the compound of Formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose is from about 0.6:1 to about 250:1.

[0134] Paragraph 4. The pharmaceutical combination of Paragraph 1 or Paragraph 2, wherein the molar ratio of carboplatin to the compound of Formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose is from about 1.4:1 to about 32:1.

[0135] Paragraph 5. The pharmaceutical combination of Paragraph 1 or Paragraph 2, wherein the molar ratio of carboplatin to the compound of Formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose is from about 3.3:1 to about 14:1.

[0136] Paragraph 6. A method for treating a neoplastic disease in a subject, particularly a human, in need thereof, comprising administering to said subject a therapeutically effective amount of a pharmaceutical combination according to any one of Paragraphs 1 to 5.

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

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

[0139] Paragraph 9. The method of Paragraph 6, wherein carboplatin is administered to said subject at least about 1 hour before the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to said subject.

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

[0141] Paragraph 11. The method of Paragraph 6, wherein carboplatin is administered to the subject from about 30 minutes to about 24 hours before the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is administered to the subject, where both carboplatin and the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, are administered to the subject within a 48 hour period.

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

[0143] Paragraph 13. The method of any one of Paragraphs 6 to 12, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin are administered to the subject according to a three week treatment cycle (preferably the same three week treatment cycle), wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered during week 1 of the treatment cycle, followed by a two week rest week, and wherein the carboplatin is administered during week 1 of the treatment cycle, followed by a two week rest week.

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

[0145] Paragraph 15. The method of any one of Paragraphs 6 to 12, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin are administered to said subject according to a 3 week treatment cycle (preferably the same 3 week treatment cycle), wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in weeks 1 and 2 of said treatment cycle, with week 3 being a rest week, and wherein carboplatin is administered in week 1 of said treatment cycle, followed by a 2 week rest week.

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

[0147] Paragraph 17. The method of any one of Paragraphs 6 to 16, wherein the molar ratio of carboplatin to the compound of Formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose is from about 0.6:1 to about 250:1.

[0148] Paragraph 18. The method of any one of Paragraphs 6 to 16, wherein the molar ratio of carboplatin to the compound of Formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose is from about 3.3:1 to about 14:1.

[0149] Paragraph 19. The method of any one of Paragraphs 6 to 16, wherein the molar ratio of carboplatin to the compound of Formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose is from about 3.3:1 to about 14:1.

[0150] Paragraph 20. The method of any one of Paragraphs 6 to 16, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) from about 5 mg to about 480 mg per week during the week in which it is administered.

[0151] Paragraph 21. The method of any one of Paragraphs 6 to 16, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 40 mg to about 200 mg per week during the week in which it is administered.

[0152] Paragraph 22. The method of any one of Paragraphs 6 to 16, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 80 mg to about 160 mg per week during the week in which it is administered.

[0153] Paragraph 23. The method of any one of Paragraphs 6 to 16, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 90 mg to about 130 mg per week during the week in which it is administered.

[0154] Paragraph 24. The method of any one of Paragraphs 6 to 16, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 140 mg to about 240 mg per week during the week in which it is administered.

[0155] Paragraph 25. The method of any one of Paragraphs 6 to 16, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 160 mg to about 220 mg per week during the week in which it is administered.

[0156] Paragraph 26. The method of any one of Paragraphs 6 to 16, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 180 mg to about 200 mg per week during the week in which it is administered.

[0157] Paragraph 27. The method of any one of Paragraphs 17 to 26, wherein carboplatin is administered to the patient according to the AUC4 per week for the week it is administered.

[0158] Paragraph 28. The method of any one of Paragraphs 17 to 26, wherein carboplatin is administered to the patient according to the AUC5 per week for the week it is administered.

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

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

[0161] Paragraph 31. The neoplastic disease is selected from the group consisting of epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, skin adnexal neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal, lobular and medullary neoplasms, acinar cell neoplasms, composite epithelial neoplasms, specialized glandular neoplasms, paragangliomas and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, composite mixed and stromal neoplasms, fibroepithelial neoplasms, synovial neoplasms, and fibroblastic neoplasms. 31. The method of any one of paragraphs 6 to 30, wherein the cancer is selected from the group consisting of neoplasms, mesothelial neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesonephromas, vascular tumors, lymphatic tumors, osseous and cartilaginous neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepithelioma neoplasms, meningiomas, neurilemmomas, granular cell tumors and alveolar soft part sarcomas, Hodgkin's and non-Hodgkin's lymphomas, other lymphoreticular neoplasms, plasma cell neoplasms, 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 said 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 of any one of Paragraphs 6 to 32, wherein said neoplastic disease is cancer.

