WO2015061481A1 - Méthodes de traitement de tumeurs liquides à l'aide de compositions comprenant des dérivés de spicamycine - Google Patents
Méthodes de traitement de tumeurs liquides à l'aide de compositions comprenant des dérivés de spicamycine Download PDFInfo
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- WO2015061481A1 WO2015061481A1 PCT/US2014/061809 US2014061809W WO2015061481A1 WO 2015061481 A1 WO2015061481 A1 WO 2015061481A1 US 2014061809 W US2014061809 W US 2014061809W WO 2015061481 A1 WO2015061481 A1 WO 2015061481A1
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- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- the present invention relates to methods of treating liquid tumors using compositions of spicamycin derivatives.
- Spicamycin is an anti-tumor antibiotic produced by the bacterium Streptomyces alansinicus 879-MT 3 (Hayakawa et al. Agric. Biol. C7zem.49:2685 (1985)).
- the naturally occurring compound has the following general structure of Formula I, varying solely in the fatty acid moiety.
- spicamycin derivatives as anti-tumor agents against solid tumors has been previously described in U.S. Patent Nos. 5,461,036 and 5,631,238 to Otake et al.
- One such spicamycin derivative is 6-[4-deoxy-4-[(2E,4E)- tetradecadienoylglycyl] amino-L-glycero-P-L-manno heptopyranosyl] amino-9H-purine (KRN5500).
- Liquid tumors occur in the blood, bone marrow, and/or lymph nodes, and can include forms of leukemia, lymphoma, and myeloma.
- Leukemia is a cancer of the bone marrow and blood that can present as acute or chronic. Leukemia can include forms such as lymphocytic leukemia and myeloid leukemia.
- Lymphoma is a blood cancer that originates in the immune system, affecting tissue in the lymph nodes, spleen, liver, bone marrow, and other sites. Lymphomas begin as liquid tumors but can form solid tumors, and can include forms such as Hodgkin lymphoma and non-Hodgkin's lymphoma.
- Myeloma is a cancer of the plasma cells, which rapidly grow and form tumors called plasmacytomas in the bone marrow and bone structure. Isolated plasmacytoma is a condition where only one tumor is present. Multiple myeloma refers to the presence of more than one plasmacytoma in a subject.
- KRN5500 has also been evaluated in clinical trials for the treatment of neuropathic pain in cancer patients.
- the known formulations have serious drawbacks because they require the use of certain excipients to formulate KRN5500.
- excipients include mono-ethanolamine, which significantly improves the solubility and stability of lipophilic compounds such as KRN5500 when diluted into an aqueous solution.
- Mono- ethanolamine is also known to impact the apoptotic process by modulating the ethanolamine phosphoglyceride content of the phospholipid polar head groups that comprise a significant portion of the inner leaflet of cell membranes (Brand and Yavin, Journal ofNeurochemistry, 2001, Vol. 78, pages 1208-1218).
- the subject matter disclosed herein provides methods of treating a liquid tumor in a subject by administering a composition comprising a spicamycin derivative.
- the spicamycin derivative is formulated in combination with a first biocompatible organic solvent that solubilizes the spicamycin derivative, a second biocompatible organic solvent that is miscible with the first biocompatible organic solvent and solubilizes the spicamycin derivative, and a surfactant. It has been found that the compositions described herein are especially suited for use in the treatment of liquid tumors. The compositions utilized by the methods are not plagued by the shortcomings of previous formulations of spicamycin derivatives.
- compositions described herein provide enhanced solubility of the spicamycin derivative while reducing levels of undesirable excipients in the final preparations that may produce unwanted side effects or promote liquid tumor cell growth.
- the compositions utilized by the methods are also easier to manufacture, prepare, and administer to a subject than previous formulations of spicamycin derivatives.
- the invention provides a method of treating a liquid tumor in a patient by administering a composition comprising a spicamycin derivative of Formula II:
- Ri and R 2 are different from each other and represent H or OH, and R represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, or cycloalkyl, or a pharmaceutically acceptable salt, prodrug, or optical isomer thereof.
- the composition further comprises a first biocompatible organic solvent that solubilizes the spicamycin derivative, a second biocompatible organic solvent that is miscible with the first biocompatible organic solvent and solubilizes the spicamycin derivative, and a surfactant.
- compositions utilized by the methods are liquids substantially free of particulates and essentially free of mono-ethanolamine.
- the compositions can be in the form of an intravenous solution, further comprising an aqueous intravenous liquid or diluent.
- the compositions can be essentially free of ⁇ , ⁇ -dimethyl acetamide (DMAC).
- Figure 1 shows a manufacturing process flow chart for the production of compositions utilized by the methods, wherein the surfactant is Lutrol F68.
- Figure 2 shows a manufacturing process flow chart for the production of compositions utilized by the methods, wherein the surfactant is polysorbate 80.
- Figure 3A shows the anti-proliferative effect of cyclophosphamide on OPM-2, RPMI-8226, and H929 liquid tumor cells in vitro.
- Figure 3B shows the anti-proliferative effect of KRN5500 on OPM-2, RPMI-8226, and H929 liquid tumor cells in vitro.
- Figure 4 shows the effect of mono-ethanolamine (1 mM and 0.1 mM) on the anti- proliferative properties of KRN5500 in RPMI-8226 cells in vitro.
- a can mean one or more than one.
- a cell can mean a single cell or a multiplicity of cells.
- the term "about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ⁇ 20%, ⁇ 10%, ⁇ 5%, ⁇ 1%, ⁇ 0.5%), or even ⁇ 0.1% of the specified amount.
- compositions can contain additional components as long as the additional components do not materially alter the
- compositions utilized by the methods refers to an increase or decrease in the therapeutic effectiveness of the compositions of at least about 20% or more as compared to the effectiveness of a composition consisting of the recited components.
- treatment-effective amount refers to that amount of compositions utilized by the methods that impart a modulating effect, which, for example, can be a beneficial effect, to a subject afflicted with a disorder, disease or illness, including improvement in the condition of the subject (e.g., in one or more symptoms), delay or reduction in the progression of the condition, prevention or delay of the onset of the disorder, and/or change in clinical parameters, disease or illness, etc., as would be well known in the art.
- a treatment- effective amount or effective amount can refer to the amount of a composition, compound, or agent that improves a condition in a subject by at least 5%, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.
- Treat” or “treating” or “treatment” refers to any type of action that imparts a modulating effect, which, for example, can be a beneficial effect, to a subject afflicted with a disorder, disease or illness, including improvement in the condition of the subject (e.g. , in one or more symptoms), delay or reduction in the progression of the condition, and/or change in clinical parameters, disease or illness, etc., as would be well known in the art.
- “Pharmaceutically acceptable,” as used herein, means a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the compositions utilized by the methods, without causing substantial deleterious biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The material would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art (see, e.g., Remington's Pharmaceutical Science; 20 ed. 2005).
- Exemplary pharmaceutically acceptable carriers for the compositions utilized by the methods include, but are not limited to, sterile pyrogen-free water and sterile pyrogen-free physiological saline solution.
- prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood, see, e.g., T. Higuchi and V. Stella, Prodrugs as Novel delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated by reference herein. See also U.S. Pat. No. 6,680,299.
- Exemplary prodrugs include a prodrug that is metabolized in vivo by a subject to an active drug having an activity of the compounds as described herein, wherein the prodrug is an ester of an alcohol or carboxylic acid group, if such a group is present in the compound; an amide of an amine group or carboxylic acid group, if such groups are present in the compound; a urethane of an amine group, if such a group is present in the compound; an acetal or ketal of an alcohol group, if such a group is present in the compound; an N- Mannich base or an imine of an amine group, if such a group is present in the compound; or a Schiff base, oxime, acetal, enol ester, oxazolidine, or thiazolidine of a carbonyl group, if such a group is present in the compound, such as described, for example, in U.S. Patent No. 6,680,324 and U.S. Patent
- pharmaceutically acceptable prodrug refers to those prodrugs of the compounds utilized by the methods which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and/or other animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable risk/benefit ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds utilized by the methods.
- Concurrently means sufficiently close in time to produce a combined effect (that is, concurrently can be simultaneously, or it can be two or more events occurring within a short time period before or after each other).
- the administration of two or more compounds "concurrently” means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other.
- the two compounds can be administered in the same or different formulations or sequentially. Concurrent administration can be carried out by mixing the compounds prior to administration, or by administering the compounds in two different formulations, for example, at the same point in time but at different anatomic sites or using different routes of administration.
- alkyl denotes a straight or branched hydrocarbon chain containing 1- 24 carbon atoms, e.g., 1-12 carbon atoms.
- alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
- alkenyl denotes a straight or branched hydrocarbon chain containing 1-24 carbon atoms, e.g., 1-12 carbon atoms, and containing one or more double bonds, e.g., 1, 2, 3, or 4 double bonds.
- alkynyl denotes a straight or branched hydrocarbon chain containing 1-24 carbon atoms, e.g., 1-12 carbon atoms, and containing one or more triple bonds, e.g., 1, 2, 3, or 4 triple bonds.
- cycloalkyl refers to non-aromatic cyclic hydrocarbon moieties containing 3-24 carbon atoms, e.g., 3-12 carbon atoms.
- the cycloalkyl group can contain one or more double bonds. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- substituted alkyl an alkyl in which an atom of the alkyl is substituted with, for example, a carbon, nitrogen, sulfur, oxygen, silicon, or halogen atom, or alternatively a nitrogen, sulfur, oxygen, or halogen atom.
- the term encompasses substituents on alkyl, alkenyl, alkynyl, and cycloalkyl groups.
- substituted alkyl include cyclyl groups, heterocyclyl groups; aryl groups, heteroaryl groups, amino groups, amido groups, nitro groups, cyano groups, azide groups, hydroxy groups, alkoxy groups, acyloxy groups, thioalkoxy groups, acyl thioalkoxy groups, halogen groups, sulfonate groups, sulfonamide groups, ester groups, carboxylic acids, oxygen (e.g., a carbonyl group), and sulfur (e.g., a thiocarbonyl group).
- oxygen e.g., a carbonyl group
- sulfur e.g., a thiocarbonyl group
- Substituents also include any chemical functional group that imparts improved water-solubility to the molecule (e.g., carboxylic acid, carboxylic ester, carboxamido, morpholino, piperazinyl, imidazolyl, thiomorpholino, or tetrazolyl groups; both unsubstituted and substituted).
- any chemical functional group that imparts improved water-solubility to the molecule e.g., carboxylic acid, carboxylic ester, carboxamido, morpholino, piperazinyl, imidazolyl, thiomorpholino, or tetrazolyl groups; both unsubstituted and substituted.
- halo and halogen refer to any radical of fluorine, chlorine, bromine or iodine.
- ring and “ring system” refer to a ring comprising the delineated number of atoms, said atoms being carbon or, where indicated, a heteroatom such as nitrogen, oxygen or sulfur.
- the ring itself, as well as any substituents thereon, can be attached at any atom that allows a stable compound to be formed.
- aryl refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system wherein 0, 1, 2, or 3 atoms of each ring can be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl and the like.
- heteroaryl refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3
- heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring can be substituted by a substituent.
- heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like.
- heterocyclyl refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3
- heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring can be substituted by a substituent.
- heterocyclyl groups include piperizinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.
- Suitable substituents for aryl, heteroaryl, and heterocyclyl groups are the same as the substituents for alkyl groups.
- biocompatible refers to organic solvents that do not induce toxic or unwanted side effects when administered to a patient in certain amounts.
- miscible refers to the ability of a liquid to mix evenly into another liquid.
- the subject matter described herein is directed to methods of treating a liquid tumor in a subject by administering a composition comprising a spicamycin derivative of Formula II, a first biocompatible organic solvent that solubilizes the spicamycin derivative, a second biocompatible organic solvent that is miscible with the first biocompatible organic solvent and solubilizes the spicamycin derivative, and a surfactant.
- a composition comprising a spicamycin derivative of Formula II, a first biocompatible organic solvent that solubilizes the spicamycin derivative, a second biocompatible organic solvent that is miscible with the first biocompatible organic solvent and solubilizes the spicamycin derivative, and a surfactant.
- the spicamycin derivative can be a pharmaceutically acceptable salt, prodrug, or optical isomer thereof.
- the compositions utilized by the methods are liquids substantially free of particulates and, advantageously, essentially free of mono-ethanolamine. Such compositions should allow for increased solubility of the spicamycin derivative, be stable in both a concentrated solution and following dilution into an aqueous solution for administration, and be free of excipients that could promote tumor cell growth or induce unwanted side effects.
- the first biocompatible organic solvent is selected from the group consisting of ethanol, t-butanol, and other biocompatible alcohols.
- the first biocompatible organic solvent is ethanol, having a purity of at least about 96% (v/v).
- the first biocompatible organic solvent is preferably a pharmaceutical grade excipient that increases the solubility of the composition components and adjusts the physical properties (i.e. viscosity) of the composition to improve manufacturability.
- the first biocompatible organic solvent can be particularly capable of enhancing the solubility of the surfactant of the composition and the spicamycin derivative of the composition.
- the first biocompatible organic solvent can also be capable of enhancing the solubility of any additional excipients added to the composition.
- the second biocompatible organic solvent is selected from the group consisting of propylene glycol, glycerin, polyethylene glycol, and
- the second biocompatible organic solvent is propylene glycol.
- the second biocompatible organic solvent is preferably a pharmaceutical grade excipient that advantageously enhances the solubility of the spicamycin derivatives described herein when compared to aqueous or ethanol-only formulations.
- the second biocompatible organic solvent can also be capable of enhancing the solubility of any additional excipients added to the composition.
- a surfactant is included in the compositions to facilitate the solubility of the spicamycin derivative when a concentrated solution of the composition is diluted into an aqueous intravenous liquid or diluent (e.g., 5% dextrose, 0.9% sodium chloride, or Lactated Ringers solution).
- the surfactant is a pharmaceutical grade excipient selected from the group consisting of polysorbate, poloxmer (e.g.
- compositions comprising a spicamycin derivative can be prepared in combination with the first biocompatible organic solvent and the second
- biocompatible solvent above as clear, colorless solutions in the absence of a surfactant, some precipitation may be observed when diluted into an aqueous intravenous liquid or diluent.
- compositions utilized by the methods are particularly advantageous because they do not require the use of certain solvents. Formulations that contain certain organic solvents can potentially induce unwanted or untold side effects, or induce the growth of tumor cells during treatment. Additionally, a multi-step procedure to prepare a dosing solution in an intravenous liquid or diluent from a vial and ampoule is not required for the present compositions.
- the compositions utilized by the methods can be prepared for administration, wherein a concentrated solution can be withdrawn from a vial with a syringe and diluted and mixed into an aqueous intravenous liquid or diluent (e.g., 5% dextrose, 0.9% sodium chloride, Lactated Ringers solution).
- the compositions utilized by the methods can also be manufactured with standardized excipients and equipment, wherein no special homogenization or other equipment is required.
- excipients used in the compositions are known, it is the specific combination of excipients disclosed herein that provide a superior formulation for the treatment of liquid tumors.
- the present subject matter is directed to a method of treating a liquid tumor in a subject comprising, administering to said subject a treatment-effective amount of a composition comprising:
- Ri and R 2 are different from each other and represent H or OH, and R represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, or cycloalkyl;
- composition is essentially free of mono-ethanolamine.
- a "liquid tumor” refers to a tumor that occurs in the blood, bone marrow, and/or lymph nodes. Any liquid tumor can be treated according to the methods described herein. In particular embodiments, the methods can be used to treat leukemia, lymphoma, or multiple myeloma.
- Leukemia is cancer of the bone marrow and blood. Types of leukemia include, but are not limited to, lymphocytic leukemia and myeloid leukemia, and can be acute or chronic.
- Lymphoma is a blood cancer that starts in the immune system, affecting the tissue in the lymph nodes, spleen, liver, bone marrow, and other sites. Lymphomas originate as liquid tumors, but can also form solid tumors. Types of lymphoma include, but are not limited to, Hodgkin lymphoma and non- Hodgkin's lymphoma.
- multiple myeloma is a cancer of the plasma cells, which rapidly grow and form tumors called plasmacytomas in the bone marrow and bone structure.
- Isolated plasmacytoma is a condition where only one tumor is present.
- Multiple myeloma refers to the presence of more than one plasmacytoma in a subject.
- Multiple myeloma is classified into three stages of progression, i.e., Stage I, Stage II, and Stage III, which are defined by the International Staging System and are based on serum beta-2 microglobulin and serum albumin levels.
- Multiple myeloma can be accompanied by a variety of symptoms including anemia, bone loss and weakening, and the overproduction of a single type of monoclonal antibody (monoclonal gammopathy).
- Multiple myeloma can be treated using one or more therapies in combination which include, but are not limited to, chemotherapy to destroy myeloma cells, treatment with bisphosphonates to prevent bone loss, radiation to target tumors, surgery to remove tumors, biologic therapy to slow myeloma cell growth and correct anemia, and stem cell transplantation to replace the bone marrow.
