Use of inhibitors of insulin-like growth factor receptor-1 for growth hormone IGF-secreting neoplasias

Abstract

Provided are methods of treating a neuroendocrine disease and / or a neuroendocrine tumor comprising administering one or more compounds that inhibit IGF-1R.

Description

USE OF INHIBITORS OF INSULIN-LIKE GROWTH FACTOR RECEPTOR- 1 FOR GROWTH HORMONE IGF-SECRETING NEOPLASIASCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 623,068 filed on January 19, 2024, the disclosure of which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Neuroendocrine tumors derive from neuroendocrine cells. Neuroendocrine tumors can be cancerous and non-cancerous. Neuroendocrine tumors include carcinoid tumors that most commonly arise in the digestive tract, lungs, appendix, thymus, lymph nodes, brain, bone, gonads, thyroid or skin. Neuroendocrine tumors can also arise as part of a hereditary tumor or tumor syndrome such as multiple endocrine neoplasia type 1 and type 2, Von Hippel-Lindau disease, tuberous sclerosis, or neurofibromatosis type 1.

[0003] Treatment options for neuroendocrine tumors are limited and often associated with significant morbidity and mortality. An effective treatment for these tumors is still required.BRIEF SUMMARY OF THE INVENTION

[0004] In certain aspects, the present disclosure provides methods of treating a subject having a neuroendocrine disease, comprising administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that inhibits insulin-like growth factor receptor- 1 (IGF-1R). In some aspects, the neuroendocrine disease is one that secretes one or more of a growth hormone releasing hormone, a growth hormone, insulin-like growth factor- 1, or insulin-like growth factor-2. In some aspects, the neuroendocrine disease is acromegaly. In some aspects, the neuroendocrine disease is a non-islet cell hypoglycemia tumor neuroendocrine tumor (NICHT-NET). In some aspects, the neuroendocrine disease is a neuroendocrine tumor including a pancreatic islet tumor; extrapancreatic tumor; pituitary adenoma; medullary thyroid carcinoma; parathyroid tumor; thymus and mediastinal carcinoid tumor; pulmonary neuroendocrinetumor including a small cell lung tumor (SCLC), large cell neuroendorine carcinoma of the lung (LCNEC), typical and atypical pulmonary carcinoid tumor; extrapulmonary small cell carcinoma; a gastro-entero-pancreatic neuroendocrine tumor including foregut, midgut, and hindgut tumor, pancreatic endocrine tumor, liver and gallbladder tumor; an adrenal tumor including adrenomedullary tumor or a phaeochromocytoma; a peripheral nervous system tumor including a Schwannoma, paraganglioma, or neuroblastoma; a breast tumor; a genitourinary tract tumor including an urinary tract carcinoid tumor or an urinary tract neuroendocrine carcinoma; an ovary tumor; a neuroendocrine tumor of the cervix; a prostate tumor with neuroendocrine differentiation; a testis tumor, or a Merkel cell carcinoma. In some aspects, the neuroendocrine disease is a phaeochromocytoma. In some aspects, the acromegaly is pituitary acromegaly. In some aspects, the acromegaly is extrapituitary acromegaly. In some aspects, the neoplasia and / or tumor comprises an IGF- 1R overexpression.

[0005] In these aspects, the one or more compounds is an antibody, or an antigen binding fragment thereof, or a small molecule or a salt or polymorph thereof. The one or more compounds can be selected from the group consisting of teprotumumab, ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, BMS- 536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, INSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, and A-928605, or a salt or polymorph of any of the foregoing. The one or more compounds can be an antibody, or an antigen binding fragment thereof. The one or more compounds can be a human, chimeric human, or humanized monoclonal antibody, or an antigen binding fragment thereof, suitable for human therapy. The one or more compounds can be a small molecule.

[0006] In these aspects, the one or more compounds that inhibits IGF-1R also inhibits insulin receptor (IR). The one of more compounds that inhibit IGF-1R and IR can be selected from the group consisting of linsitinib, or a pharmaceutically acceptable salt thereof, GSK1904529A, or a pharmaceutically acceptable salt thereof, BMS-536924, or a pharmaceutically acceptable salt thereof, GSK1838705A, or a pharmaceutically acceptable salt thereof, AG- 1024, or a pharmaceutically acceptable salt thereof, certinib, or a pharmaceutically acceptable salt thereof, and BMS-754807, or a pharmaceuticallyacceptable salt thereof. The compound that inhibits IGF-1R and IR can be linsitinib, or a pharmaceutically acceptable salt thereof.