[0164] Paragraph 34. The method of paragraph 33, wherein the cancer relating to the affected organ and body part is selected from brain, breast (including triple negative breast cancer), cervix, ovary, 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 testis.

[0165] Paragraph 35. The method of 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, 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 of Paragraph 33, wherein the cancer is breast cancer, such as triple negative breast cancer.

[0167] Paragraph 37. The method of Paragraph 33, wherein said cancer is ovarian cancer.

[0168] Paragraph 38. A method for treating a neoplastic disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, said subject being or will be undergoing treatment with carboplatin.

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

[0170] Paragraph 40. A 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 in need thereof, comprising administering a therapeutically effective amount of carboplatin to said subject, said subject being or will be undergoing treatment with a compound of formula (I) or a pharma- ceutical acceptable salt thereof.

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

[0173] Paragraph 43. A 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 pharmaceutical combination according to any one of Paragraphs 1 to 5 for use in the treatment of a neoplastic disease in a subject, particularly a human.

[0175] Paragraph 45. A pharmaceutical combination for use according to Paragraph 44, wherein carboplatin is administered to said subject before the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to said subject.

[0176] Paragraph 46. A pharmaceutical combination for use according to Paragraph 44, wherein carboplatin is administered to said subject at least about 30 minutes before the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to said subject.

[0177] Paragraph 47. A pharmaceutical combination for use according to Paragraph 44, wherein carboplatin is administered to said subject at least about 1 hour before the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to said subject.

[0178] Paragraph 48. A pharmaceutical combination for use according to Paragraph 44, wherein carboplatin is administered to said subject at least about 4 hours before the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to said subject.

[0179] Paragraph 49. A pharmaceutical combination for use according to Paragraph 44, wherein carboplatin is administered to said subject from about 30 minutes to about 24 hours before said compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to said subject, where both carboplatin and the compound of formula (I) or a pharma- ceutically acceptable salt thereof are administered to said subject within a 48 hour period.

[0180] Paragraph 50. A pharmaceutical combination for use according to any one of Paragraphs 44 to 49, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin are administered intravenously to said subject.

[0181] Paragraph 51. A pharmaceutical combination for use according to any one of Paragraphs 44 to 50, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin are administered to said subject according to a 3 week treatment cycle (preferably the same 3 week treatment cycle), wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered during week 1 of said treatment cycle, followed by a 2 week rest week, and wherein carboplatin is administered during week 1 of said treatment cycle, followed by a 2 week rest week.

[0182] Paragraph 52. A pharmaceutical combination for use according to Paragraph 51, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on day 1 of said treatment cycle and carboplatin is administered on day 1 of said treatment cycle.

[0183] Paragraph 53. A pharmaceutical combination for use according to any one of Paragraphs 44 to 50, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin are administered to said subject according to a 3 week treatment cycle (preferably the same 3 week treatment cycle), wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in weeks 1 and 2 of said treatment cycle, week 3 being a drug-free week, and wherein carboplatin is administered in week 1 of said treatment cycle, followed by a 2 week drug-free week.

[0184] Paragraph 54. A pharmaceutical combination for use according to Paragraph 53, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on day 1 of said treatment cycle, and carboplatin is administered on days 1 and 8 of said treatment cycle.

[0185] Paragraph 55. A pharmaceutical combination for use according to any one of Paragraphs 44 to 54, wherein the molar ratio of carboplatin to the compound of formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose is from about 0.6:1 to about 250:1.

[0186] Paragraph 56. The pharmaceutical combination for use according to any one of Paragraphs 44 to 54, wherein the molar ratio of carboplatin to the compound of formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose is from about 3.3:1 to about 14:1.

[0187] Paragraph 57. The pharmaceutical combination for use according to any one of Paragraphs 44 to 54, wherein the molar ratio of carboplatin to the compound of formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose is from about 3.3:1 to about 14:1.

[0188] Paragraph 58. A pharmaceutical combination for use according to any one of Paragraphs 44 to 54, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) from about 5 mg to about 480 mg per week during the week in which it is administered.

[0189] Paragraph 59. A pharmaceutical combination for use according to any one of Paragraphs 44 to 54, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 40 mg to about 200 mg per week during the week in which it is administered.