- the subject can be treated according to a schedule that is continuous or intermittent. Treatment of the subject can be for a period of about 1 to 2 weeks, about 1 to 4 weeks, about 1 to 8 weeks, about 1 to 12 weeks, about 1 to 16 weeks, about 1 to 24 weeks, or more, or for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11, weeks, about 12 weeks, about 16 weeks, about 24 weeks, or more.
- treatment of the subject can be for a period of about 1 to 2 months, about 1 to 4 months, about 1 to 6 months, about 1 to 9 months, about 1 to 12 months, about 1 to 18 months, about 1 to 24 months, or more, or for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, about 18 months, about 24 months, or more.
- the subject can be treated according to a schedule wherein the compositions are administered daily for the duration of treatment.
- the compositions are administered on 1 day about every 2 to 10 days, or on 1 day about every 2 days, about every 3 days, about every 4 days, about every 5 days, about every 6 days, about every 7 days, about every 8 days, about every 9 days, about every 10 days, or more, for the duration of treatment.
- compositions are administered on 1 day about every 1 to 24 weeks, or on 1 day about every week, about every 2 weeks, about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, about every 8 weeks, about every 9 weeks, about every 10 weeks, about once every 11 weeks, about every 12 weeks, about every 16 weeks, about every 24 weeks, or more, for the duration of treatment.
- the compositions are administered on 1 day about every 1 to 6 months, or on 1 day about every month, about every 2 months, about every 3 months, about every 4 months, about every 5 months, about every 6 months, or more, for the duration of treatment.
- the compositions can be administered to the subject 1 time, 2 times, 3 times, 4 times, or more, on the day of administration.
- the compositions can be administered to the subject by a discontinuous administration regimen.
- the subject can be treated according to a schedule wherein the compositions are administered between 1 to 7 days per week, or 1 day per week, 2 days per week, 3 days per week, 4 days per week, 5 days per week, 6 days per week, or 7 days per week, for a period of about 1 to 24 weeks, or for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 16 weeks, about 24 weeks, or more.
- the days of administration can be consecutive or non-consecutive as needed.
- compositions are administered to the subject 1 day per week for a period of about 3 to 12 weeks. In another preferred embodiment, the compositions are administered to the subject 3 days per week for a period of about 3 to 12 weeks. In each embodiment, the compositions can be administered to the subject 1 time, 2 times, 3 times, 4 times, or more, on a given day of administration.
- the subject can be treated according to a schedule of repeating treatment periods that comprise administration days and rest days.
- the compositions are administered daily for about 1 to 10 days at the beginning of each treatment period.
- the compositions can be administered on the first day of the treatment period, or can be administered for about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, or more, at the beginning of each treatment period.
- the day(s) of administration can be consecutive or non- consecutive.
- the remaining days of each treatment period, wherein the subject is not administered the compositions, are considered rest days.
- the duration of each treatment period, including the day(s) of administration and the subsequent rest days can be about 1 to 8 weeks, or about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, or more. In other embodiments, the duration of each treatment period, including the day(s) of administration and the subsequent rest days, can be about 1 to 6 months, or about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or more.
- each treatment period can comprise one or more days of administration at the beginning of the treatment period, as described above, followed by about 1 to 8 weeks of rest days, or about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, or more, of rest days.
- the day(s) of administration at the beginning of the treatment period are followed by about 1 to 6 months of rest days, or about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or more, of rest days.
- Treatment periods can be repeated any number of times for the duration of treatment using the same dosing schedule or a different dosing schedule (i.e., a different number of administration and rest days within the treatment period) as needed.
- the subject is treated according to a repeating schedule wherein the compositions are administered for 5 consecutive days at the beginning of a 3 week treatment period.
- the compositions can be administered to the subject 1 time, 2 times, 3 times, 4 times, or more, on a given day of administration.
- compositions are administered to the subject using two or more different schedules, e.g., more frequently initially (for example to build up to a certain level, e.g. , once a day or more) and then less frequently ⁇ e.g., once a week or less).
- the present invention encompasses every sub-range within the ranges of days, weeks, and months cited above for administration of the compositions of the methods.
- compositions utilized by the methods can be administered to a subject for various durations of time including about 5 minutes, 10 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours or longer.
- the compositions utilized by the methods can be delivered to the subject by parenteral administration.
- the route can be intravenous, intramuscular, sub-cutaneous, intrathecal, intraperitoneal, intraosseous, or intraarterial administration.
- the compositions utilized by the methods can be delivered to the subject at a dose that is effective to treat a liquid tumor.
- the effective dosage will depend on many factors including the gender, age, weight, and general physical condition of the subject, the stage and severity of the liquid tumor, the particular compound or composition being administered, the duration of the treatment, the nature of any concurrent treatment, the carrier used, and like factors within the knowledge and expertise of those skilled in the art.
- a treatment-effective amount in any individual case can be determined by one of ordinary skill in the art by reference to the pertinent texts and literature and/or by using routine experimentation (see, e.g.,
- compositions utilized by the methods are administered at a dose of about 0.1 to about
- the dose can be even lower, e.g., as low as 0.05. 0.01. 0.005, or 0.001 mg/m or lower. In some instances, the dose can be even higher, e.g., as high as 50, 100, 500, or 1000 mg/m or higher.
- the present invention encompasses every subrange within the cited ranges and amounts.
- the methods described herein can be used to treat a patient having Stage I, Stage II, or Stage III multiple myeloma. In a particular embodiment, the methods are used to treat multiple myeloma during Stage II or Stage III of the disease. In another embodiment, the methods decrease the level of serum beta-2 microglobulin to less than about 3.5 mg/L and increase serum albumin to at least about 3.5 g/L in said subject (i.e., Stage I or remission of the disease).
- the methods described herein are performed prior to radiation therapy, concurrently with radiation therapy, following radiation therapy, or a combination thereof.
- the method of the invention can be performed prior to bone marrow stem cell transplantation, following bone marrow stem cell transplantation, or both.
- the methods described herein are performed as consolidation treatment following bone marrow stem cell transplantation, which is defined as additional cycles of treatment following stem cell transplantation.
- the methods described herein are performed as maintenance therapy, which is defined as long-term treatment to delay the return of multiple myeloma. Appropriate dosing schedules and drug concentrations for consolidation or maintenance therapies can be determined by those of ordinary skill in the art.
- compositions utilized by the methods also exhibit enhanced solubility in both a concentrated solution and when diluted into an aqueous intravenous liquid or diluent.
- compositions utilized by the methods can comprise spicamycin derivatives at higher concentrations than formulations previously disclosed in the art, allowing for lower infusion volumes and shorter times of administration.
- levels of excipients in the compositions are within established limits for pharmaceutical products. As described elsewhere, the
- compositions benefit from judicious selection of certain excipients, thereby providing particularly useful compositions for the treatment of liquid tumors.
- compositions utilized by the methods comprise a spicamycin derivative of Formula II, wherein Ri and R 2 are different from each other and represent H or OH, and R represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, or cycloalkyl.
- the spicamycin derivative of the compositions can be a pharmaceutically acceptable salt, prodrug, or optical isomer thereof, and is dissolved in organic solvent to form a liquid that is substantially particulate free and is essentially free of mono-ethanolamine (ethanolamine).
- the spicamycin derivative in the composition is a compound of Formula II where R is selected from the group consisting of a linear alkenyl having 11-13 carbon atoms; a linear, unsubstituted alkyl having 11-13 carbon atoms and no double or triple bonds; a linear haloalkyl having 10-15 carbon atoms; CH 3 (CH 2 ) administratCH(OH)— or CH 3 (CH 2 ) deliberately-iCH(OH)CH 2 — , wherein n denotes an integer from 9-13; an alkyl having 10-15 carbon atoms substituted with an azide group or a cyano group; a linear alkyl having 10-13 carbon atoms substituted with a phenoxy group or a halogen-substituted phenoxy group;
- n denotes an integer from 0-2 and p denotes an integer from 8-13;
- n denotes an integer from 0-2 and p denotes an integer from 10-15;
- n denotes an integer from 0-3 and p denotes an integer from 10-15;
- R is selected from a straight or branched hydrocarbon chain containing 1-24 carbon atoms; a linear alkenyl having 1 1-13 carbon atoms; a linear, unsubstituted alkyl having 11-13 carbon atoms and no double or triple bonds; and CH 3 (CH 2 ) administratCH(OH)— or CH 3 (CH 2 ) administratCH(OH)CH 2 — , wherein n denotes an integer.
- R is an alkadienyl having 11-13 carbon atoms.
- Ri is H and R 2 is OH.
- R is an unsubstituted alkenyl having 1-24 carbon atoms, or is a linear alkenyl having 1 1-13 carbon atoms.