[0007] In these aspects, the one or more compounds is administered orally, intradermally, subcutaneously (SC), intravenously (IV), or by inhalation.

[0008] In these aspects, the one or more compounds that inhibit IGF-1R is administered one or more times per day. In these aspects, the one or more compounds that inhibit IGF- 1R is administered orally four times per day, three times per day, twice per day or once per day.DETAILED DESCRIPTION OF THE INVENTIONI. Definitions

[0009] So that the present disclosure can be more readily understood, certain terms are first defined. As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

[0010] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0011] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as the terms "one or more," and "at least one" can be used interchangeably herein. In certain aspects, the term "a" or "an" means "single." In other aspects, the term "a" or "an" includes "two or more" or "multiple."

[0012] Furthermore, "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0013] The term “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical valuesset forth. In general, the term “about” can modify a numerical value above and below the stated value by a variance of, e.g., 10 percent, up or down (higher or lower). In some aspects of the disclosure, the term “about” encompasses a deviation from the recited value of between 0.001% and 10%, inclusive of the endpoints. In some aspects, the term “about” encompasses an increase from the recited value of between 0.001% and 10%, inclusive of the endpoints. In some aspects, the term “about” encompasses a decrease from the recited value of between 0.001% and 10%, inclusive of the endpoints.

[0014] Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form.

[0015] Numeric ranges are inclusive of the numbers defining the range. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between such values.

[0016] The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within the disclosure. Thus, ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 10 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0017] Any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective measurements. Additionally, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range "1 to 10" should be considered to include any and all subranges between (and inclusive of) the minimum value of 1 and the maximum value of 10; that is, all subranges beginning with a minimum value of 1 or more, such as 1 to 6.1, and ending with a maximum value of 10 or less, such as 5.5 to 10.

[0018] Where a value is explicitly recited, it is to be understood that values, which are about the same quantity or amount as the recited value are also within the scope of the disclosure. Where a combination is disclosed, each sub-combination of the elements of that combination is also specifically disclosed and is within the scope of the disclosure. Conversely, where different elements or groups of elements are individually disclosed, combinations thereof are also disclosed. Where any element of a disclosure is disclosed ashaving a plurality of alternatives, examples of that disclosure in which each alternative is excluded singly or in any combination with the other alternatives are also hereby disclosed; more than one element of a disclosure can have such exclusions, and all combinations of elements having such exclusions are hereby disclosed.

[0019] An IGF-1R inhibitor is a compound that interferes with, either directly or indirectly, and reduces or blocks IGF-1R signaling. Preferably, an IGF-1R inhibitor is a compound that reduces or blocks the tyrosine kinase activity of the IGF-1R. By blocking tyrosine kinase activity of the receptor downstream signaling through the IGF-1R is reduced or blocked. In some aspects, the IGF-1R inhibitor neutralizes the growth promoting properties of the insulin-like growth factors, IGF-1 and IGF-2.

[0020] A “pharmaceutical composition” comprises an IGF-1R inhibitor (e.g., linsitinib), or a pharmaceutically acceptable salt thereof, having a desired degree of purity in a physiologically acceptable carrier, excipient or stabilizer. Pharmaceutically acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0021] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0022] The term "pharmaceutically-acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of an IGF-1R inhibitor (e.g., linsitinib). These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).

[0023] The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.

[0024] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.

[0025] As used herein, the terms "treat," "treated," and "treating" mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Thus, those in need of treatment include those already diagnosed with or suspected of having the disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of theextent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. The term "administering," as used herein, refers to any mode of transferring, delivering, introducing, or transporting a therapeutic agent to a subject in need of treatment with such an agent. Such modes of administration include, but are not limited to, oral, topical, intravenous, intraperitoneal, intramuscular, intradermal, intranasal, and subcutaneous, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrastemal injections and infusions.

