Useful Combinations of Sarcoma Treatment Methods

Abstract

One aspect described herein includes a method of treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of a small molecule compound. More specifically, another aspect described herein includes a method of treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of a small molecule compound described herein in combination with a chemotherapeutic agent.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 825,017, filed on March 27, 2019, the contents of which are incorporated herein by reference. Technical Field

[0003] Described herein are methods for treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of a small molecule compound. More specifically, described herein are methods for treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of a small molecule compound alone or in combination with a chemotherapeutic agent. Background Art

[0004] Soft tissue sarcoma (STS) is a cancer that originates from mesenchymal tissues such as smooth muscle (uterus, stomach, small intestine, retroperitoneum, blood vessels and skin), tendons, fat, lymphatic vessels, vascular tissue and nerves, as well as cartilage and other tissues around joints. Although it only accounts for about 1% of the total number of newly discovered cancers each year, about 15,000 new cases of sarcoma are diagnosed in the United States each year. Leiomyosarcoma is more common, accounting for about 5-10% of all soft tissue sarcomas. Among the examples of sarcomas, invasive, locally recurrent, unresectable and metastatic recurrent / refractory leiomyosarcoma (LMS) accounts for about 24% of these sarcomas.

[0005] Standard of care (SOC) for treating sarcomas includes surgery, radiation therapy, and chemotherapy. However, there have been few advances in the treatment of aggressive LMS. First-line treatment includes or (doxorubicin), with or without (ifosfamide), and (gemcitabine) and The cytotoxic drug trabectedin and the angiogenic receptor tyrosine kinase inhibitor pazopanib have recently been approved for second-line or later treatment of LMS, with no clear improvement in overall survival (OS) but providing a progression-free survival (PFS) benefit of several months (van der Graaf 2012, Demetri 2016).

[0006] Dacarbazine is widely used in the treatment of soft tissue sarcoma and is often used as a late-line treatment. The response rates of LMS obtained are about 10%.

[0007] Based on the modest improvement in short-term response rates with the combination of trabectedin and pazopanib, dacarbazine remains a relevant option for LMS therapy despite its low response rate. Therefore, LMS represents a relatively common sarcoma subtype that warrants new clinically effective chemotherapeutic agents or combinations thereof. Summary of the invention

[0008] One aspect described herein is a method of treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective amount of 5-fluoro-2-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-N-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-1H ... 4 -[4-(Trifluoromethyl)phenyl]pyrimidine-4,6-diamine:

[0009]

[0010] or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0011] Another aspect described herein is a method of treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with an effective dose of at least one chemotherapeutic agent.

[0012] One aspect described herein is the use of Compound 1, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, for treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of Compound 1, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0013] Another aspect described herein is the use of Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with an effective dose of at least one chemotherapeutic agent.

[0014] One aspect described herein is the use of Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of the medicament.

[0015] Another aspect described herein is the use of Compound 1 in the preparation of a medicament for treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective amount of said medicament in combination with an effective amount of at least one chemotherapeutic agent.

[0016] In one aspect, the chemotherapeutic combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is selected from (dacarbazine), (docetaxel), or (Adriamycin), (liposomal doxorubicin), gemcitabine, epirubicin, eribulin, ifosfamide, temozolomide, trabectedin, and (vincristine) group.

[0017] In another aspect, the chemotherapy combination treatment comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is selected from the group consisting of dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin, gemcitabine, epirubicin, eribulin, ifosfamide, temozolomide, trabectedin and vincristine.

[0018] In another aspect, the chemotherapeutic combination treatment comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is selected from the group consisting of dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin, gemcitabine, and vincristine.

[0019] In another aspect, the chemotherapeutic combination treatment comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is selected from the group consisting of dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin, and vincristine.

[0020] In another aspect, the chemotherapeutic combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is dacarbazine.

[0021] In another aspect, the chemotherapeutic combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is docetaxel.

[0022] In another aspect, the chemotherapeutic combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is doxorubicin.

[0023] In another aspect, the chemotherapeutic combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is liposomal doxorubicin.

[0024] In another aspect, the chemotherapeutic combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is vincristine. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1A and Figure 1B The combination of compound 1 and dacarbazine (DTIC) is shown, respectively, and the average tumor volume in the SK-LMS-1 mouse model is synergistically reduced after treatment with this combination compared with compound 1 alone, DTIC alone, and vehicle; wherein biw means twice a week, tiw means three times a week, and qd5 means once a day for five days. Figure 1A and Figure 1B A comparison of the results showed that the combination treatment with Compound 1 (12.5 mg / kg PO biw) and DTIC (4 mg / kg IP tiw) (see Figure 1A ) and combination treatment with Compound 1 (12.5 mg / kg PO biw) and DTIC (21 mg / kg IP qd5) (see Figure 1B ), showing a synergistic dose response in terms of mean tumor volume reduction.

[0026] Figure 2A and Figure 2B The combination of Compound 1 and docetaxel shows a synergistic reduction in mean tumor volume in the SK-UT-1 leiomyosarcoma (LMS) mouse model after treatment compared to Compound 1 alone, docetaxel alone, and vehicle, respectively; wherein biw indicates twice-weekly dosing, wherein qw6 indicates once-weekly dosing for 6 weeks. Figure 2A and Figure 2B A comparison of the results of the present study showed that the combination of Compound 1 (12.5 mg / kg PO biw) and docetaxel (5 mg / kg IP tiw, 6 doses) was effective in the treatment of Figure 2A ) and combination therapy with Compound 1 (12.5 mg / kg PO biw) and docetaxel (15 mg / kg IP qw6) (see Figure 2B ), the mean tumor growth was inhibited in a dose-dependent manner.

[0027] Figure 3A and Figure 3B The combination of compound 1 and liposomal doxorubicin (doxil) is shown, respectively, which synergistically reduces the mean tumor volume in the SK-LMS-1 mouse model after treatment compared with compound 1 alone, liposomal doxorubicin alone, and vehicle; wherein biw indicates twice-weekly dosing, and wherein qw5 indicates once-weekly dosing for 5 weeks. Figure 3A and Figure 3B The comparison showed that the combination treatment with compound 1 (12.5 mg / kg PO biw) and liposomal doxorubicin (3 mg / kg IPqw5) (see Figure 3A ) and combination therapy with Compound 1 (12.5 mg / kg PO biw) and liposomal doxorubicin (9 mg / kg IP qw5) (see Figure 3B ), the mean tumor growth was inhibited in a dose-dependent manner.

[0028] Figure 4The combination of Compound 1 and doxorubicin is shown to synergistically reduce mean tumor volume in the HT1080 fibrosarcoma mouse model following treatment compared to Compound 1 alone (15 mg / kg PO biw), doxorubicin alone (0.3 mg / kg IP q2d), and vehicle; wherein biw indicates twice weekly dosing and wherein q2d indicates daily dosing every other day.

[0029] Figure 5 The results of a Phase 1a clinical trial (NCT02404480) in all solid tumors (AST) in 31 evaluable patients were summarized, which used compound 1 alone to determine safety and pharmacokinetics. The initial human dose of 0.65mg / kg was based on the 40mg / kg dose of the rat model MTD, and the human dose was subsequently increased to 1.3mg / kg, 2.6mg / kg, 5.2mg / kg, 7mg / kg and 10mg / kg. The standard 3+3 trial design, with 3 patients per cohort, allowed dose escalation for each cohort in the absence of dose-limiting toxicity (DLT), allowing the next cohort to be treated with the next higher dose. If any patient in a cohort experienced a DLT at a specific dose, the next cohort would be treated at the same dose. A full pharmacokinetic study was conducted on each patient on days 1 and 29, and a partial study was conducted on day 15.

[0030] Fig. 6A -D summarizes the pharmacokinetics of Compound 1 administered twice weekly as monotherapy in humans in the AST trial (measured as AUC 持续 and C max The dashed line in each figure represents the free drug concentration. Fig. 6A and 6B It shows that the estimated target AUC 持续 About 13125hr-ng / mL ( Fig. 6A ), estimate the target C max About 688ng / mL ( Figure 6B ), respectively compared with human AUC and C max The doses of Compound 1 required to maintain above the predicted effective target concentration in human patients are associated with approximately 2.0 mg / kg or higher or approximately 1.4 mg / kg or higher, respectively.

[0031] Figure 6C and 6D It shows that the estimated target AUC 持续 (AUC Last ) is approximately 15,625 hr-ng / mL ( Figure 6C ), estimate the target C maxAbout 859 ng / mL ( Fig.6D ), respectively compared with human AUC and C max The doses of Compound 1 required to maintain above the predicted effective target concentration in human patients are associated with approximately 2.3 mg / kg or higher or approximately 1.8 mg / kg or higher, respectively.

[0032] Fig. 7A and Figure 7B The combination of Compound 1 and vincristine is shown to reduce mean tumor volume in the HT1080 fibrosarcoma xenograft mouse model after treatment compared to Compound 1 alone, vincristine alone, and vehicle, respectively; wherein biw indicates twice weekly dosing, wherein tiw indicates 3 weekly dosing. Fig. 7A and Figure 7B A comparison of the results showed that the combination treatment with Compound 1 (12.5 mg / kg PO biw) and vincristine (0.1 mg / kg IP tiw) (see Fig. 7A ) and combination treatment with Compound 1 (12.5 mg / kg PO biw) and vincristine (0.3 mg / kg IP tiw) (see Figure 7B ) for each drug, mean tumor growth decreased in a dose-dependent manner. DETAILED DESCRIPTION

[0033] One aspect described herein is a method of treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective amount of 5-fluoro-2-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-N-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-1H ... 4 -[4-(Trifluoromethyl)phenyl]pyrimidine-4,6-diamine:

[0034]

[0035] or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0036] Another aspect described herein is a method of treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with an effective dose of at least one chemotherapeutic agent.

[0037] One aspect described herein is the use of Compound 1, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, for treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of Compound 1, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0038] Another aspect described herein is the use of Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with an effective dose of at least one chemotherapeutic agent.

[0039] One aspect described herein is the use of Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of the medicament.

[0040] Another aspect described herein is the use of Compound 1 in the preparation of a medicament for treating a sarcoma in a subject in need thereof, comprising administering to the subject an effective amount of said medicament in combination with an effective amount of at least one chemotherapeutic agent.

[0041] In one aspect, the chemotherapeutic combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is selected from (dacarbazine), (docetaxel), or (Adriamycin), (liposomal doxorubicin), gemcitabine, epirubicin, eribulin, ifosfamide, temozolomide, trabectedin, and (vincristine) group.

[0042] In another aspect, the chemotherapy combination treatment comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is selected from the group consisting of dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin, gemcitabine, epirubicin, eribulin, ifosfamide, temozolomide, trabectedin and vincristine.

[0043] In another aspect, the chemotherapeutic combination treatment comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is selected from the group consisting of dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin, gemcitabine, and vincristine.

[0044] In another aspect, the chemotherapeutic combination therapy comprises administering Compound a1 in combination with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is selected from the group consisting of dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin and vincristine.

[0045] International Publication No. WO2014 / 081906 discloses Compound 1 and a method for preparing the same (referred to as Compound 109).

[0046] definition

[0047] As used herein, the term "approximately" refers to a range around a given value, wherein the resulting value is substantially the same as the value explicitly listed. On the one hand, "approximately" refers to within ±25% of a given value or range. For example, the phrase "approximately 70% by weight" includes at least all values ​​from 52% by weight to 88% by weight. On the other hand, the term "approximately" refers to within ±10% of a given value or range. For example, the phrase "approximately 70% by weight" includes at least all values ​​from 63% by weight to 77% by weight. On the other hand, the term "approximately" refers to within ±7% of a given value or range. For example, the phrase "approximately 70% by weight" includes at least all values ​​from 65% by weight to 75% by weight. Concentrations, quantities, cell counts, percentages, and other numerical values ​​can be expressed in range format here. It should be understood that such a range format is used only for convenience and brevity, and should be flexibly interpreted as including not only the numerical values ​​explicitly listed as limited ranges, but also all individual numerical values ​​or sub-ranges within the range, as if each numerical value and sub-range were explicitly listed.

[0048] As used herein, the terms "therapies" and "therapy" may refer to any regimen, method, composition, formulation, and / or agent that can be used to prevent, treat, manage, or ameliorate a condition or disorder, or one or more symptoms thereof (e.g., a sarcoma or one or more symptoms or one or more conditions associated therewith).

[0049] In one aspect, the terms "therapies" and "therapy" and "standard therapy" refer to one or more therapies, including drug therapy (e.g., chemotherapy) or adjuvant therapy, radiation therapy, surgical therapy, biological therapy, immunotherapy, supportive therapy, antiviral therapy, and / or other therapies that can be used to treat, manage, prevent, or ameliorate a condition or disorder or one or more symptoms thereof (e.g., a sarcoma or one or more symptoms or one or more conditions associated therewith).

[0050] On the other hand, the term chemotherapeutic agent refers to an agent used in chemotherapy to directly or indirectly inhibit the proliferation of rapidly growing cells (usually in the case of malignant tumors). According to their mechanism of action, such agents include alkylating agents, antimetabolites, topoisomerase inhibitors, mitotic inhibitors, agents that directly or indirectly affect RNA or DNA related mechanisms, etc.

[0051] On the other hand, the term "adjuvant therapy" refers to a therapy other than the use of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof as a monotherapy or a chemotherapeutic combination therapy (including the combined administration of Compound 1 and at least one chemotherapeutic agent).

[0052] As used herein, the term "subject" is used interchangeably with the term "patient," wherein one or both of the terms refer to an individual in need of a therapy to provide a beneficial or therapeutic effect of the therapy described herein. In specific aspects, the individual is a human.

