Combinations Containing MetAP2 Inhibitors for the Treatment of Cancer

Abstract

The present disclosure provides combination pharmaceuticals comprising a MetAP2 inhibitor for the treatment of cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 320,347, filed March 16, 2022, and U.S. Provisional Application No. 63 / 340,726, filed May 11, 2022. The contents of each of the foregoing patent applications are incorporated herein by reference in their entirety. [Background technology]

[0002] Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death among American women. Despite advances in breast cancer treatments, certain subtypes of breast cancer and specific subpopulations of breast cancer patients remain resistant to treatment and have high mortality rates.

[0003] For example, triple-negative breast cancer (TNBC) is one of four clinically classified subtypes of invasive breast cancer, accounting for 10-20% of all breast cancer cases, but exhibits higher invasiveness than other breast cancer subtypes. TNBC is phenotypically negative for estrogen receptor (ER) and progesterone receptor (PR), and lacks gene amplification / protein overexpression of human epidermal growth factor receptor 2 (HER2). These specific characteristics of TNBC mean that TNBC patients cannot benefit from hormonal therapy, or therapies that target the tumorigenic HER2 pathway. Instead, treatment of TNBC patients with recurrent and / or metastatic disease relies on cytotoxic chemotherapy, with a median survival of approximately 13 months from the time of diagnosis of recurrence or distant metastasis. Thus, there is an urgent need in the art for improved compositions and methods for the treatment of TNBC.

[0004] As another example, many cases of breast cancer are mutated in the PIK3CA gene. These breast cancers with PIK3CA gene mutations are often more aggressive, leading to increased mortality. Although some therapeutic agents (such as copanlisib) that specifically target the PIK3CA gene product, PI3Kα, or target it as part of a pan-PI3K isoform targeting therapy, have been shown to be clinically useful in patients with PIK3CA mutations, these therapeutic agents induce dangerous side effects, such as hyperglycemia and hyperinsulinemia, which limit the effectiveness of these drugs in the clinic. Thus, there is an urgent need in the art for improved compositions and methods for the treatment of breast cancer with PIK3CA gene mutations, including compositions and methods that mitigate the dangerous side effects of existing PI3Kα inhibitors.

[0005] The present disclosure provides combinations comprising a MetAP2 inhibitor for the treatment of breast cancer. Summary of the Invention

[0006] The present disclosure provides a combination comprising at least one MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, and eribulin, or a pharma- ceutically acceptable salt thereof, for use in treating cancer in a subject.

[0007] The present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof, and at least one therapeutically effective amount of eribulin or a pharma- ceutically acceptable salt thereof.

[0008] The present disclosure provides a MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, for use in a method of treating cancer in a subject, the method further comprising administering eribulin or a pharma- ceutically acceptable salt thereof.

[0009] The present disclosure provides eribulin, or a pharma- ceutically acceptable salt thereof, for use in a method of treating cancer in a subject, the method further comprising administering at least one MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof.

[0010] The present disclosure provides a combination comprising at least one MetAP2 inhibitor or a pharma- ceutical acceptable salt thereof, fulvestrant or a pharma- ceutical acceptable salt thereof, and alpelisib or a pharma- ceutical acceptable salt thereof, for use in treating cancer in a subject.

[0011] The present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharma- ceutical acceptable salt thereof, at least one therapeutically effective amount of fulvestrant or a pharma- ceutical acceptable salt thereof, and at least one therapeutically effective amount of alpelisib or a pharma- ceutical acceptable salt thereof.

[0012] The present disclosure provides a MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, for use in a method of treating cancer in a subject, the method further comprising administering fulvestrant, or a pharma- ceutically acceptable salt thereof, and alpelisib, or a pharma- ceutically acceptable salt thereof.

[0013] The present disclosure provides fulvestrant, or a pharma- ceutically acceptable salt thereof, for use in a method of treating cancer in a subject, the method further comprising administering at least one MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, and alpelisib, or a pharma- ceutically acceptable salt thereof.

[0014] The present disclosure provides alpelisib, or a pharma- ceutically acceptable salt thereof, for use in a method of treating cancer in a subject, the method further comprising administering at least one MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, and fulvestrant, or a pharma- ceutically acceptable salt thereof.

[0015] Any of the above aspects, or any other aspect described herein, may be combined with any other aspect.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification, the singular includes the plural unless the context clearly indicates otherwise. For example, the terms "a", "an" and "the" are understood to be singular or plural, and the term "or" is understood to be inclusive. By way of example, "an element" means one or more elements. Throughout this specification, the word "comprising" or variations such as "comprises" or "comprising" are understood to mean the inclusion of the described element, integer, or step, or group of elements, integers, or steps, but not the exclusion of any other element, integer, or step, or group of elements, integers, or steps. "About" can be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values ​​provided herein are modified by the term "about."

[0017] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. References cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, shall control. In addition, the materials, methods, and examples are merely illustrative and not intended to be limiting. Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. [Brief description of the drawings]

[0018] The above and further features will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings. [Figure 1] FIG. 1 is a schematic diagram of the dosing regimen of the present disclosure. [Diagram 2] FIG. 2 is a schematic diagram of the dosing regimen of the present disclosure. [Diagram 3] FIG. 3 is a graph of tumor volume in mice treated with various combinations of the present disclosure. [Figure 4] FIG. 4 is a graph of tumor volumes in individual animals treated with vehicle control or 2 mg / kg eribulin. [Diagram 5] FIG. 5 is a series of graphs showing tumor volume in mice treated with various combinations of the present disclosure. [Figure 6] FIG. 6 is a series of graphs showing tumor volume in mice treated with various combinations of the present disclosure. [Figure 7] FIG. 7 is a series of graphs showing tumor volume in mice treated with various combinations of the present disclosure. [Figure 8] FIG. 8 is a series of charts showing tumor growth inhibition in mice treated with various combinations of the present disclosure. [Figure 9] FIG. 9 is a series of graphs showing body weight and body weight change in mice treated with various combinations of the present disclosure. [Figure 10] FIG. 10 is a graph showing the survival rate of mice treated with various combinations of the present disclosure. [Figure 11] FIG. 11 is a series of graphs showing survival rates of mice treated with various combinations of the present disclosure. [Figure 12] FIG. 12 is a graph showing adipose tissue mass in mice treated with various combinations of the present disclosure. [Figure 13] FIG. 13 is a graph showing leptin levels in mice treated with various combinations of the present disclosure. [Figure 14]FIG. 14 is a graph showing plasma adiponectin levels in mice treated with various combinations of the present disclosure. [Figure 15] FIG. 15 is a graph showing the leptin / adiponectin ratio (LAR) in plasma samples isolated from mice treated with various combinations of the present disclosure. [Figure 16] FIG. 16 is a graph showing plasma insulin levels in mice treated with various combinations of the present disclosure. [Figure 17] FIG. 17 is a graph showing plasma SFRP1 levels in mice treated with various combinations of the present disclosure. [Figure 18] FIG. 18 is a series of graphs showing plasma interleukin levels in mice treated with various combinations of the present disclosure. [Figure 19] FIG. 19 is a series of graphs showing plasma hematopoietic growth factor (G-CSF and M-CSF) levels in plasma samples isolated from mice treated with various combinations of the present disclosure. [Figure 20] FIG. 20 is a series of graphs showing FABP4 and resistin levels in plasma samples isolated from mice treated with various combinations of the present disclosure. [Figure 21] FIG. 21 is a graph showing plasma FGF-21 levels in mice treated with various combinations of the present disclosure. [Figure 22] FIG. 22 is a series of graphs showing ALP, ALT, and AST levels in mice treated with various combinations of the present disclosure. [Diagram 23] FIG. 23 is a graph showing cholesterol levels in mice treated with various combinations of the present disclosure. [Figure 24] FIG. 24 is a graph showing bilirubin levels in the various treatment groups. [Diagram 25] FIG. 25 is a graph showing creatine kinase levels in mice treated with various combinations of the present disclosure. [Figure 26]FIG. 26 is a graph showing albumin levels in mice treated with various combinations of the present disclosure. [Figure 27] FIG. 27 is a graph showing globulin levels in mice treated with various combinations of the present disclosure. [Figure 28] FIG. 28 is a graph showing the albumin-globulin ratio (AGR) in mice treated with various combinations of the present disclosure. [Figure 29] FIG. 29 is a series of graphs showing red blood cell (RBC) and hematocrit (HCT) values ​​in mice treated with various combinations of the present disclosure. [Diagram 30] FIG. 30 is a graph showing hemoglobin (Hgb) levels in the various treatment groups. [Diagram 31] FIG. 31 is a series of graphs showing white blood cell (WBC) and monocyte levels in mice treated with various combinations of the present disclosure. [Diagram 32] FIG. 32 is a series of graphs showing lymphocyte and neutrophil levels in mice treated with various combinations of the present disclosure. [Diagram 33] FIG. 33 is a series of graphs showing tumor volume and tumor volume change in mice treated with various combinations of the present disclosure. [Diagram 34] FIG. 34 is a series of graphs showing body weight and body weight change in mice treated with various combinations of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Detailed Description The present disclosure provides, inter alia, methods for treating cancer or preventing treatment-induced hyperglycemia comprising administering to a subject in need thereof at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, in combination with at least one additional therapeutic agent (e.g., a second therapeutic agent, or a second and a third therapeutic agent).

[0020] Combinations and methods of the present disclosure The present disclosure provides a combination therapy comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutically acceptable salt thereof, at least one therapeutically effective amount of at least one PI3K inhibitor or a pharma- ceutically acceptable salt thereof, and at least one therapeutically effective amount of at least one selective estrogen receptor degrader (SERD).

[0021] The present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to said subject in need thereof a therapeutically effective amount of at least one of the above-described combination therapies.

[0022] The present disclosure provides methods for preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof, comprising administering to said subject in need thereof a therapeutically effective amount of at least one of the above-described combination therapies.

[0023] The present disclosure provides a pharmaceutical composition comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutical acceptable salt thereof, at least one therapeutically effective amount of at least one PI3K inhibitor or a pharma- ceutical acceptable salt thereof, and at least one therapeutically effective amount of at least one selective estrogen receptor degrader (SERD).

[0024] The present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to said subject in need thereof a therapeutically effective amount of at least one of the above-described pharmaceutical compositions.

[0025] The present disclosure provides methods for preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof, comprising administering to said subject in need thereof a therapeutically effective amount of at least one of the above-described pharmaceutical compositions.

[0026] The present disclosure provides a kit comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutically acceptable salt thereof, at least one therapeutically effective amount of at least one PI3K inhibitor or a pharma- ceutically acceptable salt thereof, and at least one therapeutically effective amount of at least one selective estrogen receptor degrader (SERD).

[0027] The present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the above-described kits.

[0028] The present disclosure provides methods for preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one of the above-described kits.

[0029] The present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutical acceptable salt thereof, at least one therapeutically effective amount of at least one PI3K inhibitor or a pharma- ceutical acceptable salt thereof, and at least one therapeutically effective amount of at least one selective estrogen receptor degrader (SERD).

[0030] The present disclosure provides a method for preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof, comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutical acceptable salt thereof, at least one therapeutically effective amount of at least one PI3K inhibitor or a pharma- ceutical acceptable salt thereof, and at least one therapeutically effective amount of at least one selective estrogen receptor degrader (SERD).

[0031] The present disclosure provides for the use of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, in combination with at least one PI3K inhibitor, or a pharma- ceutically acceptable salt thereof, and at least one SERD, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0032] The present disclosure provides use of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, in combination with at least one PI3K inhibitor, or a pharma- ceutically acceptable salt thereof, and at least one SERD, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and / or alleviation of treatment-induced hyperglycemia in a subject in need thereof.

[0033] The present disclosure provides for the use of at least one PI3K inhibitor, or a pharma- ceutically acceptable salt thereof, in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and at least one SERD, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0034] The present disclosure provides for the use of at least one PI3K inhibitor, or a pharma- ceutically acceptable salt thereof, in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and at least one SERD, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and / or alleviation of treatment-induced hyperglycemia in a subject in need thereof.

[0035] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutically acceptable salt thereof, at least one PI3K inhibitor or a pharma- ceutically acceptable salt thereof, and at least one SERD or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of cancer.

[0036] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutically acceptable salt thereof, at least one PI3K inhibitor or a pharma- ceutically acceptable salt thereof, and at least one SERD or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the prevention and / or alleviation of treatment-induced hyperglycemia in a subject in need thereof.

[0037] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, for use in combination with at least one PI3K inhibitor, or a pharma- ceutically acceptable salt thereof, and at least one SERD, or a pharma- ceutically acceptable salt thereof, in the treatment of cancer.

[0038] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, for use in combination with at least one PI3K inhibitor, or a pharma- ceutically acceptable salt thereof, and at least one SERD, or a pharma- ceutically acceptable salt thereof, in preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof.

[0039] The present disclosure provides at least one PI3K inhibitor, or a pharma- ceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and at least one SERD, or a pharma- ceutically acceptable salt thereof, in the treatment of cancer.

[0040] The present disclosure provides at least one PI3K inhibitor, or a pharma- ceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and at least one SERD, or a pharma- ceutically acceptable salt thereof, in preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof.

[0041] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutically acceptable salt thereof, at least one PI3K inhibitor or a pharma- ceutically acceptable salt thereof, and at least one SERD or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer.

[0042] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutically acceptable salt thereof, at least one PI3K inhibitor or a pharma- ceutically acceptable salt thereof, and at least one SERD or a pharma- ceutically acceptable salt thereof, for use in preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof.

[0043] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutically acceptable salt thereof, at least one PI3K inhibitor or a pharma- ceutically acceptable salt thereof, and at least one SERD or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer.The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer, further comprising at least one PI3K inhibitor or a pharma- ceutically acceptable salt thereof, and at least one SERD or a pharma- ceutically acceptable salt thereof.The present disclosure provides a combination comprising at least one PI3K inhibitor or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer, further comprising at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutically acceptable salt thereof, and at least one SERD or a pharma- ceutically acceptable salt thereof. The present disclosure provides a combination comprising at least one SERD, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, the combination further comprising at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and at least one PI3K inhibitor, or a pharma- ceutically acceptable salt thereof.

[0044] 1. A method for treating cancer, comprising administering at least one PI3K inhibitor, or a pharma- ceutically acceptable salt thereof, and at least one SERD, or a pharma- ceutically acceptable salt thereof, to a patient in need of treatment with cancer.

[0045] A PI3K inhibitor, or a pharma- ceutically acceptable salt thereof, for use in a method for treating cancer, the method further comprising administering at least one MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, and at least one SERD, or a pharma- ceutically acceptable salt thereof.

[0046] 1. A method for treating cancer, comprising administering at least one PI3K inhibitor, or a pharma- ceutically acceptable salt thereof, and at least one MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, to a subject.

[0047] In some embodiments, MetAP2 inhibitor or its pharmaceutically acceptable salt, PI3K inhibitor or its pharmaceutically acceptable salt, and SERD or its pharmaceutically acceptable salt can be administered by the same administration route.In some embodiments, MetAP2 inhibitor or its pharmaceutically acceptable salt, PI3K inhibitor or its pharmaceutically acceptable salt, and SERD or its pharmaceutically acceptable salt can be administered by different administration routes.In some embodiments, two of the three compounds in the triple combination can be administered by the same administration route, and the other one can be administered by a different administration route.

[0048] In some embodiments, the MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof, the PI3K inhibitor or a pharma- ceutically acceptable salt thereof, and the SERD or a pharma- ceutically acceptable salt thereof can be administered simultaneously. In some embodiments, two compounds of the triple combination can be administered simultaneously.

[0049] In some embodiments, the MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof, the PI3K inhibitor or a pharma- ceutically acceptable salt thereof, and the SERD or a pharma- ceutically acceptable salt thereof can be administered in close temporal proximity.

[0050] In some embodiments, the MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof, the PI3K inhibitor or a pharma- ceutically acceptable salt thereof, and the SERD or a pharma- ceutically acceptable salt thereof can be administered in any order.

[0051] The present disclosure provides a combination therapy comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and at least one therapeutically effective amount of at least one microtubule targeting compound, or a pharma- ceutically acceptable salt thereof.

[0052] The present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to said subject in need thereof a therapeutically effective amount of at least one of the above-described combination therapies.

[0053] The present disclosure provides a pharmaceutical composition comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and at least one therapeutically effective amount of at least one microtubule targeting compound, or a pharma- ceutically acceptable salt thereof.

[0054] The present disclosure provides a method of treating cancer in a subject in need of such treatment, comprising administering to the subject in need of treatment a therapeutically effective amount of at least one of the pharmaceutical compositions described above.

[0055] The present disclosure provides a kit comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutically acceptable salt thereof, and at least one therapeutically effective amount of at least one microtubule targeting compound or a pharma- ceutically acceptable salt thereof.

[0056] The present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the above-described kits.

[0057] The present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutical acceptable salt thereof, and at least one therapeutically effective amount of at least one microtubule targeting compound, or a pharma- ceutical acceptable salt thereof.

[0058] The present disclosure provides for the use of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, in combination with at least one microtubule-targeting compound, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0059] The present disclosure provides the use of at least one microtubule targeting compound, or a pharma- ceutically acceptable salt thereof, in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0060] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and at least one microtubule targeting compound, or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of cancer.

[0061] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, for use in combination with at least one microtubule-targeting compound, or a pharma- ceutically acceptable salt thereof.

[0062] The present disclosure provides at least one microtubule targeting compound, or a pharma- ceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, of the present disclosure in the treatment of cancer.

[0063] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and at least one microtubule targeting compound, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer.

[0064] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutically acceptable salt thereof and at least one microtubule targeting compound or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer.The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer, further comprising at least one microtubule targeting compound or a pharma- ceutically acceptable salt thereof.The present disclosure provides a combination comprising at least one microtubule targeting compound or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer, further comprising at least one MetAP2 inhibitor of the present disclosure or a pharma- ceutically acceptable salt thereof.