[0026] The term “therapeutically effective amount” refer to an amount of an agent (e.g., linsitinib) that provides beneficial or desired therapeutic and / or prophylactic results. For prophylactic use, beneficial or desired results can include, for example, one or more results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results can include, for example, one or more clinical results such as decreasing one or more symptoms and pathological conditions resulting from or associated with the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing the effect of other medication such as via targeting, delaying the progression of the disease, and / or prolonging survival. An effective amount can be, for example, an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As it is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an effective amount may be considered in the contextof administering one or more therapeutic agents. An effective amount can be administered in one dosage or can be divided into multiple dosages, the total of such dosages being the effective amount. For example, an effective amount can be provided in two separate administrations over a period of time, that in aggregate, provide the effective amount of the formulation.

[0027] In the case of a neuroendocrine disease, the effective amount of the IGF-1R and IR receptor inhibitor (e.g., linsitinib), or pharmaceutically acceptable salt thereof, is the amount clinically proven to treat the symptoms. For example, the therapeutically effective amount of the IGF-1R and IR receptor inhibitor (e.g., linsitinib) can have the effect of reducing one or more of neuroendocrine tumor proliferation and / or survival, improving constitutional symptoms (such as fatigue, night sweats, cough and pruritus), and / or reducing neuroendorine hormone levels.II. Methods of Treatment

[0028] The present disclosure provides methods of treating a subject having a neuroendocrine disease, comprising administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that inhibits insulin-like growth factor receptor- 1 (IGF-1R). In some aspects, the neuroendocrine disease is one that secretes one or more of a growth hormone releasing hormone, a growth hormone, insulin-like growth factor- 1, or insulin-like growth factor-2. In some aspects, the neuroendocrine disease is acromegaly. In some aspects, the neuroendocrine disease is a non-islet cell hypoglycemia tumor neuroendocrine tumor (NICHT-NET). In some aspects, the neuroendocrine disease is a neuroendocrine tumor including a pancreatic islet tumor; extrapancreatic tumor; pituitary adenoma; medullary thyroid carcinoma; parathyroid tumor; thymus and mediastinal carcinoid tumor; pulmonary neuroendocrine tumor including a small cell lung tumor (SCLC), large cell neuroendorine carcinoma of the lung (LCNEC), typical and atypical pulmonary carcinoid tumor; extrapulmonary small cell carcinoma; a gastro-entero-pancreatic neuroendocrine tumor including foregut, midgut, and hindgut tumor, pancreatic endocrine tumor, liver and gallbladder tumor; an adrenal tumor including adrenomedullary tumor or a phaeochromocytoma; a peripheral nervous system tumor including a Schwannoma, paraganglioma, or neuroblastoma; a breast tumor; a genitourinary tract tumor including an urinary tract carcinoid tumor or an urinary tract neuroendocrine carcinoma; an ovary tumor; a neuroendocrine tumor of thecervix; a prostate tumor with neuroendocrine differentiation; a testis tumor, or a Merkel cell carcinoma. In some aspects, the neuroendocrine disease is a phaeochromocytoma. In some aspects, the acromegaly is pituitary acromegaly. In some aspects, the acromegaly is extrapituitary acromegaly. In some aspects, the neoplasia and / or tumor comprises an IGF- 1R overexpression.

[0029] In some aspects, the one or more compounds that inhibit IGF-1R is an antibody, or an antigen binding fragment thereof, or a small molecule or a salt or polymorph thereof. The one or more compounds that inhibit IGF-1R can be selected from the group consisting of teprotumumab, ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, B MS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL- 2258, INSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, and A- 928605, or a salt or polymorph of any of the foregoing. The one or more compounds that inhibit IGF-1R can be an antibody, or an antigen binding fragment thereof. The one or more compounds can be a human, chimeric human, or humanized monoclonal antibody, or an antigen binding fragment thereof, suitable for human therapy. The one or more compounds that inhibit IGF-1R can be a small molecule.

[0030] In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib) is administered one or more times per day. For example, in some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib) is administered four times per day, three times per day, twice per day or once per day.

[0031] In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib), is administered orally. In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib) is administered intravenously, intraperitoneally, subcutaneously, and / or intramuscular.