[0053] In the context of administering Compound 1 to a subject with a sarcoma, as used herein, the term "effective dose" refers to a dose of Compound 1 that results in a beneficial or therapeutic effect. In one aspect, an "effective dose" of Compound 1 refers to a dose of Compound 1 sufficient to achieve at least one, two, three, four or more of the following beneficial or therapeutic effects: (i) inhibition of the sarcoma; (ii) regression of the sarcoma; (iii) eradication, elimination or complete remission of the sarcoma; (iv) prevention of the development or onset of one or more symptoms associated with the sarcoma; (v) reduction or amelioration of the severity of one or more symptoms associated with the sarcoma; (vi) reduction in the number of one or more symptoms associated with the sarcoma; (vii) improvement in the severity of one or more symptoms associated with the sarcoma; (viii) reduction in the duration of one or more symptoms associated with the sarcoma; (ix) The invention relates to the present invention to prevent the proliferation or recurrence of one or more symptoms associated with a sarcoma; (x) reduce mortality; (xi) improve the survival rate of a subject; (xii) improve the recurrence-free survival rate; (xiii) increase the number of subjects with sarcoma in remission; (xiv) reduce the number of subjects who are hospitalized for treatment; (xv) reduce the length of hospitalization; (xvi) reduce the rate of hospitalization; (xvii) improve the survival rate of a subject; (xviii) improve the symptom-free survival rate of a subject with sarcoma; (xix) prolong the length of remission of a subject with sarcoma; (xx) improve the quality of life (QOL) as assessed by methods well known in the art, such as QOL questionnaires; (xxi) improve the quality of life (QOL) of a subject who is receiving another chemotherapy Administration of Compound 1 before radiotherapy reduces proliferation; (xxii) administration of Compound 1 after treatment with another chemotherapeutic agent reduces proliferation; (xxiii) administration of Compound 1 in combination with another chemotherapeutic agent reduces proliferation; (xxiv) administration of Compound 1 in combination with another chemotherapeutic agent induces an additive anti-proliferative effect; (xxv) administration of Compound 1 in combination with another chemotherapeutic agent induces a synergistic anti-proliferative effect; (xxvi) administration of Compound 1 before radiotherapy reduces proliferation; (xxvii) administration of Compound 1 after radiotherapy reduces proliferation; (xxviii) administration of Compound 1 in combination with radiotherapy reduces proliferation; (xxix) administration of Compound 1 before surgical treatment reduces proliferation; (xxix) administration of Compound 1 in combination with radiotherapy reduces proliferation; (xxix) administration of Compound 1 before surgical treatment reduces proliferation. (xxx) reducing proliferation by administering Compound 1 in combination with surgical treatment; (xxxi) enhancing or improving the effect of therapy by administering Compound 1 and palliative therapy; (xxxii) reducing the plasma concentration of BMI-1 in a subject with sarcoma; (xxxiii) reducing circulating proliferating cells in the plasma of a subject with sarcoma; (xxxiv) altering (e.g., decreasing or increasing) the plasma concentration of a sarcoma biomarker (e.g., BMI-1, tubulin polymerization, apoptosis marker, or tissue, etc.) in a subject with sarcoma; (xxxv) reducing the concentration of BMI-1 in a biological sample (e.g., plasma, serum, urine, or any other biological fluid) of a subject with sarcoma;(xxxvi) after administration of the therapy described herein, the proliferative cell count is reduced, and the proliferative cell count is measured by conventional methods available to those skilled in the art, such as magnetic resonance imaging (MRI), dynamic contrast enhanced MRI (DCE-MRI), X-ray, computed tomography (CT) scan, positron emission tomography (PET) scan, 7-AAD fluorescence or DAPI fluorescence; (xxxvii) after administration of the therapy described herein, the proliferative cell count is maintained, and the proliferative cell count is measured by conventional methods available to those skilled in the art, such as magnetic resonance imaging (MRI), dynamic contrast enhanced MRI (DCE-MRI), X-ray, computed tomography (CT) scan, positron emission tomography (PET) scan, 7-AAD fluorescence or DAPI fluorescence; (xxxviii) after administration of the therapy described herein, the proliferative cell count does not increase or increases less than expected, and the proliferative cell count is measured by conventional methods available to those skilled in the art, such as magnetic resonance imaging (MRI), dynamic contrast enhanced MRI (DCE-MRI), X-ray, computed tomography (CT) scan, positron emission tomography (PET) scan, 7-AAD fluorescence or DAPI fluorescence.;

[0054] As used herein, the term "within 24 hours" refers to the period of time over which the condition is maintained; for example, when the average plasma concentration of Compound 1 is achieved and maintained for multiple 24-hour periods, an effective dose of Compound 1 is determined. In other words, the average plasma concentration of Compound 1 can be achieved at an appropriate time, which can be more or less than 24 hours.

[0055] As used herein, the term "therapy described herein" refers to a method of using Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof for treating or ameliorating sarcoma in a subject in need thereof, comprising administering an effective dose of Compound 1 to the subject.

[0056] In one aspect of the therapies described herein, the use or method of use of Compound 1 includes a pharmaceutically acceptable salt or pharmaceutical composition thereof. In another aspect of the therapies described herein, the use or method of use of Compound 1 includes the use or method of use of a combination of Compound 1, a pharmaceutically acceptable salt or pharmaceutical composition of Compound 1, or Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof with another chemotherapeutic agent, wherein the combination has synergistic antiproliferative activity. In another aspect, the other chemotherapeutic agent inhibits tubulin polymerization. In another aspect, the other chemotherapeutic agent inhibits BMI-1 functional activity.

[0057] As used herein, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases; for example, see Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0058] As used herein, the term "Compound 1" refers to 5-fluoro-2-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-N 4 -[4-(Trifluoromethyl)phenyl]pyrimidine-4,6-diamine or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In various aspects, the term "Compound 1" refers to Compound 109 disclosed in International Publication No. WO2014 / 081906, which is incorporated herein by reference.

[0059] How to use

[0060] Without wishing to be bound by theory, mechanistic studies suggest that compound 1 inhibits microtubule polymerization and binds to tubulin leading to G2 / M arrest, resulting in multiple cellular effects including effects on mitosis, cell cycle and apoptosis.

[0061] In one aspect, Compound 1 can be administered as a monotherapy at a dose that results in a therapeutically effective target plasma concentration.

[0062] On the other hand, Compound 1 can be administered as a combination therapy with at least one other chemotherapeutic agent at a dose that results in therapeutically effective additive or synergistic plasma concentrations. When used in combination, the use of Compound 1 significantly enhances the activity of standard chemotherapeutic agents, including dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin, gemcitabine, vincristine, and other tubulin-binding agents.

[0063] Based on these data and previous preclinical studies, Compound 1 is being evaluated in certain clinical studies, as posted on ClinicalTrials.gov, including:

[0064] NCT02404480: A Phase 1 study, open-label, first-in-human, evaluated the safety and pharmacokinetic (PK) characteristics of Compound 1 in patients with advanced solid tumor (AST) cancers and determined the RP2D (recommended Phase II clinical trial dose) based on escalating dose levels.

[0065] NCT03206645: A Phase 1b study evaluating the safety and efficacy of compound 1 in combination with standard paclitaxel and carboplatin for the treatment of ovarian cancer in women with stage III or IV epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who are receiving neoadjuvant chemotherapy.

[0066] NCT03605550: A Phase 1b study evaluating the safety and efficacy of Compound 1 in combination with radiation and chemotherapy in children newly diagnosed with diffuse intrinsic pontine glioma (DIPG) and / or high-grade glioma (HGG). Patients diagnosed with DIPG / HGG may be treated with radiation or surgery. The study will determine the dose of Compound 1 that can be administered in combination with radiation without causing severe side effects, the plasma and tumor tissue concentrations of Compound 1 before and / or during surgical resection of recurrent tumors, and possible changes in tumor biology due to treatment with Compound 1.

[0067] NCT03761095: A phase 1b study evaluating the combination of compound 1 (200 mg PO biw) and dacarbazine (DTIC) (1000 mg / m 2 The safety and efficacy of IV tiw) in the treatment of patients with advanced leiomyosarcoma and the MTD (maximum tolerated dose) were determined.

[0068] As demonstrated herein, Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof is a small molecule tubulin polymerization inhibitor for treating or ameliorating sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0069] In one aspect of the uses or methods of use described herein, the uses or methods of use of Compound 1 include a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0070] In another aspect of the uses or methods of use described herein, the uses or methods of use of Compound 1 include the uses or methods of use of Compound 1, the uses or methods of use of a pharmaceutically acceptable salt or pharmaceutical composition of Compound 1, or the uses or methods of use of a combination of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof and another chemotherapeutic agent, wherein the combination has additive or synergistic antiproliferative activity.

[0071] On the other hand, other chemotherapeutic agents inhibit tubulin polymerization. On the other hand, other chemotherapeutic agents affect DNA or DNA repair through various mechanisms.

[0072] In one aspect, the combinations described herein inhibit or reduce tubulin polymerization, which may also induce cell cycle arrest in the proliferating cells or cell lines described herein.

[0073] In another aspect, a method of inhibiting or reducing tubulin polymerization to induce cell cycle arrest in a proliferating cell or cell line comprises exposing the proliferating cell or cell line to Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In another aspect, the proliferating cell or cell line may not have been treated with a tubulin inhibitor, or may be known to be affected by inhibition or reduction of tubulin polymerization.

[0074] In another aspect, non-limiting examples of such cells or cell lines are selected from HL-60, HeLa, HT1080, HCT116, HEK293, NCI H460, U-87MG, ASPC-1, PL-45, HPAF-2, PC-3, MDA-MB-231, MDA-MB-468, A431, SNU-1, AGS, Kato III, A549, Calu-6, A375, SY5Y, SKOV3, Capan-1, sNF96.2, TIVE-L1, TIVE-L2, LNCaP cells, etc. In a more specific aspect, the cell or cell line can be a sarcoma cell.

[0075] In one aspect, a method of inhibiting or reducing tubulin polymerization in a subject with a sarcoma in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof as described herein.

[0076] In one aspect described herein, sarcomas that can be treated using the intended uses described herein include, but are not limited to, bone and connective tissue sarcomas selected from the group consisting of osteogenic sarcoma, osteosarcoma, osteogenic sarcoma, chondrosarcoma, chordoma, synovioma, sarcomatous mesothelioma, Ewing's tumor, fibrosarcoma of bone, periosteal sarcoma, soft tissue sarcoma, angiosarcoma, hemangioendothelioma, fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, rhabdomyosarcoma, synovial sarcoma, myxosarcoma, endotheliosarcoma, and lymphangioendothelial sarcoma.

[0077] In another aspect, the subject is diagnosed with a sarcoma, wherein the sarcoma is selected from the group consisting of Ewing's tumor, fibrosarcoma, leiomyosarcoma, liposarcoma, and osteosarcoma.

[0078] In specific aspects, a subject diagnosed with a sarcoma can be treated with a chemotherapeutic agent that inhibits or reduces tubulin polymerization.

[0079] In particular aspects, a subject diagnosed with a sarcoma can be treated with a chemotherapeutic agent that inhibits or reduces the function of BMI-1.

[0080] In a specific aspect, the methods of inhibiting or reducing tubulin polymerization as described herein inhibit or reduce tubulin polymerization by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95% or 100% relative to tubulin polymerization assessed using methods well known in the art prior to administration of Compound 1 to the subject.

[0081] In specific aspects, the methods of inhibiting or reducing BMI-1 function as described herein inhibit about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95% or 100% BMI-1 function relative to BMI-1 function assessed using methods well known in the art prior to administering Compound 1 to the subject.

[0082] In specific aspects, the methods of inhibiting or reducing tubulin polymerization as described herein inhibit or reduce tubulin polymerization by about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, relative to tubulin polymerization assessed using methods well known in the art prior to administration of Compound 1 to a subject.

[0083] In specific aspects, the methods of inhibiting or reducing BMI-1 function as described herein inhibit or reduce BMI-1 function by about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, relative to BMI-1 function assessed using methods well known in the art prior to administration of Compound 1 to a subject.

[0084] In specific aspects, the methods of inhibiting or reducing tubulin polymerization as described herein inhibit proliferation or reduce the number of proliferating cells or cell lines in vitro or in vivo by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95% or 100% relative to the number of proliferating cells or cell lines in vitro or in vivo assessed using methods well known in the art before administering Compound 1 to the subject.

[0085] In specific aspects, the methods of inhibiting or reducing BMI-1 function as described herein inhibit proliferation or reduce the number of proliferating cells or cell lines in vitro or in vivo by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95% or 100% relative to the number of proliferating cells or cell lines in vitro or in vivo assessed using methods well known in the art before administering Compound 1 to the subject.

[0086] In specific aspects, the methods of inhibiting or reducing tubulin polymerization as described herein inhibit proliferation or reduce the number of proliferating cells or cell lines in vitro or in vivo by about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, relative to the number of proliferating cells or cell lines in vitro or in vivo assessed using methods well known in the art prior to administration of Compound 1 to the subject.

[0087] In specific aspects, the methods of inhibiting or reducing BMI-1 function as described herein inhibit proliferation or reduce the number of proliferating cells or cell lines in vitro or in vivo by about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, relative to the number of proliferating cells or cell lines in vitro or in vivo as assessed using methods well known in the art prior to administration of Compound 1 to the subject.

[0088] In various aspects, the methods of inhibiting or reducing tubulin polymerization as described herein reduce the expression of GTP-bound αβ-tubulin subunits available for microtubule assembly in a subject as assessed using methods well known in the art (eg, ELISA).

[0089] In various aspects, the methods of inhibiting or reducing BMI-1 function as described herein reduce the plasma concentration of BMI-1 in a subject as assessed using methods well known in the art (eg, ELISA).

