Oral Octreotide for the Treatment of Diseases

Abstract

Provided herein are methods for treating one or more symptoms associated with neuroendocrine tumors, such as episodes of diarrhea and flushing associated with carcinoid tumors, and methods for treating carcinoid syndrome, comprising orally administering a composition comprising octreotide or a pharma- ceutically acceptable salt thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 313,909, filed February 25, 2022, the contents of which are incorporated by reference in their entirety for all purposes. [Background technology]

[0002] Neuroendocrine tumors (NETs) are a heterogeneous group of cancer subtypes that arise in endocrine cells present in different organ systems throughout the body. Most NETs (approximately 70%) arise in the gastrointestinal (GI) tract or pancreas. Tumors arising from the GI tract are called carcinoid tumors. NETs can also arise in the airways, central nervous system, thyroid, skin, breast, and genitourinary system.

[0003] Up to 20% of carcinoid tumors are estimated to have carcinoid syndrome (CS). CS is primarily associated with midgut metastatic carcinoid tumors. Most commonly, CS presents with episodes of diarrhea and flushing (FE) due to excessive secretion of serotonin; other common symptoms include abdominal pain, bronchospasm, and hypertension.

[0004] Somatostatin receptor ligands (SRLs), such as octreotide long-acting release (LAR), subcutaneous (SC) octreotide immediate release (IR), and lanreotide, are first-line treatments for CS-related symptoms as they significantly improve FE and diarrhea symptoms by inhibiting the secretion of serotonin among several other hormones and vasoactive substances. Current injectable SRL therapies for CS are suboptimal for patients for a variety of reasons. SRLs fail over time to maintain adequate control of CS and may follow a frequent pattern of exacerbation, especially toward the end of the SRL injection interval, thus necessitating additional medical intervention. Patients experience long-lasting sequelae associated with the injections, including significant persistent pain, nodules, bleeding, inflammation, and scarring lasting for several days. Beyond the physical effects, there are also emotional effects, such as dissatisfaction, anxiety, and loss of independence. Daily effects are reflected by scheduled injections, adverse events associated with each administration, or work loss due to worsening CS symptoms toward the end of the injection interval.

[0005] There is a need for oral somatostatin receptor ligands (SRLs), such as oral octreotide, for the treatment of a variety of diseases. Summary of the Invention

[0006] In embodiments, the disclosure provides a method for treating episodes of diarrhea and flushing associated with a carcinoid tumor in a patient in need thereof, the method comprising orally administering to the patient a total daily dose of at least about 120 mg of octreotide or a pharma- ceutically acceptable salt thereof.

[0007] In embodiments, provided herein is a method for long-term maintenance treatment of episodes of diarrhea and flushing associated with a carcinoid tumor, such as a metastatic carcinoid tumor, in a patient in need thereof, the method comprising orally administering to the patient a total daily dose of at least about 120 mg of octreotide, or a pharma- ceutically acceptable salt thereof.

[0008] In embodiments, the disclosure provides a method of treating carcinoid syndrome in a patient in need thereof, the method comprising orally administering to the patient a total daily dose of at least about 120 mg of octreotide or a pharma- ceutical acceptable salt thereof.

[0009] In an embodiment of the disclosed method, about 120 mg of octreotide is administered.

[0010] In an embodiment of the present disclosure, the method provided herein comprises: To determine the daily frequency of bowel movements (BM) of patients following administration of 120 mg of octreotide per day; (a) the patient experiences an increase in daily frequency of BMs by at least 2 BM compared to the baseline prior to administration of 120 mg of octreotide; and (b) if the patient experiences >= 4 BM / day after administration of 120 mg of octreotide, then administering to the patient about 160 mg of octreotide per day.

[0011] In an embodiment of the present disclosure, the method provided herein comprises: To determine the daily frequency of bowel movements (BM) of patients following administration of 120 mg of octreotide per day; (a) the patient experiences an increase in daily frequency of BMs by at least 2 BMs compared to the baseline prior to administration of 120 mg of octreotide; or (b) if the patient experiences >= 4 BM / day after administration of 120 mg of octreotide, then administering to the patient about 160 mg of octreotide per day.

[0012] In an embodiment of the present disclosure, the method provided herein comprises: To determine the daily frequency of flushing episodes (FE) in patients following administration of 120 mg of octreotide per day; (a) the patient experiences an increase in the daily frequency of FEs by at least 1 FE per day compared to before administration of 120 mg of octreotide; or (b) if the patient experiences an increase in the severity of FE after administration of 120 mg of octreotide, administering to the patient about 160 mg of octreotide per day.

[0013] In an embodiment of the present disclosure, the method provided herein comprises: To determine the signs / symptoms of carcinoid syndrome in patients following administration of 120 mg of octreotide per day; and if the patient experiences new or worsening signs / symptoms of carcinoid syndrome, administering to the patient about 160 mg of octreotide per day.

[0014] In an embodiment of the disclosed method, octreotide is administered in a capsule containing, for example, about 20 mg of octreotide.

[0015] In embodiments of the disclosed methods, the patient treated with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules) has previously been treated with a somatostatin receptor ligand (SRL) that has been shown to be effective and tolerable.

[0016] In embodiments of the disclosed methods, following oral administration of octreotide or a pharma- ceutically acceptable salt thereof (eg, oral octreotide capsules), patients experience improvement in episodes of diarrhea and flushing associated with carcinoid tumors. [Brief description of the drawings]

[0017] [Figure 1A] Figure 1A shows the geometric mean plasma octreotide concentrations (pg / mL) as a function of time (hours) (linear axis) following oral administration of single doses of 20 mg, 60 mg (3 × 20 mg capsules), and 80 mg (4 × 20 mg capsules) of octreotide capsules (OOC) to healthy volunteers.

[0018] [Figure 1B]Figure 1B shows the geometric mean plasma octreotide concentrations (pg / mL) as a function of time (hours) (semi-logarithmic axis) following oral administration of single doses of 20 mg, 60 mg (3 × 20 mg capsules), and 80 mg (4 × 20 mg capsules) of octreotide capsules (OOC) to healthy volunteers.

[0019] [Diagram 2] FIG. 2 is a schematic diagram of the study described in Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] definition For convenience, certain terms used in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0021] The term "about" when immediately preceding a numerical value means a range (e.g., plus or minus 10% of the value). For example, "about 50" may mean 45 to 55, and "about 25,000" may mean 22,500 to 27,500, unless the context of this disclosure indicates otherwise or is inconsistent with such an interpretation. For example, in a list of numerical values, such as "about 49, about 50, about 55...", "about 50" means a range extending less than half the interval between the preceding and succeeding values, e.g., from more than 49.5 to less than 50.5. Furthermore, the phrase "less than" with respect to a value or "more than" with respect to a value should be understood in light of the definition of the term "about" provided herein. Similarly, the term "about" when preceding a series of numerical values ​​or a range of values ​​(e.g., "about 10, 20, 30", or "about 10 to 30") refers to all values ​​in the series, or to the end points of the range, respectively.

[0022] Throughout this disclosure, numerical ranges are provided for specific quantities. These ranges include all subranges therein. Thus, the range "50-80" includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values ​​within a given range may be endpoints for the range encompassed thereby (e.g., the range 50-80 includes ranges with endpoints, e.g., 55-80, 50-75, etc.).

[0023] The term "treatment" as used herein with respect to a patient refers to improving at least one symptom of the patient's disorder. Treatment can improve or at least partially ameliorate the disorder.

[0024] As used herein, the phrase "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment, 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.

[0025] The term "salts" as used herein includes pharma- ceutically acceptable salts that are commonly used to form alkali metal salts of free acids and to form addition salts of free bases. The nature of the salt is not critical, provided that it is pharma- ceutical acceptable. Suitable pharma- ceutical acceptable acid addition salts can be prepared from inorganic acids or from organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from aliphatic, alicyclic, aromatic, arylaliphatic, and heterocyclyl including carboxylic and sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, alginic acid, 3-hydroxybutyric acid, galactaric acid, and galacturonic acid.

[0026] Detailed Description Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications are incorporated by reference in their entirety into this disclosure for all purposes to more fully describe the state of the art as known to those skilled in the art as of the date of this disclosure. This disclosure applies in the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure.

[0027] Neuroendocrine tumors (NETs)

[0028] There are three main types of neuroendocrine tumors classified according to the tumor's endocrine cell of origin: pancreatic neuroendocrine tumors, gastrointestinal neuroendocrine tumors, and pulmonary tumors. Pancreatic neuroendocrine tumors that secrete vasoactive intestinal peptide (VIP) are called VIPomas.

[0029] Neuroendocrine tumors and carcinoid syndrome, as well as the medical procedures used to treat these conditions, are described in the literature, e.g., Kloppel et al 2004, Ann. NY Acad Sci 1014:13-17; Strosberg (2014) Endocr. Prac. 20(2);167-175; Oberg et al 2004, Annals of Oncology 15:966-973; Oberg et al 2012, Annals of Oncology 23(Supplement 7):vii124-vii130; Schmidt et al (2011) Oncogene, 30:1497-1505.

[0030] Thousands of patients have neuroendocrine tumors that originate in the digestive tract and metastasize or spread to the liver or other organs. The overproduction of serotonin in these metastatic neuroendocrine tumor (mNET) cells is the driver of carcinoid syndrome, which is characterized by debilitating diarrhea, facial flushing, abdominal pain, heart valve damage, and other severe consequences. Thus, carcinoid syndrome is a subset of neuroendocrine tumors that have specific symptomatic signs due to the secretion of vasoactive substances into the systemic circulation.

[0031] The most common carcinoid symptoms and their associated complications are summarized in the table below. [Table 1]

[0032] Most typically, CS presents with diarrhea and flushing, but other common symptoms include abdominal pain, bronchospasm, and high blood pressure.

[0033] The diagnosis of CS is typically suspected when a patient presents with flushing and diarrhea, regardless of whether the patient has a known NET. Symptoms are consistent throughout the clinical course of CS, and the presentation of carcinoid symptoms often prompts the diagnosis of a NET, which may be delayed due to mild and / or nonspecific symptoms. The diagnosis of CS is confirmed by evidence of elevated levels of the serotonin breakdown product 5-hydroxy-indoleacetic acid (5-HIAA) in the urine.

[0034] The severe and unpredictable diarrhea associated with carcinoid syndrome significantly impacts the lives of cancer patients, often preventing them from participating in daily activities. Patients with carcinoid syndrome can survive for many years with metastatic cancer, necessitating the need for long-term treatment options to effectively manage their disease.

[0035] Somatostatin receptor ligand (SRL) therapy, such as Sandostatin LAR, sc Sandostatin IR, and Lanreotide, remains the backbone of therapy for patients with NETs, ​​with patients typically treated with long-acting octreotide, with injectable Lanreotide also being used more recently. The current standard of care for carcinoid syndrome is the somatostatin analogue depot injection (SSA), which was first approved in 1998. SSAs are also called somatostatin receptor ligands (SRLs). SRL injection therapy fails over time to maintain adequate control of carcinoid syndrome for most patients, with many losing adequate control within the first two years of therapy initiation. This decreased response to the drug following drug administration is called tachyphylaxis.

[0036] Current injectable SRL therapies for CS are suboptimal for patients for a variety of reasons. Injections are poorly tolerated. Patients experience long-term sequelae associated with injections, including significant persistent pain, nodules, bleeding, inflammation, and scarring lasting for several days. Beyond the physical effects, there are also emotional effects, including frustration, anxiety, and loss of independence. Daily effects are reflected by work loss due to scheduled injections, adverse events associated with each administration, or worsening CS symptoms toward the end of the injection interval. Thus, the direct and indirect costs of monthly injections are significant for patients as well as healthcare providers.