[0032] In some aspects, the one or more compounds that inhibit IGFR-1R (e.g., linsitinib), is administered with an additional anti-tumor therapy which includes any tumor therapy used to treat a neuroendocrine tumor and known to the person of skill in the art.

[0033] In some aspects, the methods comprise administering to the subject a therapeutically effect amount of one or more compounds that inhibit IGF-1R and IR. Insome aspects, the one or more compounds that inhibit IGF-1R and IR can be selected from the group consisting of linsitinib, or a pharmaceutically acceptable salt thereof, GSK1904529A, or a pharmaceutically acceptable salt thereof, BMS-536924, or a pharmaceutically acceptable salt thereof, GSK1838705A, or a pharmaceutically acceptable salt thereof, AG- 1024, or a pharmaceutically acceptable salt thereof, ceritinib, or a pharmaceutically acceptable salt thereof, or BMS-754807, or a pharmaceutically acceptable salt thereof. In some aspects, the method comprises administering to the subject a therapeutically effective amount of a compound that inhibits IGF-1R and IR that is linsitinib, or a pharmaceutically acceptable salt thereof.

[0034] In some aspects, the IGF-1R and IR receptor inhibitor (e.g., linsitinib), or a pharmaceutically acceptable salt thereof, is administered one or more times per day. For example, in some aspects, the IGF-1R and IR receptor inhibitor (e.g., linsitinib), or a pharmaceutically acceptable salt thereof, is administered orally four times per day, three times per day, twice per day or once per day.

[0035] In some aspects, the IGF-1R and IR receptor inhibitor (e.g., linsitinib), or a pharmaceutically acceptable salt thereof, is administered orally. In some aspects, the IGF- 1R and IR receptor inhibitor (e.g., linsitinib), or pharmaceutically acceptable salt thereof, is administered intravenously, intraperitoneally, subcutaneously, and / or intramuscular.

[0036] In some aspects, the IGFR-1R and IR inhibitor (e.g., linsitinib), or pharmaceutically acceptable salt thereof, is administered with an additional anti-tumor therapy which includes any tumor therapy used to treat a neuroendocrine tumor and known to the person of skill in the art.

[0037] The dosage of the one or more compounds that inhibit the IGF-1R receptor may further vary between patients, based on different factors such as the age, gender, race, and body weight of each patient. In some embodiments, the dosage varies by body weight of the patient. The dosage could range from about 1 mg of the antibody, or an antigen binding fragment thereof, per kilogram of body weight to about 100 mg of the antibody, or an antigen binding fragment thereof, per kilogram of body weight.

[0038] Small molecule compounds may be administered orally, via injection, etc. at a dose of from 0.01 to 500 mg / kg per day and / or from 0.1 mg to 5 g per day. The dose range for adult humans is generally from 5 mg to 2 g / day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of the one ormore compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, for example around 10 mg to 200 mg.III. Pharmaceutical Compositions

[0039] In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib) and / or additional therapeutic agent described herein are formulated as compositions for oral, intravenously, intraperitoneal, subcutaneous, and / or intramuscular administration.

[0040] The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

[0041] In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib) and / or additional therapeutic agent described herein are formulated by combining the components with, e.g., pharmaceutically acceptable carriers or excipients. In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib) and / or additional therapeutic agent described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0042] In some aspects, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with the compound and / or additional therapeutic agent described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.IV. Kits

[0043] In some aspect, the present disclosure relates to a kit comprising a pharmaceutical composition comprising the one or more compounds that inhibit IGF-1R (e.g., linsitinib) packaged in a manner that facilitates its use to practice methods of the present disclosure.

[0044] In some aspects, the kit further comprises instructions for administering the pharmaceutical composition comprising the one or more compounds that inhibit IGF-1R (e.g., linsitinib) to treat a neuroendocrine disease.

[0045] All of the references cited herein are incorporated herein by reference in their entireties.

[0046] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.EXAMPLE

[0047] A patient having a non-islet cell hypoglycemia tumor neuroendocrine tumor (NICHT-NET) will be administered a therapeutically effective amount of a compound that inhibits IGF-1R (e.g., linsitinib). The patient’s blood glucose levels will be monitored and the amount of the compound that inhibits IGF-1R (e.g., linsitinib) will be adjusted as necessary to maintain normal blood glucose levels.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a subject having a neuroendocrine disease, comprising administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that inhibits insulin-like growth factor receptor- 1 (IGF-1R).

