Fractionated dosing of phospholipid ether analog for treatment of cancer

Abstract

To provide a fractionated dosing regimen of 131I-labeled 18-(p-iodo-phenyl)octadecyl phosphocholine for the treatment of cancer.SOLUTION: A fractionated dosing regimen of 131I-labeled 18-(p-iodo-phenyl)octadecyl phosphocholine for the treatment of cancer provides better tolerability than an equivalent single total dose administration and reduces the mean grade of adverse events, thereby contributing to site-specific eradication of malignant tumor tissue.SELECTED DRAWING: Figure 7

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 913,522, filed October 10, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to the use of radiolabeled phospholipid analogs in specific dosing cycles for the treatment of cancer. [Background technology]

[0003] Selective retention of radiolabeled phospholipid ether analogs in various model systems has been limited by problems associated with the relatively rapid clearance of radiopharmaceutical compounds and / or their accumulation in non-target tissues, which can reduce the effectiveness of radiopharmaceutical therapy, for example, by causing excessive exposure of radiosensitive tissues to the administered radioactivity.

[0004] There remains a significant need in the art for radiopharmaceuticals that exhibit rapid clearance from non-target tissues and extended half-lives in plasma while still retaining their specificity and avidity for neoplastic tissue. Such agents would serve as carriers of cytotoxic agents for the site-specific eradication of malignant tumor tissue.

[0005] Currently, there are few compounds that preferentially target cancer cells. One such compound is CLR1404. Generally, CLR1404 is a promising new tumor-selective imaging agent used to monitor the therapeutic response of several tumor treatment modalities. The following structure

[0006] [ka]

[0007] Radioiodinated CLR1404, a second-generation phospholipid ether ("PLE") analog having the formula (I), exhibits remarkable tumor selectivity in 55 / 60 xenografts, orthotopic and transgenic cancers, and cancer stem cell-derived animal models, making the core molecule an ideal platform for anticancer drug delivery vehicles. See U.S. Patent No. 8,535,641; U.S. Patent Application Publication No. 2014 / 0030187; and Weichert, JP et al., Alkylphosphocholine analogs for broad-spectrum cancer imaging and therapy, Sci Transl Med, 2014, Jun 11, 6(240), 240ra75; which are incorporated herein by reference in their entireties. Summary of the Invention

[0008] The present disclosure relates to a method for treating cancer in a subject, the method comprising administering an effective amount of 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof, 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof may be administered as a fractionated dose. 131 The I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof can be administered according to a single dosing cycle or multiple dosing cycles. 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof can be administered according to a single administration cycle, wherein the single administration cycle may comprise or consist of a first single administration administered on day 1; a second single administration administered on day 13, 14, 15, 16, 17, or 18; a third single administration administered on day 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65; and an optional fourth single administration administered after the third single administration. In some embodiments, a single administration cycle may include a first single dose administered once on day 1, a second single dose administered once on day 15 (14 days after day 1), a third single dose administered once on day 60 (59 days after day 1), and optionally a fourth single dose administered once on day 75 (74 days after day 1). 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof can be administered according to a first administration cycle comprising or consisting of a first single dose administered on day 1, and a second single dose administered on day 13, 14, 15, 16, 17, or 18; and a second administration cycle comprising or consisting of a third single dose administered on any day between days 55 and 190, and a fourth single dose administered after the third single dose. In some embodiments, the second single dose can be administered on day 15 (14 days after day 1), and the third single dose can be administered on any day between days 57 and 180 (56 to 179 days after day 1). In some embodiments, the third single dose can be administered on any day between days 70 and 180. In some embodiments, the fourth single dose is administered 7 to 14 days after the third single dose. In some embodiments, the subject can be a human. In some embodiments, 131 The I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof may be selective for cancer cells of a subject. 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or its salts have a concentration of 1 mCi / m2 (m 2 )~100mCi / m 2 In some embodiments, the dose may be 1 mCi to 100 mCi per kg of the subject's body weight. In some embodiments, the cancer may be multiple myeloma, lymphoma, neuroblastoma, sarcoma, leukemia, metastatic tumor, liver cancer, lung cancer, brain cancer, pancreatic cancer, melanoma cancer, adenocarcinoma, diffuse intrinsic pontine glioma (DIPG), childhood lymphoma, or breast cancer. In some embodiments, the cancer may be amenable to fractionated dose radiation. In some embodiments, the method may further include another cancer therapy selected from the group consisting of chemotherapy, immunotherapy, cell therapy, radiosensitization therapy, radioprotective therapy, external beam radiation, tumor resection, ablative therapy, and cold (cryo), heat (hyperthermia), radiofrequency, and microwave-based local modalities. In some embodiments, 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is administered as a first single dose on day 1, a second single dose on day 15 (14 days after day 1), a third single dose on day 60 (59 days after day 1), and optionally a fourth single dose on day 75 (74 days after day 1) at a dose of 1 mCi / m 2 (m 2 )~100mCi / m 2 In some embodiments, the dose range is 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is administered as a first single dose on day 1, a second single dose on day 15 (14 days after day 1), a third single dose on any day between days 57 and 180 (56 to 179 days after day 1), and optionally a fourth single dose after the third single dose at a dose of 1 mCi / m 2 (m 2 )~100mCi / m 2In some embodiments, the third single dose can be administered on any day between days 70 and 180. In some embodiments, the dose can be 1 mCi to 100 mCi per kg of the subject's body weight and can be administered as a first single dose on day 1, a second single dose on day 15 (14 days after day 1), a single dose on day 60 (59 days after day 1), and optionally a fourth single dose on day 75 (74 days after day 1). In some embodiments, the dose can be 1 mCi to 100 mCi per kg of the subject's body weight and can be administered as a first single dose on day 1, a second single dose on day 15 (14 days after day 1), a third single dose on any day between days 57 and 180 (56 to 179 days after day 1), and optionally a fourth single dose after the third single dose. In some embodiments, the third single dose can be administered on any day between days 70 and 180. [Brief explanation of the drawings]