[0190] Paragraph 60. A pharmaceutical combination for use according to any one of Paragraphs 44 to 54, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 80 mg to about 160 mg per week during the week in which it is administered.

[0191] Paragraph 61. A pharmaceutical combination for use according to any one of Paragraphs 44 to 54, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 90 mg to about 130 mg per week during the week in which it is administered.

[0192] Paragraph 62. A pharmaceutical combination for use according to any one of Paragraphs 44 to 54, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 140 mg to about 240 mg per week during the week in which it is administered.

[0193] Paragraph 63. A pharmaceutical combination for use according to any one of Paragraphs 44 to 54, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 160 mg to about 220 mg per week during the week in which it is administered.

[0194] Paragraph 64. A pharmaceutical combination for use according to any one of Paragraphs 44 to 54, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 180 mg to about 200 mg per week during the week in which it is administered.

[0195] Paragraph 65. A pharmaceutical combination for use according to any one of Paragraphs 58 to 64, wherein carboplatin is administered to the patient according to the AUC4 per week in the week it is administered.

[0196] Paragraph 66. A pharmaceutical combination for use according to any one of Paragraphs 58 to 64, wherein carboplatin is administered to the patient according to the AUC5 per week in the week it is administered.

[0197] Paragraph 67. A pharmaceutical combination for use according to any one of Paragraphs 58 to 64, wherein carboplatin is administered to the patient according to the AUC6 per week in the week it is administered.

[0198] Paragraph 68. A pharmaceutical combination for use according to any one of Paragraphs 44 to 67, wherein said neoplastic disease is a solid tumor.

[0199] Paragraph 69. The neoplastic disease is selected from the group consisting of epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, skin adnexal neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized glandular 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, fibroblastic neoplasms, myxomatous ... 69. The pharmaceutical combination for use according to any one of paragraphs 44 to 68, selected from the group consisting of skin neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesonephromas, vascular tumors, lymphatic tumors, osseous and cartilaginous neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepithelioma neoplasms, meningiomas, neurilemmomas, granular cell tumors and alveolar soft part sarcomas, Hodgkin's and non-Hodgkin's lymphomas, other lymphoreticular neoplasms, plasma cell neoplasms, mast cell tumors, immunoproliferative disorders, leukemias, various myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.

[0200] Paragraph 70. A pharmaceutical combination for use according to any one of Paragraphs 44 to 69, wherein said 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 pharmaceutical combination for use according to any one of Paragraphs 44 to 70, wherein said neoplastic disease is cancer.

[0202] Paragraph 72. A pharmaceutical combination for use according to Paragraph 71, wherein the cancer relating to the organ and part of the body affected is selected from brain, breast (including triple negative breast cancer), cervix, ovary, 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, haematological malignancies (such as lymphoma, leukemia, myeloma or lymphoid malignancies), bile duct, bladder, urinary tract, kidney, skin, thyroid, head, neck, prostate and testicles.

[0203] Paragraph 73. A pharmaceutical combination for use according to Paragraph 71, wherein said 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, 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, leukemias such as acute myeloid leukemia (AML) (including complex karyotype AML) and malignant mesothelioma.

[0204] Paragraph 74. A pharmaceutical combination for use according to Paragraph 71, wherein said cancer is breast cancer, such as triple negative breast cancer.

[0205] Paragraph 75. A pharmaceutical combination for use according to Paragraph 71, wherein said cancer is ovarian cancer.

[0206] Paragraph 76. A compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in combination with carboplatin for the treatment of a neoplastic disease in a subject, particularly a human.

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

[0208] Paragraph 78. A compound of formula (I) or a pharma- ceutically acceptable salt thereof for use according to paragraph 76 or paragraph 77, wherein said neoplastic disease is as defined in any one of paragraphs 68 to 75.

[0209] Paragraph 79. Carboplatin for use in combination with a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the treatment of a neoplastic disease in a subject, particularly a human.

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

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

[0212] Paragraph 82. Use of a pharmaceutical combination according to any one of Paragraphs 1 to 5 in the preparation of a single medicament or a combination medicament for the treatment of a neoplastic disease in a subject, particularly a human.

[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 according to Paragraph 82 or Paragraph 83, wherein the neoplastic disease is as defined in any one of Paragraphs 68 to 75.

[0215] Paragraph 85. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the preparation of a single agent medicament for use in combination with carboplatin or in the preparation of a combination medicament with carboplatin, for the treatment of a neoplastic disease in a subject, particularly a human.