[0090] In one aspect, described herein is a method of preventing, treating, or ameliorating a sarcoma in a subject in need thereof, comprising administering a dose of Compound 1 effective to inhibit or reduce tubulin polymerization in the subject.

[0091] In one aspect, described herein are methods of preventing, treating, or ameliorating sarcoma in a subject in need thereof, comprising administering a dose of Compound 1 effective to inhibit or reduce BMI-1 function in the subject.

[0092] In specific aspects, the methods for preventing, treating, or ameliorating a sarcoma in a subject in need thereof as described herein inhibit or reduce tubulin polymerization by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% relative to tubulin polymerization assessed using methods well known in the art prior to administration of Compound 1 to the subject.

[0093] In specific aspects, the methods for preventing, treating or ameliorating sarcoma in a subject in need thereof as described herein inhibit or reduce about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95% or 100% BMI-1 function relative to BMI-1 function assessed using methods well known in the art prior to administering Compound 1 to the subject.

[0094] In specific aspects, the methods for preventing, treating, or ameliorating a sarcoma in a subject in need thereof as described herein inhibit or reduce tubulin polymerization by about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, relative to tubulin polymerization assessed using methods well known in the art prior to administration of Compound 1 to the subject.

[0095] In specific aspects, the methods for preventing, treating, or ameliorating sarcoma in a subject in need thereof as described herein inhibit or reduce BMI-1 function by about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, relative to BMI-1 function assessed using methods well known in the art prior to administration of Compound 1 to the subject.

[0096] In various aspects, the methods of preventing, treating, or ameliorating a sarcoma in a subject in need thereof as described herein reduce the concentration of BMI-1 in the subject as assessed using methods well known in the art (eg, ELISA).

[0097] In one aspect, described herein are methods for preventing, treating or ameliorating a sarcoma in a subject in need thereof, comprising administering a dose of Compound 1 effective to inhibit proliferation or reduce the number of proliferating cells or cell lines in vitro or in vivo in the subject.

[0098] In specific aspects, the methods for preventing, treating or ameliorating a sarcoma in a subject in need thereof as described herein inhibit proliferation or reduce the number of proliferating cells or cell lines in vitro or in vivo in the subject by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95% or 100% relative to the number of proliferating cells or cell lines in vitro or in vivo in the subject assessed using methods well known in the art prior to administration of Compound 1 to the subject.

[0099] In specific aspects, the methods for preventing, treating or ameliorating a sarcoma in a subject in need thereof as described herein inhibit proliferation or reduce the number of proliferating cells or cell lines in vitro or in vivo in the subject by about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, relative to the number of proliferating cells or cell lines in vitro or in vivo in the subject as assessed using methods well known in the art prior to administration of Compound 1 to the subject.

[0100] In various aspects, the methods of preventing, treating or ameliorating a sarcoma in a subject in need thereof as described herein inhibit proliferation or reduce the number of cells or cell lines proliferating in vitro or in vivo in the subject as assessed using methods well known in the art (eg, ELISA).

[0101] In one aspect, described herein are methods for preventing, treating, or ameliorating a sarcoma in a subject in need thereof, comprising: administering to a subject in need thereof a dose of Compound 1 effective to inhibit proliferation in the subject or to reduce the number of proliferating cells or cell lines in vitro or in vivo in combination with another therapy (e.g., one or more other therapies that do not contain Compound 1, or contain a different anti-proliferative agent).

[0102] The method may include administering Compound 1 prior to, concurrently with, or after administration of the other therapy. In certain aspects, the method has an additive or synergistic effect.

[0103] In specific aspects, provided herein are methods of preventing, treating, or ameliorating sarcoma in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of Compound 1 and an effective amount of another therapy.

[0104] One aspect described herein includes hematological cancers, including but not limited to sarcomas, that can be prevented, treated, or ameliorated according to the methods provided herein.

[0105] In one aspect, provided herein is a method for preventing, treating or ameliorating sarcoma, comprising: (a) administering one or more doses of Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a subject in need thereof; (b) monitoring the concentration of certain biomarkers before and / or after step (a).

[0106] In specific aspects, the monitoring step (b) is performed before and / or after administration of a certain number of doses (e.g., 1, 2, 4, 6, 8, 10, 12, 14, 15 or 29 doses, or more; 2 to 4, 2 to 8, 2 to 20 or 2 to 30 doses) of Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, or for a specific period of time (e.g., 1, 2, 3, 4, 5, 6 or 7 days; or 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 45, 48 or 50 weeks).

[0107] In specific aspects, one or more of these monitored parameters are detected prior to administering Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject.

[0108] In specific aspects, after administration of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the proliferation of the number of proliferating cells or cell lines in vitro or in vivo is reduced, indicating that the treatment process is effective in preventing, treating or ameliorating sarcoma.

[0109] In specific aspects, changes in the proliferation of the number of proliferating cells or cell lines in vitro or in vivo after administration of Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, indicate that the dose, frequency and / or duration of administration of Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, can be adjusted (e.g., increased, decreased or maintained).

[0110] In specific aspects, the concentration of certain biomarkers in a biological sample of a subject is monitored before, during, and / or after a course of sarcoma treatment comprising administering Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to the subject.

[0111] The dose, frequency and / or duration of Compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition administered to the subject may be changed according to the proliferation of the number of proliferating cells or cell lines in vitro or in vivo. Alternatively, changes in these monitoring parameters (e.g., the concentration of certain biomarkers) may indicate that the treatment process including the administration of Compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition is effective in preventing, treating or ameliorating sarcoma.

[0112] Any technique familiar to those skilled in the art can be used to detect the concentration of certain biomarkers in a subject. In certain aspects, methods for detecting the concentration of certain biomarkers in a subject include obtaining a biological sample (e.g., a tissue or fluid sample) from a subject, and using an immunological technique (e.g., ELISA) to detect the concentration of the biomarker in a biological sample (e.g., from plasma, serum, urine, or any other biological fluid) that has been subjected to some type of processing (e.g., centrifugation).

[0113] In specific aspects, as described herein, ELISA assays can be used to detect the concentration of biomarkers in biological samples (e.g., from plasma, serum, urine, or any other biological fluid) that have been subjected to certain types of processing (e.g., centrifugation). Other techniques known in the art that can be used to detect the concentration of biomarkers in biological samples include multiplex or proteomic analysis.

[0114] In specific aspects, the methods provided herein for preventing, treating or improving sarcomas alleviate or control one, two or more symptoms associated with sarcomas. Alleviating or controlling one, two or more symptoms of sarcomas can be used as clinical endpoints for the efficacy of compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition in preventing, treating or improving sarcomas. In some aspects, the methods provided herein for preventing, treating or improving sarcomas reduce the duration and / or severity of one or more symptoms associated with sarcomas. In some aspects, the methods provided herein for preventing, treating or improving sarcomas inhibit the onset, progression and / or recurrence of one or more symptoms associated with sarcomas. In some aspects, the methods for treating sarcomas provided herein reduce the number of symptoms associated with sarcomas.

[0115] In certain aspects, the methods provided herein for preventing, treating or improving sarcomas extend or delay the G1 / S phase or late G1 / S phase of the cell cycle (i.e., the period between the late checkpoint (quiescent phase or pre-DNA synthesis phase) and the early DNA synthesis phase). In other aspects, the methods provided herein for preventing, treating or improving sarcomas extend or delay the S phase or G2 / M phase of the cell cycle (i.e., the period between the DNA synthesis phase and the early division phase).

[0116] In some aspects, the methods provided herein for preventing, treating or improving sarcomas reduce, improve or alleviate the severity of sarcomas and / or one or more symptoms thereof. In other aspects, the methods provided herein for preventing, treating or improving sarcomas reduce the length of hospital stay (e.g., frequency or duration of hospitalization) of subjects diagnosed with sarcomas.

[0117] In certain aspects, the methods provided herein increase the survival rate of subjects diagnosed with sarcomas. In specific aspects, the methods provided herein increase the survival of subjects diagnosed with sarcomas by about 6 months or longer, about 7 months or longer, about 8 months or longer, about 9 months or longer, or about 12 months or longer.

[0118] In certain aspects, the methods provided herein for preventing, treating or improving sarcomas inhibit or reduce the progression of sarcomas, or one or more symptoms associated therewith. In specific aspects, the methods provided herein for preventing, treating or improving sarcomas enhance or improve the therapeutic effect of another therapy (e.g., anticancer agents, radiation, drug therapy, such as chemotherapy, anti-androgen therapy or surgery). In certain aspects, the methods provided herein for preventing, treating or improving sarcomas involve the use of compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as an adjuvant therapy.

[0119] In specific aspects, the methods provided herein for preventing, treating or ameliorating sarcomas reduce the mortality of subjects diagnosed with sarcomas. In certain aspects, the methods provided herein for preventing, treating or ameliorating sarcomas increase the number of subjects in remission or reduce the rate of hospitalization. In other aspects, the methods provided herein for preventing, treating or ameliorating sarcomas prevent the occurrence, onset or progression of one or more symptoms associated with sarcomas.

[0120] In certain aspects, the methods provided herein for preventing, treating or improving sarcomas increase the asymptomatic survival rate of sarcoma subjects. In some aspects, the methods provided herein for preventing, treating or improving sarcomas cannot cure the sarcoma of the subject, but can prevent the progression or deterioration of the disease. In some aspects, the methods provided herein for preventing, treating or improving sarcomas improve the quality of life of the subject.

[0121] In some aspects, the methods provided herein for preventing, treating or improving sarcomas improve the cancer-free survival rate of subjects diagnosed with cancer. In some aspects, the methods provided herein for preventing, treating or improving sarcomas improve the recurrence-free survival rate. In some aspects, the methods provided herein for preventing, treating or improving sarcomas increase the number of subjects in remission. In other aspects, the methods provided herein for preventing, treating or improving sarcomas increase the remission time of subjects.

[0122] Treatment population

[0123] In one aspect, the subject treated for a sarcoma according to the methods provided herein is a human suffering from or diagnosed with a sarcoma. In another aspect, the subject treated for a sarcoma according to the methods provided herein is a human predisposed to or susceptible to a sarcoma. In another aspect, the subject treated for a sarcoma according to the methods provided herein is a human at risk of developing a sarcoma. In another aspect, the subject treated for a sarcoma according to the methods provided herein is a human having a genetic or somatic mutation that places the subject at or predisposed to the risk of developing a sarcoma.

[0124] In one aspect, the subject treated for a sarcoma according to the methods provided herein is a human infant. In another aspect, the subject treated for a sarcoma according to the methods provided herein is a human toddler. In another aspect, the subject treated for a sarcoma according to the methods provided herein is a human child. In another aspect, the subject treated for a sarcoma according to the methods provided herein is an adult human. In another aspect, the subject treated for a sarcoma according to the methods provided herein is a middle-aged human. In another aspect, the subject treated for a sarcoma according to the methods provided herein is an elderly human.

[0125] In certain aspects, the sarcoma of a subject treated for cancer according to the methods provided herein metastasizes to other areas of the body, such as bones, lungs, and liver. In certain aspects, the sarcoma of a subject treated for sarcoma according to the methods provided herein is in remission. In certain aspects, the sarcoma of a subject treated for sarcoma according to the methods provided herein recurs. In certain aspects, the subject treated according to the methods provided herein is experiencing a recurrence of one or more symptoms associated with the sarcoma.

[0126] In certain aspects, the subject treated for a sarcoma according to the methods provided herein is i). a human toddler ranging in age from about 1 to about 5 years old; ii). a human child ranging in age from about 5 to 10 years old; or from about 10 to about 18 years old; ii). an adult ranging in age from about 18 to about 30 years old; or, from about 25 to about 35 years old; or, from about 35 to about 45 years old; ii). a middle-aged person ranging in age from about 40 to about 55 years old; or, from about 50 to about 65 years old; ii). an adult ranging in age from about 60 to about 75 years old, ii). an elderly human ranging in age from about 70 to about 85 years old, about 80 to about 90 years old, about 90 to about 95 years old, or about 95 to about 100 years old, or any age therebetween.

[0127] In specific aspects, the subject treated for sarcoma according to the methods provided herein is a human 18 years of age or older. In specific aspects, the subject treated for sarcoma according to the methods provided herein is a human child between 1 and 18 years of age. In certain aspects, the subject treated for sarcoma according to the methods provided herein is a human between 1 and 18 years of age. In certain aspects, the subject is male. In another aspect, the subject is female. In one aspect, the subject is a female who is not pregnant or not breastfeeding. In one aspect, the subject is a female who is pregnant or will / may become pregnant, or is breastfeeding.

[0128] As used herein, the term "human infant" refers to humans from newborn to 1 year old.

[0129] As used herein, the term "human child" refers to a human between 1 and 5 years old.

[0130] As used herein, the term "human child" refers to a human between the ages of 5 and 18.

[0131] As used herein, the term "adult" refers to humans over the age of 18 years.

[0132] As used herein, the term "middle-aged human" refers to humans between 40 and 65 years old.

[0133] As used herein, the term "elderly" refers to humans who are 65 years of age or older.

[0134] In specific aspects, the subject treated for sarcoma according to the methods provided herein is a person who is in an immunocompromised state or an immunosuppressed state. In certain aspects, the subject treated for sarcoma according to the methods provided herein is a person who is receiving immunosuppressive therapy or recovering from immunosuppressive therapy. In certain aspects, the subject treated for sarcoma according to the methods provided herein is a person who suffers from sarcoma or is at risk of suffering from sarcoma. In certain aspects, the subject treated for sarcoma according to the methods provided herein is a person who is, will be, or has undergone surgery, drug therapy (e.g., chemotherapy), hormone therapy, and / or radiotherapy.