[0009] [Figure 1] Figure 1 shows individual tumor volumes by dose group. Figure 1A shows tumor volume over time after treatment with vehicle alone (saline). Figure 1B shows tumor volume over time after treatment with a single dose of 50 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine. Figure 1C shows tumor volume over time after treatment with multiple doses of 50 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine (days 1 and 8). Figure 1D shows tumor volume over time after treatment with a single dose of 100 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine. Figure 1E shows tumor volume over time after treatment with multiple doses of bortezomib (days 1, 4, 8, and 11). [Figure 2]Figure 2 shows the mean tumor volume over time after treatment with vehicle alone, a single dose of 50 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine, multiple doses of 50 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine (days 1 and 8), a single dose of 100 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine, and multiple doses of bortezomib (days 1, 4, 8, and 11). [Figure 3] Figure 3 shows the survival rate of the OPM-2 mouse model after treatment with vehicle alone, a single dose of 50 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine, multiple doses of 50 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine (days 1 and 8), a single dose of 100 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine, and multiple doses of bortezomib (days 1, 4, 8, and 11). [Figure 4] Figure 4 shows the mean body weight changes in the OPM-2 mouse model from Figure 3 after treatment with vehicle alone, a single dose of 50 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine, multiple doses of 50 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine (days 1 and 8), a single dose of 100 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine, and multiple doses of bortezomib (days 1, 4, 8, and 11). [Figure 5] Figure 5 shows tumor doubling times after treatment with vehicle alone, a single dose of 50 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine, multiple doses of 50 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine (days 1 and 8), a single dose of 100 μCi of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine, and multiple doses of bortezomib (days 1, 4, 8, and 11). [Figure 6]FIG. 6 shows fractionated dosing of CLR 311 (.sup.131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine) in the OPM-2 model system. [Figure 7] Figure 7 shows a split dosing schedule in which there are two dosing cycles: Dose 1 is given on day 1, Dose 2 is given on day 15 (14 days after day 1), Dose 3 (as the start of the second cycle) can begin on any day between days 57 and 180 (56 and 179 days after day 1, respectively), and Dose 4 is optional and can begin on any day between days 71 and 194 (70 and 193 days after day 1, respectively), 14 days after Dose 3 is given. DETAILED DESCRIPTION OF THE INVENTION

[0010] Detailed Description of the Invention The present disclosure provides a dosing regimen for the administration of CLR1404 for the treatment of cancer. As described herein, split administration of CLR1404 is well tolerated and better tolerated than a single equivalent dose of CLR1404. Radioiodinated CLR1404, a second generation phospholipid ether ("PLE") analog, has the following structure:

[0011] [ka]

[0012] where I is a radiolabeled form of iodine (e.g., 122 I, 123 I, 124 I, 125 I, 131 I, etc. The present disclosure also provides methods for the treatment of cancer via a split-dose regimen of CLR1404. As described herein, CLR1404 is 131 It may also be CLR131, which is I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine.

[0013] 1. Definition As used herein, the terms "comprise(s)," "include(s)," "having," "has," "can," "contain(s)," and variations thereof are intended to be open-ended transitional phrases, terms, or words that do not exclude the possibility of additional acts or structures. The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments that "comprising," "consisting of," and "consisting essentially of" the embodiments or elements presented herein, whether explicitly stated or not.

[0014] For the recitation of numerical ranges herein, each intervening number is expressly contemplated to the same degree of precision. For example, in the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and in the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated.

[0015] As used herein, the term "about" or "approximately" refers to within an acceptable error range of a particular value as determined by one skilled in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more than 3 standard deviations, according to practice in the art. Alternatively, "about" can refer to a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can refer to within 10-fold (within an order of magnitude), preferably within 5-fold, and more preferably within 2-fold of a value.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.In the event of any discrepancy, the present document, including definitions, shall prevail.Although methods and materials similar or equivalent to those described herein can be used to implement or test this disclosure, preferred methods and materials are described below.All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.The materials, methods and examples disclosed herein are merely illustrative and are not intended to be limiting.

[0017] As used herein, the term "treating" includes prophylactic and palliative treatment of disorders, including reducing, suppressing, and inhibiting the progression or recurrence of cancer. As used herein, the terms "reducing," "suppress," and "inhibiting" have their commonly understood meanings of lessening or decreasing. As used herein, the term "progression" means increasing in extent or severity, advancing, growing, or worsening. As used herein, the terms "recurrence" and "recurrent" refer to the recurrence of disease after remission.

[0018] As used herein, the term "administering" refers to contacting a patient, tissue, organ, or cell with an anti-cancer compound of the present disclosure. As used herein, administration can be accomplished in vitro (i.e., in a test tube) or in vivo (i.e., in the cells or tissues of an organism, e.g., a human). In certain embodiments, the present disclosure encompasses administering a compound and / or composition described herein to a patient or subject. As used equivalently herein, a "patient" or a "subject" refers to a mammal, preferably a human, that is any of the following: (1) a patient receiving CLR1404 (e.g., CLR31( 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine (CLR131) or a salt thereof), or (2) a disorder that is remediable or treatable by administration of CLR1404 (e.g., CLR31( 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine (CLR131) or a salt thereof

[0019] As used herein, the term "effective amount" refers to an amount sufficient to affect a desired biological effect, such as a beneficial outcome, including, but not limited to, prevention, reduction, amelioration, or elimination of signs or symptoms of a disease or disorder. Thus, the total amount of each active ingredient of a pharmaceutical composition or method is sufficient to show a meaningful subject benefit. Thus, the "effective amount" depends on the context in which it is administered. An effective amount can be administered in one or more prophylactic or therapeutic administrations.

[0020] As used herein, the term "cancer" refers to any disease resulting from the uncontrolled division of cells that can metastasize.

[0021] The terms "malignant tumor cells" and "cancer cells" are used interchangeably throughout this specification. The terms "malignant tumor stem cells" and "cancer stem cells" are used interchangeably throughout this specification.

[0022] "Subject" and "patient," used interchangeably herein, refer to any vertebrate, including, but not limited to, mammals (e.g., cows, pigs, camels, llamas, horses, goats, rabbits, sheep, hamsters, guinea pigs, cats, dogs, rats, and mice, non-human primates (e.g., monkeys such as cynomolgous or rhesus monkeys, chimpanzees), and humans). In some embodiments, the subject may be human or non-human. The subject or patient may also be undergoing other therapies.

[0023] "Treate," "treating," or "treatment" are used interchangeably herein to describe reversing, alleviating, or inhibiting the progression of a disease or one or more symptoms of the disease to which such terms apply. Depending on the condition of the subject, the term also refers to preventing the disease, including preventing the onset of the disease or preventing symptoms associated with the disease. Treatment can be carried out in either an acute or chronic manner. The term also refers to reducing the severity of the disease or symptoms associated with the disease before the onset of the disease. Such prevention or reduction of the severity of the disease before onset refers to the administration of an antibody or pharmaceutical composition of the present disclosure to a subject who is not at the time of administration suffering from the disease. "Preventing" also refers to preventing the recurrence of the disease or one or more symptoms associated with the disease. "Treatment" and "therapeutically" refer to the act of treating, as "treating" is defined above.