- R is an unsubstituted alkenyl having the structure: wherein x denotes an integer from 1-19, or wherein x denotes an integer from 6-8.
- the spicamycin derivative in the composition is 6-[4-deoxy-4-[(2E,4E)-tetradecadienoylglycyl]amino-L-glycero-P-L- manno heptopyranosyl]amino-9H-purine (KRN5500), which has the structure of Formula III.
- spicamycin derivatives are known in the art and can be used in the methods described herein (see, e.g., U.S. Patent Nos. 5,461,036, 5,631,238, 5,905,069, 7,196,071, and 7,375,094, and U.S. Patent Application No. 13/122,771, each incorporated herein by reference in its entirety).
- exemplary compounds include the following compounds as well as pharmaceutically acceptable salts, prodrugs, and optical isomers thereof:
- the compositions further comprise a first biocompatible organic solvent that solubilizes the spicamycin derivative, a second biocompatible organic solvent that is miscible with the first biocompatible organic solvent and solubilizes the spicamycin derivative, and a surfactant.
- the compositions can also be substantially free or essentially free of additional excipients that alter an advantageous property of the formulation. Such excipients include, but are not limited to, mono-ethanolamine or DMAC. Preferred amounts of each component present in the compositions utilized by the methods are disclosed elsewhere herein.
- a spicamycin derivative can be present in the
- compositions utilized by the methods in an amount of from about 0.01 mg/mL to about 10 mg/mL, from about 0.1 mg/mL to about 5 mg/mL, or from about 2 mg/mL to about 4 mg/mL.
- the first biocompatible organic solvent can be present in an amount of from about 1 mg/mL to about 500 mg/mL, from about 100 mg/mL to about 450 mg/mL, or from about 250 mg/mL to about 350 mg/mL.
- the second biocompatible organic solvent can be present in an amount of from about 1 mg/mL to about 1 g/mL, from about 300 mg/mL to about 900 mg/mL, or from about 600 mg/mL to about 700 mg/mL.
- the surfactant can be present in the compositions utilized by the methods in an amount of from about 0.1 mg/mL to about 250 mg/mL, from about 10 mg/mL to about 150 mg/mL, or from about 20 mg/mL to about 100 mg/mL.
- compositions utilized by the methods comprise a spicamycin derivative in an amount of from about 2 mg/mL to about 4 mg/mL, the first biocompatible organic solvent in an amount of from about 250 mg/mL to about 350 mg/mL, the second biocompatible organic solvent in an amount of from about 600 mg/mL to about 700 mg/mL, and surfactant in an amount of from about 20 mg/mL to about 100 mg/mL.
- compositions utilized by the methods comprise K N5500 in an amount of from about 0.01 mg/mL to about 10 mg/mL, ethanol in an amount of from about 1 mg/mL to about 500 mg/mL, propylene glycol in an amount of from about 1 mg/mL to about 1 g/mL, and polysorbate 80 in an amount of from about 0.1 mg/mL to about 250 mg/mL.
- compositions utilized by the methods comprise K N5500 in an amount of from about 0.01 mg/mL to about 10 mg/mL, ethanol in an amount of from about 1 mg/mL to about 500 mg/mL, propylene glycol in an amount of from about 1 mg/mL to about 1 g/mL, and Lutrol F68 in an amount of from about 0.1 mg/mL to about 250 mg/mL.
- compositions utilized by the methods comprise K N5500 in an amount of from about 0.1 mg/mL to about 5 mg/mL, ethanol in an amount of from about 100 mg/mL to about 450 mg/mL, propylene glycol in an amount of from about 300 mg/mL to about 900 mg/mL, and polysorbate 80 in an amount of from about 10 mg/mL to about 150 mg/mL.
- compositions utilized by the methods comprise K N5500 in an amount of from about 0.1 mg/mL to about 5 mg/mL, ethanol in an amount of from about 100 mg/mL to about 450 mg/mL, propylene glycol in an amount of from about 300 mg/mL to about 900 mg/mL, and Lutrol F68 in an amount of from about 10 mg/mL to about 150 mg/mL.
- compositions utilized by the methods comprise K N5500 in an amount of from about 2 mg/mL to about 4 mg/mL, ethanol in an amount of from about 250 mg/mL to about 350 mg/mL, propylene glycol in an amount of from about 600 mg/mL to about 700 mg/mL, and polysorbate 80 in an amount of from about 20 mg/mL to about 100 mg/mL.
- compositions utilized by the methods comprise K N5500 in an amount of from about 2 mg/mL to about 4 mg/mL, ethanol in an amount of from about 250 mg/mL to about 350 mg/mL, propylene glycol in an amount of from about 600 mg/mL to about 700 mg/mL, and Lutrol F68 in an amount of from about 10 mg/mL to about 100 mg/mL.
- compositions utilized by the methods comprise K N5500 in an amount of about 2 mg/mL, ethanol in an amount of about 293 mg/mL, propylene glycol in an amount of about 640 mg/mL, and polysorbate 80 in an amount of about 20 mg/mL.
- compositions utilized by the methods comprise K N5500 in an amount of about 4 mg/mL, ethanol in an amount of about 293 mg/mL, propylene glycol in an amount of about 618 mg/mL, and polysorbate 80 in an amount of about 40 mg/mL.
- compositions utilized by the methods comprise K N5500 in an amount of about 5 mg/mL, ethanol in an amount of about 293 mg/mL, propylene glycol in an amount of about 618 mg/mL, and polysorbate 80 in an amount of about 40 mg/mL.
- compositions utilized by the methods comprise K N5500 in an amount of about 6 mg/mL, ethanol in an amount of about 293 mg/mL, propylene glycol in an amount of about 618 mg/mL, and polysorbate 80 in an amount of about 40 mg/mL.
- compositions utilized by the methods comprise KRN5500 in an amount of about 8 mg/mL, ethanol in an amount of about 293 mg/mL, propylene glycol in an amount of about 618 mg/mL, and polysorbate 80 in an amount of about 40 mg/mL.
- compositions utilized by the methods comprise K N5500 in an amount of about 2 mg/mL, ethanol in an amount of about 293 mg/mL, propylene glycol in an amount of about 650 mg/mL, and Lutrol F68 in an amount of about 10 mg/mL.
- compositions utilized by the methods comprise a spicamycin derivative in an amount of from about 0.01 mg/mL to about 0.03 mg/mL, the first biocompatible organic solvent in an amount of from about 2 mg/mL to about 3 mg/mL, the second biocompatible organic solvent in an amount of from about 4 mg/mL to about 7 mg/mL, and surfactant in an amount of from about 0.2 mg/mL to about 0.5 mg/mL.
- the intravenous solution comprises KR 5500 in an amount of about 0.04 mg/mL, ethanol in an amount of about 2.93 mg/mL, propylene glycol in an amount of about 6.18 mg/mL, and polysorbate 80 in an amount of about 0.40 mg/mL.
- the intravenous solution comprises K N5500 in an amount of about 0.4 mg/mL, ethanol in an amount of about 29.3 mg/mL, propylene glycol in an amount of about 61.8 mg/mL, and polysorbate 80 in an amount of about 4.0 mg/mL.
- the intravenous solution comprises K N5500 in an amount of about 1.2 mg/mL, ethanol in an amount of about 87.9 mg/mL, propylene glycol in an amount of about 185.4 mg/mL, and polysorbate 80 in an amount of about 12.0 mg/mL.
- the total excipient exposure of the first biocompatible organic solvent is in an amount of from about 10 mg/kg to about 20 mg/kg
- the total excipient exposure of the second biocompatible organic solvent is in an amount of from about 25 mg/kg to about 50 mg/kg
- the total excipient exposure of the surfactant is in an amount of from about 1 mg/kg to about 4 mg/kg.
- total excipient exposure assumes a dose of the spicamycin derivative as
- compositions utilized by the methods preferably comprise a spicamycin derivative dissolved in organic solvent to form a liquid that is substantially free of particulates and essentially free of mono-ethanolamine.
- a spicamycin derivative dissolved in organic solvent to form a liquid that is substantially free of particulates and essentially free of mono-ethanolamine.
- substantially free of particulates is considered to mean the number and size of particulates known by those of ordinary skill in the art to be in accordance with the regulations established by the U.S. Pharmaceutical Convention in General Chapter ⁇ 788> Particulate Matter in Injections and the USP Particle Count Reference Standard.
- the compositions comprise particulates in an amount of from about 0-6000 particles, or from about 0-1000 particles, or from about 0-500 particles, or from about 0-100 particles, or from about 0-50 particles, or from about 0-10 particles, or 0 particles, wherein the particle size is at least 10 ⁇ .