[0135] In some aspects, before a subject treated for sarcoma according to the methods provided herein develops any adverse reaction or intolerance to a therapy other than Compound 1, Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition or a combination therapy is administered thereto. In some aspects, a subject treated for sarcoma according to the methods provided herein is a refractory subject. In some aspects, a refractory subject is a subject refractory to standard therapy (e.g., surgery, radiotherapy, and / or drug therapy (e.g., chemotherapy)). In some aspects, when the sarcoma is not significantly eradicated and / or one or more symptoms are not significantly alleviated, the subject with the sarcoma is refractory. In this case, the art-recognized meaning of "refractory" is used, and any method known in the art for determining the effectiveness of sarcoma treatment is measured in vivo or in vitro to determine whether the subject is refractory.

[0136] In some aspects, subjects treated for sarcoma according to the methods provided herein are those who have proven refractory to therapies other than treatment with Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, but are no longer receiving these therapies. In certain aspects, subjects treated for sarcoma according to the methods provided herein are those who have received one or more conventional anticancer therapies, such as surgery, drug therapy (e.g., chemotherapy), anti-androgen therapy, or radiotherapy. Subjects who are too young for conventional therapy and subjects whose sarcoma relapses despite treatment with existing therapies are refractory subjects.

[0137] In some aspects, the subject of the sarcoma treated according to the methods provided herein is a person who is sensitive to adverse reactions of conventional therapies. In some aspects, the subject of the sarcoma treated according to the methods provided herein is a person who has not received therapy, such as drug therapy (e.g., chemotherapy), surgery, anti-androgen therapy, or radiotherapy before administering compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In other aspects, the subject of the sarcoma treated according to the methods provided herein is a person who has received therapy before administering compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In some aspects, the subject of the sarcoma treated according to the methods provided herein is a person who has experienced adverse side effects of a previous therapy or interrupted a previous therapy due to an unacceptable level of toxicity to a person.

[0138] Dosage and administration

[0139] According to the method for preventing, treating or improving sarcoma provided herein, compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition can be administered to a subject in need at a dose that produces a beneficial or therapeutic effect through a variety of routes. Compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition can be orally administered to a subject in need according to the method for preventing, treating or improving sarcoma provided herein. Oral administration of compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition may be beneficial for subjects in need of such treatment to comply with the regimen of administering compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition. Therefore, in a specific aspect, compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition is orally administered to a subject in need. On the other hand, compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition provided herein can be orally administered with food or water or not with food or water.

[0140] Other routes of administration include, but are not limited to, intravenous, intradermal, intrathecal, intramuscular, subcutaneous, intranasal, inhalation, transdermal, topical, transmucosal, intracranial, epidural, and intrasynovial. On the one hand, compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition is administered systemically (e.g., parenterally) to a subject in need. On the one hand, compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition is administered by a route (e.g., oral) that allows compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition to cross the blood-brain barrier.

[0141] According to the method for preventing, treating or ameliorating sarcoma provided herein, which comprises administering Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in combination with one or more other therapies, Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition and one or more other therapies may be administered by the same or different administration routes.

[0142] The dosage and frequency of administration of Compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition to a subject in need thereof according to the method for preventing, treating or ameliorating sarcoma provided herein will be effective while minimizing any side effects. The exact dosage and frequency of administration of Compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition can be determined by a practicing physician based on factors related to the subject in need of treatment.

[0143] Factors that may be considered include the severity of the disease state, the subject's general health, the subject's age, weight and sex, diet, time and frequency of administration, drug combination, reaction sensitivity and tolerance / response to therapy. The dosage and frequency of administration of Compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition may be adjusted over time to provide an effective dose of Compound 1 or its pharmaceutically acceptable salt or pharmaceutical composition or to maintain the desired effect.

[0144] As described herein, provided herein are methods for preventing, treating, or ameliorating sarcoma in a subject in need thereof, comprising administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0145] On the other hand, the term "effective dose" refers to the dose of Compound 1 administered to a patient as a monotherapy, which is in the range of about 0.001 mg / Kg / day to about 500 mg / Kg / day, or about 0.01 mg / Kg / day to about 500 mg / Kg / day, or about 0.1 mg to about 500 mg / Kg / day, or about 1.0 mg / day to about 500 mg / Kg / day, which is a single, divided or continuous dose for patients or subjects with a body weight in the range of about 40 to about 200 Kg (for patients or subjects with a body weight above or below this range, especially children under 40 Kg, the dose can be adjusted). The dose can be administered as a dose per kilogram, a dose per square meter, or a fixed dose expressed in weight units (e.g., milligrams, grams).

[0146] On the other hand, effective dose is the dosage applied to the subject that can increase or decrease according to the reaction of the subject.The effective dose of the subject will also depend on various factors, including the weight, body shape and health of the subject.The median weight expectation of a typical adult subject is about 60 to about 100Kg.Therefore, the effective dose of a given patient can be determined according to the skill and judgment of the clinician.

[0147] In one aspect, the daily monotherapy dosage can be adjusted according to the body weight of the subject or patient, wherein Compound 1 can be formulated to be delivered as a monotherapy at a dosage of approximately 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 10, 20, 50, 75 or 100 mg / Kg / day, or any range therebetween.

[0148] On the other hand, the daily dose can be adjusted according to the body weight of the subject or patient and administered as single, divided or continuous doses.

[0149] On the other hand, the daily dose of Compound 1 can be administered more than once a day, such as once, twice, three times or more times a day.

[0150] In another aspect, the dose of Compound 1 can be administered more than once per week, such as once, twice, three times or more per week.

[0151] On the other hand, the effective dose can be a dose administered to the subject twice a week at different times, wherein the second dose in one week is administered three days after the first dose, and wherein the first dose in the next week is administered four days after the second dose in the previous week. In another embodiment, one or more doses of an effective dose of Compound 1 can be administered to the subject, wherein the effective dose of each dose may be different.

[0152] In one aspect, the effective dosage of Compound 1 can be in the range of about 0.001 mg / Kg / day to about 500 mg / Kg / day. Within the scope described herein, an "effective dose" of Compound 1 for use in the manufacture of a medicament or in a method of treating a sarcoma in a subject in need thereof is intended to include a dose of about 0.1 ng to about 3500 mg administered daily; a dose of about 0.1 μg to about 3500 mg administered daily; a dose of about 0.1 mg to about 3500 mg administered daily; a dose of about 1 mg to about 3500 mg administered daily; a dose of about 1 mg to about 3000 mg administered daily; a dose of about 0.05 mg to about 1500 mg administered daily; a dose of about 0.5 mg to about 1500 mg administered daily; a dose of about 1 mg to about 1500 mg administered daily; a dose of about 5 mg to about 1500 mg administered daily; a dose of about 10 mg to about 600 mg administered daily; a dose of about 0.5 mg to about 2000 mg administered daily; or a dose of about 5.0 mg to about 1500 mg administered daily.

[0153] In another aspect, an effective dose of Compound 1 is from about 0.1 ng to about 3500 mg.

[0154] On the one hand, the effective dose of Compound 1 can be preliminarily estimated by results of cell culture experiments or human or relevant animal models (such as mice, chimpanzees, marmosets or marmoset animal models). Relevant animal models can also be used to determine the appropriate concentration range and route of administration. Therapeutic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell culture or experimental animals, such as ED 50 (therapeutically effective dose for 50% of the population) and LD 50 (lethal dose for 50% of the population). The dose ratio between toxic and therapeutic effects is called the therapeutic index and can be expressed as the ratio LD 50 / ED 50 On the other hand, an effective dose is one that achieves a large therapeutic index. On the other hand, an administered dose results in an ED 50The dosage may vary within this range, depending on the dosage form employed, the sensitivity of the patient, and the route of administration.

[0155] More specifically, the concentration-biological effect (pharmacodynamic) relationship observed for Compound 1 indicates that the target plasma concentration range is about 0.001 μg / mL to about 50 μg / mL, about 0.01 μg / mL to about 20 μg / mL, about 0.05 μg / mL to about 10 μg / mL, or about 0.1 μg / mL to about 5 μg / mL. In order to achieve the plasma concentration, the administered dose of Compound 1 can vary from 0.001 μg to 100,000 mg, depending on the route of administration of single, divided or continuous doses for patients weighing between about 40 kg and about 100 kg (the dose can be adjusted for patients above or below this weight range, particularly for children under 40 kg).

[0156] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition, wherein the effective dose is from about 50 mg to about 400 mg, from about 100 mg to about 200 mg, from about 125 mg to about 175 mg, from about 100 mg to about 300 mg, from about 100 mg to about 400 mg, from about 150 mg to about 200 mg, from about 150 mg to about 300 mg, from about 150 mg to about 175 mg. To about 400 mg, from about 200 mg to about 300 mg, from about 225 mg to about 275 mg, from about 225 mg to about 300 mg, from about 275 mg to about 300 mg, from about 200 mg to about 225 mg, from about 200 mg to about 275 mg, from about 200 mg to about 400 mg, from about 250 mg to about 300 mg, from about 250 mg to about 400 mg, from about 250 mg to about 350 mg, etc., the dosage is selected within the range of twice a week.

[0157] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 50 mg to about 400 mg, orally administered twice a week.

[0158] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 100 mg to about 200 mg, orally administered twice a week.

[0159] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 125 mg to about 175 mg, orally administered twice a week.

[0160] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 125 mg to about 200 mg, orally administered twice a week.

[0161] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 175 mg to about 200 mg, orally administered twice a week.

[0162] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 100 mg to about 125 mg, orally administered twice a week.

[0163] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 100 mg to about 175 mg, orally administered twice a week.

[0164] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 100 mg to about 300 mg, orally administered twice a week.

[0165] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 100 mg to about 400 mg, orally administered twice a week.

[0166] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 150 mg to about 200 mg, orally administered twice a week.

[0167] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 150 mg to about 300 mg, orally administered twice a week.

[0168] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 150 mg to about 400 mg, orally administered twice a week.

[0169] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 200 mg to about 300 mg, orally administered twice a week.

[0170] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 225 mg to about 275 mg, orally administered twice a week.

[0171] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 225 mg to about 300 mg, orally administered twice a week.

[0172] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 275 mg to about 300 mg, orally administered twice a week.

[0173] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 200 mg to about 225 mg, orally administered twice a week.

[0174] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 200 mg to about 275 mg, orally administered twice a week.

[0175] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 200 mg to about 400 mg, orally administered twice a week.

[0176] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 250 mg to about 300 mg, orally administered twice a week.

[0177] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 250 mg to about 400 mg, orally administered twice a week.

[0178] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 250 mg to about 350 mg, orally administered twice a week.

[0179] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the effective dose is selected from about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg and about 450 mg, orally administered twice a week.

[0180] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the effective dose is selected from about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg and about 300 mg, orally administered twice a week.

[0181] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the effective dose is selected from about 125 mg, about 150 mg, about 175 mg, about 225 mg, about 250 mg, about 275 mg and about 300 mg, orally administered twice a week.

[0182] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 100 mg, orally administered twice a week.

[0183] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 125 mg, orally administered twice a week.

[0184] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 150 mg, orally administered twice a week.

[0185] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 175 mg, orally administered twice a week.

[0186] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 200 mg, orally administered twice a week.

[0187] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 225 mg, orally administered twice a week.

[0188] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 250 mg, orally administered twice a week.

[0189] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 275 mg, orally administered twice a week.

[0190] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective dose is about 300 mg, orally administered twice a week.

[0191] In another aspect, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutical composition thereof, wherein the effective dose is in milligrams per square meter (mg / m 2 ) represents the dose. The mg / m 2 The dosage can be determined, for example, by multiplying the animal dose (mg per kilogram, mg / kg) by the conversion factor for animals (e.g., mice, rats, hamsters, guinea pigs, dogs, monkeys, and humans) to obtain the dosage in mg / m 2 The equivalent human dose is expressed using the following allometric conversion factors (assuming equal allometric conversion for all drugs), for example: mouse = 3, hamster = 4.1, rat = 6, guinea pig = 7.7. (Based on Freireich et al., Cancer Chemother. Rep. 50(4): 219-244 (1966)). Human height and weight can be used to calculate human surface area using Boyd's Formula of Body Surface Area.

[0192] On the other hand, the average weight of a person is generally considered to be 70 kg. However, dosing based on ideal body weight may be superior to the total body weight-based regimen currently recommended in adult subjects. The estimated ideal body weight (IBW) (kg) for men is calculated as follows: 50 kg + 2.3 kg for each inch above 5 feet. The estimated ideal body weight (IBW) (kg) for women is calculated as follows: 45.5 kg + 2.3 kg for each inch above 5 feet.

[0193] In contrast to the use of allometric conversion factors, Fig. 6A -D summarizes the pharmacokinetics of compound 1 in humans, showing that a conversion factor for compound 1 can be derived based on the free drug in humans compared to the free drug in mice, which can be used to estimate the effective target AUC and C max , thus explaining the differences in free drug between these species.

[0194] As shown in Table A1 below, Fig. 6AThe measured human AUC exposures at various doses are shown. The dashed line indicates that the minimum estimated AUC target is at least 13,125 hr-ng / mL based on the 10 mg / kg exposure in mice, taking into account free drug. As shown by the dashed line, this predicts that an estimated dose of about 2.0 mg / kg (biw) or higher of Compound 1 in human patients will be effective.

[0195] As shown in Table A1 below, Figure 6B Shows the human C at different doses tested max The dashed line indicates the minimum estimated C considering the free drug, based on the exposure of 10 mg / kg in mice. max The target is at least 688 ng / mL. As shown by the dashed line, this predicts that an estimated dose of about 1.4 mg / kg (biw) or higher of Compound 1 will be effective in human patients.

[0196] As shown in Table A1 below, Figure 6C The measured human AUC exposures at various doses are shown. The dashed line indicates that the minimum estimated AUC target is at least 15,625 hr-ng / mL, taking into account free drug, based on the exposure of 12.5 mg / kg in mice. As shown by the dashed line, this predicts that an estimated dose of about 2.3 mg / kg (biw) or higher of Compound 1 in human patients will be effective.