[0037] Long-acting SRLs may not provide a full month of somatostatin control, and some patients may report a wear-off effect with recurrence of CS symptoms toward the end of the dosing interval, sometimes necessitating supplemental short-acting injections.

[0038] When metastasis of carcinoid tumors occurs and when surgical resection is not feasible, NETs may be treated with currently recommended chemotherapy.

[0039] Antitumor agents currently in use or in clinical trials to treat or alleviate NETs include: alkylating agents, doxorubicin, fluoropyrimidines such as 5-fluorouracil, dacarbazine, actinomycin D, platinum compounds (cisplatin, carboplatin, oxaliplatin), irinotecan, etoposide, streptozotocin (STZ), interferon alpha, interferon gamma, bortezomib (iv / sc), commercially available as Velcade®, temozolomide (oral), commercially available as Temodar®, bevacizumab, capecitabine with a radioactive load, and somatostatin analogs (e.g., octreotide attached to a radioactive load using, for example, yttrium-90 or indium-111 labeling agents; one example is Lutathera®. Lutathera (lutetium Lu 177 Dotatate) is a Lu-177 labeled somatostatin analog peptide currently in development for the treatment of gastrointestinal and pancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults; see Strosberg et al (2017) New England J Med, 376:2, 125-135. The antitumor agent may be a chemotherapeutic or radiotherapeutic agent. Combinations of these chemotherapeutic / antitumor agents are typically used, e.g., cisplatin / etoposide or streptozotocin / 5-fluorouracil / doxorubicin or capecitabine / bevacizumab or temozolomide / capecitabine.

[0040] Other therapeutic agents that may be used to treat NETs include mTOR inhibitors such as everolimus (oral), commercially available as Afinitor®, temsirolimus (intravenous), commercially available as Torisel®, and sirolimus (oral), commercially available as Rapamune®; oral VEGFR inhibitors such as sunitinib (commercially available as Sutent®); Src kinase inhibitors (also called tyrosine kinase inhibitors), such as bosutinib, administered orally, commercially available as Bosulif®; and tryptophan hydroxylase inhibitors, such as telotristat etiprate, also called LX1032, administered orally. Sunitinib (sunitinib malate) is a targeted tyrosine kinase inhibitor that can inhibit members of the receptor tyrosine kinase family that contains split kinase domains, which include VEGF receptors (VEGFR) types 1, 2, and 3, as well as other receptors. Telotristat etiplate is the first investigational drug in clinical trials targeting tryptophan hydroxylase, the enzyme that triggers excess serotonin production in mNET cells that leads to carcinoid syndrome.

[0041] Chemoembolization of the hepatic artery for the treatment of metastatic carcinoid tumors has been widely used in adults for the treatment of NETs. Other treatments that may be considered as appropriate include liver-directed therapies such as radiofrequency ablation, radioembolization, chemoembolization, and rarely surgical debulking.

[0042] Breakthrough NET symptoms (due to hormonal symptoms associated with NETs) are a common phenomenon in patients receiving injectable octreotide, e.g., octreotide LAR (long-acting formulation). Patients may require short-acting octreotide, typically 100-250 μg, up to three times daily for breakthrough symptoms, in addition to octreotide LAR while waiting for therapeutic levels, especially for the first 10-14 days after LAR injection. In patients with progressive or poorly controlled symptoms, somatostatin analogue doses may be increased as needed. These additional daily subcutaneous injections can be effective in controlling breakthrough symptoms, but they significantly increase the physical, emotional, and financial burden of treatment.

[0043] In an embodiment, the present disclosure provides a method for the therapy of subjects suffering from neuroendocrine tumors and carcinoid syndrome, the method comprises administering to the subject a therapeutically effective amount of oral somatostatin receptor ligand (SRL).The oral SRL can be oral octreotide, lanreotide, or pasireotide, or an oral formulation of DG3173; DG3173 is also called somatoprim, and is a novel SRL that is administered as a subcutaneous bolus injection.The oral octreotide can be in a capsule or tablet.

[0044] Specific advantages of the use of oral octreotide administered daily as described herein (e.g., oral octreotide capsules) as an alternative to injectable SRL to maintain control of CS symptoms associated with metastatic carcinoid tumors include improved convenience of administration, avoidance of often painful injections, avoidance of injection site reactions, reduction in breakthrough symptoms, tolerability, treatment compliance, and improved quality of life.

[0045] composition In embodiments, octreotide or a pharma- ceutically acceptable salt thereof is administered in a pharmaceutical composition comprising an oil suspension comprising an admixture of a hydrophobic medium and a solid form, the solid form comprising a therapeutically effective amount of octreotide, at least one salt of a medium chain fatty acid, and at least one matrix-forming polymer, in embodiments, the matrix-forming polymer is dextran or polyvinylpyrrolidone (PVP).

[0046] In embodiments, the medium chain fatty acid salt has a chain length of about 6 to about 14 carbon atoms. In embodiments, the medium chain fatty acid salt is sodium hexanoate, sodium heptanoate, sodium octanoate, sodium nonanoate, sodium decanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoate, or sodium tetradecanoate, or the corresponding potassium or lithium or ammonium salts, or combinations thereof. In embodiments, the medium chain fatty acid salt is a lithium salt, a potassium salt, or an ammonium salt. In embodiments, the medium chain fatty acid salt is sodium octanoate. In embodiments, the amount of medium chain fatty acid salt in the compositions described herein can be from 10% up to about 50% by weight of the bulk pharmaceutical composition. For example, the medium chain fatty acid salt may be present in an amount of about 10% to 50% by weight, or about 11% to 40% by weight, or about 11% to 28% by weight, for example, about 12% to 13% by weight, 13% to 14% by weight, 14% to 15% by weight, 15% to 16% by weight, 16% to 17% by weight, 17% to 18% by weight, 18% to 19% by weight, 19% to 20% by weight, 20% to 21% by weight, 21% to 22% by weight, 22% to 23% by weight, 23% to 24% by weight, 24% to 25% by weight, 25% to 26% by weight, 26% to 28% by weight, or about 15% to 29% by weight. The compound may be present in an amount of about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40% by weight, including any value or range therebetween.In certain embodiments, the medium chain fatty acid salts (e.g., salts of octanoic acid, salts of suberic acid, salts of geranic acid) may be present at about 12% to 21% by weight, or about 11% to 18% by weight, or about 11% to 17% by weight, 12% to 16% by weight, 12% to 15% by weight, 13% to 16% by weight, 13% to 15% by weight, 14% to 16% by weight, 14% to 15% by weight, or 15% to 16% by weight, including any value or range therebetween. In embodiments, the medium chain fatty acid salts are present in the pharmaceutical composition at about 15% or 16%.

[0047] In an embodiment, the matrix-forming polymer is polyvinylpyrrolidone (PVP). In an embodiment, the PVP is present in an amount of about 2% by weight or more. In an embodiment, the PVP is present in the composition in an amount of about 2% by weight to about 20% by weight, such as about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% by weight, including any value or range therebetween. In an embodiment, the PVP is present in an amount of about 3% by weight or more. In an embodiment, the PVP is present in an amount of about 3% by weight to about 18% by weight. In an embodiment, the PVP is present in an amount of about 3% by weight to about 15% by weight. In an embodiment, the PVP is present in an amount of about 5% by weight to about 15% by weight. In embodiments, the PVP is PVP-12 and / or has a molecular weight of about 3000.

[0048] In embodiments, the hydrophobic medium comprises mineral oil, paraffin, fatty acid, monoglyceride, diglyceride, triglyceride, ether or ester, or combinations thereof. In embodiments, the hydrophobic medium comprises glyceryl tricaprylate. In embodiments, the hydrophobic medium is glyceryl tricaprylate. In embodiments, the hydrophobic medium comprises about 10% to 90% by weight of the bulk pharmaceutical composition, e.g., about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 102%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 120%, 122%, 130%, 132%, 133%, 140%, 142%, 143%, 144%, 150%, 152%, 154%, 156%, 15 %, 50% by weight, 51% by weight, 52% by weight, 53% by weight, 54% by weight, 55% by weight, 56% by weight, 57% by weight, 58% by weight, 59% by weight, 60% by weight, 61% by weight, 62% by weight, 63% by weight, 64% by weight, 65% by weight, 66% by weight, 67% by weight, 68% by weight, 69% by weight, 70% by weight, 71% by weight, 72% by weight, 73% by weight, 74% by weight, 75% by weight, 76% by weight, 77% by weight, 78% by weight, 79% by weight, 80% by weight, 81% by weight, 82% by weight, 83% by weight, 84% by weight, 85% by weight, 86% by weight, 87% by weight, 88% by weight, 89% by weight, or 90% by weight, including any value or range therebetween. In an embodiment, about 20-80% by weight of glyceryl tricaprylate is present in the composition.

[0049] In an embodiment, the composition further comprises a surfactant. Suitable surface active agents include ionic surfactants and non-ionic surfactants. Examples of ionic surfactants are lecithin (phosphatidylcholine), bile salts, and detergents. Examples of non-ionic surfactants include monoglycerides, cremophor, polyethylene glycol fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, Solutol HS15, or poloxamers, or combinations thereof. Examples of monoglycerides are glyceryl monocaprylate (also called glyceryl monooctanoate), glyceryl monodecanoate, glyceryl monolaurate, glyceryl monomyristate, glyceryl monostearate, glyceryl monopalmitate, and glyceryl monooleate. Examples of sorbitan fatty acid esters include sorbitan monolaurate, sorbitan monooleate, and sorbitan monopalmitate (Span 40), or combinations thereof. Examples of polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan monooleate (Tween 80), polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, or combinations thereof. Commercial preparations of the monoglycerides used also contain varying amounts of diglycerides and triglycerides. In an embodiment, the composition comprises less than about 12% by weight of total surfactant, such as about 10% by weight, about 9% by weight, about 8% by weight, about 7% by weight, about 6% by weight, about 5% by weight, about 4% by weight, about 3% by weight, about 2% by weight, or less than about 1% by weight, including any value or range therebetween. In an embodiment, the sum of all surfactants is about 6%. In an embodiment, the composition comprises about 3-10% by weight of surfactant.

[0050] In an embodiment, the solid form consists essentially of octreotide, polyvinylpyrrolidone having a molecular weight of about 3000, and sodium octanoate. In an embodiment, the composition comprises about 41% glyceryl tricaprylate, about 27% castor oil, about 4% glyceryl monocaprylate, about 2% polyoxyethylene sorbitan monooleate, about 15% sodium octanoate, about 10% polyvinylpyrrolidone having a molecular weight of about 3000, less than 1% water, and octreotide. In an embodiment, the composition comprises about 68% glyceryl tricaprylate, about 4% glyceryl monocaprylate, about 2% polyoxyethylene sorbitan monooleate, about 15% sodium octanoate, about 10% polyvinylpyrrolidone having a molecular weight of about 3000, about 1% water, and a therapeutically effective amount of octreotide. In an embodiment, the composition comprises a therapeutically effective amount of octreotide, about 12-21% sodium octanoate, about 5-10% polyvinylpyrrolidone having a molecular weight of about 3000, about 20-80% glyceryl tricaprylate, about 0-50% castor oil, and about 3-10% surfactant. In an embodiment, the composition comprises a therapeutically effective amount of octreotide, about 12-21% sodium octanoate, about 5-10% polyvinylpyrrolidone having a molecular weight of about 3000, about 20-80% glyceryl tricaprylate, and about 3-10% surfactant.