[0024] The phrase "therapeutically effective amount" of a compound of the present disclosure refers to a sufficient amount of compound to treat a disorder at a reasonable benefit / risk ratio applicable to any medical treatment.However, it will be understood that the total daily usage amount of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for a particular patient will depend on various factors, including, for example, the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, overall health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; and the drugs used in combination with or simultaneously with the specific compound used.

[0025] The present disclosure includes the use of pharmaceutically acceptable salts of amino-substituted compounds with organic and inorganic acids, such as citric acid and hydrochloric acid. Suitable pharmaceutically acceptable salts include, but are not limited to, acid addition salts that can be formed, for example, by mixing a solution of an alkylphosphocholine analog with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. The present disclosure also includes N-oxides of the amino substituents of the compounds described herein. Pharmaceutically acceptable salts can also be prepared from phenolic compounds by treatment with inorganic bases, such as sodium hydroxide. Esters of phenolic compounds can also be made with aliphatic and aromatic carboxylic acids, such as acetate and benzoate esters. As used herein, the term "pharmaceutically acceptable salt" refers to a compound formulated from a base compound that achieves substantially the same pharmaceutical effect as the base compound.

[0026] The present disclosure further includes derivatives of anti-cancer compounds. The term "derivative" includes, but is not limited to, ether derivatives, acid derivatives, amide derivatives, ester derivatives, and the like. Additionally, the present disclosure further includes methods utilizing hydrates of anti-tumor compounds. The term "hydrate" includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.

[0027] The present disclosure further includes metabolites of anti-cancer compounds. The term "metabolite" means any substance produced from another substance by metabolism or a metabolic process.

[0028] 2. Compounds of the Present Disclosure An exemplary compound of the present disclosure is CLR1404, a radioiodinated phospholipid ether analog. 131The compound may be I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof. The selective tumor targeting of the disclosed compounds is based on differences in the plasma membrane of cancer cells compared to that of most normal cells. Specifically, cancer cell membranes are highly enriched in "lipid rafts." Cancer cells have five to ten times more lipid rafts than healthy cells. Lipid rafts are specialized regions of the membrane phospholipid bilayer that contain high concentrations of cholesterol and sphingolipids and serve to organize cell surface and intracellular signaling molecules (e.g., growth factor and cytokine receptors, phosphatidylinositol 3-kinase (PI3K) / Akt survival pathways). Data suggest that lipid rafts serve as gateways for PLEs. The remarkable selectivity of these compounds for cancer cells versus non-cancerous cells is due to the high affinity of PLEs for cholesterol and the abundance of cholesterol-rich lipid rafts in cancer cells. The crucial role played by lipid rafts is highlighted by the fact that disruption of lipid raft structure inhibits PLE uptake into cancer cells. Blocking lipid raft formation has been shown to reduce PLE uptake by 60%.

[0029] Results obtained in over 55 xenograft and autochthonous tumor models consistently demonstrate that the compounds described herein undergo selective uptake and long-term retention in tumors. Because the compounds undergo some metabolism in the liver, the inventors have avoided previous compound evaluation in liver tumor models due to high liver background radioactivity levels.

[0030] Results obtained in various tumor models suggest that CLR1404, e.g. 131 We demonstrate that I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine is sequestered and selectively retained by cancer cells and cancer stem cells. The compounds described herein have been shown to persist in cancer cells for up to 20 days. The compounds localize to both primary and metastatic lesions, regardless of anatomical location, including those found in lymph nodes.

[0031] 3. Compositions of the Present Disclosure In another aspect, the present disclosure provides a compound of the present disclosure (e.g., 131

[0003] The present invention provides a pharmaceutical composition comprising I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine in combination with one or more pharmaceutically acceptable carriers. In a preferred embodiment, the pharmaceutical composition does not contain Kolliphor® EL (Kolliphor is a registered trademark of BASF SE). Kolliphor® EL was formerly known as Cremophor® EL (Cremophor is a registered trademark of BASF SE).

[0032] Actual dosage levels of the active ingredients in the therapeutic compositions of the present disclosure can be varied to provide an amount of the active compound effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. The selected dosage level will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated.

[0033] The present disclosure also provides pharmaceutical compositions comprising the compounds of the present disclosure formulated together with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions can be specially formulated for oral administration, parenteral administration, or rectal administration in solid or liquid form.

[0034] Any administration route may be suitable for administering the compositions and compounds described herein to a subject. The compounds and compositions may be administered to a subject via intravenous injection. The disclosed compounds and compositions may be administered to a subject via any other suitable systemic delivery route, such as oral, parenteral, intranasal, sublingual, rectal, or transdermal. The disclosed compounds and compositions may be administered to a subject, such as humans and other mammals, orally, rectally, parenterally, intracisternally, intravaginally, transdermally (e.g., using a patch), transmucosally, sublingually, pulmonary, intraperitoneally, topically (by powder, ointment, or drops), bucally, or as an oral or nasal spray. As used herein, the term "parenteral" or "parenterally" refers to modes of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intraarticular injection and infusion.

[0035] In another aspect, the present disclosure provides a pharmaceutical composition comprising the components of the present disclosure and a physiologically acceptable diluent.The present disclosure includes one or more of the above-mentioned compounds formulated into a composition with one or more physiologically tolerable or acceptable diluents, carriers, adjuvants, or vehicles, collectively referred to herein as diluents, for parenteral injection, intranasal delivery, oral administration in solid or liquid form, rectal or topical administration, among others.

[0036] Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oils (olive oil, etc.), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.

[0037] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0038] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, metahydroxyaluminum, bentonite, agar-agar and tragacanth, or mixtures of these substances.

[0039] Injectable depot forms are made by forming microencapsule matrices of the compound or composition in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the properties of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0040] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

[0041] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and citric acid; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardants such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0042] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0043] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0044] The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0045] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain, for example, water or other solvents, solubilizers, and inert diluents commonly used in the art, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor oil, sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters such as sorbitan, and mixtures thereof.

[0046] Besides inert diluents, any oral composition can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0047] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at room temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

[0048] The compounds of the present disclosure can also be administered in the form of liposomes. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present composition in liposome form may contain stabilizers, preservatives, excipients, etc. in addition to the compounds of the present disclosure. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins), used separately or together. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed.; Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33. Such compositions will affect the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance.