2. The method of claim 1, wherein the one or more compounds is an antibody, or an antigen binding fragment thereof, or a small molecule or a salt or polymorph thereof.

3. The method of claim 2, wherein the one or more compounds is selected from the group consisting of teprotumumab, ganitumab, figitumumab, MEDL573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, B MS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL- 2258, INSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, and A- 928605, or a salt or polymorph of any of the foregoing.

4. The method of claim 3, wherein the one or more compounds is an antibody, or an antigen binding fragment thereof.

5. The method of claim 4, wherein the one or more compounds is a human, chimeric human, or humanized monoclonal antibody, or an antigen binding fragment thereof, suitable for human therapy.

6. The method of claim 3, wherein the one or more compounds is a small molecule.

7. The method of any one of claims 1-6, wherein the one or more compounds that inhibits IGF-1R also inhibits insulin receptor (IR).

8. The method of claim 7, wherein the one or more compounds that inhibits IGF-1R and IR is selected from the group consisting of linsitinib, or a pharmaceutically acceptable salt thereof, GSK1904529A, or a pharmaceutically acceptable salt thereof, BMS-536924, or apharmaceutically acceptable salt thereof, GSK1838705A, or a pharmaceutically acceptable salt thereof, AG- 1024, or a pharmaceutically acceptable salt thereof, certinib, or a pharmaceutically acceptable salt thereof, and BMS-754807, or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the inhibitor of IGF-1R and IR is linsitinib, or a pharmaceutically acceptable salt thereof.

10. The method of any one of claims 1-9, wherein the one or more compounds is administered orally, intradermally, subcutaneously (SC), intravenously (IV), or by inhalation.

11. The method of any one of claims 1-10, wherein the one or more compounds that inhibit IGF-1R is administered one or more times per day.

12. The method of any one of claims 1-10, wherein the one or more compounds that inhibit IGF-1R is administered orally four times per day, three times per day, twice per day or once per day.

13. The method of any one of claims 1-12, wherein the neuroendocrine disease is one that secretes one or more of a growth hormone releasing hormone, a growth hormone, insulinlike growth factor- 1, or insulin-like growth factor-2.

14. The method of any one of claims 1-12, wherein the wherein the neuroendocrine disease is acromegaly.

15. The method of any one of claims 1-12, wherein the neuroendocrine disease is a non-islet cell hypoglycemia tumor neuroendocrine tumor (NICHT-NET).

16. The method of any one of claims 1-12, wherein the neuroendocrine disease is a neuroendocrine tumor including a pancreatic islet tumor; extrapancreatic tumor; pituitaryadenoma; medullary thyroid carcinoma; parathyroid tumor; thymus and mediastinal carcinoid tumor; pulmonary neuroendocrine tumor including a small cell lung tumor (SCLC), large cell neuroendorine carcinoma of the lung (LCNEC), typical and atypical pulmonary carcinoid tumor; extrapulmonary small cell carcinoma; a gastro-entero- pancreatic neuroendocrine tumor including foregut, midgut, and hindgut tumor, pancreatic endocrine tumor, liver and gallbladder tumor; an adrenal tumor including adrenomedullary tumor or a phaeochromocytoma; a peripheral nervous system tumor including a Schwannoma, paraganglioma, or neuroblastoma; a breast tumor; a genitourinary tract tumor including an urinary tract carcinoid tumor or an urinary tract neuroendocrine carcinoma; an ovary tumor; a neuroendocrine tumor of the cervix; a prostate tumor with neuroendocrine differentiation; a testis tumor, or a Merkel cell carcinoma.

17. The method of any one of claims 1-12, wherein the neuroendocrine disease is a phaeochromocytoma.

18. The method of claim 17, wherein the acromegaly is pituitary acromegaly.

19. The method of claim 17, wherein the acromegaly is extrapituitary acromegaly.

20. The method of any of claims 1-19, wherein the neoplasia and / or tumor comprises an IGF- 1R overexpression.