[0051] In an embodiment, the composition comprises about 15% sodium octanoate, about 10% polyvinylpyrrolidone having a molecular weight of about 3000, about 30-70% glyceryl tricaprylate, and about 6% of a surfactant, in an embodiment, the surfactant is glyceryl monocaprylate or polyoxyethylene sorbitan monooleate.

[0052] In embodiments, octreotide is present in an amount of less than 33% (e.g., 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or less than 0.1%, including any value or range therebetween).

[0053] In an embodiment, the solid form further comprises one or more excipients. In an embodiment, the solid form comprises a particle or particles. In an embodiment, the solid form further comprises a stabilizer. In an embodiment, the suspension comprises an admixture of a hydrophobic medium and a solid form, the solid form comprising a therapeutically effective amount of octreotide, at least one salt of a medium chain fatty acid, and polyvinylpyrrolidone (PVP), and the solid form comprising a therapeutic agent also comprises a stabilizer (e.g., a protein structure stabilizer). A protein structure stabilizer is a compound that can stabilize protein structure under aqueous or non-aqueous conditions or reduce or prevent aggregation of the therapeutic agent, for example during a drying process such as lyophilization or spray drying, or other processing steps. The structural stabilizer may be a polyanionic molecule, such as phytic acid, a polyvalent ion such as Ca, Zn, or Mg, a sugar such as a disaccharide (e.g., trehalose, maltose), or an oligo- or polysaccharide, such as dextrin or dextran, or a sugar alcohol such as mannitol, or an amino acid such as glycine, or a polycationic molecule such as spermine, or a surfactant such as Tween 80 or Span 40 or pluronic acid. Methylcellulose, and uncharged polymers such as polyvinyl alcohol are also suitable stabilizers.

[0054] In an embodiment of the present disclosure, the dosage forms contain octreotide in an amount of about 10 mg to about 30 mg, e.g., about 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, or 30 mg, including any value or range therebetween. In an embodiment, the octreotide in each dosage form is 18 mg to about 22 mg. In an embodiment, the octreotide in each dosage form is about 20 mg. In an embodiment, the octreotide comprises octreotide acetate. In an embodiment, the octreotide is octreotide acetate.

[0055] In embodiments, the pharmaceutical composition includes multiple therapeutic agents, i.e., octreotide and one (or more) additional therapeutic agents. The therapeutic agents can be in the same solid form (e.g., in the same particle) or each therapeutic agent can be in an independent solid form (e.g., each in a different particle). In some embodiments, the therapeutic agent is in the form of a particle, e.g., a granular particle or a solid particle. The particle is substantially associated with or in intimate contact with a hydrophobic medium, e.g., a hydrophobic medium as described herein. In embodiments, the composition can include about 1.0% to about 30% by weight of the therapeutic agent, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% by weight of the therapeutic agent. The maximum weight of the therapeutic agent included in the composition is often within the range of about 5% to 20%. In embodiments, the dosage forms described herein may be pharmaceutical products essentially in the form in which they are marketed for use, typically comprising a mixture of active pharmaceutical ingredients and non-pharmaceutical ingredients (excipients).

[0056] In embodiments, octreotide or its pharmaceutically acceptable salt is orally administered in oral dosage form as described herein.Exemplary oral dosage forms include enteric coated oral dosage forms.Octreotide oral formulations and its method of use are described in, for example, US Patent No. 8,329,198, US Patent No. 8,535,695, US Patent No. 9,265,812 and US Patent No. 9,566,246, the disclosures of which are incorporated herein by reference for all purposes.

[0057] In embodiments, octreotide is administered in a tablet or capsule. In embodiments, octreotide is administered in a capsule containing an oil suspension. In embodiments, octreotide is administered in a capsule containing a pharmaceutical composition of the present disclosure. In embodiments, octreotide is administered in an enteric coated state. In embodiments, octreotide is administered in an enteric coated capsule containing 20 mg of octreotide (20 mg calculated as the free base), polyvinylpyrrolidone (PVP-12), sodium caprylate, magnesium chloride, polysorbate 80, glyceryl monocaprylate, glyceryl tricaprylate, gelatin, a gelatin capsule, and about 6% to 7% Acryl-EZE® (methacrylate).

[0058] Treatment method In embodiments, the present disclosure provides a method of treating one or more symptoms in a patient having a neuroendocrine tumor, or a method for treating a patient having a neuroendocrine tumor, comprising orally administering to the patient an effective amount of octreotide or a pharma- ceutically acceptable salt thereof.

[0059] In embodiments, the disclosure provides a method of treating carcinoid syndrome, treating the symptoms of carcinoid syndrome, or treating a patient having carcinoid syndrome comprising orally administering to the patient an effective amount of octreotide or a pharma- ceutically acceptable salt thereof.

[0060] In embodiments, the present disclosure provides a method for treating episodes of diarrhea and flushing associated with neuroendocrine tumors or carcinoid syndrome, the method comprising orally administering to a patient an effective amount of octreotide, or a pharma- ceutically acceptable salt thereof.

[0061] It will be understood that in the embodiments of the methods provided herein, the patient is a human. In some embodiments, the patient is an adult patient.

[0062] In an embodiment of the disclosed method, octreotide is administered for maintenance therapy of diarrhea and flushing episodes associated with carcinoid tumors.In an embodiment of the disclosed method, octreotide is administered for long-term maintenance therapy of diarrhea and flushing episodes associated with carcinoid tumors.

[0063] In embodiments of the methods of the present disclosure, the carcinoid tumor is a metastatic carcinoid tumor.

[0064] Long-term maintenance therapy in patients suffering from neuroendocrine tumors (e.g., diarrhea and / or flushing episodes associated with carcinoid tumors) or signs or symptoms of carcinoid syndrome is continued as long as the patient suffers from the aforementioned condition and the patient's symptoms are adequately controlled. For example, the patient's bowel movement frequency (BM) is maintained at an average of less than about 4 bowel movements per day, and / or the patient has an acceptable FE (if present). For example, a patient treated with orally administered octreotide or a pharmacologic acceptable salt thereof (e.g., oral octreotide capsules) has a grade 1 or grade 2, or grade 3 FE as defined by the CTCAE version 5 (v5) criteria, or a grade 1 or grade 2 FE as defined by the CTCAE version 5 (v5) criteria. In embodiments, a patient treated with orally administered octreotide or a pharmacologic acceptable salt thereof (e.g., oral octreotide capsules) has an acceptable FE defined as mild or moderate, or not limiting instrumental activities of daily living [ADL]. In embodiments, patients treated with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules) do not have FE. Thus, the duration may be unlimited. In embodiments, long-term maintenance therapy may be at least one year, two years, three years, four years, or five years.

[0065] In embodiments, the methods described herein include orally administering octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules) for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 24 weeks, 26 weeks, 40 weeks, 1 year, or 2 years. In embodiments, the methods described herein include orally administering octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules) for at least about 6 months, at least about 7 months, at least about 12 months, or more than 12 months.

[0066] In embodiments, the methods described herein include orally administering octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules) for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, about 1 year, about 2 years, about 3 years, about 4 years, or more.

[0067] In embodiments of the present disclosure, about 5 mg to about 400 mg of octreotide are orally administered per day, including orally administering about 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, or 400 mg of octreotide per day, including all values ​​and subranges therebetween. In embodiments, about 10 to about 300 mg of octreotide is orally administered per day, or about 40 to about 200 mg of octreotide is orally administered per day. In embodiments, about 80 to 160 mg of octreotide is orally administered per day, for example, twice a day. In embodiments, about 80 mg of octreotide is administered per day, and the dose may be two doses of 40 mg each administered twice a day, where the 40 mg dose may be two 20 mg tablets. In embodiments, about 120 mg of octreotide is administered per day, and the dose may be two doses of 60 mg each administered twice a day, where the 60 mg dose may be three capsules containing 20 mg of octreotide, for example, as described herein. In embodiments, about 160 mg of octreotide is administered per day, and the dose may be administered twice daily in two doses of 80 mg each, which 80 mg dose may be four 20 mg capsules containing 20 mg of octreotide, e.g., as described herein.

[0068] In embodiments of the disclosure, octreotide is administered once a day, twice a day, or more than once a day.

[0069] In an embodiment of the present disclosure, octreotide is administered twice daily.

[0070] In an embodiment of the disclosed method, the oral administration of octreotide or a pharma- ceutically acceptable salt thereof is performed on an empty stomach, for example, at least 1 hour before a meal or at least 2 hours after a meal. In an embodiment, octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules) is orally administered with a glass of water.

[0071] In embodiments of the disclosed methods, the meal may contain 100-1000 calories, or 300-600 calories which may be a high fat or high calorie meal, and may also contain carbohydrates and / or fat and / or protein, for example, 100, 200, 300, 400 calories, or 500-1000 calories, or 700-800 calories.

[0072] In embodiments of the methods provided herein, the patient is dosed every 8-16 hours (e.g., every 12 hours). In embodiments, one dose is administered at least 6, 8, 10, or 12 hours before the second dose. In embodiments of the present disclosure, the first dose is in the morning (usually between 5 a.m. and noon) and the second dose is in the evening (usually between 5 p.m. and midnight). In some embodiments of the present disclosure, administration may be self-administered, and in other embodiments of the present disclosure, a caregiver or healthcare professional may administer the dosage form.

[0073] In an embodiment, the disclosure provides a method for treating one or more symptoms associated with a neuroendocrine tumor in a patient in need thereof, the method comprising orally administering to the patient a total daily dose of at least about 120 mg of octreotide or a pharma- ceutically acceptable salt thereof. In an embodiment, the disclosure provides a method for treating carcinoid syndrome in a patient in need thereof, the method comprising orally administering to the patient a total daily dose of at least about 120 mg of octreotide or a pharma- ceutically acceptable salt thereof. In an embodiment, the disclosure provides a method for treating episodes of diarrhea and flushing associated with a carcinoid tumor in a patient in need thereof, the method comprising orally administering to the patient a total daily dose of at least about 120 mg of octreotide or a pharma- ceutically acceptable salt thereof.

[0074] In any of the embodiments of the methods disclosed herein, the total daily dose is about 80 mg to about 180 mg, or about 80 mg to about 160 mg of octreotide or a pharma- ceutically acceptable salt thereof. In an embodiment, the total daily dose is about 120 mg of octreotide or a pharma- ceutically acceptable salt thereof. In an embodiment, the total daily dose is about 120 mg of octreotide or a pharma- ceutically acceptable salt thereof administered twice a day (i.e., 60 mg BID).

[0075] In embodiments, patients may be maintained on 120 mg of octreotide per day if clinical symptoms of carcinoid tumors or carcinoid syndrome (e.g., diarrhea and / or flushing episodes) are controlled (e.g., as defined herein) or if response levels (biochemical and symptomatic response) are maintained. For example, in embodiments, patients may be maintained on 120 mg of octreotide per day if they have an average number of bowel movements per day of less than 4 BM / day, less than 3 BM / day, less than 2 BM / day, or less than 1 BM / day, and / or an acceptable FE (e.g., as defined herein by CTCAE v5 criteria).

[0076] In embodiments, the disclosure provides a method for maintaining treatment of episodes of diarrhea and / or flushing associated with metastatic carcinoid tumors in a patient in need thereof, the method comprising orally administering to the patient a total daily dose of at least about 120 mg of octreotide or a pharma- ceutically acceptable salt thereof. In embodiments, the total daily dose is about 120 mg of octreotide or a pharma-ceutically acceptable salt thereof administered twice daily (i.e., 60 mg BID).