[0049] In one method of the present disclosure, the pharmaceutical composition can be delivered in a controlled release system. For example, the compound or composition can be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump can be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, a polymeric material can be used. In yet another embodiment, the controlled release system can be placed near the therapeutic target, for example, the liver, thus requiring only a fraction of the systemic dose (see, for example, Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-P8 (1984)). Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).

[0050] In another aspect, the present disclosure relates to a method of treating a disease or condition in a subject, comprising administering to the subject an effective amount of a compound of the present disclosure.

[0051] In general, the present disclosure is not limited to the treatment of any particular disease or condition, but rather encompasses the treatment of any disease or condition whose mechanisms can be affected by the compounds of the present disclosure.

[0052] 4. Split Dosage In another aspect, the present disclosure provides a split-dose regimen for the use of CLR1404 in the treatment of cancer. 131The radiotherapy may be I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine (CLR131). As used herein, "fractionation" or "fractionation" of radiotherapy refers to dividing a total dose of radiotherapy into several smaller doses delivered over a period of time. The total dose may be divided, for example, to allow time for normal cells to recover, or to allow tumor cells that were in a relatively radiation-resistant stage of the cell cycle during one treatment to cycle to a sensitive stage before the next fractional dose is administered. Alternatively, hypoxic tumor cells may be allowed to reoxygenate between fractional doses, improving tumor cell killing. The sum of the individual fractional doses may approximate the total prescribed dose of radiotherapy.

[0053] Dosage is meter 2 (m 2 The dosage may be administered on a per 1000 mg / kg or per 1000 mg / kg basis. 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or its salts can be used at a concentration of, for example, 1 mCi / m 2 (m 2 )~100mCi / m 2 ;5mCi / meter 2 (m 2 )~90mCi / m 2 ;10mCi / meter 2 (m 2 )~80mCi / m 2 ;20mCi / meter 2 (m 2 )~70mCi / m 2 ;30mCi / meter 2 (m 2 )~60mCi / m 2 ; or 40mCi / meter 2 (m 2 )~50mCi / m 2 The dose can be administered in a dose range of, for example, 10 mCi / meter. 2 (m 2 ), 20mCi / meter 2 (m2 ), 30mCi / meter 2 (m 2 ), 40mCi / meter 2 (m 2 ), 50mCi / meter 2 (m 2 ), 60mCi / meter 2 (m 2 ), 70mCi / meter 2 (m 2 ), 80mCi / meter 2 (m 2 ), 90mCi / meter 2 (m 2 ), or 100mCi / meter 2 (m 2 ) may also be used.

[0054] 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof can be administered in a dosage range of, for example, 1 mCi to 100 mCi / kg; 5 mCi to 90 mCi / kg; 10 mCi to 80 mCi / kg; 20 mCi to 70 mCi / kg; 30 mCi to 60 mCi / kg; or 40 mCi to 50 mCi / kg. The dosage may be, for example, 10 mCi / kg, 20 mCi / kg, 30 mCi / kg, 40 mCi / kg, 50 mCi / kg, 60 mCi / kg, 70 mCi / kg, 80 mCi / kg, 90 mCi / kg, or 100 mCi / kg.

[0055] In one aspect, compound or composition is administered to a subject in need thereof as a divided dose in two or more fractions.In another embodiment, compound or composition is administered as a divided dose in hyperfractionation therapy.In another aspect, compound or composition is administered as a divided dose in accelerated fractionation therapy.

[0056] In certain embodiments, the methods and compositions of the present disclosure are useful for treating cancer. Delivery modalities / regimens include, for example, conventional fractionation, hyperfractionation, hypofractionation, and accelerated fractionation.

[0057] In one embodiment, the treatment regimen is hyperfractionated therapy. Hyperfractionation allows for higher tumor doses while maintaining a clinically acceptable level of long-term tissue damage. The daily dose remains the same or increases slightly, but the dose per fraction decreases, and the overall treatment time remains constant.

[0058] In one embodiment, the treatment regimen is accelerated fractionation, in which the dose per fraction remains the same, but the daily dose is increased and the total time of treatment is shortened.

[0059] In one embodiment, the treatment regimen is sequential hyperfractionated accelerated radiation therapy (CHART) therapy, an intensive treatment schedule in which multiple daily fractions are administered within a compressed period of time.

[0060] Fractionated doses of radiation therapy can be administered at intervals. In some embodiments, fractionated doses of radiation therapy can be administered at intervals of a single cycle. In certain embodiments, fractionated doses are administered over minutes, hours, or weeks, e.g., 1 to 26 weeks, e.g., about 1 to 15 weeks, e.g., 2 to 12 weeks. In certain embodiments, fractionated doses are administered over a period of less than about 15 weeks, e.g., less than about 14 weeks, e.g., less than about 13 weeks, e.g., less than about 12 weeks, e.g., less than about 11 weeks, e.g., less than about 10 weeks, e.g., less than about 9 weeks, e.g., less than about 8 weeks, e.g., less than about 7 weeks, e.g., less than about 6 weeks, e.g., less than about 5 weeks, e.g., less than about 4 weeks. In certain embodiments, the cumulative external radiation is a therapeutically effective amount of radiation to kill cells.

[0061] CLR1404 (for example, CLR131, 131Divided doses of I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine can be administered once as a single dose on day 1, again as a single dose on day 15 (14 days after day 1), again as a single dose on day 60 (59 days after day 1), and optionally again as a single dose on day 75 (74 days after day 1). CLR1404 (e.g., CLR131, 131 The divided doses of I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine may be a single administration cycle. A single administration cycle comprises or consists of a first single administration on day 1; a second single administration on day 13, 14, 15, 16, 17, or 18; and a third single administration on day 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65. The interval after day 1 during which the second single administration can be administered may be 12, 13, 14, 15, 16, or 17 days. In certain embodiments, the interval may be 14 days. The interval after day 1 during which the third single administration can be administered may be 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64 days. In certain embodiments, the interval may be 59 days. In some embodiments, the administration cycle further includes a fourth single dose administered on day 70, day 71, day 72, day 73, day 74, day 75, day 76, day 77, day 78, day 79, or day 80. The interval after day 1 allowing for the fourth single dose may be 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, or 79 days. In certain embodiments, the interval may be 74 days. A single administration cycle may include or consist of three single doses. A single administration cycle may include or consist of four single doses. The fourth single dose is optional. The fourth single dose may be administered depending on the patient's performance and / or the patient's response to previous doses.