[0065] 1. A method for treating cancer, comprising administering at least one microtubule-targeting compound or a pharma- ceutically acceptable salt thereof to a patient in need of treatment with cancer, the method comprising administering at least one microtubule-targeting compound or a pharma- ceutically acceptable salt thereof to a patient in need of treatment with cancer.

[0066] A microtubule-targeting compound, or a pharma- ceutically acceptable salt thereof, for use in a method for treating cancer, the method further comprising administering at least one MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof.

[0067] In some embodiments, the MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof and the microtubule targeting compound or a pharma- ceutically acceptable salt thereof can be administered by the same route of administration.In some embodiments, the MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof and the microtubule targeting compound or a pharma- ceutically acceptable salt thereof can be administered by different routes of administration.

[0068] In some embodiments, the MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, and the microtubule targeting compound, or a pharma- ceutically acceptable salt thereof, can be administered simultaneously.

[0069] In some embodiments, the MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, and the microtubule targeting compound, or a pharma- ceutically acceptable salt thereof, can be administered in close temporal proximity.

[0070] In some embodiments, the MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, and the microtubule targeting compound, or a pharma- ceutically acceptable salt thereof, can be administered in any order.

[0071] The present disclosure provides a combination therapy comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and at least one therapeutically effective amount of inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof.

[0072] The present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to said subject in need thereof a therapeutically effective amount of at least one of the above-described combination therapies.

[0073] The present disclosure provides methods for preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof, comprising administering to said subject in need thereof a therapeutically effective amount of at least one of the above-described combination therapies.

[0074] The present disclosure provides pharmaceutical compositions comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutical acceptable salt thereof, and at least one therapeutically effective amount of inavolisib (GDC-0077), or a pharma- ceutical acceptable salt thereof.

[0075] The present disclosure provides a method of treating cancer in a subject in need of such treatment, comprising administering to the subject in need of treatment a therapeutically effective amount of at least one of the pharmaceutical compositions described above.

[0076] The present disclosure provides methods for preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof, comprising administering to said subject in need thereof a therapeutically effective amount of at least one of the above-described pharmaceutical compositions.

[0077] The present disclosure provides kits comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and at least one therapeutically effective amount of inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof.

[0078] The present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the above-described kits.

[0079] The present disclosure provides methods for preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one of the above-described kits.

[0080] The present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutical acceptable salt thereof, and at least one therapeutically effective amount of inavolisib (GDC-0077), or a pharma- ceutical acceptable salt thereof.

[0081] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, in combination with inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0082] The present disclosure provides the use of inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof, in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0083] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of cancer.

[0084] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, for use in combination with inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof.

[0085] The present disclosure provides inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, in the treatment of cancer.

[0086] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer.

[0087] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and inavolisib (GDC-0077) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer. The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, the combination further comprising inavolisib (GDC-0077) or a pharmaceutically acceptable salt thereof. The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, the combination further comprising inavolisib (GDC-0077) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

[0088] 1. A MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, for use in a method for treating cancer, the method further comprising administering inavolisib (GDC-0077) or a pharma- ceutically acceptable salt thereof.

[0089] Inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof, for use in a method for treating cancer, the method further comprising administering at least one MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof.

[0090] In some embodiments, the MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof and inavolisib (GDC-0077) or a pharma- ceutically acceptable salt thereof can be administered by the same route of administration. In some embodiments, the MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof and inavolisib (GDC-0077) or a pharma- ceutically acceptable salt thereof can be administered by different routes of administration.

[0091] In some embodiments, the MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, and inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof, can be administered simultaneously.

[0092] In some embodiments, the MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, and inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof, can be administered in close temporal proximity.

[0093] In some embodiments, the MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, and inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof, can be administered in any order.

[0094] The present disclosure provides methods of preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof, comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmacologic acceptable salt thereof, at least one therapeutically effective amount of inavolisib (GDC-0077) or a pharmacologic acceptable salt thereof.

[0095] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, in combination with inavolisib (GDC-0077), in the manufacture of a medicament for the prevention and / or alleviation of treatment-induced hyperglycemia in a subject in need thereof.

[0096] The present disclosure provides the use of inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof, in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and / or alleviation of treatment-induced hyperglycemia in a subject in need thereof.

[0097] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, for use in combination with inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof, in preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof.

[0098] The present disclosure provides inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, in preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof.

[0099] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and inavolisib (GDC-0077), or a pharma- ceutically acceptable salt thereof, for use in preventing and / or alleviating treatment-induced hyperglycemia in a subject in need thereof.

[0100] MetAP2 inhibitors Any of the MetAP2 inhibitors described herein can be used in the kits, pharmaceutical compositions, uses, and methods described herein.

[0101] In some embodiments, the MetAP2 inhibitor can be Compound 1, or a pharma- ceutically acceptable salt, analog, derivative, salt, or ester thereof, where Compound 1 is represented as follows: [ka] [In the formula, x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100]. In some embodiments, n is in the range of about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 55, or about 1 to about 50. In some embodiments, the ratio of x to y can be in the range of about 30:1 to about 3:1.

[0102] In some embodiments, the MetAP2 inhibitor can be compound 2, or a pharma- ceutically acceptable salt, analog, derivative, salt, or ester thereof, where compound 2 is represented as follows: [ka] [In the formula, x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100]. In some embodiments, n is in the range of about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 55, or about 1 to about 50. In some embodiments, the ratio of x to y can be in the range of about 30:1 to about 3:1.

[0103] In some embodiments, the MetAP2 inhibitor can be compound 3, or a pharma- ceutically acceptable salt, analog, derivative, salt, or ester thereof, where compound 3 is represented as follows: [ka] [In the formula, x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100]. In some embodiments, n is in the range of about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 55, or about 1 to about 50. In some embodiments, the ratio of x to y can be in the range of about 30:1 to about 3:1.

[0104] In some embodiments, the MetAP2 inhibitor can be compound 4, or a pharma- ceutically acceptable salt, analog, derivative, salt, or ester thereof, where compound 4 is represented as follows: [ka] [In the formula, x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100]. In some embodiments, n is in the range of about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 55, or about 1 to about 50. In some embodiments, the ratio of x to y can be in the range of about 30:1 to about 3:1.

[0105] In some embodiments, the MetAP2 inhibitor is [ka] or a pharma- ceutically acceptable salt, analog, derivative, salt, or ester thereof.

[0106] In some embodiments, the MetAP2 inhibitor is [ka] or a pharma- ceutically acceptable salt, analog, derivative, salt, or ester thereof.

[0107] In some embodiments, the MetAP2 inhibitor is [ka] or a pharma- ceutically acceptable salt, analog, derivative, salt, or ester thereof.

[0108] In some embodiments, the MetAP2 inhibitor is [ka] or a pharma- ceutically acceptable salt, analog, derivative, salt, or ester thereof.

[0109] In some embodiments, the MetAP2 inhibitor is [ka] or a pharma- ceutically acceptable salt, analog, derivative, salt, or ester thereof.

[0110] In some embodiments, the MetAP2 inhibitor is cis-(3aRS,9bRS)-7-(benzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonyl-amino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(3-{pyrrolidin-1-yl}propyl)-4 -fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid;cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid;cis-(3aR,9bR)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluoro-benzenesulfonylamino]-1,3a,4, 9b-Tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid;cis-(3aS,9bS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid;7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylic acid formate;7-(benzenesulfonylamino)) -1,2-Dihydrofuro[2,3-c]quinoline-6-carboxylic acid formate;cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylic acid;(1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop- cis-(3aRS,9bRS)-7-[2-(4-dimethylamino-butylamino)-benzenesulfonylamino]-1-enyl)-4-fluorobenzenesulfonylamino]-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((E)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;cis-(3aRS,9bRS)-7-[2-(4-dimethylamino-butylamino)-benzenesulfonylamino]-1-enyl)-4-fluorobenzenesulfonylamino]-1-enyl)-4-fluorobenzenesulfonylamino]-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid ]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid;(1aR,7bS)-5-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c ]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR ... 1aRS,7bSR)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;1aRS,7bSR)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;1aR,7bS ... 1aS,7bR)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;1aRS,7bSR)-5-[2-(3-dimethylaminopropylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;1aR,7bS)-5-[2-(3-dimethylaminopropylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;1aRS,7bSR)-5-[2-(3-dimethylaminopropylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (1aS,7bR)-5-[2-(3-dimethylaminopropylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-(4-dimethylamino-butylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2-(4-dimethylamino-butylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(5-dimethylamino-pentylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;( 1aRS,7bSR)-5-{2[(Z)-3-(propan-2-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2[(Z)-3-((S)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2[(Z)-3 -((R)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino] sulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-(4-ethylpiperazin-1-yl)-ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2[(Z)-3-(azetidin-1-yl)prop-1-enyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2[(Z)-3-(3-hydroxy-azetidin-1-yl)prop-1-enyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa- ... )-5-{2[(Z)-3-(azetidin-1-yl)propyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2((Z)-4-diethylaminobutyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[N-(4-dimethylaminobutyl)-N-methylamino]-benzene Sulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylcarbamoyl)-methyl]-4-fluoro-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(1-ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid doro-cyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-(pyrrolidin-1-yl)-ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; pa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-2-yl)carbonyl-aminomethyl]-4-fluorobenzene-sulfonyl; (1aRS,7bSR)-5-[2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((S)-1-ethyl-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((S)-1-ethyl-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aR S,7bSR)-5-[2-(3-dimethylaminopropylcarbamoyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{[N-((S)-1-ethyl-pyrrolidin-3-yl)-N-methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{[N-((R)-1-ethyl-pyrrolidine-3 -yl)-N-methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-((R ...}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(3-N,N-diethylaminopropylamino)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidin-2-yl)carbonyl-amino]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[(1-ethylazetidin-3-ylmethyl)amino]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzene sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{N-[((R)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methyl-aminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{N-[((S)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methyl-aminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylmethyl)amino]-benzenesulfonylamino} ... Hydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylmethyl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(1-ethylpiperidin-4-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-(1-ethylazetidin-3-yl)ethyl]-4-fluoro-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((S)-1-azabicyclo[2. 2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((R)-1-azabicyclo-[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]methyl}-4-fluoro- Benzene sulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydro cyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-3-carbonyl)amino]-methyl)}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((Z)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocycloprop per-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((S)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2, 7b-Tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]- 1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; and pharma- ceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

[0111] In some embodiments, the MetAP2 inhibitor is [ka] [ka] It may be selected from pharma- ceutically acceptable salts, analogs, derivatives, salts, or esters thereof.

[0112] In some embodiments, the MetAP2 inhibitor is [ka] or a pharma- ceutically acceptable salt, analog, derivative, salt, or ester thereof.

[0113] In some embodiments, the MetAP2 inhibitor can be administered by subcutaneous injection (SC). In some embodiments, the MetAP2 inhibitor can be administered by subcutaneous injection into the mid-abdominal area (periumbilical region). In some embodiments, the subcutaneous injection of the MetAP2 inhibitor can be performed at a constant injection rate, administered over a time frame of about 30 to about 45 seconds. In some embodiments, the maximum injection volume of the MetAP2 inhibitor is less than about 1.7 ml.

[0114] In some embodiments, the MetAP2 inhibitor can be administered about every 4 days (Q4D).

[0115] In some embodiments, the MetAP2 inhibitor can be administered about once every day (QD), about once every 2 days (Q2D), about once every 3 days (Q3D), about once every 4 days (Q4D), about once every 5 days (Q5D), about once every 6 days (Q6D), about once every 7 days (Q7D), about once every 8 days (Q8D), about once every 9 days (Q9D), about once every 10 days (Q10D), about once every 11 days (Q11D), about once every 12 days (Q12D), about once every 13 days (Q13D), about once every 14 days (Q14D), or about once every 15 days (Q15D). In some embodiments, the MetAP2 inhibitor can be administered about once every 7 days (Q7D). In some embodiments, the MetAP2 inhibitor can be administered about once every 14 days (Q14D).

[0116] In some embodiments, the MetAP2 inhibitor is administered at a dose of about 1 mg / m 2, or about 2 mg / m 2 , or about 3 mg / m 2 , or about 4 mg / m 2 , or about 5 mg / m 2 , or about 6 mg / m 2 , or about 7 mg / m 2 , or about 8 mg / m 2 , or about 9 mg / m 2 , or about 10 mg / m 2 , or about 11 mg / m 2 , or about 12 mg / m 2 , or about 13 mg / m 2 , or about 14 mg / m 2 , or about 15 mg / m 2 , or about 16 mg / m 2 , or about 17 mg / m 2 , or about 18 mg / m 2 , or about 19 mg / m 2 , or about 20 mg / m 2 , or about 21 mg / m 2 , or about 22 mg / m 2 , or about 23 mg / m 2 , or about 24 mg / m 2 , or about 25 mg / m 2 , or about 26 mg / m 2 , or about 27 mg / m 2 , or about 28 mg / m 2 , or about 29 mg / m 2 , or about 30 mg / m 2 , or about 31 mg / m 2 , or about 32 mg / m 2 , or about 33 mg / m 2 , or about 34 mg / m 2 , or about 35 mg / m 2 , or about 36 mg / m 2 , or about 37 mg / m 2 , or about 38 mg / m 2 , or about 39 mg / m 2 , or about 40 mg / m 2 , or about 41 mg / m 2 , or about 42 mg / m 2 , or about 43 mg / m 2 , or about 44 mg / m 2 , or about 45 mg / m2 , or about 46 mg / m 2 , or about 47 mg / m 2 , or about 48 mg / m 2 , or about 49 mg / m 2 , or about 50 mg / m 2 , or about 51 mg / m 2 , or about 52 mg / m 2 , or about 53 mg / m 2 , or about 54 mg / m 2 , or about 55 mg / m 2 , or about 56 mg / m 2 , or about 57 mg / m 2 , or about 58 mg / m 2 , or about 59 mg / m 2 , or about 60 mg / m 2 , or about mg / m 2 , or about 61 mg / m 2 , or about 62 mg / m 2 , or about 63 mg / m 2 , or about 64 mg / m 2 , or about 65 mg / m 2 , or about 66 mg / m 2 , or about 67 mg / m 2 , or about 68 mg / m 2 , or about 69 mg / m 2 , or about 70 mg / m 2 , or about 81 mg / m 2 , or about 82 mg / m 2 , or about 83 mg / m 2 , or about 84 mg / m 2 , or about 85 mg / m 2 , or about 86 mg / m 2 , or about 87 mg / m 2 , or about 88 mg / m 2 , or about 89 mg / m 2 , or about 90 mg / m 2 , or about 91 mg / m 2 , or about 92 mg / m 2 , or about 93 mg / m 2 , or about 94 mg / m 2 , or about 95 mg / m 2 , or about 96 mg / m 2 , or about 97 mg / m 2, or about 98 mg / m 2 , or about 99 mg / m 2 , or about 100 mg / m 2 can be administered in an amount of

[0117] In some embodiments, the MetAP2 inhibitor is administered at a dose of about 49 mg / m 2 In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 36 mg / m 2 In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 65 mg / m 2 In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 27 mg / m 2 can be administered in an amount of

[0118] In some embodiments, the MetAP2 inhibitor is administered at a dose of about 49 mg / m 2 In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 39 mg / m 2 ~about 59mg / m 2 In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 44 mg / m 2 ~about 54mg / m 2 can be administered in an amount of

[0119] In some embodiments, the MetAP2 inhibitor is administered at a dose of about 36 mg / m 2 In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 26 mg / m 2 ~ approx. 49 mg / m 2 In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 31 mg / m 2 ~about 65mg / m 2 can be administered in an amount of

[0120] In some embodiments, the MetAP2 inhibitor is administered at a dose of about 65 mg / m 2 In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 55 mg / m 2 ~about 75mg / m 2In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 60 mg / m 2 ~about 70mg / m 2 can be administered in an amount of

[0121] In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 1 mg / m 2 , or about 2 mg / m 2 , or about 3 mg / m 2 , or about 4 mg / m 2 , or about 5 mg / m 2 , or about 6 mg / m 2 , or about 7 mg / m 2 , or about 8 mg / m 2 , or about 9 mg / m 2 , or about 10 mg / m 2 , or about 11 mg / m 2 , or about 12 mg / m 2 , or about 13 mg / m 2 , or about 14 mg / m 2 , or about 15 mg / m 2 , or about 16 mg / m 2 , or about 17 mg / m 2 , or about 18 mg / m 2 , or about 19 mg / m 2 , or about 20 mg / m 2 , or about 21 mg / m 2 , or about 22 mg / m 2 , or about 23 mg / m 2 , or about 24 mg / m 2 , or about 25 mg / m 2 , or about 26 mg / m 2 , or about 27 mg / m 2 , or about 28 mg / m 2 , or about 29 mg / m 2 , or about 30 mg / m 2 , or about 31 mg / m 2 , or about 32 mg / m 2 , or about 33 mg / m 2 , or about 34 mg / m 2 , or about 35 mg / m 2 , or about 36 mg / m 2 , or about 37 mg / m 2, or about 38 mg / m 2 , or about 39 mg / m 2 , or about 40 mg / m 2 , or about 41 mg / m 2 , or about 42 mg / m 2 , or about 43 mg / m 2 , or about 44 mg / m 2 , or about 45 mg / m 2 , or about 46 mg / m 2 , or about 47 mg / m 2 , or about 48 mg / m 2 , or about 49 mg / m 2 , or about 50 mg / m 2 , or about 51 mg / m 2 , or about 52 mg / m 2 , or about 53 mg / m 2 , or about 54 mg / m 2 , or about 55 mg / m 2 , or about 56 mg / m 2 , or about 57 mg / m 2 , or about 58 mg / m 2 , or about 59 mg / m 2 , or about 60 mg / m 2 , or about mg / m 2 , or about 61 mg / m 2 , or about 62 mg / m 2 , or about 63 mg / m 2 , or about 64 mg / m 2 , or about 65 mg / m 2 , or about 66 mg / m 2 , or about 67 mg / m 2 , or about 68 mg / m 2 , or about 69 mg / m 2 , or about 70 mg / m 2 , or about 81 mg / m 2 , or about 82 mg / m 2 , or about 83 mg / m 2 , or about 84 mg / m 2 , or about 85 mg / m 2 , or about 86 mg / m 2 , or about 87 mg / m 2 , or about 88 mg / m 2 , or about 89 mg / m 2 , or about 90 mg / m2 , or about 91 mg / m 2 , or about 92 mg / m 2 , or about 93 mg / m 2 , or about 94 mg / m 2 , or about 95 mg / m 2 , or about 96 mg / m 2 , or about 97 mg / m 2 , or about 98 mg / m 2 , or about 99 mg / m 2 , or about 100 mg / m 2 It could be.