[0077] In an embodiment of the disclosed method, the patient orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules) has been previously treated with a somatostatin receptor ligand (SRL) shown to be effective and tolerable for one or more signs or symptoms associated with a neuroendocrine tumor. In an embodiment of the disclosed method, the patient has been previously treated for carcinoid syndrome with a somatostatin receptor ligand (SRL) shown to be effective and tolerable.

[0078] In an embodiment of the present disclosure, the SRL is an injectable SRL.

[0079] In an embodiment of the present disclosure, the injectable SRL is octreotide, lanreotide, or pasireotide. In an embodiment, the injectable SRL is octreotide or lanreotide. In an embodiment, the injectable octreotide is a long acting release (LAR) octreotide formulation or a subcutaneous (SC) immediate release (IR) octreotide formulation.

[0080] In an embodiment of the disclosure, patients received 10 mg, 20 mg, or 30 mg of octreotide, or 120 mg of lanreotide in their previous treatment.

[0081] In an embodiment of the disclosure, the patient received parenteral SRL monotherapy in previous treatment, e.g., Sandostatin (octreotide) 30 mg, 20 mg, or 10 mg, or Somatuline (lanreotide) 120 mg, with a 4-week dosing interval and at least 3 months of stable dose therapy.

[0082] In an embodiment of the present disclosure, the patient received 120 mg of Somatuline Depo (lanreotide) every 4 weeks in their previous SRL treatment.

[0083] In an embodiment of the present disclosure, patients received 10 mg, 20 mg, or 30 mg of Sandostatin LAR every 4 weeks in their previous SRL treatment.

[0084] Patients currently receiving or having received SRL therapy by injection (e.g., as described herein) can be switched to octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules) given orally (e.g., as described herein), e.g., administered with an initial dose of 120 mg octreotide per day given orally (e.g., as a 60 mg BID dose, e.g., as three 20 mg octreotide capsules given twice daily (120 mg total)). If clinical symptoms are controlled or response levels (biochemical and symptomatic response) are maintained, the patient can be maintained on 120 mg octreotide per day.

[0085] In the event of symptomatic worsening or breakthrough symptoms, the dose may be adjusted, for example, as described herein, from 120 mg of octreotide administered orally per day to 160 mg of octreotide administered orally per day (e.g., 80 mg BID, e.g., as four 20 mg octreotide capsules administered twice daily (160 mg total)). Once clinical symptoms are controlled, the dose may be further adjusted to 120 mg of octreotide administered orally per day.

[0086] In the event of tolerability issues (e.g., severe nausea or headache assessed as related to octreotide), the dose may be temporarily adjusted from 120 mg octreotide per day to 80 mg octreotide per day orally (e.g., 40 mg BID, e.g., as two 20 mg octreotide capsules administered twice daily (80 mg total) as described herein).

[0087] In an embodiment of the method of the present disclosure, the method comprises: To determine the daily frequency of bowel movements (BM) of patients following administration of 120 mg of octreotide per day; (a) the patient experiences an increase in daily frequency of BMs by at least 2 BM compared to the baseline prior to administration of 120 mg of octreotide; and (b) if the patient experiences >= 4 BM / day after administration of 120 mg of octreotide, then administering to the patient about 160 mg of octreotide per day.

[0088] In embodiments, 160 mg of octreotide is administered if the patient (a) experiences an increase in daily frequency of BMs of 1 BM, 2 BM, 3 BM, 4 BM, 5 BM, 6 BM, or more (including any value or range therebetween). In embodiments, 160 mg of octreotide is administered if the patient (b) experiences 4 BM, 5 BM, 6 BM, 7 BM, 8 BM, 9 BM, 10 BM, 11 BM, 12 BM, or more (including any value or range therebetween) after administration of 120 mg of octreotide.

[0089] In an embodiment of the method of the present disclosure, the method comprises: To determine the daily frequency of flushing episodes (FE) in patients following administration of 120 mg of octreotide per day; (a) the patient experiences an increase in the daily frequency of FEs by at least 1 FE per day compared to before administration of 120 mg of octreotide; or (b) if the patient experiences an increase in the severity of FE after administration of 120 mg of octreotide (e.g., as determined by eDiary or based on CTCAE v5 grade), administering to the patient about 160 mg of octreotide per day.

[0090] In an embodiment, 160 mg of octreotide is administered if the patient (a) experiences an increase in daily frequency of FEs of 1 FE, 2 FE, 3 FE, 4 FE, 5 FE, 6 FE, or more (including any value or range therebetween) after administration of 120 mg of octreotide.

[0091] In an embodiment of the method of the present disclosure, the method comprises: To determine the daily frequency of flushing episodes (FE) in patients following administration of 120 mg of octreotide per day; If the patient experiences an increase in the severity of FE after administration of 120 mg of octreotide (e.g., as determined by eDiary or based on CTCAE v5 grade), then administering about 160 mg of octreotide per day to the patient.

[0092] In embodiments of the methods disclosed herein, the patient experiences an increase in the severity of FE as determined by CTCAE v5 grade.

[0093] In embodiments of the methods disclosed herein, the increase in severity of FE is grade 2 for at least 7 of the past 14 days or grade 3 based on CTCAE v5 grading.

[0094] In an embodiment of the method of the present disclosure, the method comprises: To determine the signs / symptoms of carcinoid syndrome in patients following administration of 120 mg of octreotide per day; and if the patient experiences new or worsening signs / symptoms of carcinoid syndrome, administering to the patient about 160 mg of octreotide per day.

[0095] In an embodiment of the present disclosure, 160 mg of octreotide is administered per day for about 2 to about 40 days, including about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40 days (including all ranges and values ​​therebetween).

[0096] In an embodiment of the present disclosure, 160 mg of octreotide is administered per day for about 2 to about 14 days. In an embodiment of the present disclosure, 160 mg of octreotide is administered per day for about 4 to about 7 days.

[0097] In an embodiment of the method of the present disclosure, the method comprises: To determine the signs / symptoms of carcinoid syndrome in patients following administration of 160 mg of octreotide per day; If the patient's biochemical and / or symptomatic response is controlled, administering to the patient about 120 mg of octreotide per day.

[0098] In an embodiment of the method of the present disclosure, the method comprises: To determine patient tolerance following administration of 120 mg of octreotide per day; If the patient experiences tolerability problems after administering 120 mg of octreotide per day, administering about 80 mg of octreotide per day to the patient.

[0099] In embodiments, the disclosure provides a method of preventing or treating breakthrough symptoms (e.g., associated with carcinoid syndrome, such as diarrhea, flushing episodes, or abdominal pain) comprising orally administering octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules). In embodiments, at least about 120-160 mg of octreotide per day is orally administered to prevent or treat breakthrough symptoms.

[0100] In an embodiment of the present disclosure, octreotide is administered in a capsule. In an embodiment, each capsule contains 20 mg of octreotide. In an embodiment of the present disclosure, the capsule is enteric coated. In an embodiment, the pharma- ceutically acceptable salt is octreotide acetate.

[0101] In an embodiment of the present disclosure, octreotide is administered in a capsule containing an oil suspension (eg, as described herein).

[0102] In an embodiment of the present disclosure, the oil suspension comprises an admixture of a hydrophobic medium and a solid form, the solid form comprising octreotide and at least one salt of a medium chain fatty acid.

[0103] In an embodiment of the disclosure, the oil suspension comprises an admixture of a hydrophobic medium and a solid form, the solid form comprising octreotide, at least one salt of a medium chain fatty acid, and polyvinylpyrrolidone (PVP), wherein the at least one salt of a medium chain fatty acid is present in the dosage form in an amount of at least 12% by weight, and the PVP is present in the dosage form in an amount of 3% by weight or greater.

[0104] In an embodiment of the present disclosure, the composition comprises octreotide, about 12-21% by weight sodium octanoate, about 5-15% by weight polyvinylpyrrolidone, about 20-80% by weight glyceryl tricaprylate, and about 3-10% by weight of a surfactant.

[0105] In embodiments, particular advantages of oral administration of octreotide are the avoidance of often painful injections, the avoidance of injection site reactions, and the reduction of breakthrough symptoms. Other advantages of daily treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules) may include, for example, that there is no tapering off of the pharmacodynamic effect at the end of the dosing interval (as is seen in many patients during the final week between SRL injections).

[0106] In embodiments of the disclosed methods, following treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules), patients experience improvement in diarrhea and severity flushing episodes associated with carcinoid tumors.

[0107] In embodiments of the disclosed methods, following treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (eg, oral octreotide capsules), the patient experiences improvement in diarrhea.

[0108] In embodiments of the disclosed methods, following treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules), patients experience improvement in severity flushing episodes associated with carcinoid tumors, as determined by CTCAE v5 grade.

[0109] The CTCAE v5 grades display grades 1-5 with a specific clinical description of the severity of each adverse event (AE) based on the following comprehensive guidelines: Grade 1 Mild; asymptomatic or mild symptoms, clinical or diagnostic findings only, no need for intervention indicated. Grade 2 Moderate; limitation of instrumental activities of daily living (ADLs) appropriate for aging, with minimal, local, or non-invasive intervention (e.g., short antibiotic course). Grade 3 Severe or medically significant but not immediately life-threatening; indication of need for hospitalization or prolonged hospitalization, disability, limitation of personal ADLs. Grade 4 - Life-threatening outcome; urgent intervention required. In embodiments, a life-threatening event refers to an event that indicates the need for urgent / emergency intervention, e.g., the subject was at risk of death at the time of the event, as determined by the treating physician. Death related to grade 5 AE.

[0110] In an embodiment of the present disclosure, after treatment with orally administered octreotide or its pharma- ceutically acceptable salt (e.g., oral octreotide capsule), the patient's symptoms are adequately controlled. For example, the patient has a mean of <4.0 / day normal bowel movement frequency (BM) and / or acceptable FE (e.g., defined as grade 1, 2, or 3 based on CTCAE v5 criteria, or defined as grade 1 or 2 based on CTCAE v5 criteria). In an embodiment, acceptable FE is defined as asymptomatic or moderate and / or not limiting instrumental activities of daily living [ADL], or mild or moderate and / or not limiting activities of daily living [ADL]).

[0111] In embodiments, patients orally administered octreotide or a pharmacologic acceptable salt thereof (e.g., oral octreotide capsules) have grade 1 or 2 FE (if present) based on the CTCAE v5 criteria, e.g., asymptomatic or moderate symptoms, or limitations in instrumental activities of daily living (ADL).

[0112] In embodiments, patients orally administered octreotide or a pharmacologic acceptable salt thereof (e.g., oral octreotide capsules) have grade 1 or 2 FE (if present) based on the CTCAE v5 criteria, e.g., asymptomatic or moderate symptoms, or limitations in instrumental activities of daily living (ADL).

[0113] In embodiments, patients orally administered octreotide or a pharmacologic acceptable salt thereof (e.g., oral octreotide capsules) have grade 3 FE (if present) based on CTCAE v5 criteria, e.g., related to hypotension and / or tachycardia, or limitations in self-care ADLs.

[0114] In embodiments, patients administered orally octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules) have no episodes of flushing or a grade FE (if present) based on the CTCAE v5 criteria. In embodiments, patients administered orally octreotide or a pharma-ceutically acceptable salt thereof (e.g., oral octreotide capsules) have no episodes of flushing or a grade FE (if present) based on the CTCAE v5 criteria.

[0115] In embodiments of the disclosure, after treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules), the patient has an average number of bowel movements per day of less than about 4, less than about 3, less than about 2, or less than about 1. In embodiments, after treatment, the patient has an average number of bowel movements per day of 0-4, 0-3, 0-2, 0-1, 1-4, 1-3, 1-2, or 2-4 BM / day.