[0062] The fractionated doses of radiation therapy described herein can be administered at intervals in separate administration cycles. In some embodiments, the fractionated doses of radiation therapy can be administered in two or more administration cycles. For example, the fractionated doses of radiation therapy described herein can be administered according to a first administration cycle and a second administration cycle. A dosing regimen having two administration cycles may include a delay between the two cycles necessitated by a subject's medical reasons (e.g., inability to administer the described treatment due to a health or safety condition). For example, the third administration in a single administration cycle can be delayed by about 10 to 120 days, and the third administration can be administered after the delay to initiate the second administration cycle.

[0063] The first administration cycle may comprise or consist of a first single dose administered on day 1 and a second single dose administered on day 13, 14, 15, 16, 17, or 18. The interval after day 1 during which the second single dose can be administered may be 12, 13, 14, 15, 16, or 17 days. In certain embodiments, the interval may be 14 days. The second administration cycle may comprise or consist of a third single dose administered on any day from 55 to 190. The intervals after day 1 during which a third single dose can be administered are: 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 1 26, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 2 The interval may be 9, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, or 189 days. In certain embodiments, the interval may be 56 days. In some embodiments, the second administration cycle further includes a fourth single administration. The fourth administration is optional and can begin after the third administration. The fourth administration can begin 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 days after the third administration. In some embodiments, the fourth single dose can be administered on any one of days 62 to 208, which is 7 to 18 days after the third dose is administered.In some embodiments, the fourth single dose can be administered on any one of days 70 to 208, which is 12 to 18 days after the third dose is administered. In some embodiments, the fourth single dose can be administered on any one of days 62 to 204, which is 7 to 14 days after the third dose is administered. The intervals after day 1 when the fourth single dose can be administered are 5, 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172 , 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, or 204 days. In certain embodiments, the interval may be 70 days. The first administration cycle may comprise or consist of two single doses (first and second single doses). The second administration cycle may comprise or consist of one single dose (third single dose). The second administration cycle may comprise or consist of two single doses (third and fourth single doses). A fourth single dose may be administered depending on the patient's performance and / or response to the previous dose. Abnormal laboratory findings (e.g., WBC < 3000 / μL; ANC < 1500 / μL; hemoglobin < 8 g / dL; estimated glomerular filtration rate < 30 mL / min / 1.73 m).2 The initiation of the third single dose or second treatment cycle may be delayed for medical reasons such as: urinary tract infection (ALT > 3 × ULN; bilirubin > 1.5 × ULN), fatigue, constipation, or skin ulcers.

[0064] In a dosing regimen having two dosing cycles, for example, CLR1404 (e.g., CLR311, 131 Divided doses of I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine may be administered once on day 1 as a first dose, and again on day 15 (14 days after day 1) as a second single dose, and again on day 57, 60, 90, 120, 150, or 180 (56, 69, 89, 119, 149, or 179 days after day 1, respectively) as a third single dose, and optionally again on day 71, 84, 104, 134, 164, or 194 (70, 83, 103, 133, 163, or 193 days after day 1, respectively) as a fourth single dose, if present, administered 14 days after the third single dose. CLR1404 (e.g., CLR131, 131 The first administration cycle may comprise split doses of I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine (e.g., CLR1404 (e.g., CLR131, I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine) administered as a single dose 56, 69, 89, 119, 149, or 179 days after day 1, and optionally again as a single dose 70, 83, 103, 133, 163, or 193 days after day 1. 131 A split dose of I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine may be administered in the second administration cycle.

[0065] a. Combination therapy Some chemotherapeutic agents, as described herein, may be used in conjunction with CLR1404-based radiation therapy, e.g., 131The effects of I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine-based therapy can be enhanced. In one aspect, aspects and embodiments of the present disclosure can be used as a combination therapy with existing chemotherapy modalities. The combination (sequential or simultaneous) therapy can be co-administered or co-formulated.

[0066] For example, in those embodiments in which the patient receives two or more forms of radiation therapy in addition to the CLR1404-based treatment, the patient can receive one or more additional forms of radiation therapy simultaneously, sequentially, in simultaneous fractions, or in sequential fractions, alternating fractions, and / or any combination thereof. In certain embodiments, intraoperative radiation therapy is administered before, during, and / or after surgery, and a second form of radiation therapy is administered at a later time, such as several hours after surgery, and / or several days after surgery, and / or several weeks after surgery. The intraoperative radiation and / or second form of radiation can be administered using a CLR-1404-based (e.g., 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof). In certain embodiments, the patient may receive radiation therapy, e.g., a CLR-1404-based therapy (e.g., 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or its salt).

[0067] CLR-1404 (e.g., CLR131, 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine)-based radiation therapy can be combined with one or more other therapies, where cancer shrinkage by CLR1404 therapy occurs simultaneously with, after, or prior to another treatment. For example, the other treatments may be radiation therapy, chemotherapy, tumor resection, ablative therapy, and / or localized physical therapy based on cold (cryo), heat (hyperthermia), radiofrequency, and microwaves. CLR1404-based radiation therapy can be used in combination with hyperthermia, i.e., the use of heat. In certain embodiments, the combination of heat and radiation can increase the response of some tumors.