[0122] In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 49 mg / m 2 In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 39 mg / m 2 ~about 59mg / m 2 In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 44 mg / m 2 ~about 54mg / m 2 It could be.

[0123] In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 36 mg / m 2 In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 26 mg / m 2 ~ approx. 49 mg / m 2 In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 31 mg / m 2 ~ approx. 49 mg / m 2 It could be.

[0124] In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 65 mg / m 2 In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 55 mg / m 2 ~about 75mg / m 2 In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 60 mg / m 2 ~about 70mg / m 2 It could be.

[0125] In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg, or about 110 mg, or about 120 mg, or about 130 mg, or about 140 mg, or about 150 mg, or about 160 mg, or about 170 mg, or about 180 mg, or about 190 mg, or about 200 mg. In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 80 mg. In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 70 mg to about 90 mg. In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 75 mg to about 85 mg.

[0126] In some embodiments, the therapeutically effective amount of the MetAP2 inhibitor may be about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg, or about 110 mg, or about 120 mg, or about 130 mg, or about 140 mg, or about 150 mg, or about 160 mg, or about 170 mg, or about 180 mg, or about 190 mg, or about 200 mg. In some embodiments, the therapeutically effective amount of the MetAP2 inhibitor may be about 80 mg. In some embodiments, the therapeutically effective amount of the MetAP2 inhibitor may be about 70 mg to about 90 mg. In some embodiments, the therapeutically effective amount of the MetAP2 inhibitor may be about 75 mg to about 85 mg.

[0127] Selective estrogen receptor degraders (SERDs) Any of the selective estrogen receptor degraders (SERDs) described herein can be used in the kits, pharmaceutical compositions, uses, and methods described herein.

[0128] As one of skill in the art will appreciate, a SERD is a compound that binds to the estrogen receptor (ER) and causes the degradation and thus downregulation of the ER.

[0129] In some embodiments, the SERD is fulvestrant: [ka] Or its pharmaceutically acceptable salt, analog, derivative, salt, or ester.As those skilled in the art will understand, fulvestrant may be identified by any one of the following names: 7α-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estradiol, 7α-[9-[(4,4,5,5,5-pentafluoropentyl)-sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17β-diol, ICI-182780, ZD-182780, and ZD-9238.As those skilled in the art will understand, fulvestrant may be identified by CAS number 129453-61-8.

[0130] In some embodiments, fulvestrant can be administered intramuscularly.

[0131] In some embodiments, fulvestrant can be administered in an amount of about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, or about 375 mg, or about 400 mg, or about 425 mg, or about 450 mg, or about 500 mg, or about 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, or about 625 mg, or about 650 mg, or about 675 mg, or about 700 mg.

[0132] In some embodiments, fulvestrant may be administered in an amount of about 500 mg. In embodiments in which fulvestrant is administered in an amount of about 500 mg, that amount may be administered by two intramuscular injections of about 250 mg of fulvestrant.

[0133] In some embodiments, fulvestrant may be administered in an amount of about 250 mg. In embodiments in which fulvestrant is administered in an amount of about 250 mg, that amount may be administered by a single intramuscular injection of about 250 mg of fulvestrant.

[0134] In some embodiments, the therapeutically effective amount of fulvestrant can be any of the fulvestrant amounts described herein.

[0135] In some embodiments, an amount of about 250 mg of fulvestrant may be administered as an intramuscular injection, with the injection volume being about 5 ml and administered over a period of about 1 to about 2 minutes.

[0136] In some embodiments, fulvestrant can be administered as a pharmaceutical composition, which includes at least one of alcohol, benzyl alcohol, and benzyl benzoate as a co-solvent. In some embodiments, fulvestrant can be administered as a pharmaceutical composition, which includes castor oil as a co-solvent and release rate modifier.

[0137] In some embodiments, fulvestrant can be administered about once every two weeks. In some embodiments, fulvestrant can be administered about once every two weeks for about one month, and then once every month.

[0138] A non-limiting dosing schedule for fulvestrant can include administering an amount of fulvestrant (e.g., about 500 mg or about 250 mg) on ​​days 1, 15, and 29, and then once every month thereafter.

[0139] In some embodiments, the SERD can be selected from brilanestrant, elacestrant, giredestrant, amcenestrant (SAR439859), AZD9833, rintodestrant, LSZ102, LY3484356, elacestrant, ZN-c5, D-0502, SHR9549, and any other SERD known in the art.

[0140] PI3K inhibitors Any of the PI3K inhibitors described herein can be used in the kits, pharmaceutical compositions, uses, and methods described herein.

[0141] As one of ordinary skill in the art will appreciate, a PI3K inhibitor is a compound that binds to and inhibits one or more phosphoinositide 3-kinase enzymes. In some embodiments, a PI3K inhibitor can target one or more (e.g., two, three, or more) isoforms of the PI3K enzyme. In some embodiments, a PI3K inhibitor can target an alpha specific subunit. In some embodiments, a PI3K inhibitor can be part of a pan-PI3K targeted therapy. In some embodiments, a PI3K inhibitor can be a PI3K alpha inhibitor.

[0142] In some embodiments, the PI3K inhibitor is alpelisib: [ka] Or its pharmaceutically acceptable salt, analog, derivative, salt, or ester. As one of ordinary skill in the art would understand, alpelisib may be identified by any one of the following names: BYL-719, and (2S)-1-N-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide. As one of ordinary skill in the art would understand, alpelisib may be identified by CAS number 1217486-61-7.

[0143] In some aspects, alpelisib can be administered orally.

[0144] In some embodiments, alpelisib can be administered in an amount of about 10 mg, or about 25 mg, or about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, or about 375 mg, or about 400 mg, or about 425 mg, or about 450 mg, or about 500 mg.

[0145] In some embodiments, alpelisib can be administered in an amount of about 300 mg. In embodiments in which alpelisib is administered in an amount of about 300 mg, that amount can be administered by administration to a subject of two tablets, each containing about 150 mg of alpelisib.

[0146] In some embodiments, alpelisib can be administered in an amount of about 250 mg. In embodiments in which alpelisib is administered in an amount of about 250 mg, that amount can be administered by administration to a subject of two tablets, one of which contains about 200 mg of alpelisib and the other of which contains about 50 mg of alpelisib.

[0147] In some embodiments, alpelisib can be administered in an amount of about 200 mg. In embodiments in which alpelisib is administered in an amount of about 200 mg, that amount can be administered by administration to the subject of a tablet containing about 200 mg of alpelisib.

[0148] In some embodiments, alpelisib can be administered about once per day. Thus, alpelisib can be administered in an amount of about 300 mg / day, or about 250 mg / day, or about 200 mg / day.

[0149] In some aspects, the therapeutically effective amount of alpelisib can be any of the alpelisib amounts described herein.

[0150] In some embodiments, alpelisib can be administered as a pharmaceutical composition comprising at least one of hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, and sodium starch glycolate. In some embodiments, alpelisib can be administered as a pharmaceutical composition comprising at least one of hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, sodium starch glycolate, iron oxide black, iron oxide red, macrogol / polyethylene glycol (PEG) 4000, talc, and titanium dioxide.

[0151] In some embodiments, alpelisib can be administered as a tablet, the tablet comprising alpelisib in combination with black iron oxide, red iron oxide, macrogol / polyethylene glycol (PEG) 4000, talc, and titanium dioxide, and the tablet has a film coating comprising hypromellose, black iron oxide, red iron oxide, macrogol / polyethylene glycol (PEG) 4000, talc, and titanium dioxide. In some embodiments, the tablet can comprise about 50 mg of alpelisib. In some embodiments, the tablet can comprise about 150 mg of alpelisib. In some embodiments, the tablet can comprise about 200 mg of alpelisib.

[0152] In some embodiments, alpelisib can be administered in combination with at least one antihistamine. As one skilled in the art will appreciate, an antihistamine can be administered in combination with alpelisib as a means of minimizing skin irritation or rash resulting from exposure to alpelisib. Thus, any of the methods disclosed herein can further include administering to the subject at least one antihistamine.

[0153] In some embodiments, alpelisib can be administered in combination with metformin, insulin, an SGLT2 inhibitor, an insulin sensitizer (such as a thiazolidinedione, a dipeptidyl peptidase-4 inhibitor), or any combination thereof, as a means of treating alpelisib-induced hyperglycemia. Thus, any of the methods of the disclosure may further include administering metformin, insulin, an SGLT2 inhibitor, an insulin sensitizer (such as a thiazolidinedione, a dipeptidyl peptidase-4 inhibitor), or any combination thereof.

[0154] In some embodiments, the PI3K inhibitor is pitirisib, Ly294002, PI-103, ZSTK-474, alpelisib, AS-605240, PIK-75, A66, voxtalisib, PIK90, PF-04691502, AZD6482, apitolisib, GSK1059615, BGT226, fimepinostat pinostat, CH5132799, PKI-402, TG100713, VS-5584, KU-0060648, GNE-477, leniolisib, SF2523, AZD8835, AZD8186, PF-4989216, HS-173, copanlisib, idelalisib, bupa The inhibitor may be selected from buparlisib, inavolisib, paxalisib, rigosertib, bimiralisib, CUDC-908, dactolisib, GDC-0326, gedatolisib, omipalisib, pictilisib, HHCYH-33, men-1611, pilaralisib, serabelisib (TAK-117), GNE-477, teselisib, TL-117, HEC-68498, RLY-2608, or any other PI3K inhibitor known in the art.

[0155] The structure of inavolisib (GDC-0077), as understood by one of skill in the art: [ka] (See Hanan et al. Discovery of GDC-0077 [Inavolisib], a Highly Selective Inhibitor and Degrader of Mutant PI3Kα, Journal of Medicinal Chemistry, 2022, 65, 24, 16589-16621; incorporated by reference in its entirety for all purposes).

[0156] In some aspects, inavolisib, or a pharma- ceutically acceptable salt thereof, can be administered intravenously.

[0157] In some aspects, inavolisib can be administered orally.

[0158] In some embodiments, inavolisib is administered at about 0.5 mg, or about 1 mg, or about 1.5 mg, or about 2 mg, or about 2.5 mg, or about 3 mg, or about 3.5 mg, or about 4 mg, or about 4.5 mg, or about 5 mg, or about 5.5 mg, or about 6 mg, or about 6.5 mg, or about 7 mg, or about 7.5 mg, or about 8 mg, or about 8.5 mg, or about 9 mg, or about 9.5 mg, or about 10 mg, or about 10.5 mg. g, or about 11 mg, or about 11.5 mg, or about 12 mg, or about 12.5 mg, or about 13 mg, or about 13.5 mg, or about 14 mg, or about 14.5 mg, or about 15 mg, or about 15.5 mg, or about 16 mg, or about 16.5 mg, or about 17 mg, or about 17.5 mg, or about 18 mg, or about 18.5 mg, or about 19 mg, or about 19.5 mg, or about 20 mg.

[0159] In some aspects, the therapeutically effective amount of inavolisib can be any of the amounts of inavolisib described herein.

[0160] In some embodiments, inavolisib can be administered about once a week, about twice a week, about three times a week, about four times a week, about five times a week, or about six times a week. In some embodiments, inavolisib can be administered daily. In some embodiments, inavolisib can be administered daily on days 1-28 of a 28-day cycle.

[0161] Microtubule targeting compounds Any of the microtubule targeting compounds described herein can be used in the kits, pharmaceutical compositions, uses, and methods described herein.

[0162] As one of skill in the art will appreciate, microtubule targeting compounds (also referred to in the art as microtubule targeting agents) are compounds that directly or indirectly modulate microtubule dynamics, thereby regulating various cellular functions, including, but not limited to, cell cycle progression, mitosis, metabolism, cell signaling, intracellular trafficking, and the like.

[0163] In some embodiments, the microtubule targeting compound is eribulin: [ka] Or its pharmaceutically acceptable salt, analog, derivative, salt, or ester. As one skilled in the art would understand, eribulin may be identified by any one of the following names: E7389, ER-086526, NSC-707389, and 2-(3-amino-2-hydroxypropyl)hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy-7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2',3'-5,6)pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4H)-one. As one skilled in the art would understand, eribulin may be identified by CAS number 253128-41-5.

[0164] In some embodiments, the microtubule targeting compound can be the mesylate salt of eribulin (eribulin mesylate).

[0165] In some aspects, eribulin or a pharma- ceutically acceptable salt, analog, derivative, salt, or ester thereof can be administered intravenously.

[0166] In some embodiments, eribulin mesylate can be administered intravenously.

[0167] In some embodiments, eribulin is administered at a dose of about 0.1 mg / m 2, or about 0.2 mg / m 2 , or about 0.3 mg / m 2 , or about 0.4 mg / m 2 , or about 0.5 mg / m 2 , or about 0.6 mg / m 2 , or about 0.7 mg / m 2 , or about 0.8 mg / m 2 , or about 0.9 mg / m 2 , or about 1.0 mg / m 2 , or about 1.1 mg / m 2 , or about 1.2 mg / m 2 , or about 1.3 mg / m 2 , or about 1.4 mg / m 2 , or about 1.5 mg / m 2 , or about 1.6 mg / m 2 , or about 1.7 mg / m 2 , or about 1.8 mg / m 2 , or about 1.9 mg / m 2 , or about 2.0 mg / m 2 , or about 2.1 mg / m 2 , or about 2.2 mg / m 2 , or about 2.3 mg / m 2 , or about 2.4 mg / m 2 , or about 2.5 mg / m 2 , or about 2.6 mg / m 2 , or about 2.7 mg / m 2 , or about 2.8 mg / m 2 , or about 2.9 mg / m 2 , or about 3.0 mg / m 2 can be administered in an amount of

[0168] In some embodiments, eribulin mesylate is administered at a dose of about 0.1 mg / m 2 , or about 0.2 mg / m 2 , or about 0.3 mg / m 2 , or about 0.4 mg / m 2 , or about 0.5 mg / m 2 , or about 0.6 mg / m 2 , or about 0.7 mg / m 2 , or about 0.8 mg / m 2 , or about 0.9 mg / m 2 , or about 1.0 mg / m2 , or about 1.1 mg / m 2 , or about 1.2 mg / m 2 , or about 1.3 mg / m 2 , or about 1.4 mg / m 2 , or about 1.5 mg / m 2 , or about 1.6 mg / m 2 , or about 1.7 mg / m 2 , or about 1.8 mg / m 2 , or about 1.9 mg / m 2 , or about 2.0 mg / m 2 , or about 2.1 mg / m 2 , or about 2.2 mg / m 2 , or about 2.3 mg / m 2 , or about 2.4 mg / m 2 , or about 2.5 mg / m 2 , or about 2.6 mg / m 2 , or about 2.7 mg / m 2 , or about 2.8 mg / m 2 , or about 2.9 mg / m 2 , or about 3.0 mg / m 2 can be administered in an amount of

[0169] In some embodiments, eribulin is administered at a dose of about 1.4 mg / m 2 In some embodiments, eribulin can be administered in an amount of about 1.1 mg / m 2 In some embodiments, eribulin can be administered in an amount of about 0.7 mg / m 2 can be administered in an amount of

[0170] In some embodiments, eribulin mesylate is about 1.4 mg / m 2 In some embodiments, eribulin mesylate can be administered in an amount of about 1.1 mg / m 2 In some embodiments, eribulin mesylate can be administered in an amount of about 0.7 mg / m 2 can be administered in an amount of

[0171] In some embodiments, when an amount of eribulin or eribulin mesylate is administered intravenously to a subject, the amount of eribulin or eribulin mesylate can be administered over a period of about 2 minutes to about 5 minutes.

[0172] In some aspects, a therapeutically effective amount of eribulin can be any of the amounts of eribulin described herein.

[0173] In some embodiments, eribulin or eribulin mesylate can be administered about once a week. In some embodiments, eribulin or eribulin mesylate can be administered on days 1 and 8 of a 21-day cycle.

[0174] In some embodiments, eribulin or eribulin mesylate can be administered as a pharmaceutical composition, which further comprises ethanol and water in a ratio of about 5:95. In some embodiments, the concentration of eribulin or eribulin mesylate can be about 0.5 mg / ml in the pharmaceutical composition.

[0175] In some embodiments, the microtubule targeting compound can be selected from paclitaxel, docetaxel, vincristine, vinbiastin, nocodazole, epothilones, navelbine, and any other microtubule targeting compound known in the art.

[0176] Treatment target and cancer In some embodiments, the subject in need of treatment or prevention is an animal. In some embodiments, the animal can be a mammal. In some embodiments, the subject in need of treatment or prevention is a human.

[0177] In some embodiments, the subject in need of treatment or prevention is a human over the age of 18. In some embodiments, the subject in need of treatment or prevention is a human under the age of 18.

[0178] In some embodiments, the subject in need of treatment or prevention is a postmenopausal woman.

[0179] In some embodiments, the subject in need of treatment or prevention has cancer, hi some embodiments, the cancer is characterized by the presence of at least one tumor in the subject.