[0116] In embodiments, after at least about 1-20 weeks of treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules), the patient has an average number of bowel movements per day of less than about 4, less than about 3, less than about 2, or less than about 1.

[0117] In embodiments, after about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 52, 79, 104 or more weeks of treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules), the patient has an average number of bowel movements per day of less than about 4, less than about 3, less than about 2, or less than about 1. In embodiments, the patient has an average number of bowel movements per day of less than about 4, less than about 3, less than about 2, or less than about 1 during the past 4 weeks.

[0118] In embodiments, after about 3 to 20 weeks, or 4 to 16 weeks of treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules), including from about 3 weeks to about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, to about 20 weeks (including all values ​​and ranges therebetween), the patient has an average number of bowel movements per day of less than about 4, less than about 3, less than about 2, or less than about 1. In embodiments, the patient has an average number of bowel movements per day of less than about 4, less than about 3, less than about 2, or less than about 1 during the past 4 weeks.

[0119] In an embodiment of the present disclosure, after about 16 weeks of treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules), the patient has an average number of bowel movements per day of less than about 4 during the final 4 weeks (i.e., weeks 13-16).

[0120] In embodiments of the present disclosure, following treatment with orally administered octreotide or a pharmacologic acceptable salt thereof (e.g., oral octreotide capsules), e.g., as disclosed herein, the patient has acceptable FE (e.g., defined by CTCAE version 5 (v5) criteria, e.g., as grade 1, grade 2, or grade 3 FE by the CTCAE version 5 (v5) criteria, or as grade 1 or grade 2 FE by the CTCAE version 5 (v5) criteria). In embodiments, after treatment with orally administered octreotide or a pharma- ceutical acceptable salt thereof as disclosed herein (e.g., oral octreotide capsules) for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 25, 52, 79, 104, or more weeks, the patient has acceptable FE (e.g., defined by CTCAE Version 5 (v5) criteria, e.g., as Grade 1, Grade 2, or Grade 3 FE according to the CTCAE Version 5 (v5) criteria, or as Grade 1 or Grade 2 FE according to the CTCAE Version 5 (v5) criteria). In embodiments, after about 4-16 weeks of treatment, the patient has acceptable FE (e.g., defined by CTCAE version 5 (v5) criteria, e.g., as Grade 1, Grade 2, or Grade 3 FE by CTCAE version 5 (v5) criteria, or Grade 1 or Grade 2 FE by CTCAE version 5 (v5) criteria).

[0121] In embodiments of the present disclosure, after treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules), patients have an average number of bowel movements per day (BM / day) that is not increased by more than 1.0 BM / day compared to the pre-treatment baseline or compared to previous treatment with an injectable SRL (e.g., as disclosed herein).

[0122] In embodiments of the present disclosure, following treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof as disclosed herein (e.g., oral octreotide capsules), the average number of flushing episodes per day is reduced to an average of about 1-4 episodes / day, about 1-3 episodes / day, or about 1-2 episodes / day, or about 0.5-1 episodes / day of flushing episodes per day.

[0123] A Patient Perception Questionnaire (PPQ) can be utilized to assess patient perception of observed changes in BM frequency and / or FE severity / frequency that are meaningful to patients treated by the methods disclosed herein. In embodiments, patients can complete the PPQ to address their perception of changes in BM and FE for orally administered octreotide (e.g., oral octreotide capsules) compared to SRL injection (before treatment with oral octreotide) (three separate questions) ("much better", "a little better", "same", "a little worse", "much worse"), and their overall satisfaction with orally administered octreotide (e.g., oral octreotide capsules) compared to SRL injection in controlling BM and FE (two additional questions) ("very satisfied", "satisfied", "neither satisfied nor dissatisfied", "dissatisfied", "very dissatisfied").

[0124] In embodiments, after treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules), e.g., as described herein, the patient experiences an improvement in BM frequency and / or FE severity / frequency as assessed by a Patient Perception Questionnaire (PPQ) compared to SRL injections (prior to treatment with oral octreotide). For example, in embodiments, after treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules), the patient experiences an improvement in BM frequency and / or FE severity / frequency as assessed by a PPQ characterized as "same," "a little better," or "much better" compared to SRL injections (prior to treatment with oral octreotide). In embodiments, patients experience an improvement in BM frequency and / or FE severity / frequency characterized as "a little better" or "much better" as assessed by the PPQ compared to SRL injections (before treatment with oral octreotide). In embodiments, patients experience an improvement in BM frequency and / or FE severity / frequency characterized as "much better" as assessed by the PPQ compared to SRL injections (before treatment with oral octreotide).

[0125] To assess the presence of symptoms such as diarrhea and associated functional limitations (i.e., embarrassment, urgency, activity limitations, fear of being far from a toilet) in patients treated by the methods disclosed herein, the Functional Assessment of Cancer Therapy-Carcinoid Syndrome Symptom Index (FACT-CSI) questionnaire can be utilized. (Shaunfield, S., Webster, KA, Kaiser, K., Greene, GJ, Yount, SE, Lacson, L., et al. (2020). “Development of the Functional Assessment of Cancer Therapy-Carcinoid Syndrome Symptom Index (FACT-CSI).” Neuroendocrinology). The FACT-CSI questionnaire includes 20 items. Each item is graded on a 0-4 point scale.

[0126] In embodiments of the methods of the present disclosure, Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and radiographic imaging can be used to assess progression-free survival and objective tumor response rates in the methods disclosed herein.

[0127] In an embodiment, radiological imaging (CT or MRI) is performed approximately every three months.

[0128] In embodiments of the methods disclosed herein, following treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules), patients experience improved progression-free survival in subjects suffering from NETs (such as carcinoid tumors) or carcinoid syndrome.

[0129] In embodiments of the disclosed methods, the Carcinoid Syndrome-Treatment Satisfaction Questionnaire (CS-TSQ) can be utilized to assess treatment satisfaction for adult subjects with CS symptoms treated with oral octreotide (e.g., compared to a pre-treatment baseline or compared to an SRL injection (before treatment with oral octreotide)).

[0130] The CS-TSQ focuses on the following aspects: Symptoms of CS Injection site reactions - Difficulty in administering treatment Convenience of treatment ·Emotional impact Treatment satisfaction

[0131] In embodiments, after treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules), patients experience improved treatment satisfaction as assessed by the CS-TSQ compared to pre-treatment baseline.

[0132] In embodiments, after treatment with orally administered octreotide or a pharma- ceutically acceptable salt thereof (e.g., oral octreotide capsules), e.g., as described herein, patients experience improved treatment satisfaction as assessed by the CS-TSQ compared to SRL injections (prior to treatment with oral octreotide).

[0133] In some embodiments, the methods provide a method for determining the AUC of octreotide that correlates with one or more statistically significant therapeutic effects. 0-inf In some embodiments, the therapeutically effective AUC of octreotide provided by the methods of the present disclosure (expressed as time*pg / mL) is 0-infThe levels are approximately 5,000hr*pg / mL, approximately 10,000hr*pg / mL, approximately 15,000hr*pg / mL, approximately 20,000hr*pg / mL, approximately 25,000hr*pg / mL, approximately 30,000hr*pg / mL, approximately 35,000hr*pg / mL, approximately 40,000hr*pg / mL, approximately 45,000hr*pg / mL, approximately 50,000hr*pg / mL, approximately 55,000hr*pg / mL, approximately 60,000hr*pg / mL, approximately 65,000hr*pg / mL, approximately 70,000hr*pg / mL, approximately 75,000hr*pg / mL, approximately 80,000hr*pg / mL, approximately 85,000hr*pg / mL, The range is from about 5,000 hr*pg / mL to about 500,000 hr*pg / mL, including about 90,000 hr*pg / mL, about 100,000 hr*pg / mL, about 110,000 hr*pg / mL, about 120,000 hr*pg / mL, about 125,000 hr*pg / mL, about 150,000 hr*pg / mL, about 200,000 hr*pg / mL, about 250,000 hr*pg / mL, about 300,00 hr*pg / mL, about 350,000 hr*pg / mL, about 400,000 hr*pg / mL, about 450 hr*pg / mL, up to about 500,000 hr*pg / mL (including all ranges and values ​​in between). In embodiments, the therapeutically effective AUC of octreotide provided by the methods of the present disclosure 0-inf The levels range from about 15,000 hr*pg / mL to about 350,000 hr*pg / mL, from about 15,000 hr*pg / mL to about 50,000 hr*pg / mL, or from about 25,000 hr*pg / mL to about 35,000 hr*pg / mL, or from about 35,000 hr*pg / mL to about 45,000 hr*pg / mL. 0-inf The level is produced by administering a dose of octreotide or a pharma- ceutically acceptable salt thereof that is about 40 mg. In an embodiment, the therapeutically effective AUC 0-inf The level is produced by administering a dose of octreotide or a pharma- ceutically acceptable salt thereof that is about 60 mg. In an embodiment, the therapeutically effective AUC 0-infThe level is produced by administering a dose of octreotide or a pharma- ceutically acceptable salt thereof that is about 80 mg. In an embodiment, the therapeutically effective AUC 0-inf The level is produced by administering a dose of octreotide or a pharma- ceutically acceptable salt thereof that is about 120 mg. In an embodiment, the therapeutically effective AUC 0-inf The levels are produced by administering a dose of octreotide or a pharma- ceutically acceptable salt thereof that is about 160 mg.

[0134] In some embodiments, the methods provide a Cmax (expressed in pg / mL) level of octreotide that correlates with one or more statistically significant therapeutic effects. In some embodiments, the therapeutically effective Cmax levels of octreotide provided by the methods of the present disclosure are about 100 pg / mL, about 500 pg / mL, about 1000 pg / mL, about 2,000 pg / mL, about 2500 pg / mL, about 3,000 pg / mL, about 4,000 pg / mL, about 4,500 pg / mL, about 4,600 pg / mL, about 4,700 pg / mL, about 4,800 pg / mL, about 5,000 pg / mL, about 5,500 pg / mL, about 6,000 pg / mL, about 6,500 pg / mL, about 7,000 pg / mL, about 7,500 pg / mL, about 8,000 pg / mL, about 8,500 pg / mL, about 9,000 pg / mL, about 9,500 pg / mL, about 10,000 pg / mL, about 11,000 pg / mL, about 12,000 pg / mL, about 13,000 pg / mL, about 14,000 pg / mL, about 15,000 pg / mL, about 16,000 pg / mL, about 17,000 pg / mL, about 18,000 pg / mL, about 19,000 pg / mL, about 21,000 pg / mL, about 22,000 pg / mL, about 23,000 pg / mL, about 24,000 pg / mL, about 25,000 pg / mL, about 26,000 pg / mL, about 27,000 pg / mL, about 28,000 pg / mL, about 29, The range is from about 100pg / mL to about 100,000pg / mL, including about 9,000pg / mL, about 9,500pg / mL, about 10,000pg / mL, about 11,000pg / mL, about 12,000pg / mL, about 13,000pg / mL, about 15,000pg / mL, about 20,000pg / mL, about 30,000pg / mL, about 40,000pg / mL, about 50,000pg / mL, about 60,000pg / mL, about 70,000pg / mL, about 80,000pg / mL, about 90,000pg / mL, and up to about 100,000pg / mL (including all ranges and values ​​in between). In an embodiment, a therapeutically effective Cmax of octreotide is provided by administering a dose of octreotide or a pharma- ceutically acceptable salt thereof that is about 40 mg. In an embodiment, a therapeutically effective Cmax of octreotide is provided by administering a dose of octreotide or a pharma- ceutically acceptable salt thereof that is about 60 mg. In an embodiment, a therapeutically effective Cmax of octreotide is provided by administering a dose of octreotide or a pharma- ceutically acceptable salt thereof that is about 80 mg. In an embodiment, a therapeutically effective Cmax of octreotide is provided by administering a dose of octreotide or a pharma- ceutically acceptable salt thereof that is about 120 mg.In embodiments, a therapeutically effective Cmax of octreotide is produced by administering a dose of octreotide or a pharma- ceutically acceptable salt thereof that is about 160 mg. EXAMPLES

[0135] Example 1: Phase 1 PK Study This study was an open-label, randomized, six-sequence, three-period crossover study. The primary objective of the study was to evaluate the pharmacokinetic (PK) profiles of oral octreotide 20 mg (administered as 1 x 20 mg capsule), 60 mg (administered as 3 x 20 mg capsules), and 80 mg (administered as 4 x 20 mg capsules) in 30 healthy volunteers.