[0068] CLR-1404 (e.g., CLR131, 131In combination with I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine)-based radiotherapy, the radiosensitizer can be administered in combination with an additional agent. For example, a nitroimidazole can be administered in combination with an additional agent, such as a targeting agent, a chemotherapeutic agent, or a second radiosensitizer. Targeting agents include any suitable agent for targeting cancer cells, such as an antibody. The nitroimidazole can be attached to the targeting agent via a covalent or non-covalent bond. For example, a nitroimidazole, such as 2-nitroimidazole, can be attached to the targeting agent via a linker, such as a biodegradable linker. Alternatively, the nitroimidazole can be attached to the targeting agent via ionic interactions. In certain embodiments, the radiosensitizer and additional agent of the present disclosure may be encapsulated in a liposome. These chemotherapeutic agents can be classified according to their mechanism of action, for example, into the following groups: Antimetabolites / anticancer drugs, including pyrimidine analogs (5-fluorouracil, floxuridine, capecitabine, gemcitabine, and cytarabine) and purine analogs, folate antagonists and related inhibitors (mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine (cladribine)); vinca alkaloids (vinblastine, vincristine, and vinorelbine), taxanes (paclitaxel, docetaxel), vincristine, vinblastine, nocodazole, epothilones, and navelbine, and natural products such as epidipodophyllotoxin (teniposide) Antiproliferative / antimitotic agents, DNA damaging agents (actinomycin, amsacrine, anthracyclines, bleomycin, busulfan, camptothecin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cytoxan, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, hexamethylmelamine, oxaliplatin, ifosfamide, melphalan, merchlorthamine, mitomycin, mitoxantrone, nitrosoureas, paclitaxel, plicamycin, procarbazine, teniposide, triethylenethiophosphoramide, and etoposide (VP16));Antibiotics such as dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), and mitomycin; enzymes (L-asparaginase, which metabolizes L-asparagine systemically and eliminates cells that do not have the ability to synthesize asparagine on their own); antiplatelet drugs; nitrogen mustards (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine and thiotepa), alkylsulfonates (busulfan), nitrosoureas (carmustine (BCNU) and analogs, streptozocin), trazene (da antiproliferative / antimitotic alkylating agents such as carbazinin (DTIC); antiproliferative / antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogens, tamoxifen, goserelin, bicalutamide, nilutamide), and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts, and other thrombin inhibitors); thrombolytic agents (such as tissue plasminogen activator, streptokinase, and urokinase), aspirin, COX-2 inhibitors, dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory agents agent); antisecretory agents (bleverudin); immunosuppressants (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); antiangiogenic compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor (VEGF) inhibitors, fibroblast growth factor (FGF) inhibitors, epidermal growth factor (EGF) inhibitors); angiotensin receptor blockers; nitric oxide donors; antisense oligonucleotides; antibodies (trastuzumab); cell cycle inhibitors and differentiation inducers (tretinoin);mTOR inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), amsacrine, camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan (CPT-11), and mitoxantrone, topotecan, and irinotecan), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, and prednisolone); growth factor signaling kinase inhibitors; mitochondrial dysfunction inducers and caspase activators; chromatin disrupting agents;

[0069] A radioprotector can be administered to a patient in combination with the methods described herein. Radioprotectors, also known as radioprotectants, are drugs that protect normal (non-cancerous) cells from damage caused by radiation therapy. These drugs promote the repair of normal cells exposed to radiation. An exemplary radioprotector includes amifostine.

[0070] In certain embodiments, the methods of the present disclosure further comprise administering bacteria, such as Salmonella or genetically engineered variants thereof. Studies have shown that combining radiation therapy with Salmonella enhances the effectiveness of tumor suppression, especially in the presence of inflammatory cells called neutrophils. Combining nitroimidazoles with bacteria, such as Salmonella, and CLR1404-based radiation therapy may enhance tumor suppression.

[0071] The radiosensitizers of the present disclosure can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, the compounds of the present disclosure and their physiologically acceptable salts and solvates can be formulated for administration, for example, by injection (e.g., subcutaneous, intramuscular, parenteral), inhalation or insufflation (through either the mouth or nose), or oral, buccal, buccal, sublingual, transdermal, nasal, parenteral, or rectal administration. In one embodiment, the compounds of the present disclosure can be administered locally to the site where tumor cells are present, i.e., to a specific tissue, organ, or body fluid (e.g., blood, cerebrospinal fluid, etc.). Typically, the compounds and compositions of the present disclosure are administered intravenously.

[0072] b. Cancer Cancers that can be treated with the compounds and compositions of the present disclosure can be any cancer. Cancers that can be treated with the compounds and compositions described herein include, but are not limited to, multiple myeloma, lymphoma, metastatic cancer, sarcoma, neuroblastoma, leukemia, breast cancer, including male breast cancer; adenocarcinoma, diffuse intrinsic pontine glioma (DIPG), childhood lymphoma, anal cancer, appendix cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumor, colon cancer, esophageal cancer, gallbladder cancer, gastric cancer, digestive / gastrointestinal cancer, including gastrointestinal stromal tumor ("GIST"), pancreatic islet cell tumor, adult primary liver cancer, pediatric liver cancer, pancreatic cancer, rectal cancer, small intestine cancer, and stomach (stomach) cancer. endocrine and neuroendocrine cancers, including pancreatic adenocarcinoma, adrenocortical carcinoma, pancreatic neuroendocrine tumor, Merkel cell carcinoma, non-small cell lung neuroendocrine tumor, small cell lung neuroendocrine tumor, parathyroid carcinoma, pheochromocytoma, pituitary tumor, and thyroid cancer; eye cancer, including intraocular melanoma and retinoblastoma; genitourinary cancers, including bladder cancer, kidney (renal cell) cancer, penile cancer, prostate cancer, renal pelvis transitional cell carcinoma and ureteral cancer, testicular cancer, urethral cancer, and Wilms' tumor; germ cell cancers, including pediatric central nervous system cancer, pediatric extracranial germ cell tumor, extragonadal germ cell tumor, ovarian germ cell tumor, and testicular cancer; gynecological cancers, including cervical cancer, endometrial cancer, gestational trophoblastic tumor, epithelial ovarian cancer, ovarian germ cell tumor, uterine sarcoma, vaginal cancer, and vulvar cancer; hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, and metastatic squamous neck cancer with unknown primary gynecological cancers, including oral cavity cancer, nasopharyngeal cancer, oropharynx cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, pharyngeal cancer, salivary gland cancer, and throat cancer; leukemias, including adult acute lymphoblastic leukemia, childhood acute lymphoblastic leukemia, adult acute myeloid leukemia, childhood acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia;Lymphomas, including AIDS-related lymphoma, cutaneous T-cell lymphoma, adult Hodgkin lymphoma, childhood Hodgkin lymphoma, Hodgkin lymphoma during pregnancy, mycosis fungoides, adult non-Hodgkin lymphoma, childhood non-Hodgkin lymphoma, non-Hodgkin lymphoma during pregnancy, primary central nervous system lymphoma, Sezary syndrome, and Waldenstrom's macroglobulinemia; musculoskeletal cancers, including Ewing's sarcoma, osteosarcoma and malignant fibrous histiocytoma of bone, childhood rhabdomyosarcoma and soft tissue sarcoma; neurological cancers, including adult brain tumors, childhood brain tumors, astrocytoma, brain stem glioma, atypical teratoid / rhabdoid tumor, central nervous system embryonal tumor, craniopharyngioma, ependymoma, neuroblastoma, and primary central nervous system (CNS) lymphoma cancer); respiratory / thoracic cancers, including non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, thymoma, and thymic carcinoma; and skin cancers, including Kaposi's sarcoma, melanoma, and squamous cell carcinoma. Multiple myeloma (MM) is a type of cancer that arises in circulating blood cells (i.e., plasma B cells) rather than solid tissue. It is a universally fatal disease, accounting for 15% of hematologic malignancies and 1% of all cancers. The median survival from diagnosis is 5-7 years. Although newer drugs, such as bortezomib and lenalidomide, have shown increased response to treatment, patients inevitably relapse and become resistant to treatment. [Example]

[0073] 5. Working Example The foregoing can be better understood by reference to the following examples, which are presented for illustrative purposes and are not intended to limit the scope of the present disclosure. The present disclosure has multiple aspects, which are illustrated by the following non-limiting examples.