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

[0217] Paragraph 87. The use according to Paragraph 85 or Paragraph 86, wherein the neoplastic disease is as defined in any one of Paragraphs 68 to 75.

[0218] Paragraph 88. Use of carboplatin in the preparation of a single agent medicament for use in combination with a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or in the preparation of a combination medicament with a compound of formula (I) or a pharma- ceutically acceptable salt thereof, for the treatment of a neoplastic disease in a subject, particularly a human.

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

[0220] Paragraph 90. The use according to Paragraph 88 or Paragraph 89, wherein the neoplastic disease is as defined in any one of Paragraphs 68 to 75.

[0221] Paragraph 91. A kit comprising a pharmaceutical combination according to any one of Paragraphs 1 to 5, wherein component (a) and component (b) are provided as single pharmaceutical agents.

[0222] Paragraph 92. A kit according to Paragraph 91, wherein the kit is for use in treating a neoplastic disease, in particular as defined in any one of Paragraphs 68 to 75.

[0223] Paragraph 93. A kit according to Paragraph 91 or Paragraph 92, further comprising instructions for the simultaneous, separate or sequential administration thereof for use in the treatment of a neoplastic disease, particularly cancer, in a subject, particularly a human.

[0224] Several publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which it pertains. Each of these references is incorporated by reference in its entirety into this disclosure to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

[0225] Certain embodiments of the present invention are described in the following examples which serve to more fully illustrate the present invention and should not be construed as limiting the invention in any way.

[0226] Working Example method Kinase assay A radiometric protein kinase assay (33PanQinase® Activity Assay) was used to measure the kinase activity of TTK and PLK1. 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) and 10 μL of ATP solution (in water), 5 μL of test compound and 10 μL of enzyme / substrate mixture. Protein kinase assays contained 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3 mM MnCl2, 3 μM Na 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 a BeckmanCoulter / SAGIAN™ Core System. The fitting model for IC50 determination was "sigmoidal response (variable slope)" with the parameters "highest" fixed at 100% and "lowest" fixed at 0%. The fitting method used was least squares fitting.

[0227] Target residence time assay The affinity of the compounds of formula (I) for TTK and PLK1, i.e., the equilibrium dissociation constant (KD) (referred to as residence time), was determined using recombinantly expressed TTK kinase domain (amino acids 519-808) or biotinylated PLK1 using a Biacore T200™ surface plasmon resonance instrument. 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. Subsequent single cycle kinetic assays were performed at 22 °C using compound concentration gradients of 1, 3.6, 10, 31.6 and 100 nM for TTK and 10, 31.6, 100, 316 and 1000 nM for PLK1, a contact time of 100 s and a flow rate of 30 µL / min. Dissociation times were 1200-1800 s and corrections for the unstable surface were performed using blank runs with buffer. Binding kinetics were calculated based on the binding curves and demonstrated good signal-to-noise ratios for all compounds tested (data not shown).

[0228] PDX research In the first PDX study, tumor fragments (3 x 3 x 3 mm) from stock mice, BR1282, bearing patient-derived xenograft (PDX) triple-negative breast cancer (TNBC) tumors were inoculated subcutaneously (sc) into the right flank of female BALB / c nude mice (CrownBio) weighing at least 20 g. When the mean tumor size was 150-200 mm3, they were randomly assigned to five different treatment groups (8 mice per group). Mice were administered intravenously (iv) with 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, with compound of formula (I) administered after carboplatin using either a 4-h or 24-h interval when both compounds were administered on the same / consecutive days. A fifth group received both vehicles with a 4 hour time interval, and all groups were dosed twice via the tail vein. Dosing was delayed for one day in any mice showing a transient weight loss of 10% or more at any time point.

[0229] The second PDX study used the same model as the first study (TNBC BR1282 PDX model), but this time, compound of formula (I) (8 mg / kg, iv, qw, 5 mL / kg) was administered first, carboplatin (60 mg / kg, iv, qw, 6 mL / kg) was administered second, with a 4 hour interval between both doses, and compound of formula (I) was given qw, such that mice received both compounds on the same day (4 hour interval).