- the compositions comprise particulates in an amount of from about 0-600 particles, or from about 0-300 particles, or from about 0-100 particles, or from about 0- 50 particles, or from about 0-10 particles, or 0 particles, wherein the particle size is at least 25 ⁇ .
- the compositions comprise particulates in an amount of from about 0-25 particles/mL, or from about 0-10 particles/mL, or from about 0-5 particles/mL, or from about 0-2 particles/mL, or 0 particles/mL, wherein the particle size is at least 10 ⁇ .
- the compositions comprise particulates in an amount of from about 0-3 particles/mL, or from about 0-2
- particles/mL or from about 0-1 particles/mL, or 0 particles/mL, wherein the particle size is at least 25 ⁇ .
- the compositions can comprise particulates in an amount of from about 6000 particles to about 12,000 particles, wherein the particles are at least 10 ⁇ in size. In another such embodiment, the compositions can comprise particulates in an amount of from about 600 particles to about 1200 particles, wherein the particles are at least 25 ⁇ in size.
- the compositions can comprise particulates in an amount of from about 25 particles/mL to about 50 particles/mL, wherein the particles are at least 10 ⁇ in size. In another such embodiment, the compositions can comprise about
- compositions utilized by the methods can be "substantially free” of mono-ethanolamine or DMAC, wherein “substantially free” is defined as having no more than a trace amount of mono-ethanolamine or DMAC in the composition.
- compositions are "essentially free” of mono-ethanolamine or DMAC, wherein “essentially free” specifically means that the compositions do not comprise any mono-ethanolamine or any DMAC.
- compositions utilized by the methods comprise a spicamycin derivative described herein and further comprise at least one additional therapeutic compound.
- the additional therapeutic compound is a chemotherapeutic agent, a corticosteroid, an immunomodulating agent, a
- PPAR peroxisome proliferator-activated receptor
- the compositions are in the form of a concentrated solution that is substantially free of particulates and essentially free of mono-ethanolamine.
- the concentrated solution comprises particulates in an amount of from about 0-6000 particles, or from about 0-1000 particles, or from about 0-500 particles, or from about 0-100 particles, or from about 0-50 particles, or from about 0-10 particles, or 0 particles, wherein the particle size is at least 10 ⁇ .
- the concentrated solution comprises particulates in an amount of from about 0-600 particles, or from about 0-300 particles, or from about 0-100 particles, or from about 0-50 particles, or from about 0-10 particles, or 0 particles, wherein the particle size is at least 25 ⁇ .
- the concentrated solution can comprise particulates in an amount of from about 6000 particles to about 12,000 particles, wherein the particles are at least 10 ⁇ in size. In another such embodiment, the concentrated solution can comprise particulates in an amount of from about 600 particles to about 1200 particles, wherein the particles are at least 25 ⁇ in size.
- a concentrated solution of the methods is substantially free of mono-ethanolamine or DM AC.
- the concentrated solution is essentially free of mono-ethanolamine or DMAC.
- the compositions can be in the form of an intravenous solution, further comprising an aqueous intravenous liquid or diluent selected from the group consisting of 0.9% sodium chloride, 5% dextrose, and Lactated Ringers solution.
- an aqueous intravenous liquid or diluent selected from the group consisting of 0.9% sodium chloride, 5% dextrose, and Lactated Ringers solution.
- the compositions of these aqueous intravenous liquids or diluents are well-known in the art.
- the compositions or concentrated solution of the method can be diluted into the aqueous intravenous infusion liquid or diluent at a ratio selected from the group consisting of 1 : 10 (v/v), 1 :30 (v/v), and 1 : 100 (v/v).
- the intravenous solution comprises particulates in an amount of from about 0-25 particles/mL, or from about 0-10 particles/mL, or from about 0-5 particles/mL, or from about 0-2 particles/mL, or 0 particles/mL, wherein the particle size is at least 10 ⁇ .
- the intravenous solution comprises particulates in an amount of from about 0-3 particles/mL, or from about 0-2 particles/mL, or from about 0-1 particles/mL, or 0 particles/mL, wherein the particle size is at least 25 ⁇ .
- the intravenous solution can comprise particulates in an amount of from about 25 particles/mL to about 50 particles/mL, wherein the particles are at least 10 ⁇ in size. In other embodiments, the intravenous solution can comprise particulates in an amount of from about 3 particles/mL to about 6 particles/mL, wherein the particles are at least 25 ⁇ in size.
- the intravenous solution comprises a spicamycin derivative described herein and further comprises at least one additional therapeutic compound.
- the additional therapeutic compound is a chemotherapeutic agent, a corticosteroid, an immunomodulating agent, a
- PPAR peroxisome proliferator-activated receptor
- the spicamycin derivatives used in the compositions of the methods include all pharmaceutically acceptable salt forms thereof.
- Examples of such salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
- Suitable acid salts include, without limitation, acetate, adipate, alginate, aspartate, benzoate, butyrate, citrate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, hydroxynapthoate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate.
- Other acids such as oxalic, while not in themselves pharmaceutically acceptable, can be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
- Salts derived from appropriate bases include, without limitation, alkali metal
- the spicamycin derivatives also include those having quaternization of any basic nitrogen-containing group therein.
- spicamycin derivatives used in the compositions of the methods can contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single optical isomers, individual diastereomers, and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention.
- spicamycin derivatives containing a double bond can exist in the form of geometric isomers, which can be readily separated and recovered by conventional procedures. Such isomeric forms are included in the scope of this invention.
- the spicamycin derivatives used in the methods described herein include prodrugs that are converted to the active compound in vivo.
- the compound can be modified to enhance cellular permeability (e.g., by esterification of polar groups) and then converted by cellular enzymes to produce the active agent.
- Methods of masking charged or reactive moieties as a pro-drug are known by those skilled in the art (see, e.g., P. Korgsgaard-Larsen and H. Bundgaard, A Textbook of Drug Design and Development, Reading U.K., Harwood Academic Publishers, 1991).
- the compositions utilized by the methods are administered in combination with at least one additional therapeutic compound.
- the additional therapeutic compound can be delivered in the same composition as the spicamycin derivative or in a separate composition.
- the additional therapeutic compound can be delivered to the subject on a different schedule or by a different route as compared to the spicamycin derivative.
- the additional therapeutic compound can be any agent that provides a benefit to the subject.
- the additional therapeutic compound can be, without limitation, a chemotherapeutic agent, a corticosteroid, an immunomodulating agent, a bisphosphonate, a proteasome inhibitor, a biologic agent, an antiemetic agent, an analgesic agent, an anti-inflammatory agent, a peroxisome proliferator-activated receptor (PPAR) agonist (e.g., PPAR ⁇ agonist), or any combination thereof.
- a chemotherapeutic agent e.g., a corticosteroid, an immunomodulating agent, a bisphosphonate, a proteasome inhibitor, a biologic agent, an antiemetic agent, an analgesic agent, an anti-inflammatory agent, a peroxisome proliferator-activated receptor (PPAR) agonist (e.g., PPAR ⁇ agonist), or any
- chemotherapeutic agents include, without limitation, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefmgol, chlorambucil,
- mitindomide mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safmgol, safmgol hydrochloride, semustine, suppressrazene, sparfosate sodium, sparsomycin, spirogermanium hydro
- chemotherapeutic agents include, but are not limited to, 20- epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; prostatic carcinoma antiandrogen; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA
- BCR/ABL antagonists benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine;
- budotitane buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole;
- ICOS castanospermine
- cecropin B cecropin B
- cetrorelix chlorins
- diethylnorspermine dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; camrabine;
- fenretinide filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine;
- gadolinium texaphyrin gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin- like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane;
- iododoxorubicin 4-ipomeanol; iroplact; irsogladine; isobengazole; isohomohalicondrin
- B itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum
- losoxantrone lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin;
- methioninase metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;
- molgramostim monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted
- benzamides nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin;
- nartograstim nedaplatin
- nemorubicin nedaplatin
- neridronic acid neutral endopeptidase
- nilutamide nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06- benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; odansteron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel;
- paclitaxel analogues paclitaxel derivatives
- palauamine palmitoylrhizoxin
- pamidronic acid panaxytriol
- panomifene parabactin
- pazelliptine pegaspargase
- peldesine pegaspargase
- sarcophytol A sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid;
- spicamycin D spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfmosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine;
- telomerase inhibitors tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors;
- temoporfm temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;
- ubenimex urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfm; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
- Corticosteroids are useful in combination with chemotherapeutic agents to decrease nausea and vomiting and include, without limitation, dexamethasone and prednisone.