[0180] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. This definition includes benign and malignant cancers. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, leukemia, and germ cell tumors. More specific examples of such cancers include adrenocortical carcinoma, urothelial carcinoma of the bladder, invasive carcinoma of the breast, squamous cell carcinoma of the cervix, endocervical adenocarcinoma, bile duct carcinoma, adenocarcinoma of the colon, lymphoid neoplasm diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, squamous cell carcinoma of the head and neck, chromophobe renal carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, acute myeloid leukemia, brain low-grade glioma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, cutaneous melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid carcinoma, thymoma, uterine carcinoma sarcoma, and uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, renal cancer, or gastric cancer.Further examples of cancer include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, bile duct cancer, esophageal cancer, anal cancer, salivary gland cancer, vulvar cancer, cervical cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumors, anal cancer, bile duct cancer, bladder cancer, bone cancer, intestinal cancer, brain tumor, breast cancer, cancer of unknown primary (CUP), cancer that has spread to the bone, cancer that has spread to the brain, cancer that has spread to the liver, cancer that has spread to the lungs, carcinoid, cervical cancer, childhood cancer, chronic lymphocytic leukemia (CLL), Chrome myeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell sarcoma, gallbladder cancer, gastric cancer cancer), gastroesophageal junction cancer, germ cell tumors, gestational trophoblastic disease (GIT), hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, gastritis plastica, liver cancer, lung cancer, lymphoma, malignant neurilemmoma, mediastinal germ cell tumor, melanoma skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, molar pregnancy, oral and oropharyngeal cancer, myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, non-Hodgkin's lymphoma (NHL), esophageal cancer, ovarian cancer, pancreatic cancer, penile cancer, persistent trophoblastosis and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma peritonei, rectal cancer, retinoblastoma, salivary gland cancer, secondary cancer, signet ring cell carcinoma, skin cancer, small intestine cancer, soft tissue sarcoma, gastric cancer Cancers include, but are not limited to, hematological malignancies, lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, Chrome lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, myelodysplastic syndrome, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid cancer, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, Merkel cell carcinoma, uveal melanoma, or glioblastoma multiforme.

[0181] In some embodiments, the cancer is carcinoma, lymphoma, blastoma, sarcoma, leukemia, brain cancer, breast cancer, blood cancer, bone cancer, lung cancer, skin cancer, liver cancer, ovarian cancer, bladder cancer, renal cancer, kidney cancer, gastric cancer, thyroid cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, uterine cancer, stomach cancer, soft tissue cancer, laryngeal cancer, small intestine cancer, testicular cancer, anal cancer, vulvar cancer, joint cancer, oral cavity cancer, pharyngeal cancer, or colorectal cancer.

[0182] In some embodiments, the cancer is breast cancer.

[0183] In some embodiments, the breast cancer is aggressive breast cancer.

[0184] In some embodiments, the breast cancer is metastatic breast cancer. As used herein, "metastatic breast cancer" refers to stage III or IV breast cancer that has spread to other parts of the body, including but not limited to the liver, brain, bones, etc.

[0185] In some embodiments, the breast cancer is human epidermal growth factor 2 (HER2)-negative breast cancer.

[0186] In some embodiments, the breast cancer is hormone receptor (HR) positive breast cancer.

[0187] In some embodiments, the breast cancer is HR positive / HER2 negative (HR+HER2-) breast cancer.

[0188] In some embodiments, the breast cancer is triple-negative breast cancer. In some embodiments, the breast cancer is triple-negative metastatic breast cancer.

[0189] In some embodiments, as one of skill in the art will appreciate, a subject may be identified as having triple-negative breast cancer if a sample from the subject exhibits less than about 10% estrogen and progesterone receptor staining and a HER2 immunohistochemistry (IHC) score of 0-1+.

[0190] In some embodiments, the subject in need of treatment or prevention is a postmenopausal woman with HR+HER2- breast cancer.

[0191] In some embodiments, the breast cancer can be luminal A breast cancer. In some embodiments, the breast cancer can be luminal B breast cancer. In some embodiments, the breast cancer can be triple negative or basal-like breast cancer. In some embodiments, the breast cancer can be HER2-enriched breast cancer.

[0192] In some embodiments, the subject in need of treatment or prevention has breast cancer and at least one PIK3CA mutation.

[0193] In some embodiments, the subject in need of treatment or prevention is a postmenopausal woman with HR+HER2- breast cancer, and said subject in need of treatment or prevention has at least one PIK3CA mutation.

[0194] In some embodiments, the subject in need of treatment or prevention has recurrent breast cancer, and the subject has been previously treated with neoadjuvant and / or adjuvant endocrine therapy. In some embodiments, the subject in need of treatment or prevention is a postmenopausal woman with recurrent HR+HER2- breast cancer, the subject in need of said treatment or prevention has at least one PIK3CA mutation, and the subject has been previously treated with neoadjuvant and / or adjuvant endocrine therapy. In some embodiments, the recurrent breast cancer is characterized by progressive disease more than about 12 months from completion of neoadjuvant and / or adjuvant endocrine therapy.

[0195] Non-limiting examples of endocrine therapies include, but are not limited to, Anastrozole (Arimidex), Exemestane (Aromasin), Fulvestrant (Faslodex), Goserelin (Zoladex), Letrozole (Femara), Leuprolide acetate (Eligard, Fensolvi, Lupron), Megestrol (Megace ES), Tamoxifen (Nolvadex, Soltamox), Toremifene (Fareston), and the like.

[0196] In some embodiments, the subject in need of treatment or prevention has recurrent breast cancer, and the subject has been previously treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor. In some embodiments, the subject may have been treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor for at least about 12 months.

[0197] Non-limiting examples of CDK4 / 6 inhibitors include palbociclib, abemaciclib, ribociclib, trilaciclib, SHR-6390, FCN-437c, lerociclib, milciclib, PF-06873600, XZP-3287, zotiraciclib, BEBT-209, BPI-16350, CS-3002, and fadoriciclib. Examples of suitable pharmacokinetic and pharmacokinetic agents include, but are not limited to, fadraciclib, HS-10342, ON-123300, PF-06842874, TQ-05510, BPI-1178, JS-101, NUV-422, AU-294, CCT-68127, ETH-155008, HEC-80797, JRP-890, JS-104, NEOS-518, PF-07104091, PF-07220060, RMC-4550, SRX-3177, VS-2370, VS-2370, or a pharmaceutically acceptable salt thereof.

[0198] Thus, in some embodiments, the subject in need of treatment or prevention is a postmenopausal woman with recurrent HR+HER2- breast cancer, the subject in need of said treatment or prevention has at least one PIK3CA mutation, the subject has been previously treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor. Thus, in some embodiments, the subject in need of treatment or prevention is a postmenopausal woman with recurrent HR+HER2- breast cancer, the subject in need of said treatment or prevention has at least one PIK3CA mutation, the subject has been previously treated with neoadjuvant and / or adjuvant endocrine therapy, the recurrent breast cancer is characterized by disease progression more than about 12 months after completion of the neoadjuvant and / or adjuvant endocrine therapy, the subject has been further treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor. In some embodiments, the additional treatment with a combination of at least one endocrine therapy and at least one CDK4 / 6 inhibitor may be a treatment administered to the subject for at least about 12 months.

[0199] In some embodiments, the subject in need of treatment or prevention has breast cancer identified as progressive during treatment with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor.Thus, in some embodiments, the subject in need of treatment or prevention is a postmenopausal woman with HR+HER2- breast cancer identified as progressive during treatment with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor, and the subject in need of treatment or prevention has at least one PIK3CA mutation.In some embodiments, the subject may be a subject who has been treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor for at least about 12 months.

[0200] In some embodiments, the subject in need of treatment or prevention has breast cancer that is identified as progressive after being treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor.Thus, in some embodiments, the subject in need of treatment or prevention is a postmenopausal woman with HR+HER2- breast cancer that is identified as progressive after being treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor, and the subject in need of treatment or prevention has at least one PIK3CA mutation.In some embodiments, the subject may be a subject that has been treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor for at least about 12 months.

[0201] In some embodiments, the subject in need of treatment or prevention is a subject at risk for hyperglycemia. In some embodiments, the subject at risk for hyperglycemia has an HbA1c value of about 5.7% to about 6.4%. In some embodiments, the subject at risk for hyperglycemia has an HbA1c value of about 5.5% to about 6.4%. In some embodiments, the subject at risk for hyperglycemia has a fasting plasma glucose (FPG) value of greater than about 100 mg / dL (5.6 mmol / L) and less than about 140 mg / dL (7.7 mmol / L). In some embodiments, the subject at risk for hyperglycemia has an HbA1c value of about 5.7% to about 6.4% and a fasting plasma glucose (FPG) value of greater than about 100 mg / dL (5.6 mmol / L) and less than about 140 mg / dL (7.7 mmol / L). In some embodiments, subjects at risk for hyperglycemia have HbA1c values ​​between about 5.5% and about 6.4% and fasting plasma glucose (FPG) values ​​greater than about 100 mg / dL (5.6 mmol / L) and less than about 140 mg / dL (7.7 mmol / L). In some embodiments, subjects at risk for hyperglycemia have HbA1c values ​​between about 5.7% and about 6.4% and fasting plasma glucose (FPG) values ​​less than about 140 mg / dL (7.7 mmol / L). In some embodiments, subjects at risk for hyperglycemia have HbA1c values ​​between about 5.5% and about 6.4% and fasting plasma glucose (FPG) values ​​less than about 140 mg / dL (7.7 mmol / L). In some embodiments, subjects at risk for hyperglycemia have HbA1c values ​​greater than about 5.5%. In some embodiments, a subject at risk for hyperglycemia has an HbA1c value of greater than or equal to about 5.5%. In some embodiments, a subject at risk for hyperglycemia has an HbA1c value of greater than about 5.6%. In some embodiments, a subject at risk for hyperglycemia has a fasting blood glucose value of greater than about 100 mg / dL. In some embodiments, a subject at risk for hyperglycemia has an HbA1c value of greater than about 5.5% and / or a fasting blood glucose value of greater than about 100 mg / dL. In some embodiments, a subject at risk for hyperglycemia has an HbA1c value of about 39 mmol / mol to about 47 mmol / mol.

[0202] In some embodiments, the subject has an HbA1c value greater than about 5.5%.

[0203] In some embodiments, subjects at risk for hyperglycemia have a Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score of greater than about 1.8. As those skilled in the art will appreciate, the HOMA-IR score is calculated as follows: fasting serum insulin (μU / ml)×fasting plasma glucose (mmol / L) / 22.5 (see Matthews et al. Diabetologia, 1985, 28(7); the entire contents of which are incorporated by reference for all purposes).

[0204] In some embodiments, the subject in need of treatment or prevention has a body mass index (BMI) of about 20 kg / m 2 In some embodiments, the subject in need of treatment or prevention has a body mass index (BMI) of about 30 kg / m 2 Greater than or equal to.

[0205] In some embodiments, the subject in need of treatment or prevention has triple-negative metastatic breast cancer and: i) a breast cancer severity greater than or equal to about 30 kg / m 2 and ii) a BMI of greater than or equal to about 5.5%. In some embodiments, the subject has previously received at least one line of treatment for metastatic breast cancer. In some embodiments, the subject has previously received at least two lines of treatment for metastatic breast cancer.

[0206] In some embodiments, the subject in need of treatment or prevention has at least one metabolic dysfunction, which may be visceral adiposity, dyslipidemia, obesity (BMI≧30), high leptin, low adiponectin, high leptin-adiponectin ratio, high fasting insulin, high fasting insulin with chronic inflammation, insulin resistance, fasting hyperglycemia, high HbA1c, or any combination thereof.

[0207] Dosage regimen In some embodiments of the disclosed method of administering a combination of a MetAP2 inhibitor and a microtubule targeting compound to a subject, the subject can be administered a MetAP2 inhibitor every 14 days (Q14D), and the microtubule targeting compound can be administered on days 1 and 8 of a 21-day cycle. In other words, the microtubule targeting compound can be administered on days 1 and 8 of a 21-day cycle, and the MetAP2 inhibitor can be administered on days 1 and 15 of odd-numbered cycles (e.g., cycles 1, 3, 5, etc.) and on day 8 of even-numbered cycles (e.g., cycles 2, 4, 6, etc.). A schematic diagram of this administration schedule is shown in Figure 1.

[0208] In some embodiments of the method of the present disclosure, which is to administer a combination of a MetAP2 inhibitor and a microtubule targeting compound to a subject, the MetAP2 inhibitor and the microtubule targeting compound can be administered in a 21-day cycle, and the 21-day cycle includes administering both the MetAP2 inhibitor and the microtubule targeting compound to the subject once every 7 days (Q7D) for 2 weeks, and then not administering the MetAP2 inhibitor and the microtubule targeting compound for 1 week.Thus, in a non-limiting example, the MetAP2 inhibitor and the microtubule targeting compound can be administered on the 1st and 8th days of the 21-day cycle.

[0209] In some embodiments of the disclosed method of administering a combination of a MetAP2 inhibitor and a microtubule targeting compound to a subject, the MetAP2 inhibitor and the microtubule targeting compound can be administered in a 21-day cycle, the 21-day cycle including administering the MetAP2 inhibitor once every 21 days (Q21D) and administering the microtubule targeting compound once every 7 days (Q7D) for 2 weeks, followed by not administering the microtubule targeting compound for 1 week.Thus, in a non-limiting example, the MetAP2 inhibitor can be administered on day 1 of a 21-day cycle, and the microtubule targeting compound can be administered on days 1 and 8 of the 21-day cycle.In another non-limiting example, the MetAP2 inhibitor can be administered at least once during a 21-day cycle, and the microtubule targeting compound can be administered on days 1 and 8 of the 21-day cycle.

[0210] In some embodiments of the disclosed methods of administering a combination of a MetAP2 inhibitor and a microtubule targeting compound to a subject, the subject can be administered the MetAP2 inhibitor every 14 days (Q14D), and the microtubule targeting compound can be administered on day 1 and on a day between days 5 and 11 (including days 5 and 11) of a 21-day cycle. In other words, the microtubule targeting compound can be administered on day 1 and on a day between days 5 and 11 (including days 5 and 11) of a 21-day cycle, and the MetAP2 inhibitor can be administered on days 1 and 15 of odd-numbered cycles (e.g., cycles 1, 3, 5, etc.) and on day 8 of even-numbered cycles (e.g., cycles 2, 4, 6, etc.).

[0211] In some embodiments of the disclosed methods of administering a combination of a MetAP2 inhibitor, a SERD, and a PI3K inhibitor to a subject, the subject can be administered a MetAP2 inhibitor and a SERD inhibitor for a 14-day pretreatment phase, followed by administration of a PI3K inhibitor starting on the 15th day.

[0212] In some embodiments of the disclosed methods of administering a combination of a MetAP2 inhibitor, a PI3K inhibitor, and a SERD to a subject, the MetAP2 inhibitor can be administered to the subject every 14 days (Q14D) starting on day 1 of a 28-day cycle, the SERD can be administered to the subject every 14 days (Q14D) starting on day 1 of said 28-day cycle, and the PI3K inhibitor can be administered once a day (QD) starting on day 15 of said cycle. In other words, the MetAP2 inhibitor can be administered on days 1 and 15 of said 28-day cycle, the SERD can be administered on days 1 and 15 of said 28-day cycle, and the PI3K inhibitor can be administered on days 15-28 of said 28-day cycle. After completion of one 28-day cycle of the previous triple combination therapy, subsequent 28-day cycles can be performed, in which the MetAP2 inhibitor is administered to the subject every 14 days (Q14D) starting on day 1 of the new 28-day cycle, the SERD is administered once every 28 days (Q28D) starting on day 1 of the new 28-day cycle, and alpelisib is administered once a day (QD) starting on day 1 of the new 28-day cycle. In other words, in the second or subsequent cycles, the MetAP2 inhibitor can be administered on days 1 and 15 of the 28-day cycle, the SERD can be administered on day 1 of the 28-day cycle, and alpelisib can be administered on days 1 to 28 of the 28-day cycle. A schematic diagram of these dosing schedules is shown in FIG. 2.

[0213] In some embodiments of the disclosed methods of administering a combination of a MetAP2 inhibitor, a PI3K inhibitor, and a SERD to a subject, the MetAP2 inhibitor can be administered to the subject every 14 days (Q14D) starting on day 1 of a 28-day cycle, the SERD can be administered to the subject every 14 days (Q14D) starting on day 1 of the 28-day cycle, and the PI3K inhibitor can be administered once a day (QD) starting on day 1 of the cycle. In other words, the MetAP2 inhibitor can be administered on days 1 and 15 of the 28-day cycle, the SERD can be administered on days 1 and 15 of the 28-day cycle, and the PI3K inhibitor can be administered on days 1-28 of the 28-day cycle. After completion of one 28-day cycle of the previous triple combination therapy, subsequent 28-day cycles can be performed, in which the MetAP2 inhibitor is administered to the subject every 14 days (Q14D) starting on day 1 of the new 28-day cycle, the SERD is administered once every 28 days (Q28D) starting on day 1 of the new 28-day cycle, and alpelisib is administered once a day (QD) starting on day 1 of the new 28-day cycle. In other words, in the second or subsequent cycles, the MetAP2 inhibitor can be administered on days 1 and 15 of the 28-day cycle, the SERD can be administered on day 1 of the 28-day cycle, and alpelisib can be administered on days 1 to 28 of the 28-day cycle. A schematic diagram of these dosing schedules is shown in FIG. 2.

[0214] General definition Certain compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates and is within the scope of the present disclosure all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers and mixtures thereof are intended to be included in the present disclosure. Any specific isomers shown are merely exemplary (e.g., if a trans-isomer is exemplified, the cis-isomer is also included).

[0215] For example, if a particular enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, the resulting diastereomeric mixture separated, and the auxiliary cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, a diastereomeric salt is formed with an appropriate optically active acid or base, and the diastereomers thus formed are then separated by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomer.