[0230] Carboplatin was purchased as a solution (10 mg / mL in 5% (w / v) glucose in pure water) from Qilu Pharmaceutical Co. Ltd. Compound of formula (I) was supplied as a powder by Basilea Pharmaceutica International Ltd. and prepared immediately before use as a solution in ethanol:PEG400:citric acid 20 mM 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 weekly, the latter by measuring two dimensions with calipers and applying the formula "V = (L × W2) / 2," where V is the tumor volume, and L and W are the length and width of the tumor, respectively. Individual mice were sacrificed when tumors reached 1500 mm3 or greater or when body weight loss (BWL) was evident above 20%. Mice were also sacrificed if the BWL was determined to be >15% for three consecutive days. Any mice with a BWL of >10% were automatically dosed on one of the subsequent days as soon as the BWL returned to <10%. All animal protocols were reviewed and approved by the relevant local committees in China, where the study was conducted.

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

[0233] result TTK and PLK1 are kinases that play an essential role in regulating the spindle assembly checkpoint (SAC), a cell cycle surveillance mechanism that ensures optimal cell division through proper chromosome alignment. TTK and PLK1 cooperate to recruit SAC components to the SAC protein complex at the centromeres of chromosomes, so 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 to be true in tumor cell lines when comparing the compound of formula (I) with TKK inhibitors that do not have significant PLK1 inhibitory activity (data not shown).

[0234] In general, the compounds of formula (I) show strong specificity for TTK, with IC50s for other kinases at least 10-fold higher than the IC50 for TTK. The above TTK kinase assay confirmed that the compounds of formula (I) are highly potent for TTK, giving an IC50 of 7 nM (0.4 nM when measured as described in WO2015 / 155042).

[0235] The above PLK1 kinase assay 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 WO 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 or no activity for PLK1 compared to their activity for TTK (data not shown). Importantly, the compound of formula (I) has an extremely long target retention for TTK of more than 12 hours, but only a few minutes for PLK1. This long-term inhibition of TTK, combined with the transient effect on PLK1, led to the rapid destruction of the SAC, leaving cells with insufficient time for correct chromosome segregation.

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

[0237] In cell lines, the compound of formula (I) has high potency against sensitive cells. In a 5-day anti-proliferative screening of 18 different triple-negative breast cancer cell lines, the compound of formula (I) has a median GI50 of 35nM. In mice, the compound of formula (I) shows 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 a standard treatment in numerous oncology indications. To determine the combined efficacy of the compound of formula (I) with carboplatin, we first defined the maximum tolerated dose (MTD) of the compound of formula (I) in combination with an optimal dose of carboplatin 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 highest tolerated dose of the compound of formula (I) administered intravenously, 2 qw, in combination with the optimal dose of carboplatin was 6-7 mg / kg using the schedule described above. 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. For this reason, 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 both doses or a 2qw schedule of the compound of formula (I) was not tolerated, 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 bearing BR1282 PDX TNBC tumors were treated with 60 mg / kg qw iv carboplatin and 7 mg / kg 2 qw iv of the compound of formula (I) (4 or 24 hours later when administered on the same or consecutive days). This model was chosen because it was known to have an intermediate response to the compound of formula (I) and a minimal response to carboplatin. As previously shown, single agent treatment with either compound was well tolerated with little or no weight loss (Figure 1B). Furthermore, both combination regimens were well tolerated, although some individual mice had transient weight loss. Individual mice with weight loss greater than 10% were treated one day later than scheduled to allow for recovery. The 24-hour interval group tolerated the combination slightly better than the 4-hour interval group, with the latter experiencing a greater loss in weight within one week of treatment initiation.

[0240] Both combination regimens resulted in reduced tumor growth similar to that observed with the compound of formula (I) alone, whereas little effect on tumor growth was observed with carboplatin alone (Figures 1A and 2). A Clark's Combination Index (CCI) of approximately 0.1 on day 10 of treatment within this study demonstrated a trend toward additivity in both combination groups. At that time point, none of the comparisons are significantly different from each other by using ΔT / C (Table 1). Furthermore, the treatment is well tolerated, as the weight changes on day 10 in the compound treatment groups are not statistically different between groups (p>0.05; Table 1). Treatment of the combination group could not be extended beyond 31 days due to damage to the tail vein as a result of repeated intravenous administration. An exponential curve fit from day 0 to the sacrifice date for each group (most recent day 31) provided more statistical power and showed a much stronger effect, such that both combination groups were highly significantly different to carboplatin monotherapy, but not significantly different to compound of formula (I) monotherapy (Figure 3 and Tables 1 and 2), with the CCI showing additivity (CCI=0.02) for the 4 hr combination group and antagonism (CCI=0.16) for the 24 hr combination group.