[0197] As shown in Table A1 below, Fig.6D Shows the human C at different doses tested max The dashed line indicates the minimum estimated C considering free drug based on the exposure of 12.5 mg / kg in mice. max The target is at least 859 ng / mL. As shown by the dashed line, this predicts that an estimated dose of about 1.8 mg / kg (biw) or higher of Compound 1 will be effective in human patients.

[0198] The difference in free drug concentration between humans and mice is 8:5.

[0199] Table A1

[0200]

[0201] As shown in Table A2 below, the estimated target AUC and Cmax for total drug in humans and mice would be the same if free drug concentration was not considered.

[0202] As shown in Table A2 below, a preclinical dose of 10 mg / kg administered orally twice weekly to mice, as described herein, would result in a predicted estimated minimum effective human dose range of about 3.2 mg / kg to about 2.3 mg / kg (biw) to reduce AUC and C to 1. maxMaintain above target concentration to achieve the desired therapeutic effect.

[0203] As shown in Table A2 below, the preclinical dose of 12.5 mg / kg administered orally twice weekly to mice, as described herein, would result in a predicted estimated minimum effective human dose range of about 4.2 mg / kg to about 3.2 mg / kg (biw) to reduce AUC and C to 1. max Maintain above target concentration to achieve the desired therapeutic effect.

[0204] Table A2

[0205]

[0206] Based on 12.5 mg / kg of target free drug in mice, the corresponding minimum effective dose of Compound 1 as a monotherapy in humans is about 2.3 mg / kg to about 1.8 (for AUC and C max ), for a 70 kg human subject, the dosage is about 162 mg to about 124 mg, administered orally twice a week.

[0207] Based on a target total drug of 12.5 mg / kg in mice, the corresponding minimum effective dose of Compound 1 as a monotherapy in humans is approximately 4.2 mg / kg to approximately 3.2 mg / kg (for AUC and C max ), for a 70 kg human subject, the dosage is about 290 mg to about 226 mg, administered orally twice a week.

[0208] In a specific aspect, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutical composition thereof, wherein the effective dose is about 0.1 mg / m 2 Up to about 1000 mg / m 2 , or any range of dosages therebetween.

[0209] On the one hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutical composition thereof, wherein the effective dose is a dose that achieves a target mean plasma concentration of Compound 1 in a subject with sarcoma or an animal model with a predetermined sarcoma.

[0210] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutical composition thereof, wherein the effective dose is in an animal model having sarcoma or having a predetermined sarcoma, and within 24 hours, Compound 1 reaches the following average maximum plasma concentration (C max) dose: about 0.1 hr-μg / mL to about 1.0 hr-μg / mL, about 0.2 hr-μg / mL to about 1.0 hr-μg / mL, about 0.3 hr-μg / mL to about 1.0 hr-μg / mL, about 0.4 hr-μg / mL to about 1.0 hr-μg / mL, about 0.5 hr-μg / mL to about 1.0 hr-μg / mL, about 0.6 hr-μg / mL to about 1.0 hr-μg / mL, about 0.7 hr-μg / mL to about 1.0 hr-μg / mL, about 0.8 hr-μg / mL to about 1.0 hr-μg / mL, about 0.9 hr-μg / mL to about 1.0 hr-μg / mL, about 3 hr-μg / mL to about 70 hr-μg / mL, about 3 hr-μg / mL to about 60 hr-μg / mL, about 3 hr-μg / mL to about 50 hr-μg / mL, about 3 hr-μg / mL to about 40 hr-μg / mL, about 3 hr-μg / mL to about 30 hr-μg / mL, about 3 hr-μg / mL to about 20 hr-μg / mL, about 3 hr-μg / mL to about 10 hr-μg / mL, etc., or any range therebetween.

[0211] On the other hand, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutical composition thereof, wherein the effective dose is a dose that achieves the following average plasma concentration of Compound 1 within 24 hours in an animal model of sarcoma or a predetermined sarcoma: 0.1 hr-μg / mL, about 0.2 hr-μg / mL, about 0.3 hr-μg / mL, about 0.4 hr-μg / mL, about 0.5 hr-μg / mL, about 0.6 hr-μg / mL, about 0.7 hr-μg / mL, about 0.8 hr-μg / mL, about 0.9 hr-μg / mL, about 1.0 hr-μg / mL, about 1.1 hr-μg / mL, about 1.2 hr-μg / mL, about 1.3 hr-μg / mL, about 1.4 hr-μg / mL, about 1.5 hr-μg / mL mL, about 1.6 hr-μg / mL, about 1.7 hr-μg / mL, about 1.8 hr-μg / mL, about 1.9 hr-μg / mL, about 2.0 hr-μg / mL, about 2.1 hr-μg / mL, about 2.2 hr-μg / mL, about 2.3 hr-μg / mL, about 2.4 hr-μg / mL, about 2.5 hr-μg / mL, about 2.6 hr-μg / mL, about 2.7 hr-μg / mL, about 2.8 hr-μg / mL, about 2.9 hr-μg / mL, about 3.0 hr-μg / mL, about 10 hr-μg / mL, about 20 hr-μg / mL, about 30 hr-μg / mL, about 40 hr-μg / mL, about 50 hr-μg / mL, about 60 hr-μg / mL, about 70 hr-μg / mL, etc., or any range therebetween.

[0212] To achieve the plasma concentration, the dose of Compound 1 or its pharmaceutical composition described herein may be administered. In certain aspects, subsequent doses of Compound 1 or its pharmaceutical composition may be adjusted accordingly based on the average plasma concentration of Compound 1 achieved by the dose of Compound 1 or its pharmaceutical composition administered to the subject.

[0213] In a specific aspect, a method for preventing, treating, or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutical composition thereof, wherein the effective dose is a dose that achieves a target mean plasma concentration reduction of one or more biomarkers in a subject with sarcoma or an animal model with a predetermined sarcoma.

[0214] In a specific aspect, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering to the subject an effective dose of Compound 1 or a pharmaceutical composition thereof, wherein the effective dose is a dose of Compound 1 or a pharmaceutical composition thereof that achieves a desired tissue to mean plasma concentration ratio (determined using any imaging technique familiar in the art) in a subject suffering from sarcoma or an animal model suffering from a predetermined sarcoma.

[0215] In some aspects, the method for preventing, treating or improving sarcoma in a subject in need includes administering an effective dose of compound 1 or its pharmaceutical composition to the subject, wherein the effective dose of each dose may be the same or different. In a specific aspect, a first (ie, initial) dose of compound 1 or its pharmaceutical composition is administered to a subject in need within a first time period, and then a second (ie, loading) dose of compound 1 or its pharmaceutical composition is administered to the subject within a second time period, followed by a third (ie, maintenance) dose of compound 1 or its pharmaceutical composition administered to the subject within a second time period. The first dose may be greater than the second dose, or the first dose may be less than the second dose. Similarly, the third dose of compound 1 or its pharmaceutical composition may be greater than or less than the second dose, and greater than or less than the first dose.

[0216] In some aspects, the dosages described herein refer to the total dosage administered; that is, if more than one compound is administered, in some aspects, the dosage corresponds to the total dosage administered. In specific aspects, the oral composition comprises from about 5% to about 95% by weight of Compound 1.

[0217] According to the method of preventing, treating or ameliorating sarcoma in a subject in need thereof, the length of time for which Compound 1 or its pharmaceutical composition is administered to a subject in need thereof will be determined by cancer-free or symptom-free survival. In certain aspects, the method of treating sarcoma presented herein comprises administering Compound 1 or its pharmaceutical composition for a period of time until the severity and / or number of one or more symptoms associated with the sarcoma decreases.

[0218] In some aspects, the method of preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering compound 1 or its pharmaceutical composition for up to 48 weeks. In other aspects, the method of preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering compound 1 or its pharmaceutical composition for up to 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 26 weeks (0.5 years), 52 weeks (1 year), 78 weeks (1.5 years), 104 weeks (2 years) or 130 weeks (2.5 years) or longer.

[0219] In certain aspects, a method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering Compound 1 or its pharmaceutical composition indefinitely. In some aspects, the method for treating sarcoma presented herein comprises administering Compound 1 or its pharmaceutical composition for a period of time, then resting for a period of time (i.e., a period in which Compound 1 or its pharmaceutical composition is not administered), and then resuming administration of Compound 1 or its pharmaceutical composition.

[0220] In a specific aspect, the method for preventing, treating or ameliorating sarcoma in a subject in need thereof comprises periodic administration of compound 1 or its pharmaceutical composition, for example, 1 week cycle, 2 week cycle, 3 week cycle, 4 week cycle, 5 week cycle, 6 week cycle, 8 week cycle, 9 week cycle, 10 week cycle, 11 week cycle or 12 week cycle. In such a cycle, compound 1 or its pharmaceutical composition may be administered once or twice a week. In a specific aspect of a weekly cycle, compound 1 or its pharmaceutical composition may be administered twice a week. In a specific aspect of the weekly cycle, compound 1 or its pharmaceutical composition may be administered once a day.

[0221] In particular aspects, the administration period of Compound 1 or a pharmaceutical composition thereof can be determined by one or more monitored parameters, such as the concentration of certain biomarkers.

[0222] In certain aspects, the administration period of Compound 1 or a pharmaceutical composition thereof can be adjusted based on one or more monitored parameters, such as the concentration of certain biomarkers.

[0223] In certain aspects, according to the method for preventing, treating or improving sarcoma in a subject in need thereof, before, at the same time or after a meal (e.g., breakfast, lunch or dinner), Compound 1 or its pharmaceutical composition is administered to a subject in need thereof. In specific aspects, according to the method for treating sarcoma provided herein, Compound 1 or its pharmaceutical composition is administered to a subject in need thereof in the morning (e.g., between 5 a.m. and 12 noon).

[0224] In certain aspects, according to the method of preventing, treating or ameliorating sarcoma in a subject in need thereof, at noon (i.e., 12 noon), Compound 1 or its pharmaceutical composition is administered to a subject in need thereof. In specific aspects, according to the method for treating sarcoma provided herein, Compound 1 or its pharmaceutical composition is administered to a subject in need thereof in the afternoon (e.g., between 12 noon and 5 p.m.), in the evening (e.g., from 5 p.m. to bedtime) and / or before bedtime.

[0225] In specific aspects, a dose of Compound 1 or a pharmaceutical composition thereof is administered to a subject once daily and twice weekly.

[0226] Combination therapy

[0227] Provided herein are combination therapies for treating sarcomas, which involve administering Compound 1 or a pharmaceutical composition thereof in combination with one or more other therapies to a subject in need thereof. In a specific aspect, provided herein are combination therapies for treating sarcomas, which involve administering an effective dose of Compound 1 or a pharmaceutical composition thereof in combination with an effective dose of another therapy to a subject in need thereof.

[0228] As used herein, the term "combination" in the context of administering Compound 1 or a pharmaceutical composition thereof means administering Compound 1 or a pharmaceutical composition thereof before, simultaneously with, or after administering one or more other therapies (e.g., drugs, surgery, or radiation therapy) for treating sarcoma. The use of the term "combination" does not limit the order in which the one or more therapeutic agents and one or more other therapies are administered to a subject. In specific aspects, the time interval between the administration of Compound 1, or a pharmaceutical composition thereof, and the administration of one or more other therapies can be about 1-5 minutes, 1-30 minutes, 30 minutes to 60 minutes, 1 hour, 1-2 hours, 2-6 hours, 2-12 hours, 12-24 hours, 1-2 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 15 weeks, 20 weeks, 26 weeks, 52 weeks, 11-15 weeks, 15-20 weeks, 20-30 weeks, 30-40 weeks, 40-50 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, or any time interval therebetween. In certain aspects, the interval between administration of Compound 1, or a pharmaceutical composition thereof, and one or more other therapies is less than 1 day, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or 5 years.

[0229] In some aspects, the combination therapy provided herein involves daily administration of compound 1 or its pharmaceutical composition, and once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once a month, once every 2 months (e.g., about 8 weeks), once every 3 months (e.g., about 12 weeks) or once every 4 months (e.g., about 16 weeks) One or more other therapies are administered. In some aspects, compound 1 or its pharmaceutical composition and one or more other therapies are periodically administered to the subject. Cyclic therapy includes administering compound 1 or its pharmaceutical composition for a period of time, then administering one or more other therapies for a period of time, and repeating this sequential administration. In some aspects, cyclic therapy can also include a rest period, wherein compound 1 or its pharmaceutical composition or other therapies are not administered for a period of time (e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 10 weeks, 20 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years or 3 years). In one aspect, the number of cycles administered is 1 to 12 cycles, 2 to 10 cycles, or 2 to 8 cycles.

[0230] In some aspects, the method of preventing, treating or ameliorating sarcoma in a subject in need thereof comprises administering Compound 1 or its pharmaceutical composition as a single agent for a period of time, followed by administration of Compound 1 or its pharmaceutical composition in combination with other therapies. In certain aspects, the method of treating sarcoma provided herein comprises administering other therapies alone for a period of time, followed by administration of Compound 1 or its pharmaceutical composition in combination with other therapies.

[0231] In some aspects, administration of Compound 1 or its pharmaceutical composition and one or more other therapies according to the methods provided herein has an additive effect relative to administration of Compound 1 or its pharmaceutical composition alone or administration of the one or more other therapies alone. In some aspects, administration of Compound 1 or its pharmaceutical composition and one or more other therapies according to the methods provided herein has a synergistic effect relative to administration of Compound 1 or its pharmaceutical composition alone or administration of the one or more other therapies alone.