[0216] In this specification, the structural formula of a compound may conveniently represent a specific isomer, but the present disclosure includes all isomers, such as geometric isomers, optical isomers due to asymmetric carbon atoms, stereoisomers, tautomers, and the like. Furthermore, the compound represented by the formula may have crystalline polymorphism. Note that any crystalline form, crystalline mixture, or anhydride or hydrate thereof is also within the scope of the present disclosure. Furthermore, the so-called metabolites produced by the decomposition of the present compound in vivo are also within the scope of the present disclosure.

[0217] "Isomeric" means compounds that have the same molecular formula but differ in the order of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereoisomers" and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture".

[0218] A carbon atom bonded to four nonidentical substituents is called a "chiral center".

[0219] "Chiral isomer" means a compound with at least one chiral center. Compounds with two or more chiral centers may exist as individual diastereomers or as a mixture of diastereomers (called a "diastereomeric mixture"). When one chiral center is present, a stereoisomer is characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the "ranking rules" of Cahn, Ingold, and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0220] "Geometric isomers" refers to diastereomers that exist due to hindered rotation about a double bond. These configurations are distinguished in the names by the prefixes cis and trans, or Z and E. These prefixes indicate whether groups are on the same or opposite sides of a double bond in a molecule, according to the Cahn-Ingold-Prelog rules.

[0221] Additionally, the structures and other compounds discussed in this disclosure include all atropic isomers. An "atropic isomer" is a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers exist due to restricted rotation caused by a large group being prevented from rotating around a central bond. Such atropic isomers typically exist as mixtures, although recent advances in chromatographic techniques have made it possible in some cases to separate mixtures of two atropic isomers.

[0222] A "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solid form, one tautomer usually predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are capable of interconversion by tautomerization is called tautomerism.

[0223] There can be many different types of tautomerism, of which two are commonly seen: keto-enol tautomerism, in which a simultaneous shift of an electron and a hydrogen atom occurs; and ring-chain tautomerism, which occurs when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to give a cyclic (ring-like) form, such as that exhibited by glucose.

[0224] Common tautomeric pairs include: ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomers in heterocycles (e.g., in nucleobases such as guanine, thymine, and cytosine), amine-enamine, and enamine-enamine.

[0225] It is understood that the compounds of the present disclosure may be represented as different tautomeric forms, and when the compounds have tautomeric forms, it should be understood that all tautomeric forms are intended to be included within the scope of the disclosure, and that the name of the compound does not exclude any tautomeric form.

[0226] The term "crystalline polymorph", "polymorph" or "crystalline form" refers to the crystalline structures in which a compound (or a salt or solvate thereof) can crystallize in a variety of different crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, rate of crystallization, storage temperature, and other factors, one crystalline form may predominate. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

[0227] Furthermore, the compounds of the present disclosure, such as salts of the compounds, may exist in hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0228] "Solvate" refers to a solvation form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to form solvates by trapping a fixed molar ratio of solvent molecules in the crystalline solid state. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is a combination of one or more molecules of water with one molecule of a substance, where the water is H 2 It is formed when the molecule retains its molecular state as O.

[0229] The term "analog" as used herein refers to a compound that is structurally similar to another compound but differs slightly in composition (such as when an atom is replaced with an atom of a different element, when a particular functional group is present, or when one functional group is replaced with another). Thus, an analog is a compound that is similar or comparable to the reference compound in function and appearance, but not in structure or origin.

[0230] The term "derivative," as defined herein, refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0231] The term "bioisomer" refers to a compound obtained by replacing one atom or group of atoms with another similar atom or group of atoms. The purpose of bioisosteric replacement is to create a new compound with biological properties similar to the parent compound. Bioisosteric replacements can be physicochemical or topological. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonimides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0232] Women can be defined as "postmenopausal" using any of the following criteria: i) age 45 years or older and no menses for >2 years; ii) amenorrhea for >2 years without hysterectomy and oophorectomy, with follicle-stimulating hormone levels assessed as being in the postmenopausal range; and / or iii) following hysterectomy with oophorectomy.

[0233] As used herein, the term "temporal proximity" refers to administration of one therapeutic agent (e.g., a MetAP2 inhibitor compound disclosed herein) during a period before or after administration of another therapeutic agent (e.g., palbociclib) such that the therapeutic effects of the one therapeutic agent overlap with the therapeutic effects of the other therapeutic agent. In some embodiments, the therapeutic effects of the one therapeutic agent completely overlap with the therapeutic effects of the other therapeutic agent. In some embodiments, "temporal proximity" refers to administration of one therapeutic agent during a period before or after administration of another therapeutic agent such that the therapeutic effects of the one therapeutic agent are synergistic with the other therapeutic agent. "Temporal proximity" may vary depending on a variety of factors, including, but not limited to, the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the subject to whom the therapeutic agent is administered; the disease or condition to be treated or improved; the therapeutic outcome to be achieved; the dosage, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route by which the therapeutic agent is administered. In some embodiments, "temporal proximity" means within 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks. In some embodiments, multiple administrations of one therapeutic agent can be administered in close temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity can vary during a treatment cycle or within a dosing regimen.

[0234] The terms "effective amount" and "therapeutically effective amount" of an agent or compound are used in the broadest sense and refer to a nontoxic but sufficient amount of an active agent or compound to provide a desired effect or benefit.

[0235] The term "benefit" is used in the broadest sense and refers to any desired effect, specifically including clinical benefit as defined herein.Clinical benefit can be measured by evaluating various endpoints, examples of which include: suppression of disease progression to some extent, including slowing down and complete halting of disease progression; reduction in the number of disease episodes and / or symptoms; reduction in lesion size; suppression (i.e., reduction, slowing, or complete halting) of disease cell invasion into adjacent surrounding organs and / or tissues; suppression (i.e., reduction, slowing, or complete halting) of disease spread; reduction in autoimmune response (which may or may not result in regression or disappearance of lesions); alleviation of one or more symptoms associated with the disorder to some extent; prolonged disease-free period after treatment, such as progression-free survival; increased overall survival; high response rate; and / or reduced mortality at any time after treatment.

[0236] As used herein, the term "pharmacologically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

[0237] As used herein, the term "combination therapy" or "co-therapy" includes the administration of a compound of the present disclosure, or a pharma- ceutically acceptable salt, polymorph, or solvate thereof, and at least a second agent as part of a specific treatment regimen intended to provide a beneficial effect resulting from the interaction of these therapeutic agents, including, but not limited to, a pharmacokinetic or pharmacodynamic interaction resulting from the combined use of the therapeutic agents.

[0238] It will be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharma- ceutically acceptable excipient or carrier.

[0239] Unless otherwise indicated, reference to any method of treatment is understood to include the use of the compounds to provide treatment or prophylaxis as described herein, as well as the use of the compounds for the preparation of a medicament for treating or preventing such conditions. Treatment includes the treatment of humans or non-human animals, including rodents and other disease models.

[0240] The term "subject" as used herein is interchangeable with the term "subject in need of treatment or prevention", both of which refer to a subject having a disease or at high risk of developing a disease. "Subject" includes mammals. A mammal can be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. A subject can also be a bird or poultry. In one embodiment, the mammal is a human.

[0241] The term "treatment" or "treating" as used herein describes the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharma- ceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treating" also includes the treatment of a cell in vitro or in an animal model.

[0242] The compounds of the present disclosure, or pharma- ceutically acceptable salts, polymorphs, or solvates thereof, can be or may be used to prevent the associated disease, condition, or disorder, or to identify suitable candidates for such purposes.

[0243] As used herein, the terms "prevention," "preventing," or "protection against" refer to reducing or eliminating the onset of symptoms or complications of such a disease, condition, or disorder.

[0244] Preferred Embodiments EMBODIMENT 1 1. A combination comprising at least one MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof and eribulin or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer in a subject.

[0245] EMBODIMENT 2 1. A method of treating cancer in a subject in need of cancer treatment, comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharma- ceutical acceptable salt thereof, and at least one therapeutically effective amount of eribulin or a pharma- ceutical acceptable salt thereof.

[0246] EMBODIMENT 3 1. A MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, for use in a method for treating cancer in a subject, said method further comprising administering eribulin or a pharma- ceutically acceptable salt thereof.

[0247] EMBODIMENT 4 1. Eribulin or a pharmaceutically acceptable salt thereof for use in a method for treating cancer in a subject, said method further comprising administering at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.

[0248] EMBODIMENT 5 The combination for use of embodiment 1, the method of embodiment 2, the MetAP2 inhibitor for use of embodiment 3, or the eribulin for use of embodiment 4, wherein said at least one MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof and said eribulin or a pharma- ceutically acceptable salt thereof are administered simultaneously or closely in time.

[0249] EMBODIMENT 6 The MetAP2 inhibitor, [ka] and a pharma- ceutically acceptable salt thereof; wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, and preferably the ratio of x to y is in the range of about 30:1 to about 3:1, and preferably the ratio of x to y is about 11:1. The combination for use of embodiment 1 or 5, the method of embodiment 2 or 5, the MetAP2 inhibitor for use of embodiment 3 or 5, or eribulin for use of embodiment 4 or 5.

[0250] EMBODIMENT 7 The MetAP2 inhibitor, [ka] or a pharma- ceutically acceptable salt thereof; wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, and preferably the ratio of x to y is in the range of about 30:1 to about 3:1, and preferably the ratio of x to y is about 11:1. The combination for use of embodiment 1 or 5-6, the method of embodiment 2 or 5-6, the MetAP2 inhibitor for use of embodiment 3 or 5-6, or eribulin for use of embodiment 4 or 5-6.

[0251] EMBODIMENT 8 The combination for use of embodiment 1 or 5-7, the method of embodiment 2 or 5-7, the MetAP2 inhibitor for use of embodiment 3 or 5-7, or the eribulin for use of embodiment 4 or 5-7, wherein said eribulin is eribulin mesylate.

[0252] EMBODIMENT 9 The eribulin or eribulin mesylate is i) About 1.4mg / m 2 ; ii) Approximately 1.1mg / m 2 or iii) About 0.7mg / m 2 ; and (is intended to be administered to the subject) in an amount of Preferably, the eribulin or eribulin mesylate is (is to be) administered intravenously; The combination for use of embodiment 1 or 5-8, the method of embodiment 2 or 5-8, the MetAP2 inhibitor for use of embodiment 3 or 5-8, or eribulin for use of embodiment 4 or 5-8.

[0253] EMBODIMENT 10 The MetAP2 inhibitor or a pharma- ceutical acceptable salt thereof is i) Approximately 49 mg / m 2 ; ii) About 36mg / m 2 or iii) About 65mg / m 2 ; and (is intended to be administered to the subject) in an amount of Preferably, the MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof is (is intended to be) administered subcutaneously; The combination for use of embodiment 1 or 5-9, the method of embodiment 2 or 5-9, the MetAP2 inhibitor for use of embodiment 3 or 5-9, or eribulin for use of embodiment 4 or 5-9.

[0254] EMBODIMENT 11 The combination for use of embodiment 1 or 5-10, the method of embodiment 2 or 5-10, the MetAP2 inhibitor for use of embodiment 3 or 5-10, or eribulin for use of embodiment 4 or 5-10, wherein said MetAP2 inhibitor is (is to be) administered once every 14 days (Q14D).

[0255] EMBODIMENT 12 The eribulin or eribulin mesylate is administered on day 1 and on a day between days 5 and 11 (including days 5 and 11) of a 21-day cycle, Preferably, said eribulin or eribulin mesylate is administered on days 1 and 8 of a 21-day cycle; The combination for use of embodiment 1 or 5-11, the method of embodiment 2 or 5-11, the MetAP2 inhibitor for use of embodiment 3 or 5-11, or eribulin for use of embodiment 4 or 5-11.

[0256] EMBODIMENT 13 the eribulin or eribulin mesylate and the MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, are administered to the subject in a first 21 day cycle, followed by a second 21 day cycle; said first 21 day cycle comprising: i) administering said MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, on days 1 and 15 of said first 21-day cycle; and ii) administering said eribulin or eribulin mesylate on day 1 and on a day between days 5 and 11 (inclusive), preferably on day 8, of said first 21-day cycle; Including, the second 21 day cycle comprising: i) administering the MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof on day 8 of the second 21-day cycle; and ii) administering said eribulin or eribulin mesylate on day 1 and on a day between days 5 and 11 (inclusive), preferably on day 8, of said second 21-day cycle; Including, The combination for use of embodiment 1 or 5-12, the method of embodiment 2 or 5-10, the MetAP2 inhibitor for use of embodiment 3 or 5-12, or eribulin for use of embodiment 4 or 5-12.

[0257] EMBODIMENT 14 the first 21 day cycle and the second 21 day cycle i) repeated at least once resulting in a total of at least four 21-day cycles; ii) repeated at least twice, resulting in a total of at least six 21-day cycles; iii) repeated at least three times resulting in a total of at least eight 21-day cycles; iv) repeated at least four times resulting in a total of at least 10 21-day cycles; or v) repeated at least five times resulting in a total of at least 12 21-day cycles; The combination for use of embodiment 13, the method of embodiment 12, the MetAP2 inhibitor for use of embodiment 13, or eribulin for use of embodiment 13.

[0258] EMBODIMENT 15 The combination for use of embodiment 1 or 5-14, the method of embodiment 2 or 5-14, the MetAP2 inhibitor for use of embodiment 3 or 5-14, or eribulin for use of embodiment 4 or 5-14, wherein said subject has breast cancer, preferably said breast cancer is triple negative breast cancer, preferably said triple negative breast cancer is metastatic.

[0259] EMBODIMENT 16 The object is i) About 30kg / m 2 BMI above 18.5; and ii) HbA1c levels greater than approximately 5.5%; having at least one of The combination for use of embodiment 1 or 5-15, the method of embodiment 2 or 5-15, the MetAP2 inhibitor for use of embodiment 3 or 5-15, or eribulin for use of embodiment 4 or 5-15.

[0260] EMBODIMENT 17 The combination for use of embodiment 1 or 5-16, the method of embodiment 2 or 5-16, the MetAP2 inhibitor for use of embodiment 3 or 5-16, or eribulin for use of embodiment 4 or 5-16, wherein the subject has previously received at least one line of treatment for said cancer.

[0261] EMBODIMENT 18 1. A combination comprising at least one MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof, fulvestrant or a pharma- ceutically acceptable salt thereof, and alpelisib or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer in a subject.

[0262] EMBODIMENT 19 1. A method of treating cancer in a subject in need of such treatment, comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharma- ceutical acceptable salt thereof, at least one therapeutically effective amount of fulvestrant or a pharma- ceutical acceptable salt thereof, and at least one therapeutically effective amount of alpelisib or a pharma- ceutical acceptable salt thereof.

[0263] EMBODIMENT 20 1. A MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, for use in a method for treating cancer in a subject, said method further comprising administering fulvestrant, or a pharma- ceutically acceptable salt thereof, and alpelisib, or a pharma- ceutically acceptable salt thereof.

[0264] EMBODIMENT 21 1. Fulvestrant or a pharmaceutically acceptable salt thereof for use in a method for treating cancer in a subject, the method further comprising administering at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and alpelisib, or a pharmaceutically acceptable salt thereof.

[0265] EMBODIMENT 22 1. Alpelisib, or a pharmaceutically acceptable salt thereof, for use in a method for treating cancer in a subject, the method further comprising administering at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and fulvestrant, or a pharmaceutically acceptable salt thereof.

[0266] EMBODIMENT 23 The combination for use of embodiment 18, the method of embodiment 19, the MetAP2 inhibitor for use of embodiment 20, the fulvestrant for use of embodiment 21, or the alpelisib for use of embodiment 22, wherein said at least one MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof, said alpelisib or a pharma-ceutically acceptable salt thereof, and said fulvestrant or a pharma-ceutically acceptable salt thereof are administered simultaneously or closely in time.

[0267] EMBODIMENT 24 The MetAP2 inhibitor, [ka] and a pharma- ceutically acceptable salt thereof; wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, and preferably the ratio of x to y is in the range of about 30:1 to about 3:1, and preferably the ratio of x to y is about 11:1. The combination for use of embodiment 18 or 22, the method of embodiment 19 or 22, the MetAP2 inhibitor for use of embodiment 20 or 22, the fulvestrant for use of embodiment 21 or 22, or the alpelisib for use of embodiment 22 or 22.

[0268] EMBODIMENT 25 The MetAP2 inhibitor, [ka] and wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, and preferably the ratio of x to y is in the range of about 30:1 to about 3:1, and preferably the ratio of x to y is about 11:1. The combination for use of embodiment 18 or 23-24, the method of embodiment 19 or 23-24, the MetAP2 inhibitor for use of embodiment 20 or 23-24, the fulvestrant for use of embodiment 21 or 23-24, or the alpelisib for use of embodiment 22 or 23-24.

[0269] EMBODIMENT 26 The alpelisib or a pharma- ceutically acceptable salt thereof is i) About 300mg; ii) about 250 mg; or iii) Approximately 200mg; and (is intended to be administered to the subject) in an amount of Preferably, the alpelisib or a pharma- ceutically acceptable salt thereof is (is intended to be) administered orally. The combination for use of embodiment 18 or 23-25, the method of embodiment 19 or 23-25, the MetAP2 inhibitor for use of embodiment 20 or 23-25, the fulvestrant for use of embodiment 21 or 23-25, or the alpelisib for use of embodiment 22 or 23-25.

[0270] EMBODIMENT 27 The fulvestrant or a pharma- ceutically acceptable salt thereof is i) about 500 mg; or ii) Approximately 250mg; and (is intended to be administered to the subject) in an amount of Preferably, the fulvestrant or a pharma- ceutically acceptable salt thereof is (is intended to be) administered intramuscularly, The combination for use of embodiment 18 or 23-26, the method of embodiment 19 or 23-26, the MetAP2 inhibitor for use of embodiment 20 or 23-26, the fulvestrant for use of embodiment 21 or 23-26, or the alpelisib for use of embodiment 22 or 23-26.