[0074] Example 1 OPM-2 cell line (human multiple myeloma) was purchased from the American Type Culture Collection (ATCC, Rockville, MD) and maintained in McCoy's 5a medium supplemented with 10% fetal bovine serum. Approximately 5-7 week-old female CB17 SCID mice were inoculated with 1 × 10 cells. 7Viable cells (in ~100 μL of Dulbecco's PBS) were injected subcutaneously into the right flank. Tumor size was adjusted to a predetermined size (approximately 150–200 mm). 3 The study began when tumor volume reached 100%. Mice were administered potassium iodide at a concentration of 0.1% in their drinking water 3 days before injection to eliminate the possibility of free iodide in the formulation and continued for up to 2 weeks after injection. Mice were randomly assigned to dose groups. Tumor volumes were measured with calipers over the course of the study. Tumor doubling time was calculated as follows: TDT = D × log(2) / log(1 + r / 100), where D is the number of days between measurements and R = growth rate; r / 100 = (V2 - V1 / V1) × 100%. Statistical analysis: One-way ANOVA, Dunnett's test.

[0075] [Table 1]

[0076] Example 2 Repeated / fractionated dosing of CLR 311 was well tolerated and better tolerated than a single equivalent dose. All doses of CLR 131 demonstrated significant antitumor activity in this model of multiple myeloma. Single-dose infusion results in similar inhibition of MM as bortezomib. Fractionated dosing results in a statistically significant reduction in tumor volume compared to controls from day 26 onwards. Fractionated dosing results in a statistically significant reduction in tumor volume compared to all other treatments at day 52 (p<0.05). Tumor doubling time was significantly increased with fractionated dosing compared to all other treatments. Fractionated dosing resulted in a statistically significant survival benefit.

[0077] Example 3 As shown in Table 2, the split-dose regimen (Cohort 5) delivered 18% more drug to patients than the single-bolus regimen (Cohort 4), as measured by the actual dose of millicuries delivered to them. However, even though more drug was delivered to patients, the mean grade of adverse events decreased, and the median grade remained the same. Furthermore, efficacy assessments also showed improvements between the single-bolus and split-dose regimens. Median overall survival increased from 6.5 months (bolus) to 7.4 months (split-dose), and evaluation of median overall survival in the split-dose group is still ongoing. Mean progression-free survival increased from 2.8 months to 2.9 months, respectively. Again, evaluation of progression-free survival is ongoing. The mean decline in surrogate markers of efficacy was greater between the cohorts of patients receiving the single-bolus regimen, with a mean decline of 40% in patients receiving the split-dose regimen versus a mean decline of 29% in surrogate markers.

[0078] Dosage is given in millicuries per square meter (mCi / m 2 ) based on body surface area or BSA. Patients received a 31.25 mCi / m on Day 1. 2 or 15.625 mCi / m on day 1. 2 were administered in 30-minute divided infusion doses of 100 mg / kg of ethanol, which was then repeated on the 8th day.

[0079] [Table 2]

[0080] The foregoing description of specific embodiments fully discloses the general nature of the present disclosure so that others, by applying knowledge within the skill of those skilled in the art, may readily modify and / or adapt the specific embodiments, etc., for various uses without undue experimentation, without departing from the general concepts of the present disclosure. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology used herein is for the purpose of description, not limitation, and as such, the terminology or terminology used herein will be interpreted by one of ordinary skill in the art in light of the teaching and guidance.

[0081] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0082] All publications, patents, patent applications, and / or other documents cited in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, and / or other document was individually indicated to be incorporated by reference for all purposes.

[0083] For reasons of completeness, various aspects of the disclosure are set out in the following numbered sections:

[0084] Section 1. A method for treating cancer in a subject, comprising the steps of: a) administering, in fractionated doses, an effective amount of 131 1. A step of administering I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof.

[0085] Section 2. 13110. The method of claim 1, wherein the I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is administered according to a single dosing cycle, wherein the single dosing cycle comprises or consists of: a first single dose administered on day 1; a second single dose administered on day 13, 14, 15, 16, 17, or 18; a third single dose administered on day 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65; and an optional fourth single dose administered after the third single dose.

[0086] Section 3. The method of clause 2, wherein the single administration cycle comprises a first single dose administered once on day 1, a second single dose administered once on day 15 (14 days after day 1), a third single dose administered once on day 60 (59 days after day 1), and optionally a fourth single dose administered once on day 75 (74 days after day 1).

[0087] Section 4. 131 The method of clause 1, wherein the I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is administered according to the following: a first administration cycle comprising, or consisting of, a first single dose administered on day 1, and a second single dose administered on day 13, 14, 15, 16, 17, or 18; and a second administration cycle comprising, or consisting of, a third single dose administered on any day between days 55 and 190, and a fourth single dose administered after the third single dose.

[0088] Clause 5. The method of clause 4, wherein the second single dose is administered on day 15 (14 days after day 1) and the third single dose is administered on any day between days 57 and 180 (56 and 179 days after day 1).

[0089] Clause 6. The method of clause 5, wherein the third single dose is administered on any day between days 70 and 180.

[0090] Clause 7. The method of any one of clauses 4-6, wherein the fourth single dose is administered 7 to 14 days after the third single dose.

[0091] Clause 8. The method of any one of clauses 1-7, wherein the subject is a human.

[0092] Section 9. 131 9. The method according to any one of clauses 1 to 8, wherein the I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is selective for cancer cells of the subject.

[0093] Section 10. 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or its salts have a concentration of 1 mCi / m 2 (m 2 )~100mCi / m 2 10. The method of any one of clauses 1 to 9, wherein the compound is administered in a dose range of

[0094] Clause 11. The method of any one of clauses 1-9, wherein the dose is between 1 mCi and 100 mCi per kg of subject body weight.

[0095] Clause 12. The method of any one of clauses 1-11, wherein the cancer is multiple myeloma, lymphoma, neuroblastoma, sarcoma, leukemia, metastatic tumor, liver cancer, lung cancer, brain cancer, pancreatic cancer, melanoma cancer, adenocarcinoma, diffuse intrinsic pontine glioma (DIPG), childhood lymphoma, or breast cancer.