[0232] As used herein, the term "synergistic" refers to the effect of administering Compound 1 or a pharmaceutical composition thereof in combination with one or more other therapies (e.g., agents) that is more effective than the additive effects of any two or more single therapies (e.g., agents).

[0233] In specific aspects, the synergistic effect of the combination therapy allows the use of lower doses (ie, suboptimal doses) of Compound 1 or its pharmaceutical composition or other therapy and / or less frequent administration of Compound 1 or its pharmaceutical composition or other therapy to the subject.

[0234] In certain aspects, the ability to use lower doses of Compound 1, or its pharmaceutical composition, or other therapy and / or to administer Compound 1, or its pharmaceutical composition, or the other therapy less frequently reduces the toxicity associated with administering Compound 1, or its pharmaceutical composition, or the other therapy, respectively, to a subject, but does not reduce the effectiveness of Compound 1, or its pharmaceutical composition, or the other therapy, respectively, in the treatment of sarcoma.

[0235] In some aspects, the synergistic effect results in an improvement in the efficacy of Compound 1, or a pharmaceutical composition thereof, and each of the other therapies in treating sarcoma. In some aspects, the synergistic effect of Compound 1, or a pharmaceutical composition thereof, in combination with one or more other therapies avoids or reduces adverse or unwanted side effects associated with the use of any single therapy.

[0236] The combination of Compound 1 or its pharmaceutical composition and one or more other therapies can be administered to the subject in the same pharmaceutical composition. Alternatively, Compound 1 or its pharmaceutical composition and one or more other therapies can be administered to the subject simultaneously in different pharmaceutical compositions. Compound 1 or its pharmaceutical composition and one or more other therapies can be administered to the subject sequentially in different pharmaceutical compositions. Compound 1 or its pharmaceutical composition and one or more other therapies can also be administered to the subject by the same or different routes of administration.

[0237] The combination therapies provided herein involve administering Compound 1 or a pharmaceutical composition thereof in combination with conventional or known therapies for treating sarcomas to subjects in need thereof. Other therapies for sarcomas or conditions associated therewith are intended to control or alleviate one or more symptoms. Thus, in some aspects, the combination therapies provided herein involve administering an analgesic or other therapy intended to alleviate or control one or more symptoms associated with a sarcoma or a condition associated therewith to a subject in need thereof.

[0238] On the one hand, examples of anticancer agents that can be used in combination with Compound 1 or its pharmaceutical composition for the treatment of sarcoma include: hormonal agents (e.g., aromatase inhibitors, selective estrogen receptor modulators (SERMs) and estrogen receptor antagonists), chemotherapeutic agents (e.g., microtubule decomposition blockers, antimetabolites, topoisomerase inhibitors and DNA cross-linking agents or damaging agents), anti-angiogenic agents (e.g., VEGF antagonists, receptor antagonists, integrin antagonists, vascular targeting agents (VTA) / vascular disrupting agents (VDA)), radiotherapy and conventional surgery.

[0239] On the other hand, non-limiting examples of hormone agents that can be used in combination with Compound 1 or its pharmaceutical composition for the treatment of sarcoma include aromatase inhibitors, SERMs, and estrogen receptor antagonists. Hormonal agents that are aromatase inhibitors can be steroidal or non-steroidal. Non-limiting examples of non-steroidal hormone agents include letrozole, anastrozole, aminoglutethimide, fadrozole, and vorozole. Non-limiting examples of steroidal hormone agents include aromatase (exemestane), formestane, and testolactone. Non-limiting examples of hormone agents that are SERMs include tamoxifen (trademark / sale name ), afeloxifene, arzoxifene, bazedoxifene, clomiphene, femarelle, lasofoxifene, ormeloxifene, raloxifene and toremifene. Non-limiting examples of hormone agents that are estrogen receptor antagonists include fulvestrant. Other hormone agents include, but are not limited to, abiraterone and lonaprisan.

[0240] On the other hand, non-limiting examples of chemotherapeutic agents that can be used in combination with Compound 1 or a pharmaceutical composition thereof for treating cancer include microtubule disassembly blockers, antimetabolites, topoisomerase inhibitors, and DNA cross-linking agents or damaging agents.

[0241] On the other hand, chemotherapeutic agents that are microtubule disassembly inhibitors include, but are not limited to, taxanes (e.g., paclitaxel (trade / sale name ), docetaxel (trademark / sales name ), albumin-bound paclitaxel (trademark / sales name ), larotaxel, ortataxel, and tesetaxel); epothilones (e.g., ixabepilone); and vinca alkaloids (e.g., vinorelbine, vinblastine, vindesine, and vincristine (trade / sale names )).

[0242] On the other hand, chemotherapeutic agents that are antimetabolites include, but are not limited to, folic acid antimetabolites (e.g., methotrexate, aminopterin, pemetrexed, raltitrexed); purine antimetabolites (e.g., cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine); pyrimidine antimetabolites (e.g., 5-fluorouracil, capecitabine, gemcitabine (trade / sale name ), cytarabine, decitabine, floxuridine, tegafur); and deoxyribonucleotide antimetabolites (e.g., hydroxyurea).

[0243] In another aspect, chemotherapeutic agents that are topoisomerase inhibitors include, but are not limited to, Class I (camptotheca) topoisomerase inhibitors (e.g., topotecan (trade / sold under the name ), irinotecan, rubitecan, and belotecan); Class II (podophyllotoxin) topoisomerase inhibitors (e.g., etoposide or VP-16 and teniposide); anthracyclines (e.g., doxorubicin, liposomal doxorubicin, epirubicin, aclarubicin, amrubicin, daunorubicin, idarubicin, pirarubicin, valrubicin, and daunorubicin); and anthracenediones (e.g., mitoxantrone and pixantrone.

[0244] On the other hand, chemotherapeutic agents that are DNA cross-linking agents (or DNA damaging agents) include, but are not limited to, alkylating agents (e.g., cyclophosphamide, nitrogen mustard, ifosfamide (trade / sold under the name ), cyclophosphamide, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, estramustine, carmustine (trademark / sales name ), lomustine, semustine, fotemustine, nimustine, ranimustine, streptozotocin, busulfan, mannosulfan, thiosulfan, carboquinone, N,N'N'-triethylenethiophosphoramide, triiminoquinone, triethylenemelamine); alkylating agents (e.g., carboplatin (trade / sale name ), cisplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, satraplatin, picoplatin); non-classical DNA cross-linking agents (e.g., procarbazine, dacarbazine (trade / sale name ), Temozolomide (trademark / sales name ), hexamethylmelamine, dibromomannitol); and intercalating agents (such as actinomycin, bleomycin, mitomycin and plicamycin).

[0245] On the other hand, non-limiting examples of anti-angiogenic agents that can be used in combination with Compound 1 or its pharmaceutical composition for the treatment of sarcoma include VEGF antagonists, receptor antagonists, integrin antagonists (e.g., vitaxin, cilengitide and S247), and VTA / VDA (e.g., fortabulin). VEGF antagonists include, but are not limited to, anti-VEGF antibodies (e.g., bevacizumab (trademark / sold under the name ) and ranibizumab (trademark / marketing name )), VEGF inhibitors (e.g., aflibercept), VEGF antisense or siRNA or miRNA and aptamers (e.g., pegaptanib sodium (trade / sold under the name )). Anti-angiogenic agents that are receptor antagonists include, but are not limited to, antibodies (e.g., ramucirumab) and kinase inhibitors (e.g., sunitinib, sorafenib, cediranib, panzopanib, vandetanib, axitinib, and AG-013958), such as tyrosine kinase inhibitors. Other non-limiting examples of anti-angiogenic agents include ATN-224, anecortave acetate (trade / sale name ), microtubule depolymerization inhibitors (such as Compretin A4 prodrug) and proteins or protein fragments (such as collagen 18 (endostatin)).

[0246] On the other hand, non-limiting examples of other therapies for treating sarcoma that can be administered to a subject in combination with Compound 1 or a pharmaceutical composition thereof include:

[0247] (1) Statins, such as lovastatin (e.g., brand / sales name );

[0248] (2) mTOR inhibitors, such as sirolimus, also known as rapamycin (e.g., brand / sale name ), temsirolimus (e.g., brand / sales name ), everolimus (e.g., brand / sales name ), and deforolimus;

[0249] (3) Farnesyl transferase inhibitors, such as tipifarnib (e.g., brand / sale name );

[0250] (4) antifibrotic agents such as pirfenidone;

[0251] (5) pegylated interferon, such as PEG-interferon α-2b;

[0252] (6) CNS stimulants, such as methylphenidate (trademark / marketing name );

[0253] (7) HER-2 antagonists, such as anti-HER-2 antibodies (such as trastuzumab) and kinase inhibitors (such as lapatinib);

[0254] (8) IGF-1 antagonists, such as anti-IGF-1 antibodies (e.g., AVE1642 and IMC-A11) or IGF-1 kinase inhibitors;

[0255] (9) EGFR / HER-1 antagonists, such as anti-EGFR antibodies (e.g., cetuximab, panitumumab) or EGFR kinase inhibitors (e.g., erlotinib (e.g., brand / sold under the name ), gefitinib);

[0256] (10) SRC antagonists, such as bosutinib;

[0257] (11) Cyclin-dependent kinase (CDK) inhibitors, such as seliciclib;

[0258] (12) Janus kinase 2 inhibitors, such as lestaurtinib;

[0259] (13) Proteasome inhibitors, such as bortezomib;

[0260] (14) Phosphodiesterase inhibitors, such as anagrelide;

[0261] (15) inosine monophosphate dehydrogenase inhibitors, such as thiazofurine;

[0262] (16) Lipoxygenase inhibitors, such as masoprocol;

[0263] (17) Endothelin antagonists;

[0264] (18) Retinoic acid receptor antagonists, such as tretinoin or alitretinoin;

[0265] (19) Immunomodulators, such as lenalidomide, pomalidomide, or thalidomide (e.g., brand / sales name );

[0266] (20) Kinase (e.g., tyrosine kinase) inhibitors, such as imatinib (e.g., brand / sale name ), dasatinib, erlotinib, nilotinib, gefitinib, sorafenib, sunitinib (e.g., brand / marketing name ), lapatinib, AEE788, or TG100801;

[0267] (21) Nonsteroidal anti-inflammatory drugs, such as celecoxib (trademark / sales name );

[0268] (22) Human granulocyte colony-stimulating factor (G-CSF), such as filgrastim (trademark / sales name );

[0269] (23) Folinic acid or calcium folinate;

[0270] (24) integrin antagonists, such as integrin α5β1-antagonists (e.g., JSM6427);

[0271] (25) Nuclear factor κβ (NF-κβ) antagonists, such as OT-551, which is also an antioxidant;

[0272] (26) Hedgehog inhibitors, such as CUR61414, cyclopamine, GDC-0449 or anti-hedgehog antibodies;

[0273] (27) Histone deacetylase (HDAC) inhibitors, such as SAHA (also known as vorinostat (trademark / sales name )), PCI-24781, SB939, CHR-3996, CRA-024781, ITF2357, JNJ-26481585 or PCI-24781;

[0274] (28) Retinoids, such as isotretinoin (e.g., brand / sale name );

[0275] (29) Hepatocyte growth factor / scatter factor (HGF / SF) antagonists, such as HGF / SF monoclonal antibodies (e.g. AMG 102);

[0276] (30) Synthetic chemicals, such as anti-tumor substances;

[0277] (31) Antidiabetic drugs, such as rosiglitazone maleate (e.g., brand / sales name );

[0278] (32) Antimalarials and amebicides, such as chloroquine (e.g., brand / sales name );

[0279] (33) Synthetic bradykinins, such as RMP-7;

[0280] (34) Platelet-derived growth factor receptor inhibitors, such as SU-101;

[0281] (35) Receptor tyrosine kinase inhibitors of Flk-1 / KDR / VEGFR2, FGFR1, and PDGFRβ, such as SU5416 and SU6668;

[0282] (36) Anti-inflammatory drugs, such as sulfasalazine (e.g., brand / sales name );

[0283] (37) TGF-β antisense therapy.

[0284] On the other hand, non-limiting examples of other therapies that can be administered to a subject in combination with Compound 1 or a pharmaceutical composition thereof for treating sarcoma include: synthetic nonapeptide analogs of natural gonadotropin-releasing hormone, such as leuprolide acetate (trademark / sold under the name ); nonsteroidal antiandrogens, such as flutamide (trade / sales name ) or Nilutamide (trademark / sales name ); nonsteroidal androgen receptor inhibitors, such as bicalutamide (trade / sales name ); steroid hormones, such as progesterone; antifungal agents, such as ketoconazole (trade / sale name ); glucocorticoids, such as prednisone; estramustine sodium phosphate (trade / sale name ); and bisphosphonates, such as pamidronate, alendronate, and risedronate.

[0285] On the other hand, examples of therapies that can be used in combination with Compound 1 or a pharmaceutical composition thereof for treating sarcoma include, but are not limited to, agents related to cancer immunotherapy (eg, cytokines, interleukins, and cancer vaccines).

[0286] In one aspect, the chemotherapy combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the chemotherapeutic agent is selected from (dacarbazine), (docetaxel), or (Adriamycin), (liposomal doxorubicin), gemcitabine, epirubicin, eribulin, ifosfamide, temozolomide, trabectedin, and (vincristine) group.

[0287] In another aspect, the chemotherapy combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the chemotherapeutic agent is selected from the group consisting of dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin, gemcitabine, epirubicin, eribulin, ifosfamide, temozolomide, trabectedin and vincristine.

[0288] In another aspect, the chemotherapeutic combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the chemotherapeutic agent is selected from the group consisting of dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin, gemcitabine, and vincristine.

[0289] In another aspect, the chemotherapeutic combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the chemotherapeutic agent is selected from the group consisting of dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin, and vincristine.