- Immunomodulating agents are useful in the treatment of multiple myeloma and include, without limitation, thalidomide, lenalidomide, and pomalidomide.
- Proteasome inhibitors interfere with the breakdown of proteins by proteasomes in myeloma cells and include, without limitation, bortezomib and carfilzomib.
- Bisphosphonates are useful in preventing bone weakening and bone loss and include, without limitation, pamidronate and zoledronic acid.
- Biologic agents have various uses in the treatment of multiple myeloma, such as slowing the growth of myeloma cells or correcting anemia.
- Biologic agents include, without limitation, interferon, erythropoietin, and darbepoietin.
- antiemetic agents include, without limitation, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, odansteron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxypemdyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.
- analgesic agents include, without limitation, the opioids
- anti-inflammatory agents include, without limitation, aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal,
- Examples of PPAR ⁇ agonists include, without limitation, those disclosed in U.S.
- Suitable subjects are mammalian subjects.
- mammalian subjects includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dog, rabbits, rodents ⁇ e.g., rats or mice), etc.
- Human subjects include neonates, infants, juveniles, adults and geriatric subjects.
- the subject is a human subject that has a liquid tumor
- the subject treated by the methods is an animal model of a liquid tumor.
- the subject can be a subject "in need of the methods described herein, e.g., in need of the therapeutic effects of the inventive methods.
- the subject can be a subject that has a liquid tumor ⁇ e.g., leukemia, lymphoma, or multiple myeloma) and the methods are used for therapeutic treatment.
- the subject can further be a laboratory animal, e.g., an animal model of a liquid tumor.
- the compositions utilized by the methods, and the spicamycin derivatives described herein can be formulated for administration in a pharmaceutical vehicle, biocompatible formulation, or biocompatible solvent, in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (21 st ed. 2005).
- the vehicle, formulation, or solvent must be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient.
- compositions of the invention include parenteral routes of administration, including intravenous, intramuscular, sub-cutaneous, intrathecal or intraarterial administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound which is being used.
- compositions utilized by the methods which are suitable for parenteral administration include, but are not limited to, sterile aqueous and non-aqueous injection solutions that are preferably isotonic or hypertonic with the blood of the intended recipient. These compositions can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
- Aqueous sterile suspensions can include suspending agents and thickening agents.
- the formulations can be presented in unit ⁇ dose ⁇ e.g., in a syringe or other injection device) or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water- for-injection immediately prior to use.
- a syringe or other injection device for example sealed ampoules and vials
- a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water- for-injection immediately prior to use.
- Extemporaneous injection solutions can be prepared from sterile powders, granules and tablets of the kind previously described.
- an injectable, stable, sterile composition comprising the composition of the method in a unit dosage form in a sealed container.
- the compositions utilized by the methods can also be provided in the form of a lyophilizate which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject.
- the unit dosage form typically comprises from about 1 mg to about 10 grams of the compound.
- compositions utilized by the methods can contain further additives including, but not limited to, pH-adjusting additives, osmolality adjusters, tonicity adjusters, anti-oxidants, reducing agents, and preservatives.
- Useful pH-adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate.
- the compositions of the invention can contain microbial preservatives.
- Useful microbial preservatives include methylparaben, propylparaben, and benzyl alcohol. The microbial preservative is typically employed when the formulation is placed in a vial designed for multidose use.
- additives that are well known in the art include, e.g., detackifiers, anti-foaming agents, antioxidants (e.g., ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherols, e.g., a-tocopherol (vitamin E)), preservatives, chelating agents (e.g., EDTA and/or EGTA), viscomodulators, tonicifiers (e.g., a sugar such as sucrose, lactose, and/or mannitol), flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
- detackifiers e.g., anti-foaming agents
- antioxidants e.g., ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy to
- a method of treating a liquid tumor in a subject comprising,
- Ri and R 2 are different from each other and represent H or OH, and R represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, or cycloalkyl;
- composition is essentially free of mono-ethanolamine. 2. The method of embodiment 1 , wherein the composition is in the form of an intravenous solution further comprising an aqueous intravenous liquid or diluent.
- composition is substantially free of particulates.
- composition is substantially free of particulates for about two weeks after the composition is formulated. 6. The method of embodiment 4, wherein the composition is substantially free of particulates for at least 1 year after the composition is formulated.
- composition is essentially free of ⁇ , ⁇ -dimethyl acetamide (DMAC).
- DMAC ⁇ , ⁇ -dimethyl acetamide
- n denotes an integer from 9-13; e) an alkyl having 10-15 carbon atoms substituted with an azide group or a cyano group;
- n denotes an integer from 0-2 and p denotes an integer from
- n denotes an integer from 0-2 and p denotes an integer from
- R is an unsubstituted alkenyl having the structure: wherein x denotes an integer from 1 to 19.
- KRN5500 heptopyranosyl]amino-9H-purine
- the spicamycin derivative is present in an amount of from about 0.1 mg/mL to about 5 mg/mL. 19. The method of any one of the previous embodiments, wherein the spicamycin derivative is present in an amount of from about 2 mg/mL to about 4 mg/mL.
- the spicamycin derivative is present in an amount of from about
- the first biocompatible organic solvent is present in an amount of from about 250 mg/mL to about 350 mg/mL;
- the second biocompatible organic solvent is present in an amount of from about 600 mg/mL to about 700 mg/mL;
- the surfactant is present in an amount of from about 20 mg/mL to about 100 mg/mL.
- the spicamycin derivative is present in an amount of from about
- the first biocompatible organic solvent is present in an amount of from about 2 mg/mL to about 3 mg/mL;
- the second biocompatible organic solvent is present in an amount of from about 4 mg/mL to about 7 mg/mL;
- the surfactant is present in an amount of from about 0.2 mg/mL to about 0.5 mg/mL.
- composition comprises: a) KRN5500 in an amount of about 4 mg/mL;
- composition comprises: a) KRN5500 in an amount of about 0.04 mg/mL; b) ethanol in an amount of about 2.93 mg/mL;
- composition further comprises at least one additional therapeutic compound.
- the at least one additional therapeutic compound is selected from the group consisting of a chemotherapeutic agent, a corticosteroid, an immunomodulating agent, a bisphosphonate, a proteasome inhibitor, a biologic agent, an antiemetic agent, an analgesic agent, an anti-inflammatory agent, a peroxisome proliferator-activated receptor (PPAR) agonist, and any combination thereof.
- composition is administered between 1 to 7 days per week for a period of about 1 to 24 weeks.
- composition is administered 1 day per week for a period of about 3 to 12 weeks, or 3 days per week for a period of about 3 to 12 weeks.
- composition is administered to the subject according to a schedule of repeating treatment periods that comprise administration days and rest days, wherein said treatment periods have a duration of about 1 to 8 weeks or about 1 to 6 months.
- composition is administered for about 5 consecutive days at the beginning of said treatment periods, and wherein said treatment periods have a duration of about 3 weeks.
- composition is administered to the subject for a duration of about 5 minutes, about 10 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 18 hours, or about 24 hours.
- composition is administered by parenteral administration.
- parenteral administration is intravenous administration, intramuscular administration, sub-cutaneous administration, intrathecal administration, intraperitoneal administration, intraosseous administration, or intraarterial administration.
- composition is administered to the subject at a dose between about 0.001 mg/m and about 1000 mg/m 2 .
- composition is administered to the subject at a dose of about 0.1 mg/m to about 30.0 mg/m 2 .
- the composition is administered to the subject at a dose of about 1.0 mg/m to about 10.0 mg/m 2 .
- composition is administered to the subject at a dose of about 4.0 mg/m to about 6.0 mg/m 2 .
- liquid tumor is selected from the group consisting of leukemia, lymphoma, and multiple myeloma.
- Example 1 Formulations of KRN5500
- compositions were formulated using combinations of the spicamycin derivative KR 5500 with ethanol (i.e., a first biocompatible organic solvent), propylene glycol (i.e., a second biocompatible organic solvent), and a surfactant.
- concentration of the spicamycin derivative K N5500 in a concentrated solution was determined by high performance liquid chromatography (HPLC).
- HPLC high performance liquid chromatography
- properties of the concentrated solutions and in diluted intravenous solutions were also determined at the time of formulation and at various time points following storage at different temperatures. It would be known to those of ordinary skill in the art that clear solutions with the presence of very few particles in suspension would be in accordance with the regulations established by the U.S.
- Active pharmaceutical ingredient (API) KRN5500 theoretical concentration 0.116 mg/ml, ethanol 30% w/v and propylene glycol 70 % w/v.