[0096] Clause 13. The method of any one of clauses 1-12, wherein the cancer is amenable to fractionated dose radiation.

[0097] Clause 14. The method of any one of clauses 1-13, further comprising another cancer therapy selected from the group consisting of chemotherapy, immunotherapy, cell therapy, radiosensitization therapy, radioprotective therapy, external beam radiation, tumor resection, ablative therapy, and cold (cryo), heat (hyperthermia), radiofrequency, and microwave based local modalities.

[0098] Section 15. 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is administered as a first single dose on day 1, a second single dose on day 15 (14 days after day 1), a third single dose on day 60 (59 days after day 1), and optionally a fourth single dose on day 75 (74 days after day 1) at a dose of 1 mCi / m 2 (m 2 )~100mCi / m 2 11. The method of clause 10, wherein the patient is administered in a dose range of

[0099] Section 16. 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is administered as a first single dose on day 1, a second single dose on day 15 (14 days after day 1), a third single dose on any day between days 57 and 180 (56 to 179 days after day 1), and optionally a fourth single dose after the third single dose at a dose of 1 mCi / m 2 (m 2 )~100mCi / m 2 11. The method of clause 10, wherein the patient is administered in a dose range of

[0100] Clause 17. The method of clause 16, wherein the third single dose is administered on any day between days 70 and 180.

[0101] Clause 18. The method of clause 11, wherein the dose is 1 mCi to 100 mCi per kg of subject body weight and is administered as a first single dose on day 1, and a second single dose on day 15 (14 days after day 1), and a single dose on day 60 (59 days after day 1), and optionally a fourth single dose on day 75 (74 days after day 1).

[0102] Clause 19. The method of clause 11, wherein the dose is 1 mCi to 100 mCi per kg of subject body weight and is administered on day 1 as a first single dose, and on day 15 (14 days after day 1) as a second single dose, and on any day between day 57 and day 180 (56 and 179 days after day 1) as a third single dose, and optionally after the third single dose as a fourth single dose.

[0103] Clause 20. The method of clause 19, wherein the third single dose is administered on any day between days 70 and 180.

Claims

1. A method for treating cancer in a subject, comprising the steps of: a) an effective amount of 131 administering I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof.

2. The aforementioned 131 10. The method of claim 1, wherein the I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is administered according to a single dosing cycle, wherein the single dosing cycle comprises or consists of: a first single dose administered on day 1; a second single dose administered on day 13, 14, 15, 16, 17, or 18; a third single dose administered on day 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65; and An optional fourth single dose administered after the third single dose.

3. 3. The method of claim 2, wherein the single administration cycle comprises a first single dose administered once on day 1, a second single dose administered once on day 15 (14 days after day 1), a third single dose administered once on day 60 (59 days after day 1), and optionally a fourth single dose administered once on day 75 (74 days after day 1).

4. The aforementioned 131 2. The method of claim 1, wherein the I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is administered according to the following: a first administration cycle comprising or consisting of a first single dose administered on day 1 and a second single dose administered on day 13, 14, 15, 16, 17, or 18; and A second administration cycle comprising or consisting of a third single dose administered on any day between days 55 and 190, and a fourth single dose administered after the third single dose.

5. 5. The method of claim 4, wherein the second single dose is administered on day 15 (14 days after day 1) and the third single dose is administered on any day between days 57 and 180 (56 to 179 days after day 1).

6. 6. The method of claim 5, wherein the third single dose is administered on any day between days 70 and 180.

7. 7. The method of any one of claims 4 to 6, wherein the fourth single dose is administered 7 to 14 days after the third single dose.

8. The method of any one of claims 1 to 7, wherein the subject is a human.

9. The aforementioned 131 The method according to any one of claims 1 to 8, wherein the I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is selective for cancer cells of the subject.

10. The aforementioned 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or its salts have a concentration of 1 mCi / m 2 (m 2 )~100mCi / m 2 The method of any one of claims 1 to 9, wherein the dose range is 0.05 to 0.

15.

11. 10. The method of any one of claims 1 to 9, wherein the dose is between 1 mCi / kg and 100 mCi / kg of the subject's body weight.

12. The method of any one of claims 1 to 11, wherein the cancer is multiple myeloma, lymphoma, neuroblastoma, sarcoma, leukemia, metastatic tumor, liver cancer, lung cancer, brain cancer, pancreatic cancer, melanoma cancer, adenocarcinoma, diffuse intrinsic pontine glioma (DIPG), childhood lymphoma, or breast cancer.

13. The method of any one of claims 1 to 12, wherein the cancer is suitable for fractionated dose radiation.

14. 14. The method of any one of claims 1 to 13, further comprising another cancer therapy selected from the group consisting of chemotherapy, immunotherapy, cell therapy, radiosensitization therapy, radioprotective therapy, external beam radiation, tumor resection, ablative therapy, and cold (cryo), heat (hyperthermia), radiofrequency, and microwave-based local modalities.

15. The aforementioned 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is administered at a dose of 1 mCi / m as the first single dose on day 1, the second single dose on day 15 (14 days after day 1), the third single dose on day 60 (59 days after day 1), and optionally the fourth single dose on day 75 (74 days after day 1). 2 (m 2 )~100mCi / m 2 11. The method of claim 10, wherein the dose range is

16. The aforementioned 131 I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is administered as the first single dose on day 1, as the second single dose on day 15 (14 days after day 1), as the third single dose on any one of days 57 to 180 (56 to 179 days after day 1), and optionally as the fourth single dose after the third single dose at a dose of 1 mCi / m 2 (m 2 )~100mCi / m 2 11. The method of claim 10, wherein the dose range is

17. 17. The method of claim 16, wherein the third single dose is administered on any day between days 70 and 180.

18. 12. The method of claim 11, wherein the dose is 1 mCi to 100 mCi per kg of body weight of the subject and is administered on day 1 as the first single dose, and on day 15 (14 days after day 1) as the second single dose, and on day 60 (59 days after day 1) as the single dose, and optionally on day 75 (74 days after day 1) as the fourth single dose.

19. 12. The method of claim 11, wherein the dose is 1 mCi to 100 mCi per kg of body weight of the subject and is administered on day 1 as the first single dose, and on day 15 (14 days after day 1) as the second single dose, and on any day between days 57 and 180 (56 to 179 days after day 1) as the third single dose, and optionally after the third single dose as the fourth single dose.

20. 20. The method of claim 19, wherein the third single dose is administered on any day between days 70 and 180.

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