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

[0242] [Table 5]

[0243] Table 2 presents a summary of the statistical analysis of the mean proliferation rates (k) from FIG. 3 for each individual comparison based on one-way analysis of variance (1WA) with Holm-Sidak post-hoc test for group comparison. [Table 6]

[0244] In a second combination study of the same model, 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, vehicle control and compound-treated, reached the ethical endpoint on day 14. At that time, it was apparent that only the compound of formula (I) group had a level of efficacy (Figures 4A, 5 and 6, Table 3), but this was not statistically significant (all comparisons p>0.05). After exponential growth, the differences between groups were still not statistically significant (Table 3). The CCI showed a negative interaction, also called antagonism, with a value of 0.42. Overall, there was no significant difference in body weight change in the treated groups compared to the vehicle group on day 14, and the treatment was well tolerated (Figure 4B and Table 3). In conclusion, when mice are given the compound of formula (I) first and then carboplatin 4 hours later, antagonism occurs, in contrast to the additive effect observed in the first study, where carboplatin was applied 4 hours before the compound of formula (I).Therefore, it is crucial to treat first with carboplatin and then with the compound of formula (I) in order to obtain at least the additive effect.

[0245] [Table 7]

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

[0247] The antitumor activity of compounds 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 above experiments, the maximum tolerated dose (MTD) of the compound of formula (I) in combination with an 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 the present study, using a human ovarian cell line-derived xenograft (CDX) model, we applied that schedule and directly compared it to the same administration sequence with either a 1-hour or 24-hour interval between the compounds. Furthermore, we compared the twice-weekly schedule using a 4-hour interval with a once-weekly schedule of 7 mg / kg BAL0891 (a weekly dose well below the MTD of the compound of formula (I) monotherapy). Treatment was continued until day 24, and tumor volumes and body weights were monitored until day 51.

[0249] The complete experiment, showing mean ± SEM (n=8) for efficacy (TVol) and tolerability (BW), where mice were sacrificed starting on day 23 when individual tumors reached at least 1500 mm3, is shown in Figure 7. For this reason, the chosen endpoint for efficacy T / C comparison was day 23 (Figures 8, 9, Table 5). Individual plots for each tumor are also shown in Figure 10 along with exponential fits to tumor growth. [Table 9]

[0250] ΔT / C showed only slight anticancer effects for the three different monotherapies, each of which was significantly different from the vehicle group at day 23 (p<0.05). However, all combinations showed highly significant differences against the vehicle (p<0.001), although the combination of carboplatin and the compound of formula (I) administered once a week was clearly the least effective (ΔT / C=0.46). Nevertheless, multiple comparisons (one-way ANOVA) showed no significant differences between the combinations at this time point. Based on ΔT / C on day 23, the most effective combination was carboplatin combined with the compound of formula (I) (2qw) using an interval of 1 hour or 4 hours between treatments (carboplatin always first), and indeed in each of these two groups there was one tumor that had completely regressed. This was confirmed at day 51 by immunohistochemistry (IHC), where no tumor cells could be seen. Assessment of synergy by Clark Combination Index (CCI) showed synergy for three combinations (1, 4 or 24 hour intervals) with BAL0891 administered twice weekly, whereas a once weekly BAL0891 schedule only conferred additivity (Table 5).

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

[0252] In conclusion, in nude mice bearing subcutaneous human ovarian tumors SKOV-3, the combination of carboplatin (60 mg / kg, iv, qw) administration followed by the compound of formula (I) (7 mg / kg, i.v., 2 qw) was well tolerated and showed synergistic efficacy. The most effective combination was carboplatin combined with the compound of formula (I) (2 qw) using either a 1-hour or 4-hour interval between treatments. In fact, in each of these two groups, there was one tumor that completely regressed. Evaluation of synergy by Clark Combination Index (CCI) showed synergy for the three combinations (1, 4 or 24-hour interval) using the compound of formula (I) administered twice weekly. However, the low-dose, once-weekly schedule of the compound of formula (I) only gave additivity.

Claims

1. (a) A compound of formula (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof; (b) carboplatin; 23. A pharmaceutical combination comprising:

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

1.

3. 3. A pharmaceutical combination according to claim 1 or claim 2 for use in the treatment of a neoplastic disease in a subject, particularly a human.

4. 4. The pharmaceutical combination for use according to claim 3, wherein carboplatin is administered to said subject before said compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to said subject.