[0136] treatment

[0137] Subjects will receive each of the following treatments separated by a 48 hour washout period:

[0138] Treatment A: Oral octreotide capsule 1×20 mg (20 mg)

[0139] Treatment B: Oral octreotide capsules 3 x 20 mg (60 mg)

[0140] Treatment C: Oral octreotide capsules 4 x 20 mg (80 mg)

[0141] To maintain a balanced design with three treatments, a Williams design with six sequences and three periods is used. The sequences are as follows: ABC, BCA, CAB, CBA, ACB, and BAC. Subjects are randomly assigned to one of the six sequences.

[0142] Screening stage

[0143] Eligibility is determined during the screening phase.

[0144] Treatment Phase

[0145] For each treatment period, after an overnight fast of at least 10 hours, subjects receive a single dose of one of the three treatments (on days 1, 3, and 5). Subjects continue to fast for 4 hours after dosing. Subjects are then provided with a standardized lunch, dinner, and midnight snack.

[0146] During each treatment period, blood samples for determination of octreotide plasma concentrations will be taken over a 24 hour period after each dose (from the time the last capsule is consumed) at the following time points: pre-dose (within 15 minutes prior to dosing), 0.083 (5 minutes), 0.167 (10 minutes), 0.33 (20 minutes), 0.5 (30 minutes), 0.67 (40 minutes), 0.75 (45 minutes), 1, 1.33, 1.67, 2, 2.33, 2.67, 3, 3.33, 3.67, 4, 4.5, 5, 6, 8, 10, 12, 15, and 24 hours after dosing.

[0147] Plasma concentrations of octreotide are determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS / MS) assay.

[0148] The following PK parameter estimates will be calculated by noncompartmental methods for each treatment: Area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration (AUC 0-last ) AUC extrapolated from time 0 to infinity (AUC 0-inf ) Observed peak concentration (C max ) Time to peak concentration (T max ) Absorption lag time (T lag ) Elimination rate constant (λz) and half-life (t1 / 2) Additional PK parameter estimates will be calculated if deemed necessary.

[0149] safety

[0150] Safety will be assessed descriptively based on assessment of the following: adverse events (AEs, including serious AEs [SAEs]), vital signs (blood pressure, heart rate, respiratory rate, and temperature), 12-lead ECG, physical examination, and safety laboratory assessments.

[0151] All doses will be removed from the blisters and administered one at a time, separated by a 30 second gap between each capsule of Treatment B and C.

[0152] Subjects will be confined to the clinic from check-in on day 1 until discharge on day 6.

[0153] Tracking Phase

[0154] Approximately 7 days after completion of the last treatment period (i.e., last study-condition administration), subjects will return to the clinic for a follow-up EOS / ET visit to undergo safety assessments.

[0155] result

[0156] 1A and 2A show the geometric mean plasma octreotide concentrations—linear (FIG. 1A) and semi-logarithmic (FIG. 2A) axes—following single oral doses of 20 mg, 60 mg, and 80 mg octreotide capsules (OOC) to healthy volunteers. [Table 2]

[0157] As shown in Table 1A, 80 mg oral octreotide had a 3.9-fold higher AUC (inf) (geometric mean ratio of 0.01 to 0.01), and provides 1.24-fold higher exposure than 60 mg oral octreotide.

[0158] 60 mg provides 3.1 times higher exposure than 20 mg.

[0159] Safety and tolerability were acceptable. No serious adverse events were reported.

[0160] [Table 3]

[0161] As shown in Table 1B, the measured concentrations for subject #02 were much higher than any of the other subjects. In the Grubbs test for Cmax for the three treatments, subject #02 was a significant outlier (p<0.05). When excluded, variability (overall between subjects' geometric CVs) is low for Cmax and AUC. However, subject is consistent across the three treatments and high for all compared to the others, suggesting that this subject may handle octreotide differently. Because subject #02 is high for all three treatments, the subject was included in the analysis (Table 1).

[0162] Example 2: Clinical Trials This study is a phase 3, randomized, double-blind, placebo-controlled, multicenter trial evaluating the efficacy and safety of oral octreotide capsules (OOC) in subjects with a documented history of carcinoid syndrome (with diarrhea, flushing episodes (FE) or without flushing episodes (FE)) associated with stable, well-differentiated metastatic carcinoid tumors who have been treated with SRL injections (octreotide or lanreotide) at a stable dose for at least 3 months and whose symptoms are adequately controlled.

[0163] The core study consists of two periods: a screening period followed by a double-blind, placebo-controlled (DPC) period. The DPC core study is a phase 3, randomized, double-blind, placebo-controlled, multicenter, 16-week study evaluating the efficacy, PK, safety, and subject-reported outcomes of OOC.

[0164] The core study will be followed by an open-label extension (OLE), multicenter, ≥48 week study to evaluate the long-term safety and tolerability of OOC and progression-free survival.

[0165] A schematic diagram of the study design is shown in Figure 2, and the study duration is shown in the table below. [Table 4]

[0166] Screening period (4–8 weeks prior to baseline)

[0167] After signing informed consent, subjects are screened for study eligibility.

[0168] The screening period consists of two in-clinic screening visits, Screening Visit 1 (SV1) should occur 3 days after or within 3 days of the last SRL injection and Screening Visit 2 (SV2). SV2 should be scheduled at the beginning of the 3rd week of the SRL injection interval (-3 days). The screening period is expected to last ≥ 4 weeks, and up to 8 weeks.

[0169] During the screening period, daily eDiaries of BM and FE, as well as antidiarrheal medication and / or Sandostatin SC use will be collected. Eligibility will be determined based on BM and FE during the approximately 4-week pre-baseline SRL injection interval.

[0170] Collection of plasma 5-HIAA and single time point octreotide PK assessments will be performed in SV1 and SV2. Collection of 24 hour urinary 5-HIAA will be performed in SV2. Radiological scans, computed tomography (CT) or magnetic resonance imaging (MRI) scans will be performed during the screening period and will be evaluated locally by the investigator to assess tumor stability. Radiological scans will be collected for evaluation by BICR.

[0171] Eligibility Criteria

[0172] Selection Criteria

[0173] To be eligible to participate in this study, subjects must meet all of the following:

[0174] Gender and age 1. Male and female subjects ≥ 18 years of age at the time of signing the Informed Consent Form (ICF) prior to the start of any study-specific activities / procedures.

[0175] Subject type and disease characteristics 2. Definitive diagnosis of metastatic well-differentiated carcinoid tumor based on most recent histopathology with associated documented evidence of CS (active diarrhea with or without FE) at any time in the past as confirmed by IAC. IAC confirmation is based on medical history to exclude conditions (other than CS) or treatments that may cause diarrhea. 3. Abnormal plasma or 24-hour urinary 5-HIAA assessed at SV1 or SV2 (or within the last 6 months prior to SV1 if both assessments during screening are normal, and after the most recent tumor-directed treatment (e.g., cytoreduction, radiolabeled somatostatin analogue [SSA] therapy, chemoembolization) as confirmed by sponsor on a case-by-case basis). 4. Stable / non-progressing tumor as determined by the investigator. 5. Ki-67 (MIB1 antibody) <20% (or if the Ki-67 index cannot be reliably quantified, 10 high-power fields (2 mm 2 ) mitotic index of ≤20 mitoses per s. 6. Received parenteral SRL monotherapy, Sandostatin (octreotide) 30 mg or 20 mg, or Somatuline (lanreotide) 120 mg at stable doses for at least 3 months of treatment with 4-week dosing intervals. 7. Stable BM (mean <4.0 BM / day) during approximately 4 weeks between pre-baseline SRL injections as assessed during screening (not including the last day prior to randomization to allow for timely calculations and evaluations).

[0176] 1 / 2 Contraception 8. Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP must agree to follow contraception instructions during treatment with IP and for 30 days after the last dose of IP. Contraception should be consistent with local regulations. 9. WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day 1. 10. Women who are not of childbearing potential must be postmenopausal (defined as the end of regular menstrual periods for at least 12 months) or surgically sterile.

[0177] Informed consent 11. Subject is able to give signed informed consent, including adherence to the requirements and restrictions set forth in the ICF and this protocol.

[0178] Exclusion criteria A subject must be excluded from participation in the study if any of the following apply:

[0179] Medical conditions 1. Diarrhea associated with any of the following causes: a) Short bowel syndrome b) Pancreatic insufficiency; subjects with stable pancreatic enzymes are allowed if the diarrhea is not related to pancreatic insufficiency. c) Diarrhea is related only to SRL treatment and not to CS (e.g., diarrhea that began after initiation of SRL treatment or diarrhea occurring after each injection without evidence of CS-related diarrhea). d) known bacterial overgrowth 2. Evidence of current enteric bacterial or viral infection. 3. Diarrhea meeting the definition of CTCAE v5 grade 2 (i.e., increase of ≥ 4.0-6.0 BM / day or limitation of instrumental ADL) or higher at any time during screening. 4. FE meeting the definition of CTCAE v5 grade 2 (i.e., moderate symptoms or limitation of instrumental ADLs) or above at any time during screening. 5. Unstable CS symptoms (mainly BM and FE) or, at the subject's discretion, labile use of antidiarrheal or anticonvulsant medications in the most recent past 3 months (month-to-month fluctuations associated with use of long-acting SRLs or sporadic symptomatic exacerbations not associated with disease progression are permitted). Unstable BM is defined as a BM frequency that changes significantly from one month to another (eg, from an average of 1-3 BM / day to >4 BM / day). Unstable FE is defined as the frequency and / or severity of FE that changed significantly from one month to another (e.g., from 1 FE / week to 1 FE / day, or from FE that does not affect daily activities or quality of life to FE that affects daily activities or quality of life). 6. Biliary tract symptoms abnormalities. 7. History of unstable angina or acute myocardial infarction within 12 weeks prior to SV1, or other clinically significant cardiac disease at screening as determined by the investigator. 8. Any clinically significant uncontrolled neurological, GI, renal, pulmonary, hepatic intercurrent disease, or carcinoid tumor-related complications or severe symptoms that, in the opinion of the Investigator, would prevent the subject from participating (e.g., carcinoid heart disease, or subjects unable to tolerate oral medications due to GI complications). 9. Uncontrolled diabetes defined as having fasting glucose >150 mg / dL (8.3 mmol / L) or glycosylated hemoglobin (HbA1c) ≥ 8% (patients may be rescreened once diabetes is under adequate control or if HbA1c < 8%). Subjects with controlled diabetes are allowed (insulin is tolerated). 10. Known hypothyroidism or hypocortisolism not adequately treated with stable doses of thyroid or steroid hormone replacement therapy for ≥ 12 weeks. 11. Known active hepatitis B (defined as hepatitis B surface antigen [HbsAg] reactivity) or known active hepatitis C virus (defined as detectable HCV RNA [qualitative]) infection. NOTE: Hepatitis B and C testing is not required unless mandated by local health authorities. 12. History or current evidence of any condition, therapy, or laboratory abnormality that, in the opinion of the treating investigator, may confound the outcome of the study, prevent the subject's participation for the full duration of the study, or be not in the best interest of the subject participating. 13. Known history of illicit drug or alcohol abuse within 2 years of screening. 14. Known malignancy, other than metastatic carcinoid tumor, that has progressed or required active treatment within the past 3 years. NOTE: Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast cancer, cervical cancer in situ) receiving potentially curative therapy are not excluded. 15. Active infection requiring systemic therapy. 16. Pregnant or lactating female subjects.