[0271] EMBODIMENT 28 The MetAP2 inhibitor or a pharma- ceutical acceptable salt thereof is i) Approximately 49 mg / m 2 ; ii) About 36mg / m 2 ; iii) About 65mg / m 2 or iv) Approximately 27mg / m 2 and (is intended to be administered to the subject) in an amount of Preferably, the MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof is (is intended to be) administered subcutaneously; The combination for use of embodiment 18 or 23-27, the method of embodiment 19 or 23-27, the MetAP2 inhibitor for use of embodiment 20 or 23-27, the fulvestrant for use of embodiment 21 or 23-27, or the alpelisib for use of embodiment 22 or 23-27.

[0272] EMBODIMENT 29 The combination for use of embodiment 18 or 23-28, the method of embodiment 19 or 23-28, the MetAP2 inhibitor for use of embodiment 20 or 23-28, the fulvestrant for use of embodiment 21 or 23-28, or the alpelisib for use of embodiment 22 or 23-28, wherein said MetAP2 inhibitor is (is to be) administered once every 14 days (Q14D).

[0273] EMBODIMENT 30 The combination for use of embodiment 18 or 23-29, the method of embodiment 19 or 23-29, the MetAP2 inhibitor for use of embodiment 20 or 23-29, the fulvestrant for use of embodiment 21 or 23-29, or the alpelisib for use of embodiment 22 or 23-29, wherein said alpelisib inhibitor is (is to be) administered once daily (QD).

[0274] EMBODIMENT 31 The combination for use of embodiment 18 or 23-30, the method of embodiment 19 or 23-30, the MetAP2 inhibitor for use of embodiment 20 or 23-30, the fulvestrant for use of embodiment 21 or 23-30, or alpelisib for use of embodiment 22 or 23-30, wherein said fulvestrant is (is to be) administered once every 14 days (Q14D), and after the third dose of fulvestrant, said fulvestrant is (is to be) administered once every 28 days (Q28D).

[0275] EMBODIMENT 32 the MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof, the alpelisib or a pharma- ceutically acceptable salt thereof, and fulvestrant or a pharma- ceutically acceptable salt thereof are administered to the subject for a first 28 day cycle, followed by a second 21 day cycle; The first 28 day cycle comprises: i) administering said MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, on days 1 and 15 of said first 28-day cycle; ii) administering said fulvestrant or a pharma- ceutically acceptable salt thereof on days 1 and 15 of said first 28-day cycle; and iii) administering said alpelisib or a pharma- ceutically acceptable salt thereof on each of days 15 to 28 of said first 28-day cycle; Including, the second 21 day cycle comprising: i) administering said MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, on days 1 and 15 of said second 28-day cycle; ii) administering said fulvestrant or a pharma- ceutically acceptable salt thereof on day 1 of said second 28-day cycle; and iii) administering said alpelisib or a pharma- ceutically acceptable salt thereof on each of days 1 to 28 of said second 28-day cycle; Including, The combination for use of embodiment 18 or 23-31, the method of embodiment 19 or 23-31, the MetAP2 inhibitor for use of embodiment 20 or 23-31, the fulvestrant for use of embodiment 21 or 23-31, or the alpelisib for use of embodiment 22 or 23-31.

[0276] EMBODIMENT 33 the second 28 day cycle comprising: i) at least one repeat resulting in a total of at least three 28-day cycles; ii) repeated at least twice resulting in a total of at least four 28-day cycles; iii) repeated at least three times resulting in a total of at least five 28-day cycles; iv) repeated at least four times resulting in a total of at least six 28-day cycles; or v) repeated at least five times resulting in a total of at least seven 28-day cycles; The combination for use of embodiment 18 or 23-32, the method of embodiment 19 or 23-32, the MetAP2 inhibitor for use of embodiment 20 or 23-32, the fulvestrant for use of embodiment 21 or 23-32, or the alpelisib for use of embodiment 22 or 23-32.

[0277] EMBODIMENT 34 The combination for use of embodiment 18 or 23-33, the method of embodiment 19 or 23-33, the MetAP2 inhibitor for use of embodiment 20 or 23-33, the fulvestrant for use of embodiment 21 or 23-33, or the alpelisib for use of embodiment 22 or 23-33, wherein the subject has breast cancer, preferably wherein the breast cancer is HR+HER2- breast cancer, preferably wherein the breast cancer is recurrent breast cancer.

[0278] EMBODIMENT 35 The combination for use of embodiment 18 or 23-34, the method of embodiment 19 or 23-34, the MetAP2 inhibitor for use of embodiment 20 or 23-34, the fulvestrant for use of embodiment 21 or 23-34, or the alpelisib for use of embodiment 22 or 23-34, wherein the subject has at least one PIK3CA mutation.

[0279] EMBODIMENT 36 The combination for use of embodiment 18 or 23-35, the method of embodiment 19 or 23-35, the MetAP2 inhibitor for use of embodiment 20 or 23-35, the fulvestrant for use of embodiment 21 or 23-35, or the alpelisib for use of embodiment 22 or 23-35, wherein the subject has previously been treated with neoadjuvant and / or adjuvant endocrine therapy, and preferably the breast cancer is characterized by disease progression more than about 12 months after completion of the neoadjuvant and / or adjuvant endocrine therapy.

[0280] EMBODIMENT 37 The combination for use of embodiment 18 or 23-36, the method of embodiment 19 or 23-36, the MetAP2 inhibitor for use of embodiment 20 or 23-36, the fulvestrant for use of embodiment 21 or 23-36, or the alpelisib for use of embodiment 22 or 23-36, wherein the subject has previously been treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor, preferably wherein the subject has been treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor for at least about 12 months.

[0281] EMBODIMENT 38 The combination for use of embodiment 18 or 23-37, the method of embodiment 19 or 23-37, the MetAP2 inhibitor for use of embodiment 20 or 23-37, the fulvestrant for use of embodiment 21 or 23-37, or the alpelisib for use of embodiment 22 or 23-37, wherein the breast cancer is identified as progressive during or after the subject is treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor.

[0282] EMBODIMENT 39 The combination for use of embodiment 18 or 23-38, the method of embodiment 19 or 23-38, the MetAP2 inhibitor for use of embodiment 20 or 23-38, the fulvestrant for use of embodiment 21 or 23-38, or the alpelisib for use of embodiment 22 or 22-31, wherein the subject is a postmenopausal woman.

[0283] EMBODIMENT 40 The object is i) HbA1c value of about 5.7% to about 6.4%; ii) a fasting plasma glucose (FPG) level greater than about 100 mg / dL (5.6 mmol / L) and less than about 140 mg / dL (7.7 mmol / L); iii) About 20kg / m 2 Body Mass Index (BMI) of over ; iv) a homeostasis model assessment of insulin resistance (HOMA-IR) score of greater than about 1.8; having at least one of The combination for use of embodiment 18 or 23-39, the method of embodiment 19 or 23-39, the MetAP2 inhibitor for use of embodiment 20 or 23-39, the fulvestrant for use of embodiment 21 or 23-39, or the alpelisib for use of embodiment 22 or 23-39.

[0284] EMBODIMENT 41 The object is i) About 30kg / m 2 BMI above 18.5; and ii) HbA1c levels greater than approximately 5.5%; having at least one of The combination for use, the method, the MetAP2 inhibitor for use, the eribulin for use, the fulvestrant for use, or the alpelisib for use of any one of embodiments 1 to 40.

[0285] EMBODIMENT 42 The combination for use, the method for use, the MetAP2 inhibitor for use, the eribulin for use, the fulvestrant for use, or the alpelisib for use of any one of embodiments 1-41, wherein said subject has at least one metabolic dysfunction, said at least one metabolic dysfunction being visceral adiposity, dyslipidemia, obesity (BMI≧30), high leptin, low adiponectin, high leptin-adiponectin ratio, high fasting insulin, high fasting insulin with chronic inflammation, insulin resistance, fasting hyperglycemia, high HbA1c, or any combination thereof.

[0286] EMBODIMENT 43 1. A combination comprising at least one MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, and inavolisib, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer in a subject.

[0287] EMBODIMENT 44 1. A method of treating cancer in a subject in need of such treatment, comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharma- ceutical acceptable salt thereof, and at least one therapeutically effective amount of inavolisib or a pharma- ceutical acceptable salt thereof.

[0288] EMBODIMENT 45 1. A MetAP2 inhibitor, or a pharma- ceutically acceptable salt thereof, for use in a method for treating cancer in a subject, said method further comprising administering inavolisib or a pharma- ceutically acceptable salt thereof.

[0289] EMBODIMENT 46 1. Inavolisib, or a pharmaceutically acceptable salt thereof, for use in a method for treating cancer in a subject, said method further comprising administering at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0290] EMBODIMENT 47 The combination for use, method, MetAP2 inhibitor for use, or inavolisib for use of any one of embodiments 1 to 46, wherein said at least one MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof and said inavolisib or a pharma- ceutically acceptable salt thereof are administered simultaneously or closely in time.

[0291] EMBODIMENT 48 The MetAP2 inhibitor, [ka] and a pharma- ceutically acceptable salt thereof; wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, and preferably the ratio of x to y is in the range of about 30:1 to about 3:1, and preferably the ratio of x to y is about 11:1. The combination for use, the method, the MetAP2 inhibitor for use, or the inavolisib for use according to any one of embodiments 1 to 47.

[0292] EMBODIMENT 49 The MetAP2 inhibitor, [ka] or a pharma- ceutically acceptable salt thereof; wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, and preferably the ratio of x to y is in the range of about 30:1 to about 3:1, and preferably the ratio of x to y is about 11:1. The combination for use, the method, the MetAP2 inhibitor for use, or the inavolisib for use according to any one of embodiments 1 to 48.

[0293] EMBODIMENT 50 The combination for use, the method, the MetAP2 inhibitor for use, or the inavolisib for use of any one of embodiments 1 to 49, wherein said inavolisib is (is to be) administered orally.

[0294] EMBODIMENT 51 The inavolisib is i) About 3mg; ii) Approximately 6 mg; iii) about 9 mg; or iv) Approximately 12 mg; is administered to the subject in an amount of The combination for use, the method, the MetAP2 inhibitor for use, or the inavolisib for use according to any one of embodiments 1 to 50.

[0295] EMBODIMENT 52 The MetAP2 inhibitor or a pharma- ceutical acceptable salt thereof is i) Approximately 49 mg / m 2 ; ii) About 36mg / m 2 or iii) About 65mg / m 2 ; and (is intended to be administered to the subject) in an amount of Preferably, the MetAP2 inhibitor or a pharma- ceutically acceptable salt thereof is (is intended to be) administered subcutaneously; The combination for use, the method, the MetAP2 inhibitor for use, or the inavolisib for use according to any one of embodiments 1 to 51.

[0296] EMBODIMENT 53 The combination, method, MetAP2 inhibitor for use, or inavolisib for use of any one of embodiments 1 to 52, wherein said MetAP2 inhibitor is (is to be) administered once every four days (Q4D).

[0297] EMBODIMENT 54 The combination for use, the method, the MetAP2 inhibitor for use, or the inavolisib for use of any one of embodiments 1 to 53, wherein said inavolisib is (is to be) administered once daily.

[0298] EMBODIMENT 55 The combination, method, MetAP2 inhibitor, or inavolisib for use according to any one of embodiments 1 to 54, wherein the subject has breast cancer, preferably wherein the breast cancer is triple negative breast cancer, preferably wherein the triple negative breast cancer is metastatic.

[0299] EMBODIMENT 56 The object is i) About 30kg / m 2 BMI above 18.5; and ii) HbA1c levels greater than approximately 5.5%; having at least one of The combination for use, the method, the MetAP2 inhibitor for use, or the inavolisib for use according to any one of embodiments 1 to 55.

[0300] EMBODIMENT 57 The combination for use, the method, the MetAP2 inhibitor for use, or the inavolisib for use of any one of embodiments 1-56, wherein said subject has previously received at least one line of treatment for said cancer.

[0301] EMBODIMENT 58 The combination, method, MetAP2 inhibitor, or inavolisib for use according to any one of embodiments 1 to 57, wherein the subject has breast cancer, preferably wherein the breast cancer is HR+HER2- breast cancer, preferably wherein the breast cancer is recurrent breast cancer.

[0302] EMBODIMENT 59 The combination for use, the method, the MetAP2 inhibitor for use, or the inavolisib for use of any one of embodiments 1-58, wherein said subject has at least one PIK3CA mutation.

[0303] EMBODIMENT 60 The object is i) About 30kg / m 2 BMI above 18.5; and ii) HbA1c levels greater than approximately 5.5%; having at least one of A combination for use, a method for use, a MetAP2 inhibitor for use, or an inavolisib for use.

[0304] EMBODIMENT 61 61. The combination, method, MetAP2 inhibitor or inavolisib for use of any one of embodiments 1-60, wherein said subject has at least one metabolic dysfunction, said at least one metabolic dysfunction being visceral adiposity, dyslipidemia, obesity (BMI≧30), high leptin, low adiponectin, high leptin-adiponectin ratio, high fasting insulin, high fasting insulin with chronic inflammation, insulin resistance, fasting hyperglycemia, high HbA1c, or any combination thereof. EXAMPLES

[0305] Example 1 – Phase 1b / 2 study of compound 1 in combination with alpelisib and fulvestrant in postmenopausal women with metastatic breast cancer and a PIK3CA mutation at risk for hyperglycemia following treatment with a CDK4 / 6 inhibitor The following non-limiting example describes a Phase 1b / 2 study to evaluate the antitumor efficacy of the combination of Compound 1, alpelisib, and fulvestrant in a specific HR+HER2- breast cancer population. Non-limiting objectives of the study include evaluating the safety of the triple drug combination (alpelisib, fulvestrant, and Compound 1), determining whether Compound 1, when combined with alpelisib and fulvestrant, reduces the number and severity of hyperglycemic events and / or reduces the number of antidiabetic medications required to control hyperglycemia in patients considered at risk for alpelisib-induced hyperglycemia (those with high baseline HbA1c or well-controlled type 2 diabetes), and preliminary evaluation of antitumor efficacy and changes in key biomarkers and quality of life in the study population. The study population included postmenopausal adult women with histologically and / or cytologically confirmed HR+, HER2- breast cancer progression or metastasis, PIK3CA mutations, progression on or after endocrine therapy plus a CDK4 / 6 inhibitor, and at risk for hyperglycemia (i.e., HbA1c between 5.7% and 6.4% (inclusive) and / or HOMA-IR >1.8).

[0306] Up to 52 patients will be enrolled, starting with a dose escalation cohort of 6 patients. Once the maximum tolerated dose (MTD) of the triplet is defined, additional patients will be enrolled until a total of up to 20 patients have completed at least 2 cycles of triplet therapy at that dose. 20 additional patients per new cohort may be enrolled for the various doses to further evaluate the safety profile and / or antitumor efficacy of the triplet and to identify a biologically active dose that is as low as possible below the MTD.

[0307] At the start of the planned escalation scheme, a dose of 36 mg / m 2 of compound 1 (49 mg / m 2 Alpelisib and fulvestrant will be administered at marketed or adjusted doses according to their respective labeling in combination with 49 mg / m2 of fulvestrant (one dose less than 49 mg / m2). Based on the compilation of safety data from the first two cycles in the first six patients, if there are no more than two dose-limiting toxicities (DLTs), the dose of Compound 1 will be increased to 49 mg / m2 in subsequent cohorts. 2 May be increased to 36 mg / m 2 If there were two or more DLTs at the dose of 2 The dose of Compound 1 may be reduced to 49 mg / m2, and the dose of alpelisib may be adjusted as needed. The dose of fulvestrant will not be adjusted. 2 If it is determined that the combination of alpelisib and fulvestrant is not tolerated, current and future patients will receive Compound 1 at 36 mg / m 2 Administer at .

[0308] 49 mg / m 2 The drug exposure of the active moiety of Compound 1 was significantly lower at the dose of 24 <200 pg / mL) and poor biomarker response (e.g., little / no change from baseline in insulin / leptin / adiponectin) with a favorable safety profile, Compound 1 was administered at 65 mg / m 2 Additional cohorts of patients may be enrolled who will receive this dose, which, if tolerated, will represent future doses of the combination.

[0309] Patients will remain on study triplet therapy for up to seven cycles to evaluate the safety and tolerability of the triplet therapy as well as to obtain initial efficacy data (i.e., ORR and PFS after 6 months of triplet therapy). At the discretion of their oncologist, patients may continue on triplet therapy beyond the initial seven cycles if they are experiencing clinical benefit, such as stable disease.

[0310] The study consisted of a 14-day pretreatment phase with Compound 1 and fulvestrant starting on day 1 of cycle 1 (C1D1), followed by the addition of alpelisib on C1D15.

[0311] Starting with the first cohort, patients received 36 mg / m on day 1 of cycle 1 (C1D1). 2 of Compound 1 administered subcutaneously and 500 mg of Fulvestrant administered intramuscularly. Starting on Day 15 of Cycle 1 (C1D15) after fasting blood draw, patients will receive 36 mg / m 2 of compound 1 subcutaneously, 500 mg of fulvestrant intramuscularly, followed by alpelisib 300 mg once daily (QD) orally (PO) (i.e., "triple therapy").

[0312] From cycle 2 (C2) onwards, all patients received 36 mg / m 2 The patient will receive a triple combination therapy of Compound 1 subcutaneously every other week (CxD1 and CxD15) + 500mg of Fulvestrant intramuscularly once every 28 days (CxD1) + 300mg of Alpelisib orally once daily.