5. 4. The pharmaceutical combination for use according to claim 3, wherein carboplatin is administered to said subject up to 24 hours before said compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to said subject, where both carboplatin and said compound of formula (I) or a pharma- ceutically acceptable salt thereof are administered to said subject within a 48 hour period.

6. 4. The pharmaceutical combination for use according to claim 3, wherein carboplatin is administered to said subject up to 6 hours before said compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to said subject, where both carboplatin and said compound of formula (I) or a pharma- ceutically acceptable salt thereof are administered to said subject within a 24 hour period.

7. 4. The pharmaceutical combination for use according to claim 3, wherein carboplatin is administered to said subject from about 30 minutes to about 24 hours before said compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to said subject, where both carboplatin and said compound of formula (I) or a pharma- ceutically acceptable salt thereof are administered to said subject within a 48 hour period.

8. said compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin are administered to said subject according to a three week treatment cycle; the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered during week 1 of the treatment cycle, followed by a two-week drug holiday, and carboplatin is administered during week 1 of the treatment cycle, followed by a two-week drug holiday; or said compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in weeks 1 and 2 of said treatment cycle, with week 3 being a drug-free week; and carboplatin is administered in week 1 of said treatment cycle, followed by a two-week drug-free week; Preferably, in each case, said compound of formula (I) or a pharma- ceutically acceptable salt thereof and carboplatin are administered to said subject according to the same three-week treatment cycle. A pharmaceutical combination for use according to any one of claims 3 to 7.

9. 9. The pharmaceutical combination for use according to any one of claims 3 to 8, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 40 mg to about 200 mg per week during the week in which it is administered.

10. 9. The pharmaceutical combination for use according to any one of claims 3 to 8, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 80 mg to about 160 mg per week during the week in which it is administered.

11. 9. The pharmaceutical combination for use according to any one of claims 3 to 8, wherein carboplatin is administered to the patient at a dose according to AUC5 per week in the week it is administered, or carboplatin is administered to the patient at a dose according to AUC6 per week in the week it is administered.

12. The neoplastic disease may be selected from the group consisting of epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, skin adnexal neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized glandular 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, and fibroblastic neoplasms.

12. The pharmaceutical combination for use according to any one of claims 3 to 11, selected from the group consisting of neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesonephromas, vascular tumors, lymphatic tumors, osseous and cartilaginous neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepithelioma neoplasms, meningiomas, neurilemmomas, granular cell tumors and alveolar soft part sarcomas, Hodgkin's and non-Hodgkin's lymphomas, other lymphoreticular neoplasms, plasma cell neoplasms, mast cell tumors, immunoproliferative diseases, leukemias, myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.

13. The pharmaceutical combination for use according to any one of claims 3 to 12, wherein said neoplastic disease is a neoplastic disease treatable by inhibition of PLK1 in addition to treatment with carboplatin and a TTK inhibitor.

14. 14. The pharmaceutical combination for use according to any one of claims 3 to 13, wherein said neoplastic disease is cancer, in particular 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, 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.

15. The pharmaceutical combination for use according to any one of claims 3 to 13, wherein said neoplastic disease is breast cancer.

16. The pharmaceutical combination for use according to any one of claims 3 to 13, wherein said neoplastic disease is triple negative breast cancer.

17. The pharmaceutical combination for use according to any one of claims 3 to 13, wherein said neoplastic disease is a cancer treatable with carboplatin.

18. 14. The pharmaceutical combination for use according to one of claims 3 to 13, wherein said neoplastic disease is ovarian cancer (e.g. advanced ovarian epithelial cancer, 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 progressive or recurrent glioma, medulloblastoma such as recurrent medulloblastoma), neuroblastoma, testicular cancer, bladder cancer, retinoblastoma, breast cancer (e.g. metastatic breast cancer), endometrial cancer, e.g. advanced or recurrent endometrial cancer).

19. The pharmaceutical combination for use according to any one of claims 3 to 13, wherein said neoplastic disease is ovarian cancer.

20. 2. A compound of formula (I) as claimed in claim 1 or a pharma- ceutically acceptable salt thereof for use in combination with carboplatin for the treatment of a neoplastic disease in a subject, particularly a human.

21. 2. Carboplatin for use in combination with a compound of formula (I) as defined in claim 1 or a pharma- ceutically acceptable salt thereof for the treatment of a neoplastic disease in a subject, particularly a human.

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