- Ethanol (96%) was added to KRN5500. The appearance of the solution after 50 minutes of stirring was clear without precipitate. The solution was then brought to final volume with propylene glycol. The solution remained clear and then was filtered with PVDF 0.22 ⁇ . The solution was then divided into two aliquots. The first aliquot was stored in at 2-8°C while the second aliquot was stored at 40°C. After 24 hours, the solutions remained clear. An aliquot of the solution was analyzed by HPLC and the assay was 0.21 mg/mL. The solution was then diluted with 0.9%> sodium chloride or 5% Dextrose. Initially, in both diluted solutions, there were free particles and after 2 hours there increase in the precipitate.
- Active pharmaceutical ingredient (API) KRN5500 theoretical concentration 1.012 mg/ml, ethanol 30% w/v, Tween 10%> w/v and propylene glycol 60%> w/v.
- Ethanol (96%) (7.82 g) was added to K N5500.
- the appearance of the solution after 45 minutes of stirring was opalescent with precipitate.
- To the solution was added 2.504 g of Tween 80 but it remained opalescent.
- the solution was then brought to final volume with 15 g of propylene glycol.
- the solution became clear with some particles and then was filtrated with PVDF 0.22 ⁇ .
- the density of the final solution was 0.961 g/mL and the pH was 6.3.
- the solution was divided into two aliquots. The first aliquot was stored in at 2-8°C while the second aliquot was stored at 25°C.
- the solution was analyzed by HPLC.
- the solution was then diluted with 0.9%> sodium chloride, 5% Dextrose or Lactated Ringers solution in different ratios.
- the properties of the solutions are shown in Table 2 below.
- Formulation F4c was then kept under stability for up to 2 weeks at 2-8°C. After 2 weeks a slight increase of the number of particles was observed in the solutions.
- the properties of the solutions prepared from this solution are shown in Table 3 below.
- Active pharmaceutical ingredient (API) KRN5500 theoretical concentration 1.019 mg/ml, ethanol 30% w/v, Tween 5% w/v and propylene glycol 65 %> w/v.
- Ethanol (96%) (7.82 g) was added to K N5500 along with 1.25 g of Tween 80. The appearance of the solution after 65 minutes of stirring was opalescent with precipitate. The solution was then brought to final volume with 16.25 g of propylene glycol. After 30 minutes of stirring the solution was clear and was filtered with PVDF 0.22 ⁇ . The density of the final solution was 0.955 g/mL and the pH was 6.3. The solution was divided into two aliquots. The first aliquot was stored in at 2-8°C while the second aliquot was stored at 25°C. Another aliquot was analyzed by HPLC. The solution was then diluted with 0.9%> sodium chloride, 5%> Dextrose or Lactated Ringers solution in different ratios. The properties of the solutions are shown in Table 4 below.
- Ethanol (96%) (7.81 g) was added to K N5500 along with 0.499 g of Tween 80.
- the appearance of the solution after 65 minutes of stirring was opalescent with precipitate.
- the solution was then brought to final volume with 16.99 g of propylene glycol. After 35 minutes of stirring the solution was clear and was filtered with PVDF 0.22 ⁇ . The density of the final solution was 0.954 g/mL and the pH was 6.4. The solution was divided into two aliquots. The first aliquot was stored in at 2-8°C while the second aliquot was stored at 25°C. Another aliquot was analyzed by HPLC. The solution was then diluted with 0.9% sodium chloride, 5% Dextrose or Lactated Ringers solution in different ratios. The properties of the solutions are shown in Table 5 below.
- Active pharmaceutical ingredient (API) KR 5500 theoretical concentration 1.923 mg/ml, ethanol 30% w/v, Tween 5% w/v and propylene glycol 65 % w/v.
- Ethanol (96%) (7.81 g) was added to K N5500 along with 1.259 g of Tween 80. The appearance of the solution was opalescent with precipitate. The solution was then brought to final volume with 16.25 g of propylene glycol. After 30 minutes of stirring the solution was clear and was filtered with PVDF 0.22 ⁇ . The density of the final solution was 0.953 g/mL and the pH was 6.6. The solution was divided into two aliquots. The first aliquot was stored in at 2-8°C while the second aliquot was stored at 25°C. Another aliquot was analyzed by HPLC. The solution was then diluted with 0.9% sodium chloride, 5% Dextrose or Lactated Ringers solution in different ratios. The properties of the solutions are shown in Table 6 below.
- Active pharmaceutical ingredient (API) KRN5500 theoretical concentration 1.826 mg/ml, ethanol 30% w/v, Tween 2% w/v and propylene glycol 68 % w/v.
- Ethanol (96%) (7.81 g) was added to KRN5500 along with 0.499 g of Tween 80.
- the appearance of the solution after 65 minutes of stirring was opalescent with precipitate.
- the solution was then brought to final volume with 17.00 g of propylene glycol. After 35 minutes of stirring the solution was clear and was filtered with PVDF 0.22 ⁇ .
- the density of the final solution was 0.952 g/mL and the pH was 6.0.
- the solution was divided into two aliquots. The first aliquot was stored in at 2-8°C while the second aliquot was stored at 25°C. Another aliquot was analyzed by HPLC. The solution was then diluted with 0.9%> sodium chloride, 5% Dextrose or Lactated Ringers solution in different ratios. The properties of the solutions are shown in Table 7 below. Table 7
- Active pharmaceutical ingredient (API) KR 5500 concentration 2.0 mg/mL, ethanol 293.33 mg/mL, Lutrol F68 10 mg/mL, and propylene glycol 650.0 mg/mL.
- Formulation 01 was prepared according to the process outlined in Figure 1. Briefly, 3.00 g of Lutrol F68 was added to 88.00 g of ethanol (96%) and mixed for 6 minutes until the Lutrol F68 was completely dissolved. KR 5500 (theoretical weight of 600 mg) was then slowly added and the solution was stirred for 17 minutes. Propylene glycol (195.0 g) was then added and the solution was stirred for 46 minutes until complete dissolution of the KR 5500. Prior to filtration, the solution was clear and colorless. Following filtration through a 0.2 ⁇ nylon membrane, the solution remained clear and colorless and had a density of 0.954 g/mL. The formulation was prepared in a lot of 300 mL for packaging in 5 mL vials using the amounts of each component/excipient in Table 8 below. Table 8
- Active pharmaceutical ingredient (API) KR 5500 concentration 2.0 mg/mL, ethanol 293.33 mg/mL, polysorbate 80 20.00 mg/mL, and propylene glycol 640.0 mg/mL.
- Formulation 02 was prepared according to the process outlined in Figure 2. Briefly, 6.00 g of polysorbate 80 was added to 88.00 g of ethanol (96%>) and mixed for 8 minutes until the polysorbate 80 was completely dissolved. K N5500 (theoretical weight of 600 mg) was then slowly added and the solution was stirred for 21 minutes. Propylene glycol (192.0 g) was then added and the solution was stirred for 45 minutes until complete dissolution of the KRN5500. Prior to filtration, the solution was clear and colorless. Following filtration through a 0.2 ⁇ nylon membrane, the solution remained clear and colorless and had a density of 0.955 g/mL. The formulation was prepared in a lot of 300 mL for packaging in 5 mL vials using the amounts of each component/excipient in Table 9 below.
- KR 5500 concentration 4.0 mg/mL, ethanol 293.30 mg/mL, polysorbate 80 40.00 mg/mL, and propylene glycol 617.75 mg/mL.
- Formulation 03 was prepared according to the process outlined in Figure 2. Briefly, 8.00 g of polysorbate 80 was added to 58.66 g of ethanol (96%) and mixed for 10 minutes until the polysorbate 80 was completely dissolved. K N5500 (theoretical weight of 800 mg) was then slowly added and the solution was stirred for 15 minutes. Propylene glycol (123.55 g) was then added and the solution was stirred for 48 minutes until complete dissolution of the K N5500. Prior to filtration, the solution was clear and colorless.
- the formulation was prepared in a lot of 200 mL for packaging in 2.5 mL vials using the amounts of each
- Table 13 indicates the TRS levels when formulations 01, 02, and 03 were diluted into 0.9% NaCl and stored at 5°C and 25°C for 24 hours.
- Table 14 indicates the osmolality when formulations 01, 02, and 03 were diluted into 0.9% NaCl, 5% Dextrose, or Lactated Ringers.
- Example 2 Treatment of Liquid Tumors Using
- compositions described herein including the formulations of KRN5500 prepared in Example 1 above, will be assayed for the treatment of liquid tumors in vitro and in vivo.
- the compositions utilized by the methods will be used to treat immortalized liquid tumor cell lines and/or primary cells obtained from patients having liquid tumors (e.g., leukemia, lymphoma, multiple myeloma). Prior to treating the cells, the compositions can be diluted into an appropriate aqueous solution, such as sterile saline, 5% dextrose, Lactated Ringers, or culture media.