[0290] In certain aspects, Compound 1 or a pharmaceutical composition thereof is not used in combination with a drug that is primarily metabolized by CYP2D6 (e.g., antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors, etc.), antipsychotics, beta-adrenergic receptor blockers, or certain types of antiarrhythmics) to treat sarcoma.

[0291] On the other hand, the combination therapies provided herein for treating sarcomas can include the combined administration of Compound 1, or a pharmaceutical composition thereof, with at least one or more agents for treating and / or managing side effects, such as bleeding (usually transient, low-grade epistaxis), subungual hemorrhage, hemorrhagic cystitis (bladder bleeding and irritation), arterial and venous thrombosis, hypertension, delayed wound healing, asymptomatic proteinuria, nasal septum perforation, reversible posterior leukoencephalopathy syndrome associated with hypertension, dizziness, ataxia, headache, hoarseness, nausea, vomiting, diarrhea, rash, myelodysplastic syndrome, bone marrow suppression, fatigue, hypothyroidism, prolonged QT interval, or heart failure.

[0292] On the other hand, examples of agents that can be used as a therapy in combination with Compound 1 or a pharmaceutical composition thereof for alleviating side effects associated with sarcomas include, but are not limited to: antiemetics, such as ondansetron hydrochloride (trade / sale name ), Granisetron Hydrochloride (trademark / sales name ), lorazepam (trademark / sales name ) and dexamethasone (trade / sales name ).

[0293] On the other hand, examples of agents that can be used as a therapy in combination with Compound 1 or a pharmaceutical composition thereof for alleviating side effects associated with sarcoma chemotherapeutic agents include, but are not limited to: anti-hemorrhagic agents, such as mesna (trademark / sale name ).

[0294] On the other hand, treatment for sarcoma may include surgery or radiation therapy.

[0295] In one aspect, the chemotherapeutic combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the chemotherapeutic agent is selected from the group consisting of dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin, gemcitabine, epirubicin, eribulin, ifosfamide, temozolomide, trabectedin and vincristine.

[0296] In another aspect, the chemotherapeutic combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the chemotherapeutic agent is selected from the group consisting of dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin, gemcitabine, and vincristine.

[0297] In another aspect, the chemotherapeutic combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the chemotherapeutic agent is selected from the group consisting of dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin, and vincristine.

[0298] In another aspect, the chemotherapy combination therapy may include administering Compound 1 in combination with dacarbazine and doxorubicin, wherein the combination is administered tiw (once every three weeks), wherein dacarbazine is administered at 250 mg / m2 / day intravenous infusion for 5 consecutive days (equivalent to 800-1000 mg / m intravenous infusion every 3 weeks 2 ), doxorubicin 15 mg / m 2 Continuous intravenous infusion / day for 1-4 days.

[0299] In another aspect, the chemotherapy combination therapy may include administering Compound 1 in combination with doxorubicin, ifosfamide, and dacarbazine, wherein the combination is administered tiw (once every three weeks), and doxorubicin is administered at 20 mg / m 2 Ifosfamide was administered by continuous intravenous infusion at 2.5 mg / m 2 Dacarbazine was administered by continuous intravenous infusion at 300 mg / m 2 Continuous intravenous infusion / day for 3 days.

[0300] In one aspect, the effective dosage of Compound 1 and the effective dosage of the chemotherapeutic agent are reduced or administered less frequently when administered in combination with each other compared to regimens tested and known in the art.

[0301] In another aspect, the chemotherapeutic combination therapy comprises administering Compound 1 in combination with at least one chemotherapeutic agent, wherein the chemotherapeutic agent is selected from the group consisting of dacarbazine, docetaxel, doxorubicin, liposomal doxorubicin, and vincristine.

[0302] Reagent test kit

[0303] Provided herein are pharmaceutical packages or kits comprising one or more containers containing Compound 1 or a pharmaceutical composition thereof. In addition, one or more other therapeutics or other related agents useful for treating sarcomas may also be included in the pharmaceutical packages or kits. Also provided herein are pharmaceutical packages or kits comprising one or more containers containing one or more ingredients of the pharmaceutical compositions described herein. Optionally associated with the kit are precautions, which may be in the form prescribed by a governmental agency regulating the manufacture, use or sale of drugs or biological products, and which reflect the approval of the governmental agency of manufacture, use or sale for the administration of the agent to humans.

[0304] Biological Examples

[0305] Compound 1 was tested for its usefulness in affecting sarcoma proliferation using a comprehensive panel of in vitro and in vivo models.

[0306] background

[0307] Leiomyosarcoma accounts for 5-10% of soft tissue sarcomas. Typically, leiomyosarcoma has a complex karyotype and is associated with p53 mutations (Yang J, Du X, Chen K, A, Lazar AJ, Trent J, Lev D, Pollock R, Hao X, Hunt K, Zhang W. Genetic aberrations in soft tissue leiomyosarcoma. Cancer Lett. 2009 Mar 8; 275 (1): 1-8). The cell line SK-LMS-1 has a complex karyotype and a mutated p53 gene. Chemotherapy with doxorubicin-based drug regimens, such as a combination of doxorubicin and ifosfamide, is the standard of care. However, these regimens often lead to cardiotoxicity, rapid development of drug resistance, and no significant survival advantage. In a previous study using the SK-LMS-1 model, a constant dose (12.5 mg / kg biw) of compound 1 (Cpd 1) was tested in combination with different doses / schemes of doxorubicin and gemcitabine. The combination of compound 1 and gemcitabine was more effective than each as a monotherapy. Doxorubicin was not active as a monotherapy or in combination with compound 1. Here, SK-LMS-1 cells were passaged in vivo for a longer period of time than in previous studies, resulting in a more aggressive tumor model. The study tested the efficacy of compound 1 alone and in combination with the chemotherapy drugs liposomal doxorubicin (Doxil) and DTIC in treating mice with SK-LMS-1 human leiomyosarcoma.

[0308] Example 1

[0309] As shown in Table 1, the combination of Compound 1 and dacarbazine (DTIC) was tested in the SK-LMS-1 leiomyosarcoma mouse model. Figure 1A and Figure 1B As further shown, the combination of Compound 1 (12.5 mg / kg, PO, biw) and low-dose DTIC (4 mg / kg, IP, tiw) and the combination of Compound 1 (12.5 mg / kg, PO, biw) and high-dose DTIC (21 mg / kg, IP, qd5) were tested and compared with the results of Compound 1 alone, low-dose DTIC alone, high-dose DTIC alone, and vehicle, wherein biw means twice a week; wherein tiw means 3 times a week; wherein qd5 means once a day for 5 days; wherein IP means intraperitoneal administration; wherein IV means intravenous administration; and wherein PO means oral (oral gavage). As shown in each figure, the combination resulted in a synergistic reduction in mean tumor volume. Figure 1A and Figure 1B The comparison showed that the combination treatment with compound 1 (12.5 mg / kg, PO, biw) and DTIC (4 mg / kg, IP, tiw) (see Figure 1A) and combination therapy with Compound 1 (12.5 mg / kg, PO, biw) and DTIC (21 mg / kg, IP, qd5) (see Figure 1B ) compared to the control group, showing a dose response of reduced mean tumor volume. Table 1 further shows the percentage (%) reduction in tumor volume of the test mice (N) on day 28 in each treatment group, the tumor volume of a single mouse reaching 1000mm 3 The median time (days) and the corresponding interaction coefficient (IC) for each group, where * Represents p<0.05 (ANOVA, multiple comparisons vs. vehicle). Negative coefficients indicate that the inhibitory effect of the combination group is greater than expected based on the activity of the monotherapy. The more negative the coefficient, the greater the activity of the combination.

[0310] Table 1

[0311]

[0312] When dosing began, the tumor volume was approximately 222 mm 3 .like Figure 1A and 1B As shown in Figures 3A and 3A, the average tumor volume of mice treated with vehicle alone reached 1766 mm on day 28. 3 On day 28, most of the mice receiving vehicle were euthanized due to large tumor size (7 / 8; one mouse had no tumor growth). In mice receiving vehicle, the mean tumor volume reached 1000 mm 3 In mice treated with compound 1, tumor growth was moderately delayed, with the average volume reaching 1388 mm on day 28. 3 , reaching 1607mm on the 32nd day 3 At this time, all mice in the group had large tumors and were euthanized. The interaction coefficients for evaluating whether the measured effect of each combination was greater than the predicted effect are summarized in Table 1. The interaction coefficients were determined using the AUC of the tumor volume vs day curve from day 0 to day 28. Considering the data after day 28, the interaction coefficients for reaching 1000 mm 3 A negative interaction coefficient indicates a synergistic effect.

[0313] Results of Example 1

[0314] Compound 1 (12.5 mg / kg, biw) as monotherapy modestly delayed tumor growth. High-dose DTIC (21 mg / kg, IP, qd5) as monotherapy delayed tumor growth more effectively than compound 1. Low-dose DITC (4 mg / kg, IP, tiw) as monotherapy had little efficacy.

[0315] The combination of Compound 1 and low-dose DITC was more effective than Compound 1 alone or low-dose DTIC alone at a low dose. This result was unexpected because low-dose DTIC had little efficacy as a monotherapy. The combination of Compound 1 and high-dose DITC was more effective than Compound 1 alone or high-dose DTIC alone.

[0316] Figure 1A Shown are the mean tumor volumes over time after administration of vehicle, Compound 1, DTIC (4 mg / kg IP tiw) or a combination of Compound 1 and DTIC (4 mg / kg IP tiw). DTIC was not active at the dose / schedule of 4 mg / kg IP tiw. Surprisingly, the combination of Compound 1 and DTIC was more effective than either of them alone. Three mice continued in the study until day 136, and two mice continued in the study until day 150 before being withdrawn from the study. On day 150, one of the two tumors was too small to be measured.

[0317] Figure 2B Shown are the average tumor volumes over time after administration of vehicle, compound 1 alone, DTIC (4 mg / kg IP tiw) alone, and DTIC (21 mg / kg IP qd5) alone, or a combination of compound 1 and DTIC (4 mg / kg IP tiw), or a combination of compound 1 and DTIC (21 mg / kg IP qd5). With this dose and DTIC regimen, DTIC was more effective than compound 1 and completely prevented tumor growth on day 18, although escape of rapidly growing tumors occurred after day 21. The efficacy of the combination of compound 1 and DTIC (21 mg / kg IP qd5) was much greater than the administration of either of them alone, and on day 98, tumor growth was almost completely inhibited. After day 98, compound 1 was no longer administered to mice. From day 98 to day 150, when mice withdrew from the study, of the 8 mice that continued to study, three had enlarged tumors, but five had no enlarged tumors. On day 123, one mouse withdrew from the study due to a larger tumor. When the remaining seven mice were withdrawn from the study on day 165, five mice had tumors that were too small to measure, and two other mice had tumors that were palpable but smaller than 100 mm. 3 .

[0318] For both doses, the effect of the combination of Compound 1 and DTIC was greater than either therapy alone (interaction coefficient was negative; Table 1). Greater additivity was observed at the 21 mg / kg qd5 dose than at the 4 mg / kg tiw dose.

[0319] Example 2

[0320] As shown in Table 2, the combination of Compound 1 and docetaxel was tested in the SK-UT-1 leiomyosarcoma mouse model. Figure 2A and Figure 2B As further shown, Compound 1 (12.5 mg / kg PO biw) and low-dose docetaxel (5 mg / kg IP biw5.5, administered 11 times in total) and Compound 1 (12.5 mg / kg PO biw) and high-dose docetaxel (15 mg / kg IP qw6) (administered 6 times in total) were tested and compared with the results of Compound 1 alone, low-dose docetaxel alone, high-dose docetaxel alone, and vehicle, wherein biw means twice-weekly dosing; wherein qw6 means once-weekly dosing for 6 weeks; wherein IP means intraperitoneal administration; wherein PO means oral (oral gavage). As shown in each figure, the combination resulted in a synergistic reduction in mean tumor volume. Figure 2A and Figure 2B The comparison showed that the combination treatment with compound 1 (12.5 mg / kg PO biw) and docetaxel (5 mg / kg IP tiw, 11 doses in total) (see Figure 2A ) and combination therapy with Compound 1 (12.5 mg / kg PO biw) and docetaxel (15 mg / kg IP qw6) (see Figure 2B ) compared with the control group, the average tumor growth was inhibited in a dose-dependent manner. Table 2 further shows the percentage (%) reduction in tumor volume of the test mice (N) on day 28 in each treatment group, the tumor volume of a single mouse reaching 1000mm 3 The median time (days) and the corresponding interaction coefficient (IC) for each group, where * Represents p<0.05 (ANOVA, multiple comparisons vs. vehicle). Negative coefficients indicate that the inhibitory effect of the combination group is greater than expected based on the activity of the monotherapy. The more negative the coefficient, the greater the activity of the combination.

[0321] Table 2

[0322]

[0323] The mean tumor volume at the start of dosing was ~163 mm 3 .like Figure 2A and 2B As shown in Figure 2, the average tumor volume of mice treated with vehicle alone (Group 1) reached 1520 mm on day 25. 3 On day 25, vehicle-administered mice were euthanized due to large tumor size. In vehicle-administered mice, the mean tumor volume reached 1000 mm 3In mice treated with compound 1 (Group 2), tumor growth was delayed, with the average volume reaching 983 mm on day 25. 3 (35% inhibition vs vehicle; p<0.05, analysis of covariance (ANOVA), multiple comparisons vs vehicle), reaching 1508 mm on day 42 3 In mice treated with docetaxel, tumor growth was delayed at 15 mg / kg intraperitoneally (IP) once weekly for 6 weeks (QW6; Group 5), but not at 5 mg / kg IP BIW x 5.5 (11 administrations in total; Group 3).