[0180] Diagnostic evaluation 17. Eastern Cooperative Oncology Group (ECOG) performance status ≥ 3 at screening. 18. At screening, alanine transaminase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) >3x upper limit of normal (ULN). 19. Total bilirubin >1.5×ULN at screening. 20. Estimated glomerular filtration rate (eGFR) < 45 mL / min / 1.73 m as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2 . 21. Bradycardia (heart rate <50 bpm) or a mean QT interval corrected for heart rate (QTcF) using Fridericia's formula of ≥450 ms for men or >470 ms for women at screening.

[0181] Pretreatment 22. Use of telotristat within 4 weeks prior to screening. 23. Use of SC Sandostatin IR for >7 days out of 28 days during the screening period. 24. Treatment with interferon-alpha, chemotherapy, and / or surgical cytoreduction within the last 3 months prior to study enrollment (SV1). 25. Treatment with selective internal radiation (SIR) therapy (e.g., SIRSpheres) or radionuclide-labeled peptide therapy (PRRT) within the last 6 months prior to study enrollment (SV1). 26. Hepatic arterial embolization or hepatic arterial chemoembolization within the last 3 months prior to study enrollment (SV1). 27. Major surgery / surgical therapy for any cause within 4 weeks prior to enrollment or planned procedure during the study. 28. Anticipate receiving additional medical or surgical treatment for CS during the study.

[0182] Pre-clinical / concurrent clinical trial experience 29. Currently participating or have participated in a study of an investigational drug or have used an investigational device within 4 weeks prior to the first dose of an investigational drug (IP). NOTE: Subjects participating in observational studies are an exception to this criterion and may be eligible for the trial with sponsor approval. NOTE: Subjects who have entered the follow-up phase of the study may participate as long as 4 weeks have passed since their last dose of study drug.

[0183] Other Exclusions

[0184] Known allergy or hypersensitivity to any investigational medicinal product (IP) or materials.

[0185] Penalty rating

[0186] Single-point PK assessments will be collected three times (twice during screening and once at baseline, pre-dose) to allow characterization of SRL blood levels in the target population of subjects with CS associated with metastatic carcinoid tumors at different time points after SRL injection.

[0187] To characterize the PK of OOC in this target population at multiple time points, 12-hour PK collections will be performed at 12 and 20 weeks after the DPC baseline visit.

[0188] For example, 12-hour PK collections (at the following blood collection times: pre-dose (within 15 minutes), and 20, 40, 60, 80, 100, 120, 140, 160 minutes, and 3, 3.5, 4, 6, 8, 10, and 12 hours after the morning dose) will be performed 12 weeks after the DPC Baseline Visit and 20 weeks after the DPC Baseline Visit for subjects enrolled in the OLE.

[0189] In addition, 12-hour PK will be collected at baseline to the OLE in subjects who meet the TFC or who discontinue IP due to treatment failure (not meeting the TFC) and are determined to be eligible by the Sponsor's Medical Monitor (or designee) for early rollover to the OLE, as well as in subjects whose early termination during the OLE occurs less than 20 weeks after DPC baseline, to evaluate OOC PK in subjects with active disease, e.g., active diarrhea.

[0190] Biomarkers

[0191] Plasma and 24-hour urine samples are collected to assess levels of 5-HIAA.

[0192] statistical methods

[0193] The primary analysis of the primary evaluand / endpoint will be based on the full analysis set, defined as all randomized subjects. The primary analysis will use a stratified Cochran-Mantel-Haenszel (CMH) test, with strata defined by randomization strata. The primary analysis of the secondary endpoints will use the same approach as the primary endpoint.

[0194] A fixed order of testing will be used to adjust for multiplicity between the primary and secondary endpoints. Secondary endpoints will be tested only if the primary endpoint is statistically significant at a two-sided 5% significance level. Among the secondary endpoints, the second secondary endpoint will be tested only if the first secondary endpoint is statistically significant at a two-sided 5% significance level.

[0195] Investigational Drug

[0196] Oral octreotide capsules: OOC (each capsule strength is 20 mg formulated with a transient permeability enhancer (TPE) excipient) should be administered as 3 capsules (60 mg) twice daily (BID) (approximately 8-12 h apart) at approximately the same time each day on an empty stomach, i.e., at least 1 h before or at least 2 h after a meal. On PK sample collection days, subjects will be asked to withhold their evening dose until after the 12-h PK timepoints have been collected.

[0197] Placebo: Matching placebo capsules identical in appearance to the OOC, containing no octreotide but TPE excipients, should be administered as 3 capsules BID.

[0198] Double-blind placebo-controlled (DPC) treatment period

[0199] The baseline visit (first IP dose) should be scheduled within ±3 days of the intended routine dosing interval after the last SRL injection.

[0200] On Day 1 / Baseline, eligible subjects will be randomized in a 1:1 ratio to receive one of the following treatments for up to 16 weeks or until the subject meets treatment failure criteria (TFC): OOC 60 mg BID (3 x 20 mg capsules), total daily dose 120 mg. Placebo (3 capsules)

[0201] The study will utilize centralized stratified randomization based on mean bowel movements (BM) / day (during the last 4 weeks prior to randomization) at baseline (<3.0 BM / day vs. ≧3.0 BM / day) and mean flushing episodes (FE) / day (during the last 4 weeks prior to randomization) at baseline (<1.0 FE / day vs. ≧1 FE / day).

[0202] The first dose of investigational drug (IP) will be administered at the clinic. After IP initiation on Day 1 (baseline), subjects will return to the clinic and be evaluated as specified. Evaluations will include, but are not limited to, collection of daily eDiary (for BM and FE, and for use of anti-diarrheal medications and / or prohibited Sandostatin SC), patient-reported outcomes (PROs), 5-HIAA, and radiology scans (assessed by BICR).

[0203] During the DPC period, the use of Sandostatin SC or telotristat, or any other systemic treatment for NET or CS, is not permitted. Stable use of antidiarrheal and anticonvulsant medications (compared to doses and days used in the last 4 weeks before randomization) is permitted during the DPC period and should be reported in the eDiary.

[0204] complementary treatment

[0205] In case of symptomatic worsening of CS, supplemental treatment of an additional 40 mg / day (i.e., one additional 20 mg capsule BID) to a total of 4 capsules BID (equivalent to 80 mg OOC BID, i.e., 160 mg / day) will be permitted in case of symptomatic worsening assessed by the investigator as related to CS, based on the following recommendations: To maintain blinding, matched placebo subjects will also receive sham supplemental treatment during symptomatic worsening of CS symptoms.

[0206] Standards of Complementary Treatment: Increase in daily frequency of BMs by at least 2 BM / day and up to ≥ 4 BM / day compared to baseline or Increase in frequency of FE by at least 1.0 FE / day or increase in severity of FE (reported by eDiary or based on CTCAE v5 grade, respectively) compared to baseline. or -New or worsening other CS signs / symptoms determined to be clinically significant and reported as adverse events (AEs).

[0207] Upon symptomatic control, discontinuation of supplementation and resumption to 3 capsules BID is recommended. Supplementation should not exceed 1 week.

[0208] De-escalation of dose

[0209] Dose may be temporarily de-escalated to 2 capsules BID (equivalent to 40 mg OOC BID) on a case-by-case basis in case of tolerability issues (e.g., severe nausea or headache assessed as IP related) and after consultation with the sponsor.

[0210] DPC treatment failure criteria

[0211] The TFC is defined as follows:

[0212] Subjects can meet any of the following criteria (i.e., 1 or 2): 1. An increase in the frequency of BMs that meet all of the following criteria (i.e., a, b, and c): a. Increase in BM (below, any of i to iv) i. Mean BM increases by ≥ 2.0 / day compared to baseline and ≥ 4.0 / day over the last 14 days ii. Grade 2 diarrhea per CTCAE v5 criteria (i.e., increase in BM of ≥ 4.0-6.0 compared to baseline or limitation of instrumental ADL) for at least 7 consecutive days iii. Grade 3 diarrhea based on CTCAE v5 criteria (i.e., ≥ 7.0 BM compared to baseline or limitation in personal ADL) iv. Grade 4 diarrhea based on CTCAE v5 criteria (i.e., life-threatening or indicating the need for urgent intervention) b. Subject has received supplementation for intermittent exacerbations with IP 4 capsules BID (corresponding to an OOC dose level of 80 mg / BID in the active group) for at least 4 of the last 14 days, except for cases iii or iv above which do not require this. c. The increase in BM is not associated with GI infection, systemic antibiotics, or other non-CS etiology. 2. Worsening of FE compared to the screening period, meeting all of the following criteria (i.e., a, b, and c): a. Worsening of FE (i or ii below) i. Grade 2 FE per CTCAE v5 criteria (i.e., moderate symptoms, limitation of instrumental ADLs) for at least 7 of the last 14 days. ii. Grade 3 FE based on CTCAE v5 criteria (i.e., associated with hypotension and / or tachycardia or limiting self-care ADLs). b. Subjects received supplementation for intermittent exacerbations for at least 4 of the last 14 days with IP 4 capsules BID (equivalent to an OOC dose level of 80 mg / BID in the active group). c. Worsening of FE is not associated with changes in diet and alcohol.

[0213] Evaluation items

[0214] Primary endpoint

[0215] The primary endpoint of the study is the proportion of responders at the end of the DPC period. Response is defined as a mean BM < 4.0 / day during the last 4 weeks of the DPC or no increase in mean BM / day during the last 4 weeks of the DPC of > 1.0 BM / day compared to mean baseline BM / day, where baseline is based on the average of the last 4 weeks before randomization.

[0216] Secondary endpoints

[0217] A secondary endpoint of this study is to determine the proportion of subjects who met BM- or FE-related TFC during DPC.

[0218] The first secondary endpoint is defined as the proportion of subjects who met BM-related TFC.

[0219] The second secondary endpoint will be defined as the proportion of subjects who met the TFC associated with FE during DP.

[0220] Other evaluation items

[0221] This study will examine the proportion of subjects who experience loss of response over the DPC period based on FE, defined as meeting any of the following criteria: -TFC for FE is met - FE frequency at least doubled from screening (last 4 weeks before randomization) to the last 4 weeks of treatment to >1 FE / day

[0222] This study will examine change from DPC baseline (last 4 weeks prior to randomization) to end of treatment (last 4 weeks of IP during the DPC) in: -Average BM / day -Average FE / day

[0223] The study will examine changes during the DPC from DPC baseline (defined as the assessment at the baseline visit) to the end of treatment in: - Urinary and plasma 5-HIAA -PROs (Carcinoid Syndrome Treatment Satisfaction Questionnaire [CS-TSQ] and Functional Assessment of Cancer Therapy Carcinoid Syndrome Symptom Index [FACT-CSI])

[0224] This study examines the change in mean BM / day from the end of DPC (last 2 weeks of IP during DPC) to the last 2 weeks of OLE (up to OLE week 12)

[0225] This study examines the change in mean FE / day from the end of DPC (last 2 weeks of IP during DPC) to the last 2 weeks of OLE (up to OLE week 12)

[0226] This study examines changes in urinary and plasma 5-HIAA from the end of DPC (last assessment) to the last available measurement (OLE week 12).