- the compositions will be evaluated at multiple concentrations of the spicamycin derivative (0-1000 nmol/L or more) to determine its effect on cell growth, apoptosis, and cell cycle regulation. The effect of the compositions on tumor cell survival will also be determined at multiple times points (e.g., 0, 24, 48, and 72 hours or more) following treatment with each concentration of the spicamycin derivative tested.
- compositions utilized by the methods will be used to treat a mouse model of a liquid tumor.
- SCID mice will receive a subcutaneous injection of liquid tumor cells to induce the formation of a liquid tumor in the animal.
- the liquid tumor cells can be primary multiple myeloma cells or, alternatively, cells of an immortalized multiple myeloma cell line.
- Control animals will receive a subcutaneous injection of a vehicle control solution.
- compositions utilized by the methods or a vehicle control solution on a schedule of one treatment per week, or three treatments per week, for a total of three weeks.
- the compositions Prior to treatment, the compositions can be diluted into an appropriate aqueous solution for administration, such as sterile saline, 5% dextrose, or Lactated Ringers. Mice will be treated by
- intraperitoneal injection or intravenous infusion and multiple concentrations of the spicamycin derivative will be evaluated (e.g., 0, 0.5, 2.5, 5, 10 mg/kg or more).
- concentrations of the spicamycin derivative e.g., 0, 0.5, 2.5, 5, 10 mg/kg or more.
- the progression of tumor development, and the efficacy of treatment, will be determined by measuring tumor volume over time.
- compositions utilized by the methods will be used to treat a rabbit bone xenograft model in mice.
- rabbit bone will be engrafted subcutaneously under the skin of SCID mice.
- Control animals will receive no xenograft (i.e., sham surgery).
- experimental animals will receive an intra-bone injection of liquid tumor cells, whereas control animals will receive an intra-bone injection of a vehicle control solution.
- the liquid tumor cells can be primary multiple myeloma cells or, alternatively, cells of an immortalized multiple myeloma cell line.
- mice will be treated with the compositions utilized by the methods or a vehicle control solution on a schedule of one treatment per week, or three treatments per week, for a total of three weeks.
- the compositions Prior to treatment, the compositions can be diluted into an appropriate aqueous solution for administration, such as sterile saline, 5% dextrose, or Lactated Ringers.
- Mice will be treated by intraperitoneal injection or intravenous infusion, and multiple concentrations of the spicamycin derivative will be evaluated (e.g., 0, 0.5, 2.5, 5, 10 mg/kg or more).
- the progression of tumor development, and the efficacy of treatment will be evaluated by measuring soluble interleukin-6 receptor, X-ray photography of the xenografted bones, and histopathological examination.
- compositions utilized by the methods diluted into a vehicle appropriate for treatment such as sterile saline, 5% dextrose, Lactated Ringers, or culture medium;
- vehicle appropriate for treatment such as sterile saline, 5% dextrose, Lactated Ringers, or culture medium;
- the vehicle including mono-ethanolamine such as sterile saline, 5% dextrose, Lactated Ringers, or culture medium;
- the vehicle including mono-ethanolamine v
- the solution of (ii) further comprising mono-ethanolamine a solution of (ii) further comprising mono-ethanolamine
- the solution of (iii) further comprising mono- ethanolamine can be any one of the formulations described herein, in particular, those described in Example 1 above comprising
- KRN5500 ethanol, propylene glycol, and polysorbate 80.
- Example 3 In Vitro Treatment of Liquid Tumor Cell Lines
- IC 50 of the growth inhibitory activity of KRN5500 and a positive control, cyclophosphamide, against selected human myeloma cell lines.
- Cell growth was determined based on quantitation of ATP present, which signals the presence of metabolically active cells, using the Cell Titer-Glo® Luminescent Cell Viability assay (Promega).
- Cell lines included RPMI 8226 (human peripheral blood myeloma), OPM-2 (human multiple myeloma), and H929 (human multiple myeloma).
- Cyclophosphamide and KRN5500 were dissolved in DMSO and diluted in cell culture medium for treatment. Cyclophosphamide was evaluated at concentrations ranging from 0.1 ⁇ to 1.0 mM. KRN5500 was evaluated at concentrations ranging from 1 nM to 10 ⁇ .
- Human tumor cells were seeded in a clear polystyrene 96-well microculture plate in a total volume of 90 ⁇ . After 24 hours of incubation in a humidified incubator at 37 °C with 5% CO, and 95% air, 10 ⁇ of 10X, serially diluted test agents in growth medium were be added to each well in duplicate. After 72 hours of culture in a humidified incubator at 37°C, in an atmosphere of 5% C0 2 and 95% air, the plated cells and Cell Titer-Glo® reagents were be brought to room temperature to equilibrate for 30 minutes. 100 of Cell Titer-Glo reagent was added to each well. The plate was shaken for two minutes and then left to equilibrate for ten minutes.
- the medium/Cell Titer-Glop reagent was then transferred to a white polystyrene 96-well microculture plate before reading luminescence on a GENios (Tecan) microplate reader. Percent inhibition of cell growth was calculated relative to untreated control wells. All tests were performed in duplicate at each test concentration. The IC 50 value for each agent was estimated using Prism 6.05 by curve fitting the data.
- the IC 50 values calculated for cyclophosphamide were 223030 ⁇ , 1289 ⁇ , and 15721 ⁇ in the OPM-2, RPMI-8226, and H929 cell lines, respectively (see, Figure 3A).
- the IC 50 values calculated for KR 5500 were 10.8 nM, 30.1 nM, and 33.3 nM in the OPM-2, RPMI-8226, and H929 cell lines, respectively (see, Figure 3B). Therefore, KRN5500 exhibits a potent anti-pro liferative effect against human liquid tumor cell lines.
- RPMI-8226 cells were treated for 72 hours according to the protocol described above. Treatment groups included a negative control, KRN5500 (1 ⁇ ) alone, KRN5500 (1 ⁇ ) with mono-ethanolamine (1 mM), and KRN5500 (1 ⁇ ) with mono-ethanolamine (0.1 mM). RPMI-8226 cell proliferation was determined after 72 hours using the Cell Titer-Glo® Luminescent Cell Viability assay.
- Figure 4 illustrates that mono-ethanolamine (0.1 mM or 1 mM) attenuated the anti-proliferative effect of KRN5500 on RPMI-8226 cells.
- This effect of mono-ethanolamine is apparent from the increased percent of control when compared to KRN5500 alone, which indicates that mono-ethanolamine induced a proliferative effect on RPMI-8226 cells.
- KRN5500 Increasing concentrations of KRN5500 overcame any proliferative effect induced by mono-ethanolamine at 0.1 mM or 1 mM. KRN5500 exhibited an IC 50 of 33.1 nM. The addition of mono-ethanolamine to KRN5500 at concentrations of 1 mM and 0.1 mM resulted in IC 50 values of 31.6 nM and 34.7 nM, respectively.
- Treatment groups include: 1) vehicle control (0.9% saline or dextrose 5%), 2) cyclophosphamide (100 mg/kg), 3) KRN5500 (5 mg/kg) formulated with ethanol (626 mg), polysorbate 80 (300 mg), propylene glycol (400 mg), mono-ethanolamine (100 mg), and ⁇ , ⁇ -dimethyl acetamide (DMAC) (50 mg), 4) KR 5500 (5 mg/kg) formulated in ethanol (293 mg), polysorbate 80 (40 mg), and propylene glycol (618 mg), and 5) KR 5500 (2.5 mg/kg) formulated in ethanol (293 mg), polysorbate 80 (40 mg), and propylene glycol (618 mg). All formulations are diluted into 0.9% saline prior to administration.
- mice Female CB.17 SCID mice (8 to 12 weeks old) are injected subcutaneously in the flank with lxlO 7 RPMI-8226 tumor cells in 50% MATRIGELTM (BD). Cell injection volume is 0.1 mL. Tumors are allowed to grow to an average size of 100-150 mm prior to treatment. Treatments are administered intravenously except for cyclophosphamide, which is administered by intraperitoneal injection. Mouse weight and tumor volume, determined by a caliper, are measured biweekly. Experiments are concluded after 30 days or when the mean tumor weight of the control group reaches 2000 mm .
Abstract
La présente invention concerne des méthodes de traitement d'une tumeur liquide chez un sujet par administration d'une composition comprenant un dérivé de spicamycine. La composition de la méthode est essentiellement exempte de mono-éthanolamine et, dans des modes de réalisation préférés, la tumeur liquide est un myélome multiple et le dérivé de spicamycine de la composition est KRN5500.
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