[0324] This study utilized SK-UT-1 leiomyosarcoma tumor cells implanted into the flanks of athymic nude mice. In this model, compound 1 at a dose of 12.5 mg / kg BIW6 was shown to be effective as a monotherapy, reducing tumor growth by approximately 35% on day 25 and limiting tumor growth to 1000 mm 3 The median time to progression was delayed by approximately 1.7-fold. As a monotherapy, the high-dose docetaxel (15 mg / kg IP QW6) group had a tumor volume of 1486 mm on day 25 (when mice were withdrawn from the study). 3 , showing 78% inhibition, p<0.05, analysis of variance (ANOVA, multiple comparisons vs vehicle). Low-dose docetaxel (5 mg / kg IPBIW5.5) had no effect as a monotherapy, but the combination of compound 1 and low-dose docetaxel significantly delayed tumor growth. On day 25, the average tumor volume of mice administered the combination of compound 1 and low-dose docetaxel was 128 mm 3 , showing 92% inhibition compared to vehicle, p < 0.05 (ANOVA, multiple comparisons vs vehicle), on day 84, the tumor volume was 1251 mm 3 The combination of Compound 1 and high-dose docetaxel was more effective than either of them alone. On day 25, the mean tumor volume of mice dosed with the combination was 77 mm 3 , showing 95% inhibition compared to vehicle (p<0.05, ANOVA, multiple comparisons vs vehicle). On day 145, 8 / 10 mice continued on study, and all 8 mice had tumors that were too small to measure (<50 mm 3 ).

[0325] Results of Example 2

[0326] Compound 1 (12.5 mg / kg BIW6) as monotherapy modestly delayed tumor growth. Low-dose docetaxel as monotherapy had no efficacy at 5 mg / kg IP BIW5.5 (administered 11 times), but high-dose docetaxel at 15 mg / kg IP QW6 was more effective than compound 1.

[0327] The combination of low-dose or high-dose docetaxel and Compound 1 was more effective than either of them as monotherapy.

[0328] Higher morbidity / mortality was observed in the combination of Compound 1 and docetaxel. Using the combination of low-dose docetaxel (5 mg / kg IP BIW5.5) and Compound 1, patients with tumors reaching 1000 mm 3 Previously, 5 / 10 mice were moribund or euthanized and dropped out of the study. In the combination of high-dose docetaxel (15 mg / kg IP QW6) and compound 1, when tumors reached 1000 mm 3 Previously, 2 / 10 mice were moribund or euthanized and dropped out of the study.

[0329] Figure 2A The mean tumor volume over time after administration of vehicle, compound 1 alone, low-dose docetaxel alone (5 mg / kg IP BIW5.5; twice weekly for 51 / 2 weeks, 11 times) and a combination of compound 1 and low-dose docetaxel is shown. Low-dose docetaxel alone (5 mg / kg IP BIW5.5) had no efficacy as a monotherapy, but the combination of compound 1 and low-dose docetaxel significantly delayed tumor growth. On day 25, the average tumor size of mice administered the combination was 128 mm 3 , showing 92% inhibition compared to vehicle (p<0.05, ANOVA, multiple comparisons vs vehicle), with the mean tumor size at day 84 being 1251 mm 3 .

[0330] Figure 2B The mean tumor volume over time after administration of vehicle, Compound 1, high-dose docetaxel (15 mg / kg IP QW6), or a combination of Compound 1 and high-dose docetaxel is shown. As a monotherapy, the tumor volume on day 25 with high-dose docetaxel was 1486 mm 3 , showing 78% inhibition, at which point mice were withdrawn from the study (p<0.05, ANOVA, multiple comparisons vs vehicle). The combination of Compound 1 and high-dose docetaxel was more effective than either of them alone. On day 25, the mean tumor size of mice dosed with the combination was 77 mm 3, showing 95% inhibition compared to vehicle (p<0.05, ANOVA, multiple comparisons vs vehicle). On day 145, 8 / 10 mice continued on study, and all 8 mice had tumors that were too small to measure (<50 mm 3 ).

[0331] To compare tumor growth, the area under the curve comparing tumor volume vs. day for each mouse was calculated and then averaged for each group. As shown in Figure 1, the combination of Compound 1 and docetaxel had a higher efficacy compared to monotherapy.

[0332] The interaction coefficients for assessing whether the measured effect was greater than the predicted effect are summarized in Table 2. The interaction coefficients were determined using the AUC of the tumor volume vs day curve from day 0 to day 25. Considering the data after day 25, the interaction coefficients for reaching 1000 mm 3 A negative interaction coefficient indicates a synergistic effect.

[0333] Example 3

[0334] As shown in Table 3, the combination of Compound 1 and liposomal doxorubicin was tested in the SK-LMS-1 leiomyosarcoma mouse model. Figure 3A and Figure 3B As further shown, the combination of Compound 1 (12.5 mg / kg, PO, biw) and low-dose liposomal doxorubicin (3 mg / kg, IV, qw5) and high-dose liposomal doxorubicin (9 mg / kg, IV, qw5) was tested and compared with the results of Compound 1 alone, liposomal doxorubicin alone, and vehicle alone, wherein biw means twice weekly administration alone; wherein qw5 means once weekly administration alone for 5 weeks; wherein IV means intravenous administration; wherein PO means oral (oral gavage). As shown in each figure, the combination resulted in a synergistic reduction in mean tumor volume. Figure 3A and Figure 3B A comparison of the results of the present study showed that the combination therapy of Compound 1 (12.5 mg / kg PO biw) and low-dose liposomal doxorubicin (3 mg / kg IV qw5) was effective in the treatment of patients with Figure 3A ) and combination therapy with Compound 1 (12.5 mg / kg PO biw) and high-dose liposomal doxorubicin (9 mg / kg IV qw5) (see Figure 3B ) compared with the control group, the average tumor growth was inhibited in a dose-dependent manner. Table 1 further shows the percentage (%) reduction in tumor volume of the test mice (N) on day 28 in each treatment group, the tumor volume of a single mouse reaching 1000mm 3 The median time (days) and the corresponding interaction coefficient (IC) for each group, where *Represents p<0.05 (ANOVA, multiple comparisons vs. vehicle). Negative coefficients indicate that the inhibitory effect of the combination group is greater than expected based on the activity of the monotherapy. The more negative the coefficient, the greater the activity of the combination.

[0335] Table 3

[0336]

[0337]

[0338] When dosing began, the tumor volume was approximately 222 mm 3 .like Figure 3A and 3B As shown in Figure 2, the average tumor volume of mice treated with vehicle alone reached 1766 mm on day 28. 3 On day 28, most mice receiving vehicle were euthanized due to large tumor size (7 / 8; one mouse had no tumor growth). In mice receiving vehicle, the mean tumor volume reached 1000 mm 3 In mice treated with compound 1, tumor growth was moderately delayed, with the average volume reaching 1388 mm on day 28. 3 , reaching 1607mm on the 32nd day 3 At this time, all mice in this group had large tumors and were euthanized. The interaction coefficients assessing whether the measured effect of each combination was greater than the predicted effect are summarized in Table 3. The interaction coefficients were determined using the AUC of the tumor volume vs day curve from day 0 to day 28. Considering the data after day 28, the interaction coefficients for reaching 1000 mm 3 A negative interaction coefficient indicates a synergistic effect.

[0339] Results of Example 3

[0340] Compound 1 (12.5 mg / kg, biw) as monotherapy modestly delayed tumor growth. Liposomal doxorubicin was more effective than compound 1 as monotherapy at both low and high doses, delaying tumor growth. However, the high-dose liposomal doxorubicin regimen was poorly tolerated.

[0341] The combination of Compound 1 and low-dose liposomal doxorubicin is more effective than Compound 1 alone or low-dose liposomal doxorubicin alone. The combination of Compound 1 and high-dose liposomal doxorubicin is more effective than Compound 1 alone or high-dose liposomal doxorubicin alone. However, the combination of Compound 1 and high-dose liposomal doxorubicin is poorly tolerated.

[0342] Figure 3AShown are mean tumor volumes over time following administration of vehicle, Compound 1, liposomal doxorubicin (3 mg / kg IV qw5), or a combination of Compound 1 and liposomal doxorubicin (3 mg / kg IV qw5).

[0343] Figure 3B Mean tumor volume over time after administration of vehicle, compound 1 alone, liposomal doxorubicin alone (9 mg / kg IV, on days 0, 9, 15, 21, and 28), or a combination of compound 1 and liposomal doxorubicin (9 mg / kg IV) is shown. Liposomal doxorubicin delayed the growth of SK-LMS-1 more effectively than compound 1 as a monotherapy, and was more effective at a dose of 9 mg / kg IV (days 0, 9, 15, 21, and 28) than at a dose of 3 mg / kg IV qw5. Although compound 1 had limited efficacy as a monotherapy, compound 1 enhanced the efficacy of liposomal doxorubicin in both regimens (the interaction coefficient was negative, indicating a synergistic effect).

[0344] Example 4 and Results

[0345] The combination of compound 1 and doxorubicin was tested in the HT1080 fibrosarcoma mouse model. Figure 4 As shown, the combination of Compound 1 (15 mg / kg PO biw) and doxorubicin (0.3 mg / kg IP q2d) was tested and resulted in a synergistic reduction in mean tumor volume compared to Compound 1 alone, doxorubicin alone, and vehicle alone, wherein biw indicates twice-weekly dosing; wherein q2d indicates once-every-two-day dosing.

[0346] Example 5 and Results

[0347] Compound 1 was administered as first-line therapy in NCT02404480, a Phase 1a clinical trial designed to evaluate the safety and PK characteristics of Compound 1 in patients with advanced solid tumors (AST). Figure 5 As shown, for 31 evaluable patients, 2 / 31 patients had mixed / partial responses and 5 / 31 patients had stable disease.

[0348] Example 6 and Results

[0349] The PK curve of the NCT02404480 clinical trial shown in Figure 6 (by AUC 持续 and C max Measured) showed that for a target AUC of 13.1 ng-hr / mL 持续 and a target C of 679 ng / mL max, the effective dose of compound 1 at 2.6 mg / kg was selected as the dose for Phase II clinical trial.

[0350] Example 7 and Results

[0351] The combination of compound 1 and vincristine was tested in the HT1080 fibrosarcoma xenograft mouse model. Fig. 7A and Figure 7B As shown, the combination of Compound 1 (12.5 mg / kg PO biw) and vincristine (0.1 mg / kg IP tiw) was tested and compared to the results of Compound 1 alone, vincristine alone, and vehicle, where biw means twice weekly dosing; where tiw means 3 weekly dosing. Fig. 7A and Figure 7B A comparison of the results showed that the combination treatment with Compound 1 (12.5 mg / kg PO biw) and vincristine (0.1 mg / kg IP tiw) (see Fig. 7A ) and combination treatment with Compound 1 (12.5 mg / kg PO biw) and vincristine (0.3 mg / kg IP tiw) (see Figure 7B ) showed a dose-dependent decrease in mean tumor growth compared to the control group.

[0352] As shown herein, preclinical in vivo activity of Compound 1 in combination therapy with standard of care chemotherapeutic agents for the treatment of sarcomas has been demonstrated, showing synergistic and additive activity when administered in combination with at least one such chemotherapeutic agent. These results strongly demonstrate the potential clinical therapeutic utility of the combination of Compound 1 and at least one chemotherapeutic agent for the treatment of sarcomas.

[0353] References

[0354] Regardless of whether or not a document cited herein is specifically and individually indicated as incorporated by reference, all documents mentioned herein are hereby incorporated by reference in their entirety into this application for any and all purposes to the same extent as if each individual document were fully set forth herein.

[0355] Having now fully described the claimed subject matter, those skilled in the art will appreciate that the same may be implemented within a broad range of equivalents without affecting the scope of the subject matter or aspects described herein. The appended claims are intended to be interpreted as including all such equivalents.

Claims

1. An effective dose of 5-fluoro-2-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-N-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)- 4 -[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising Compound 1 and a chemotherapeutic agent for the preparation of a medicament for treating a sarcoma in a subject in need thereof: in, The chemotherapeutic agent is dacarbazine; Dacarbazine was administered at 1000 mg / m every 3 weeks. 2 The amount is administered to the subject.

2. The use according to claim 1, wherein the effective dose of Compound 1 is selected from 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg and 300 mg, and is orally administered twice a week.

3. The use according to claim 2, wherein the effective dose of Compound 1 is selected from 125 mg, 150 mg, 175 mg, 225 mg, 250 mg, 275 mg and 300 mg, and is orally administered twice a week.

4. The method according to claim 1, further comprising an additional chemotherapeutic agent, wherein the additional chemotherapeutic agent is selected from the group consisting of docetaxel, doxorubicin, liposomal doxorubicin, gemcitabine, epirubicin, eribulin, ifosfamide, temozolomide, trabectedin and vincristine.

5. The use according to claim 4, wherein the additional chemotherapeutic agent is selected from the group consisting of docetaxel, doxorubicin, liposomal doxorubicin and vincristine.

6. The use according to claim 5, wherein the additional chemotherapeutic agent is docetaxel.

7. The use according to claim 5, wherein the additional chemotherapeutic agent is doxorubicin.

8. The use according to claim 5, wherein the additional chemotherapeutic agent is liposomal doxorubicin.

9. The use according to claim 5, wherein the additional chemotherapeutic agent is vincristine.

10. The use according to claim 1, wherein the effective dose of Compound 1 is 100 mg to 400 mg, administered orally twice a week.

11. The use according to claim 1, wherein the effective dose of Compound 1 is 200 mg to 400 mg, administered orally twice a week.

12. The use according to claim 1, wherein the effective dose of Compound 1 is 200 mg, administered orally twice a week.

13. The use according to claim 1, wherein the effective dose of Compound 1 is 300 mg, administered orally twice a week.

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