[0227] This study will examine change in PROs from end of DPC (last assessment) to last available measurement (through OLE Week 12): -CS-TSQ -FACT-CSI

[0228] The study will examine PFS, defined as the time from the start of OOC to the assessment date of objective tumor progression (>20% growth for measurable disease at baseline or measurable disease for non-measurable disease at baseline) or death from any cause.

[0229] This study will examine objective tumor control rates (complete response, partial response, or stable disease.

[0230] This study examines change in subjects who respond to OOC during the DPC from the end of the DPC (last 2 weeks of IP during the DPC) to the end (last 2 weeks) of each year of the OLE (e.g., before OLE week 48 of the first OLE year, before OLE week 96 of the second year) in the following: -Average BM / day -Average FE / day

[0231] This study will examine change in subjects who respond to OOC during the DPC from the end of the DPC (last assessment) to the end of each year of the OLE (last assessment on treatment) (e.g., before OLE week 48 of the first OLE year, before OLE week 96 of the second year) in the following: - Urinary and plasma 5-HIAA -PRO (CS-TSQ and FACT-CSI).

[0232] Efficacy evaluation

[0233] Clinical evaluation of CS symptoms

[0234] A self-administered daily eDiary will be used to collect data on BM and FE, as well as on the use of antidiarrheal or anticonvulsant medications and / or Sandostatin SC (prohibited during DPC) during the DPC and OLE at specific time points.

[0235] Patient-reported outcomes (PROs)

[0236] Carcinoid Syndrome-Treatment Satisfaction Questionnaire (CS-TSQ)

[0237] The Treatment Satisfaction Questionnaire for adult subjects with CS symptoms is intended to be used in the study and completed by subjects (i.e., PRO). This is a modified version of the Acromegaly (ACRO)-TSQ, developed by Chiasma (acquired by Amryt) following best practices for PRO development and validated in 79 Acromegaly patients.

[0238] The CS-TSQ focuses on the following aspects: Symptoms of CS Injection site reactions Difficulty in administering treatment Convenience of treatment emotional impact Treatment satisfaction

[0239] patient perception questionnaire

[0240] The Patient Perception Questionnaire (PPQ), which is meaningful to patients to assess subject perception of observed changes in BM frequency and changes in severity / frequency of FE, will be utilized as an anchor-based analysis. At the Week 16 / ET visit, subjects will be asked to complete the Patient Perception Questionnaire to address their perception of changes in BM and FE (before enrollment in the study) during IP compared to SRL injection (three separate questions) ("much better", "a little better", "same", "a little worse", "much worse"), and their overall satisfaction with IP compared to SRL injection in controlling for BM and FE (two additional questions) ("very satisfied", "satisfied", "neither satisfied nor dissatisfied", "dissatisfied", "very dissatisfied").

[0241] Functional Assessment of Cancer Therapy-Carcinoid Syndrome Symptom Index (FACT-CSI)

[0242] The FACT-CSI assesses the presence of symptoms such as diarrhea and associated functional limitations (i.e., embarrassment, urgency, activity limitations, and fear of being far from a toilet) (Shaunfield, 2020). The questionnaire includes 20 items. Each item is graded on a 0-4 point scale.

[0243] Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and Radiographic Imaging

[0244] Progression-free survival and objective tumor response rates will be assessed using RECIST v1.1 (Eisenhauer, 2009).

[0245] Radiological imaging (CT or MRI) will be collected for evaluation by BICR at the time points specified in the SoA (Section 1.3.1-DPC and Section 1.3.2-OLE). During the OLE, radiological imaging (CT or MRI) will be performed every 3 months.

[0246] Safety assessment

[0247] Safety will be assessed throughout with AE monitoring and other safety assessments.

[0248] Open-label extension study

[0249] Eligibility criteria for open-label extension 1. Subjects who complete the entire DPC per protocol or meet a TFC during the DPC, or who discontinue IP due to treatment failure (without meeting a TFC) and are determined by the Sponsor's Medical Monitor (or designee) to be eligible for early rollover to OLE. Such decision will be based on eDiary information, the clinical narrative provided by the Investigator, and the Sponsor's Medical Monitor's (or designee's) determination that the described symptomatic deterioration is related to CS and is clinically meaningful. 2. For subjects who complete the entire DPC, carcinoid tumors and CS symptoms are adequately controlled as determined by the investigator. 3. No tumor progression based on radiological imaging at the end of DPC (imaging within the last month prior to week 16 DPC is acceptable). 4. For IP-related TEAEs, IP will not be withheld. 5. For subjects who discontinue IP during the DPC due to grade 3 diarrhea, need for hospitalization, or grade 4 diarrhea, resolution of these TEAEs is required. 6. No clinically significant or unstable medical or surgical condition is detected or worsened during the study that would prevent safe participation and completion of the OLE. 7. The OOC is not commercially available for the treatment of CS in the applicable region or country. 8.Are willing and able to comply with the requirements of the protocol during the OLE period. 9. Agree to continue treatment with OOC and are able to understand and sign additional written informed consent prior to entering OLE

[0250] Planned sample size

[0251] A total of up to 100 people are planned to be included.

[0252] treatment

[0253] Beginning at the OLE enrollment visit (equal to the last DPC visit), all subjects will receive OOC 60 mg BID until they meet the TFC for the OLE, the last subject enrolled in the OLE completes 96 weeks, or until IP marketing for this indication or end of study.

[0254] Use of Sandostatin SC or telotristat, or any other systemic treatment for NET or CS, is not permitted during the OLE. Stable use of antidiarrheal and anticonvulsant medications (compared to doses and days used in the last 4 weeks prior to randomization) is permitted during the OLE period and should be reported in the eDiary. Supplemental treatment for CS symptomatic exacerbations is permitted as described above.

[0255] During the first 12 weeks of the OLE, daily eDiaries of BM and FE, and antidiarrheal medication and / or Sandostatin SC use will be collected. After OLE week 12, eDiaries will be collected only 2 weeks before each clinic visit. PROs will be assessed (CS-TSQ and FACT-CSI) at OLE weeks 12, 48, and 96. Radiographic imaging (CT / MRI) will be performed every 3 months and radiological scans will be assessed by BICR.

Claims

1. A pharmaceutical composition for treating episodes of diarrhea and flushing associated with carcinoid tumors in a patient in need thereof, comprising at least about 120 mg of oral octreotide or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1, wherein oral octreotide is administered for long-term maintenance treatment of episodes of diarrhea and flushing associated with carcinoid tumors.

3. The pharmaceutical composition of claim 1, wherein the carcinoid tumor is a metastatic carcinoid tumor.

4. The pharmaceutical composition of claim 1, wherein the oral octreotide is administered for at least about 2 weeks, 4 weeks, 12 weeks, 16 weeks, 20 weeks, 26 weeks, 40 weeks, 1 year, or 2 years.

5. 10. The pharmaceutical composition of claim 1 for administering about 120 mg of oral octreotide per day.

6. 6. The pharmaceutical composition of claim 5, determining the patient's daily frequency of bowel movements (BM) after administration of 120 mg of oral octreotide per day; (a) the patient experiences an increase in daily frequency of BMs by at least 2 BMs compared to the baseline before administration of the 120 mg oral octreotide; and (b) if the patient experiences ≧4 BM / day after administration of 120 mg oral octreotide; administering to said patient about 160 mg of oral octreotide per day.

7. 6. The pharmaceutical composition of claim 5, determining the daily frequency of flushing episodes (FE) in said patient after administration of 120 mg of oral octreotide per day; (a) the patient experiences an increase in the daily frequency of FEs by at least 1 FE per day compared to before administration of the 120 mg oral octreotide; or (b) if the patient experiences an increase in the severity of FE after administration of 120 mg oral octreotide; administering to said patient about 160 mg of oral octreotide per day.

8. 6. The pharmaceutical composition of claim 5, determining signs / symptoms of carcinoid syndrome in said patient after administration of 120 mg of oral octreotide per day; administering to said patient about 160 mg of oral octreotide per day if said patient experiences new or worsening signs / symptoms of carcinoid syndrome.

9. The pharmaceutical composition of any one of claims 6 to 8, wherein 160 mg of oral octreotide is administered per day for about 4 to about 7 days.

10. The pharmaceutical composition according to any one of claims 6 to 8, determining signs / symptoms of carcinoid syndrome in said patient after said administration of 160 mg of oral octreotide per day; If the patient's biochemical and / or symptomatic response is controlled, administering to the patient about 120 mg of oral octreotide per day.

11. The pharmaceutical composition of claim 1, wherein oral octreotide is administered twice daily.

12. The pharmaceutical composition of claim 1, wherein the oral octreotide is administered in a capsule.

13. 13. The pharmaceutical composition of claim 12, wherein each capsule contains 20 mg of oral octreotide.

14. 10. The pharmaceutical composition of claim 1, wherein the administration of the oral octreotide or a pharmaceutically acceptable salt thereof is at least 1 hour before a meal or at least 2 hours after a meal.

15. The pharmaceutical composition of claim 1, wherein the oral octreotide is administered in a capsule containing an oily suspension.

16. 16. The pharmaceutical composition of claim 15, wherein the oil suspension comprises an admixture of a hydrophobic medium and a solid form, the solid form comprising oral octreotide and at least one salt of a medium chain fatty acid.

17. The pharmaceutical composition according to any one of claims 12 to 16, wherein the capsule is enterically coated.

18. A pharmaceutical composition for treating carcinoid syndrome in a patient in need thereof, comprising at least about 120 mg of oral octreotide or a pharmaceutically acceptable salt thereof.

19. 19. The pharmaceutical composition of claim 18 for administering about 120 mg of oral octreotide per day.

20. 20. The pharmaceutical composition of claim 19, determining the patient's daily frequency of bowel movements (BM) after administration of 120 mg of oral octreotide per day; (a) the patient experiences an increase in daily frequency of BMs by at least 2 BMs compared to the baseline before administration of the 120 mg oral octreotide; and (b) if the patient experiences ≧4 BM / day after administration of 120 mg oral octreotide; administering to said patient about 160 mg of oral octreotide per day.

21. 20. The pharmaceutical composition of claim 19, determining the daily frequency of flushing episodes (FE) in said patient after administration of 120 mg of oral octreotide per day; (a) the patient experiences an increase in the daily frequency of FEs by at least 1 FE per day compared to before administration of the 120 mg oral octreotide; or (b) if the patient experiences an increase in the severity of FE after administration of 120 mg oral octreotide; administering to said patient about 160 mg of oral octreotide per day.

22. 20. The pharmaceutical composition of claim 19, determining signs / symptoms of carcinoid syndrome in said patient after administration of 120 mg of oral octreotide per day; If the patient experiences new or worsening signs / symptoms of carcinoid syndrome, administering to said patient about 160 mg of oral octreotide per day.

23. The pharmaceutical composition of any one of claims 18 to 22, wherein the oral octreotide is administered in a capsule.

24. The pharmaceutical composition of any one of claims 18 to 22, wherein the oral octreotide is administered in a capsule containing an oily suspension.

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