[0313] As mentioned above, the dose of Compound 1 was 49 mg / m2 in each cycle of the study, depending on the pharmacokinetic and safety analysis. 2 and 65 mg / m 2 or 27 mg / m 2 can be reduced to

[0314] Outcome measures Primary Outcome 1: To examine whether Compound 1, when combined with alpelisib and fulvestrant, reduces the number and severity of hyperglycemic events and / or the number of antidiabetic medications needed to control hyperglycemia in patients considered at risk for alpelisib-induced hyperglycemia (high baseline HbA1c or well-controlled type 2 diabetes). The criterion used to evaluate this outcome is a measure of fasting plasma glucose, and the primary efficacy analysis includes the number and proportion of patients who experience at least one grade 3 or 4 hyperglycemia during the first four cycles of triple therapy.

[0315] Primary outcome 2: Preliminary evaluation of the antitumor effect of the combination of alpelisib, fulvestrant, and compound 1. Tumor response will be evaluated using RECIST v1.1 criteria, and the objective response rate (ORR) consisting of CR and PR will be calculated. ORR from 24 weeks after the start of the study and CBR of CR+PR+SD will be calculated.

[0316] Other prespecified outcome measures: number and type of antidiabetic medications needed for glucose control, changes in major fasting metabolic hormones (insulin, leptin, adiponectin), insulin resistance (using HOMA-IR score), and HbA1c. The number and type of antidiabetic medications needed for glycemic control will be assessed, plus changes in major fasting metabolic hormones (insulin, leptin, adiponectin), FPG, insulin resistance (using HOMA-IR score), and HbA1c will be measured at C5D15 and end of treatment compared to baseline values. Blood levels of glucose, insulin, HbA1C, leptin, adiponectin, apelin, FGF21, and lipids will be measured in clinical chemistry laboratories. Other preliminary biomarkers measured in the clinical chemistry laboratory include, for example, angiogenesis markers bFGF, VEGF (A, C, and D), inflammatory markers IL-5, IL-6, hs-CRP, GM-CSF, resistin, metastasis markers sFRP-1, sFRP-5, MetAP2 marker cyclophilin A, as well as SHBG, and circulating tumor DNA (ctDNA).

[0317] Eligibility Criteria 1. Patients are adults aged 18 years or older at the time of informed consent and have signed informed consent in accordance with local guidelines prior to any study-related activity.

[0318] 2. Patients with histologically and / or cytologically confirmed HR+, HER2- breast cancer diagnosed by a local laboratory.

[0319] 3. The patient has been identified as having a PIK3CA mutation status using an FDA-approved test, which was determined during screening, or the patient has previously been determined to have said mutation and has documented documentation of it.

[0320] 4. Patients have advanced (locally regionally recurrent or metastatic for which curative therapy is not possible) breast cancer that fits into any of the following categories: Documented evidence of progressive disease (PD) >12 months after completion of (neo)adjuvant endocrine therapy, Documented evidence of PD during or after 1 line of endocrine therapy plus a CDK4 / 6 inhibitor for metastatic disease for at least 12 months, Recurrent disease. Newly diagnosed advanced breast cancer with recurrent disease (i.e., documented evidence of PD) during or after only one line of endocrine therapy plus a CDK4 / 6 inhibitor for at least 12 months. Recurrent disease or PD during or after aromatase inhibitor (AI) therapy (i.e., letrozole, anastrozole, exemestane) with concomitant treatment with a CDK4 / 6 inhibitor for at least 12 months.

[0321] 5. Patients have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or at least one evaluable, primarily lytic, bone lesion.

[0322] 6.Patients have an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 1 or less.

[0323] 7. The patient has a fasting plasma glucose (FPG) test result of 140 mg / dL (7.7 mmol / L) or less and an HbA1c of 5.7% or more and 6.4% or less (39 mmol / mol and 47 mmol / mol, respectively). Both criteria must be met.

[0324] 8. The patient's body mass index (BMI) is 20 kg / m 2 That's all.

[0325] 9. Patient is postmenopausal. Postmenopausal is defined as any of the following: If you are over 45 years old and have not had a period for more than 2 years. Amenorrhea for more than 2 years without hysterectomy and oophorectomy, and follicle-stimulating hormone levels in the postmenopausal range at prestudy (screening) evaluation. Following hysterectomy with oophorectomy. Documentation of hysterectomy or oophorectomy must be confirmed in the medical record of the actual surgery or confirmed by ultrasound. If oophorectomy alone, local hormone assessment (follicle stimulating hormone, estradiol) will be performed at screening to confirm postmenopausal status. Patients undergoing ovarian suppression are also eligible.

[0326] 10. Patient agrees, is willing and able to arrive at the hospital / clinic in a fasted state (>8 hours) on the designated fasting date.

[0327] 11. Patients will have adequate bone marrow and organ function as defined by the following laboratory values ​​(eligibility will be assessed by a central laboratory): Platelet count ≧140×109 / L Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN) if there are no liver metastases. If the patient has liver metastases, ALT and AST < 5 x ULN. Total bilirubin ≤ 1.5 x ULN, except for patients with Gilbert's syndrome who may be included only if their total bilirubin is ≤ 3.0 x ULN or their direct bilirubin is ≤ 1.5 x ULN. Fasting serum amylase ≤ 2 × ULN Fasting serum lipase ≦ULN Hemoglobin ≥ 9 g / dL Absolute neutrophil count [ANC] ≥ 1500 / mL Creatinine clearance >60mL / min (using the Cockcroft-Gault formula) Albumin >3.5 gm / dL

[0328] Example 2 – Phase 2 study of compound 1 in combination with eribulin mesylate in patients with metastatic triple-negative breast cancer and metabolic dysfunction The following non-limiting example is a description of a Phase 2 study to evaluate the antitumor efficacy of a combination of Compound 1 and eribulin mesylate in a specific triple-negative breast cancer population.

[0329] Summary: This example describes a placebo-controlled, phase 2, randomized, controlled trial to test the use of compound 1 in combination with eribulin mesylate to treat histologically confirmed hormone receptor-negative, HER2-negative (i.e., triple-negative) metastatic breast cancer and concomitant metabolic dysfunction. The trial included a safety run-in period during which 15 patients were treated with 49 mg / m 2 Compound 1 is administered every 2 weeks in combination with eribulin mesylate on days 1 and 8 of a 21-day cycle. After safety confirmation, 40 additional patients will be randomly assigned (2:1) to receive a combination of compound 1 and eribulin mesylate or a combination of placebo and eribulin mesylate. The primary objective of this study is to evaluate the preliminary biological efficacy. This outcome will be evaluated by changes in insulin resistance. Secondary objectives of this study include, but are not limited to, objective response rate (ORR), progression-free survival (PFS), duration of response, safety and tolerability, patient-reported outcomes, and changes in metabolic and other biomarkers.

[0330] Patient population: Men and women with histologically confirmed triple-negative metastatic breast cancer (MBC) who have received up to two lines of prior treatment for metastatic disease and have baseline metabolic dysfunction (baseline hemoglobin A1c >5.5 and / or body mass index (BMI) ≥30 kg / m 2 ) Patients with

[0331] Design: An initial safety run-in period will involve allocating the first 15 enrolled patients to receive the investigational drug combination of Compound 1 and eribulin mesylate. Once safety has been confirmed, the next 40 enrolled patients will be allocated to receive the previously identified MTD of 49 mg / m 2 Patients will be randomly assigned (2:1) to receive either a standard dose of eribulin mesylate in combination with compound 1 of the present invention administered every 2 weeks (investigational group) or placebo and eribulin mesylate chemotherapy (control group). The primary objective of this study is to evaluate the preliminary biological efficacy. This outcome will be measured by changes in insulin resistance. Secondary objectives of this study include, but are not limited to, objective response rate (ORR), progression-free survival (PFS), duration of response, safety and tolerability, patient-reported outcomes, and changes in metabolic and other biomarkers.

[0332] Treatment plan: Patients in both the investigational and control arms were administered a standard dose of 1.4 mg / m on days 1 and 8 of a 21-day cycle. 2 One week before starting eribulin mesylate, patients were administered 49 mg / m 2 Treatment with the combination of Compound 1 and eribulin mesylate will continue until progressive disease (PD) occurs or other discontinuation criteria are met. Compound 1 doses will range from 65 mg / m2 to 65 mg / m2 depending on PK and safety analyses. 2 or 36 mg / m 2 can be reduced to

[0333] Eligibility Criteria: Male or female. Histologically and / or cytologically confirmed triple-negative metastatic breast cancer defined as estrogen and progesterone receptor staining <10% and HER2 negative defined as IHC 0-1+ (Note: if IHC is equivocal, non-amplified status by FISH is acceptable). Advanced (local recurrence not capable of curative therapy or surgery) or metastatic disease and has received up to two lines of treatment in the advanced or metastatic setting. HbA1c>5.5 and / or BMI>30kg / m 2 Evidence of metabolic dysfunction defined as Measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) or at least one evaluable, primarily lytic bone lesion. - Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤ 1 Are an adult aged 18 years or older at the time of informed consent and have provided written informed consent in accordance with local guidelines prior to any study-related activity. Adequate bone marrow and organ function as defined by the following laboratory values ​​(eligibility will be assessed by a central laboratory): Absolute neutrophil count (ANC) ≥ 1000μL ·Platelet count ≧140,000μL Hemoglobin level ≥ 9.0g / dL Calcium (corrected for serum albumin) and magnesium grade ≤1 according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and not judged clinically significant by the investigator. Potassium is within the normal range with or without correction by supplements. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN) if there are no liver metastases. ALT and AST ≤ 5 x ULN if the patient has liver metastases. Total bilirubin ≤ 1.5 x ULN, except that patients with Gilbert's syndrome may be included only if their total bilirubin is ≤ 3.0 x ULN or their direct bilirubin is ≤ 1.5 x ULN. Creatinine level ≦1.5mg / dL Patients are willing and able to comply with the requirements of the study, e.g., are able to fast prior to treatment days. For sexually active women of childbearing potential, willingness to use barrier contraception. For sexually active men, willingness to use barrier contraception.

[0334] Primary Objective: The primary endpoint of the study is to evaluate the biological efficacy of the combination of Compound 1 and eribulin mesylate, as defined by the change in insulin resistance score (HOMA-IR) from cycle 4 (i.e., approximately 12 weeks) of treatment onwards. Such evaluation will be performed within 2 weeks from day 1 of cycle 4. Study participants who have completed at least 3 cycles of treatment will be considered evaluable for the primary endpoint. Insulin resistance will be assessed using the homeostatic model assessment of insulin resistance (HOMA-IR). HOMA-IR is calculated as follows: fasting serum insulin (μU / mL) × fasting plasma glucose (mmol L-1) / 22.5).

[0335] Secondary Objectives Safety and Tolerability: Type, frequency, and severity of treatment-emergent adverse events (TEAEs) and laboratory toxicities according to NCI CTCAE version 5.0.

[0336] 3- and 6-month ORR: Response rates will be assessed by RECIST v1.1 as follows: A partial response (PR) is a reduction in the sum of the diameters of target lesions of at least 30% compared to the sum of the diameters at baseline. Complete response (CR) is defined as the disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must shrink to less than 10 mm in their short axis. Stable disease (SD) is defined as neither sufficient shrinkage to be considered PR nor sufficient growth to be considered PD, based on the sum of the smallest diameters during the study period. Disease progression (PD) requires a 20% increase in the sum of the diameters of the target lesions from the smallest sum during the study (including the baseline sum, if that sum was the smallest during the study). In addition to the 20% relative increase, the sum must show an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions also counts as progression.) Duration of response is defined as the time from first documented objective tumor response to radiographic progression (by investigator using RECIST v1.1) or death from any reason on study, whichever occurs first.

[0337] 3 months, 6 months, and median PFS: PFS was assessed using RECIST v1.1 and is defined as the time from treatment assignment to disease progression or death, whichever occurs first.

[0338] Changes in blood metabolism and other biomarkers: Fasting blood samples will be taken at baseline and each cycle. Blood levels of glucose, insulin, HbA1C, leptin, adiponectin, apelin, FGF21, and lipids will be measured in a clinical chemistry laboratory. Other preliminary biomarkers will be measured in a clinical chemistry laboratory, including angiogenesis markers bFGF, VEGF (A, C, and D), inflammatory markers IL-5, IL-6, hs-CRP, GM-CSF, resistin, metastasis markers sFRP-1, sFRP-5, MetAP2 marker cyclophilin A, SHBG, and circulating tumor DNA (ctDNA).

[0339] Changes in body composition: Body composition will be assessed using computed tomography (CT). Fat and muscle volumes at the level of the third lumbar vertebra will be analyzed using commercially available software (iNtuition, TeraRecon) using CT scans performed for evaluation of total body tumor burden (baseline, every 3 months). Lumbar muscle mass based on CT (30 mm above the level of L3) will be evaluated using the CT scans performed for evaluation of total body tumor burden (baseline, every 3 months). 3) are measured by two readers. Using a semi-automated technique, volumetric slabs are analyzed for the presence of skeletal muscle. First, attenuation thresholds of -29 and 150 HU are applied to the entire image volume. A color-coded map of voxels with mean attenuation values ​​in the range of -29 to 150 HU is generated. Non-muscle soft tissues (abdominopelvic organs, large vessels, spinal cord, and parts of bone marrow) are manually excluded by drawing regions of interest around identified tissue areas. Organs containing smooth muscle are excluded because muscle mass changes during intestinal peristalsis. A series of images containing only skeletal muscle is generated, thereby allowing a volumetric calculation of whole-body skeletal muscle. Subcutaneous and visceral adipose tissue volumes are segmented from the same L3 volumetric slabs using a similar semi-automated approach with iNtuition.

[0340] Quality of Life: QOL, Functional Assessment of Cancer Treatment - Breast Cancer The FACT-B includes 37 items divided into four main subscales that make up the FACT-General (FACT-G) scale: physical well-being (7 items), functional well-being (7 items), emotional well-being (6 items), and social / family well-being (7 items), plus a breast cancer subscale (10 items). The FACT-B score is obtained by summing these five subscales (total score 148). A FACT-G score (27 items excluding the breast cancer subscale; total score 108) is also calculated. All items are rated on a Likert scale from 0 to 4, with the following response format: 0 = not at all, 1 = a little, 2 = a little, 3 = a lot, 4 = a lot. Respondents are asked to answer each question as it applies to the past 7 days. A higher score on FACT-B indicates a higher quality of life.

[0341] Plasma concentration-time (PK): PK profiles of Compound 1 and its primary and other metabolites when coadministered with eribulin mesylate are collected in the study group as follows: for the first 15 patients, samples are collected 3 hours (±10 min) after Compound 1 administration (C1D1), 24 hours (C1D2), 48 hours (C1D3), before Compound 1 administration (C1D8), before and 3 hours after Compound 1 administration (C1D15), before Compound 1 administration (C2D1), and before Compound 1 administration (C2D8). For the remaining 40 patients, PK samples are collected 3 hours (±10 min) after Compound 1 administration (C1D1), before Compound 1 administration (C1D8), before and 3 hours after Compound 1 administration (C1D15), before Compound 1 administration (C2D1), and before Compound 1 administration (C2D8).

[0342] Example 3 – Treatment of Breast Cancer with a Combination of Compound 1 and Eribulin Mesylate Below are non-limiting examples showing the treatment of breast cancer in a mouse model with a combination of Compound 1 and eribulin.

[0343] Animals: 110 female C57BL / 6J mice were obtained from Jackson Labs and housed 3 mice per cage. Starting at 6 weeks of age, mice were placed on a high-fat, high-sucrose diet (D12451) for 16 weeks prior to tumor implantation. Mice were maintained on this diet for the duration of the study.

[0344] Cell Culture: EO771 cell line was obtained from CH3 Biosystems and cultured in DMEM supplemented with 10% FBS. As one skilled in the art would understand, EO771 cells are a model of triple-negative breast cancer. On the day of implantation, cells were washed with phosphate-buffered saline (PBS) and harvested by trypsinization (incubated with 0.25% trypsin for 5 min at 37°C), after which the trypsin was inactivated with 2 volumes of complete medium. Harvested cells were pelleted by centrifugation at 2500 rpm for 5 min at 18°C. After the cells were pelleted, the supernatant was removed and the pellet was resuspended in 30 mL of PBS. After counting cell number and viability, cells were pelleted at 2500 rpm for 5 min at 18°C ​​and cultured at 1 x 10 per mL in 50% PBS, 50% Matrigel. 6 pieces (1×10 5 The cells were resuspended at a final concentration of 100x100 cells / mouse and used for transplantation.

[0345] Tumor cell implantation: EO771 cells in a mixture of PBS and Matrigel were implanted into the fourth mammary gland in a volume of 100 μl per mouse. Mice were anesthetized with 4% isoflurane and 1.2% oxygen, and cells were injected into the right lower mammary fat pad while anesthetized.

[0346] Tumor assessment: Starting 7 days after cell implantation, all animals were weighed, marked, and tumors (length and width) were measured twice weekly using a wireless Mitutoyo UWAVE-T digital caliper linked to a UWAVE-R for recording measurements. Tumor volumes were calculated using Microsoft Office Excel software ((l*w 2 )*π / 6). The mean tumor volume was approximately 100 mm 3 At that time, mice were randomized into treatment groups of six (based on tumor volume). The actual mean tumor volume was 118 mm. 3 / group.

[0347] Treatment: Nine groups of mice were treated as shown in Table A. Body weights were recorded twice weekly from study day 1, and tumor measurements were taken on the same days as body weights throughout the study. Mice in group 1 were administered vehicle 1 (5% EtOH, 95% water) intraperitoneally (IP) Q4D and vehicle (5% mannitol in water) subcutaneously (SC) Q4D for a total of seven doses. Mice treated with eribulin mesylate were administered intraperitoneally Q4D at varying dose frequencies due to poor tolerance of the 2 mg / kg dose. Mice treated with compound 1 at 6 mg / kg and 12 mg / kg were administered subcutaneously (SC) Q4D for a total of seven doses. All IP and SC dose volumes were calculated at 10 mL / kg body weight.

[0348] [Table 1]

[0349] Figure 3 is a graph of the tumor volume in each treatment group during the study. Treatment groups 5, 7, and 9 did not receive eribulin mesylate on day 8.

[0350] Figure 4 is a graph of tumor volumes in individual animals treated with vehicle control or 2 mg / kg eribulin mesylate. As shown in Figure 4, 2 mg / kg eribulin mesylate IP / Q4D was poorly tolerated, leading to multiple early discontinuations. Thus, eribulin mesylate administration was stopped on day 8 and resumed on day 11, but on a Q7D dosing schedule. This change was also implemented in treatment groups 8 and 9.

[0351] FIG. 5 is a series of graphs showing tumor volumes in treatment groups 1-5 over the course of the study.

[0352] FIG. 6 is a series of graphs showing tumor volumes in treatment groups 1, 2-4, 6, and 8 over the course of the study.

[0353] FIG. 7 is a series of graphs showing tumor volumes in treatment groups 1-3, 5, 7, and 9 over the course of the study.

[0354] FIG. 8 is a series of charts showing tumor growth inhibition in the various treatment groups on days 18 and 22 of the study.

[0355] Figure 9 is a series of graphs showing body weight and body weight change in various treatment groups over the course of the study. As shown in Figure 9, all groups, including the vehicle group, lost weight. The weight loss in the Compound 1 group and the Eribulin mesylate group (Groups 2-5) was greater than the vehicle group. The weight loss in the combination group was consistently greater than the vehicle group.

[0356] Figure 10 is a graph showing the survival rate in various treatment groups during the study. As shown in Figure 10, the combination of 12mg / kg compound 1 and 1mg / kg eribulin mesylate increased the survival rate compared with the vehicle group.

[0357] FIG. 11 is a series of graphs showing survival rates in treatment groups 1-4, and 8 over the course of the study.

[0358] 12 is a graph showing the adipose tissue mass measured in various treatment groups. As shown in FIG 12, a decrease in adipose tissue mass was observed in treatment groups 5 to 8.

[0359] FIG. 13 is a graph showing leptin levels in the various treatment groups.

[0360] FIG. 14 is a graph showing plasma adiponectin levels in various treatment groups.

[0361] FIG. 15 is a graph showing the leptin / adiponectin ratio (LAR) in plasma samples isolated from the various treatment groups.

[0362] FIG. 16 is a graph showing plasma insulin levels in the various treatment groups.

[0363] FIG. 17 is a graph showing plasma SFRP1 levels in the various treatment groups.

[0364] FIG. 18 is a series of graphs showing plasma interleukin levels in various treatment groups.

[0365] FIG. 19 is a series of graphs showing plasma hematopoietic growth factor (G-CSF and M-CSF) levels in plasma samples isolated from various treatment groups.

[0366] FIG. 20 is a series of graphs showing FABP4 and resistin levels in plasma samples isolated from various treatment groups.

[0367] FIG. 21 is a graph showing plasma FGF-21 levels in various treatment groups.

[0368] FIG. 22 is a series of graphs showing ALP, ALT, and AST levels in various treatment groups.

[0369] FIG. 23 is a graph showing cholesterol levels in the various treatment groups.

[0370] FIG. 24 is a graph showing bilirubin levels in the various treatment groups.

[0371] FIG. 25 is a graph showing creatine kinase levels in the various treatment groups.

[0372] FIG. 26 is a graph showing albumin levels in the various treatment groups.

[0373] FIG. 27 is a graph showing globulin levels in the various treatment groups.

[0374] FIG. 28 is a graph showing the albumin-globulin ratio (AGR) in the various treatment groups.

[0375] FIG. 29 is a series of graphs showing red blood cell (RBC) and hematocrit (HCT) values ​​in various treatment groups.

[0376] FIG. 30 is a graph showing hemoglobin (Hgb) levels in the various treatment groups.

[0377] FIG. 31 is a series of graphs showing white blood cell (WBC) and monocyte values ​​in various treatment groups.

[0378] FIG. 32 is a series of graphs showing lymphocyte and neutrophil values ​​in various treatment groups.

[0379] Without wishing to be bound by theory, the results described in this example indicate that a combination of compound 1 and eribulin can be used to treat cancer, including breast cancer.

[0380] Example 4 –Treatment of Breast Cancer with a Combination of Compound 1 and Inavolisib Below are non-limiting examples demonstrating the treatment of breast cancer in a mouse model using a combination of Compound 1 and inavolisib.

[0381] Animals: Female NU / j mice were obtained at 6 weeks of age at birth and were acclimated for a minimum of 7 days, 5 per cage. Mice were housed in autoclaved cages with autoclaved water for the duration of the study. Animals were provided with food (irradiated chow 2920X) and water ad libitum. Animals were housed in a temperature- and humidity-controlled room with a 12-hour light cycle.

[0382] Cell culture: MCF-7 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% FBS.

[0383] Tumor cell implantation: On the day of implantation, cells were washed once with phosphate-buffered saline (PBS). After washing, cells were pelleted (5 min, 1000 rpm, RT) and counted in a hemocytometer. Cells were implanted at 5 × 10 per mouse. 6The cells were resuspended in an appropriate amount of PBS and Matrigel (1:1) at a concentration of 10 cells / mL (kept on ice until transplantation). 48 hours prior to cell transplantation, 17-β estradiol pellets (0.36 mg 60-day sustained release pellets) were subcutaneously implanted between the shoulder blades of each mouse. The mammary cell line MCF-7 was injected into the mammary fat pad. Anesthesia was required to ensure cell placement in the mammary fat pad. Mice were anesthetized using a combination of 4% isoflurane and 2.5 L / min O2 in an induction chamber. After achieving deep anesthesia, the animals were placed ventral side up and anesthesia was maintained via an attached nose cone. MCF-7 cells were then injected into the mammary fat pad at a concentration of 5 × 10 cells / mL. 6 Each mouse was injected with a volume of 100 μl containing 10 cells. The injection site was cleaned with alcohol prior to injection to prevent any infection.

[0384] Tumor assessment: All animals were ear-tagged prior to cell implantation. Starting 5 days after cell implantation, tumors (length x width) were measured twice weekly using a wireless Mitutoyo UWAVE-T digital caliper linked to a UWAVE-R for recording measurements. The average tumor volume was approximately 50 mm. 3 ((Length x Width 2 At the time of tumor growth (Tg) of 1000 mg / kg / day (Tg / kg / day), animals were randomly divided into 8 groups of 15 animals each based on the mean tumor volume. Randomization was assessed by the tumor volume of all mice. Randomization was based on the tumor size of each group being similar (approximately 50 mm 3 ) was carried out.

[0385] Treatment: Four groups of mice were treated as shown in Table B. Group 1 mice received vehicle control orally (PO). Inavolisib was administered orally (PO) at 25 mg / kg once daily (QD) for the duration of the study. Compound 1 was administered subcutaneously (SC) at 8 mg / kg once every 4 days (Q4D) for the duration of the study. All PO and SC dose volumes were calculated at 10 mL / kg body weight.

[0386] [Table 2]

[0387] FIG. 33 is a graph showing the tumor volume (left panel) and the change in tumor volume (right panel) in each treatment group during the study period.

[0388] Tumor growth inhibition in the various treatment groups on day 25 of the study is shown in Table C. [Table 3]

[0389] Figure 34 is a series of graphs showing body weight and body weight change in various treatment groups over the course of the study. As shown in Figure 34, all groups, including the vehicle group, lost weight. Compound 1 and Inavolisib (Groups 2-5) lost more weight than the vehicle group. The combined groups consistently lost more weight than the vehicle group.

[0390] Without wishing to be bound by theory, the results described in this example indicate that a combination of compound 1 and inavolisib can be used to treat cancer, including breast cancer.

Claims

1. A combination pharmaceutical for the treatment of cancer in a subject, wherein the pharmaceutical comprises at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, and eribulin or a pharmaceutically acceptable salt thereof. The aforementioned MetAP2 inhibitor 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, In the equation, x is in the range of 1 to approximately 450, y is in the range of 1 to approximately 30, and n is in the range of 1 to approximately 100. Combination medicine.

2. The combination drug according to Claim 1, wherein the ratio of x to y is in the range of approximately 30:1 to approximately 3:

1.

3. The combination pharmaceutical according to claim 1, wherein the eribulin is eribulin mesylate.

4. The combination pharmaceutical product according to any one of claims 1 to 3, wherein the at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and the eribulin or a pharmaceutically acceptable salt thereof are administered simultaneously or in close proximity in time.

5. The eribulin or a pharmaceutically acceptable salt thereof i) Approximately 1.4 mg / m ２ ; ii) Approximately 1.1 mg / m ２ ; or (ii) Approximately 0.7 mg / m ２ ; This is administered to or intended to be administered to the subject in the amount of, The aforementioned MetAP2 inhibitor or a pharmaceutically acceptable salt thereof i) Approximately 49 mg / m² ２ ; (ii) Approximately 36 mg / m ２ ; iii) Approximately 65mg / m ２ ; or iv) approximately 27 mg / m ２ ; This amount is administered to or intended to be administered to the subject. A combination pharmaceutical product according to any one of claims 1 to 3.

6. The aforementioned MetAP2 inhibitor i) Once every 14 days (Q14D); ii) Once every 7 days (Q7D); or iii) Once every 21 days (Q21D); To be administered or intended to be administered A combination pharmaceutical for use according to any one of claims 1 to 3.

7. A combination pharmaceutical for use according to any one of claims 1 to 3, wherein the eribulin or a pharmaceutically acceptable salt thereof is administered or intended to be administered on one day between day 1 and day 5 through 11 of a 21-day cycle (including day 5 and day 11).

8. The eribulin or a pharmaceutically acceptable salt thereof, and the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof are administered to the subject in a first 21-day cycle, followed by a second 21-day cycle, or are intended to be administered to the subject in such a manner. The first 21-day cycle described above is i) Administering the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof on the 1st and 15th days of the first 21-day cycle; and ii) Administering eribulin or a pharmaceutically acceptable salt thereof on day 1 and on one day between days 5 and 11 of the first 21-day cycle (including days 5 and 11); Includes, The second 21-day cycle described above is i) Administering the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof on the 8th day of the second 21-day cycle; and ii) Administering eribulin or a pharmaceutically acceptable salt thereof on day 1 and on one day between days 5 and 11 of the second 21-day cycle (including days 5 and 11); including, A combination pharmaceutical for use according to any one of claims 1 to 3.

9. The eribulin or a pharmaceutically acceptable salt thereof, and the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof are administered to the subject in a 21-day cycle, or are intended to be administered to the subject in a 21-day cycle. The aforementioned 21-day cycle, i) Administering the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof on the 1st and 8th days of the 21-day cycle; and ii) Administering eribulin or a pharmaceutically acceptable salt thereof on the 1st and 8th days of the 21-day cycle; or i) Administering the MetAP2 inhibitor once during the 21-day cycle; and ii) Administering eribulin or a pharmaceutically acceptable salt thereof on the 1st and 8th days of the 21-day cycle; including, A combination pharmaceutical for use according to any one of claims 1 to 3.

10. The aforementioned subject is, i) Having breast cancer; ii) The following a) Approximately 30kg / m ２ The above BMI; and b) HbA1c levels exceeding approximately 5.5%; Having at least one of the following; and / or iii) Having previously received at least one line of treatment for the aforementioned cancer, A combination pharmaceutical for use according to any one of claims 1 to 3.

11. The combination drug according to claim 10, wherein the subject has previously received at least one line of cancer treatment.

12. The combination drug according to claim 10, wherein the breast cancer is triple-negative breast cancer or metastatic triple-negative breast cancer.

13. A combination pharmaceutical for the treatment of cancer in a subject, wherein the pharmaceutical comprises at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, fulvestrant or a pharmaceutically acceptable salt thereof, and alpelisib or a pharmaceutically acceptable salt thereof, The aforementioned MetAP2 inhibitor 【Chemistry 2】 And, In the equation, x is in the range of 1 to approximately 450, y is in the range of 1 to approximately 30, and n is in the range of 1 to approximately 100. Combination medicine.

14. The combination drug according to claim 13, wherein the ratio of x to y is in the range of approximately 30:1 to approximately 3:

1.

15. The combination pharmacopoeia according to claim 13 or 14, wherein at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, alpelisib or a pharmaceutically acceptable salt thereof, and fulvestrant or a pharmaceutically acceptable salt thereof are administered simultaneously or in close proximity in time.

16. The aforementioned alpelisib or a pharmaceutically acceptable salt thereof i) Approximately 300 mg; ii) Approximately 250 mg; or iii) Approximately 200 mg; This is administered to or intended to be administered to the subject in the amount of, The aforementioned fulvestrant or a pharmaceutically acceptable salt thereof i) Approximately 500 mg; or ii) about 250 mg; This is administered to or intended to be administered to the subject in the amount of, The aforementioned MetAP2 inhibitor or a pharmaceutically acceptable salt thereof i) approximately 49 mg / m ２ ; (ii) Approximately 36 mg / m ２ ; iii) Approximately 65mg / m ２ ; or iv) approximately 27 mg / m ２ ; This amount is administered to or intended to be administered to the subject. The combination pharmaceutical product according to claim 13 or 14.

17. The aforementioned MetAP2 inhibitor or a pharmaceutically acceptable salt thereof is administered once every 14 days (Q14D), or is intended to be administered once every 14 days. The alpelisib inhibitor or a pharmaceutically acceptable salt thereof is administered once daily (QD), or is intended to be administered once daily. The fulvestrant or a pharmaceutically acceptable salt thereof is administered or intended to be administered once every 14 days (Q14D). The combination pharmaceutical product according to claim 13 or 14.

18. The combination pharmaceutical according to claim 17, wherein, after the third administration of fulvestrant, fulvestrant is administered once every 28 days (Q28D), or is intended to be administered once every 28 days (Q28D).

19. The MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, the alpelisib or a pharmaceutically acceptable salt thereof, and the fulvestrant or a pharmaceutically acceptable salt thereof are administered to the subject in a first 28-day cycle, and then in a second 21-day cycle, or are intended to be administered to the subject in a second 21-day cycle. The first 28-day cycle described above is i) Administer the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof on the 1st and 15th days of the first 28-day cycle; ii) Administering fulvestrant or a pharmaceutically acceptable salt thereof on the 1st and 15th days of the first 28-day cycle; and iii) Administer the alpelisib or a pharmaceutically acceptable salt thereof on each of the 15th to 28th days of the first 28-day cycle; Includes, The second 21-day cycle described above is i) Administer the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof on the 1st and 15th days of the second 28-day cycle; ii) Administering fulvestrant or a pharmaceutically acceptable salt thereof on the first day of the second 28-day cycle; and iii) Administer the alpelisib or a pharmaceutically acceptable salt thereof on each of days 1 through 28 of the second 28-day cycle; including, The combination pharmaceutical product according to claim 13 or 14.

20. A combination pharmaceutical for the treatment of cancer in a subject, wherein the pharmaceutical comprises at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, and inavolisib or a pharmaceutically acceptable salt thereof, The aforementioned MetAP2 inhibitor 【Transformation 3】 And, In the equation, x is in the range of 1 to approximately 450, y is in the range of 1 to approximately 30, and n is in the range of 1 to approximately 100. Combination medicine.

21. The combination drug according to claim 20, wherein the ratio of x to y is in the range of approximately 30:1 to approximately 3:

1.

22. The aforementioned inavolicib or a pharmaceutically acceptable salt thereof i) Approximately 3 mg; ii) about 6 mg; iii) Approximately 9 mg; or iv) Approximately 12 mg; It is administered to or intended to be administered to the subject in the amount of, The aforementioned MetAP2 inhibitor or a pharmaceutically acceptable salt thereof i) Approximately 49 mg / m² ２ ; ii) Approximately 36mg / m ２ ; or (ii) Approximately 65 mg / m ２ ; This amount is administered to or intended to be administered to the subject. The combination pharmaceutical product according to claim 20 or 21.

23. The MetAP2 inhibitor or a pharmaceutically acceptable salt thereof is administered once every four days (Q4D), and The inavolicib or a pharmaceutically acceptable salt thereof is administered once daily, or is intended to be administered once daily. The combination pharmaceutical product according to claim 20 or 21.

24. The combination pharmaceutical according to claim 20 or 21, wherein the target is i) breast cancer, ii) HR+HER2- breast cancer, or iii) recurrent breast cancer.

25. The breast cancer is i) Characterized by disease progression at a time approximately 12 months or more after completion of neoadjuvant and / or adjuvant endocrine therapy; and / or ii) The subject is identified as progressive during or after treatment with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor; The combination pharmaceutical product according to claim 20 or 21.

26. The aforementioned subject is, i) previously treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor; ii) Having at least one PIK3CA mutation; iii) A postmenopausal woman; and / or iv) The following a) HbA1c levels of approximately 5.5% to 6.4%; b) Fasting plasma glucose (FPG) levels greater than approximately 100 mg / dL (5.6 mmol / L) and less than approximately 140 mg / dL (7.7 mmol / L); c) Approximately 20kg / m ２ Body Mass Index (BMI); d) An insulin resistance homeostasis model assessment (HOMA-IR) score greater than approximately 1.8; e) Approximately 30kg / m ２ The above BMI; and f) HbA1c levels exceeding approximately 5.5%; One of them will be responsible; The combination pharmaceutical product according to claim 20 or 21.

27. ​​The combination pharmacopoeia according to claim 26, wherein the subject is treated for at least about 12 months with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor.

28. The combination pharmaceutical according to claim 20 or 21, wherein the subject has at least one metabolic disorder, and the at least one metabolic disorder is visceral fat excess, dyslipidemia, obesity (BMI ≥ 30), high leptin levels, low adiponectin levels, high leptin-adiponectin ratio, high fasting insulin levels, high fasting insulin levels with chronic inflammation, insulin resistance, fasting hyperglycemia, high HbA1c, or any combination thereof.

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