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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present disclosure relates to the field of chemistry and medicine. More particularly, the present disclosure relates to compositions containing Plinabulin, and its use in treatment.
• Gastric cancer is a disease in which malignant cells form in the lining of the stomach.
• Stomach or gastric cancer can develop in any part of the stomach and may spread throughout the stomach and to other organs, particularly the esophagus, lungs, and liver.
• Stomach cancer is the fourth most common cancer worldwide, with 930,000 cases diagnosed in 2002. In addition, it is a disease with a high death rate (-800,000 per year), making it the second most common cause of cancer death worldwide after lung cancer.
• SCLC Small cell lung cancer
• NSCLC nonsmall cell lung cancer
• Both lung cancers are the second most common cancer in both men and women.
• Lung cancer is the leading cause of cancer death, which accounts for about 25%. Thus, more people die of lung cancer than colon, breast, and prostate cancers combined yearly. Furthermore, lung cancers account for about 13% (more than 1.8 million) of all new cancers. Lung cancer mainly occurs in older people. The average age at the time of diagnosis is about 70. Fewer than 2% of all cases are diagnosed in people younger than 45.
• the treatment and prognosis of SCLC depend strongly on the diagnosed cancer stage.
• the staging of SCLC based on clinical results is more common than pathologic staging. The clinical staging uses the results of the physical examination, various imaging tests, and biopsies. According to the data introduced by the American Cancer Society, the 5 -year relative survival rate accounts to 31% for stage I, 19% for stage II, 8% for stage III, and 2% for stage IV.
• TNBC triple-negative breast cancer
• ER estrogen receptor
• PR progesterone receptor
• HER2 human epidermal growth factor receptor 2
• TNBCs constitute 10%-20% of all breast cancers, more frequently affect younger patients, and are more prevalent in African-American women (Morris G J, et al. Cancer. 2007; 110(4):876-884).
• TNBC tumors are generally larger in size, are of higher grade, have lymph node involvement at diagnosis, and are biologically more aggressive (Haffty B G, et al. J Clin Oncol. 2006; 24(36):5652-5657).
• presurgical (neoadjuvant) chemotherapy TNBC patients have a higher rate of distant recurrence and a poorer prognosis than women with other breast cancer subtypes (Haffty B G, et al. J Clin Oncol.
• Some aspects relate to a method of treating a cancer in a subject in need thereof.
• the method includes administering to the subject a compound of Formula (I) as a monotherapy,
• Ri, R4, and Re are each separately selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, and saturated Ci,-C24 alkyl, unsaturated Ci- C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, — CO — O — R7, cyano, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl — CH2CO — R7, wherein R7 is selected from a hydrogen atom, a halogen atom, and saturated C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalky
• Ri' and Ri" are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, and saturated C1-C24 alkyl, unsaturated Ci- C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, — CO — O — R7, cyano, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl — CH2CO — R7, wherein R7 is selected from a hydrogen atom, a halogen atom, and saturated C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl
• R, Ri' and Ri are either covalently bound to one another or are not covalently bound to one another;
• R2, R3, and R5 are each separately selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, and saturated C1-C12 alkyl, unsaturated Ci- C12 alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, and substituted nitro groups, sulfonyl and substituted sulfonyl groups;
• m is an integer equal to zero, one or two;
• Xi and X2 are separately selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, and
• Y is selected from the group consisting of a NR5, an oxygen atom, a sulfur atom, a oxidized sulfur atom, a methylene group and a substituted methylene group;
• Z for each separate n, if non-zero, and Zi, Z2, Za and Z4 are each separately selected from a carbon atom, a sulfur atom, a nitrogen atom or an oxygen atom; and the dashed bonds may be either single or double bonds, wherein the cancer is selected from gastric cancer, small cell lung cancer, osteosarcoma, bladder cancer, and triple negative breast cancer.
• the cancer is gastric cancer. In some embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is triple negative breast cancer. In some embodiments, the compound of Formula (I) is administered at a dose from about 5 mg/m 2 to 150 mg/m 2 . In some embodiments, the compound of Formula (I) is administered at a dose greater than 30 mg/m 2 . In some embodiments, the compound of Formula (I) is administered at a dose of about 40 mg/m 2 . In some embodiments, the compound of Formula (I) is administered on day 1 of a 14 day dosing cycle. In some embodiments, the compound of Formula (I) is administered on day 1 of a 21 day dosing cycle.
• the compound of Formula (I) is selected from plinabulin, (3Z,6Z)-3-(phenyl- 2,3,4,5,6-d5)-methylene-6-((5-(tert-butyl)-lH-imidazol-4-yl)methylene)piperazine-2,5-dione; (3Z,6Z)-3-(phenyl-2, 3,4,5, 6-d5)-methylene-d-6-((5-(tert-butyl)- lH-imidazol-4- yl)methylene)piperazine-2, 5-dione; (3Z,6Z)-3-(phenylmethylene-d)-6-((5-(tert-butyl)-lH- imidazol-4-yl)methylene-d)piperazine-2, 5-dione; (3Z, 6Z)-3-(phenyl-2, 3,4,5, 6-ds)-methylene- 6-((5-(tert-butyl)-lH-imid
• the compound of Formula (I) is plinabulin or a pharmaceutically acceptable salt thereof.
• the cancer includes a tumor and a mass of the tumor is reduced from about 50% to about 100%. In some embodiments, the tumor mass is reduced from about 50% to about 70%.
• Some aspects relate to a method of halting or reversing progressive cancer in a subject.
• the method includes administering a compound of Formula (I) as a monotherapy, or a pharmaceutically acceptable salt thereof, wherein:
• Ri, R4, and Re are each separately selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, and saturated Ci,-C24 alkyl, unsaturated Ci- C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, — CO — O — R7, cyano, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl — CH2CO — R7, wherein R7 is selected from a hydrogen atom, a halogen atom, and saturated C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalky
• Ri' and Ri" are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, and saturated C1-C24 alkyl, unsaturated Ci- C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, — CO — O — R7, cyano, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl — CH2CO — R7, wherein R7 is selected from a hydrogen atom, a halogen atom, and saturated C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl
• R, Ri' and Ri are either covalently bound to one another or are not covalently bound to one another;
• R2, R3, and R5 are each separately selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, and saturated C1-C12 alkyl, unsaturated Ci- C12 alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, and substituted nitro groups, sulfonyl and substituted sulfonyl groups; m is an integer equal to zero, one or two;
• Xi and X2 are separately selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, and
• Y is selected from the group consisting NR5, an oxygen atom, a sulfur atom, a oxidized sulfur atom, a methylene group and a substituted methylene group;
• Z for each separate n, if non-zero, and Zi, Z2, Za and Z4 are each separately selected from a carbon atom, a sulfur atom, a nitrogen atom or an oxygen atom; the dashed bonds may be either single or double bonds, wherein the cancer is selected from gastric cancer, small cell lung cancer, osteosarcoma, bladder cancer, and triple negative breast cancer.
• the compound of Formula (I) is plinabulin or a pharmaceutically acceptable salt thereof.
• Some aspects relate to a method of inhibiting proliferation of a cancer cell.
• the method includes contacting the cancer cell with an effective amount of plinabulin and no other chemotherapeutic agent, wherein the cancer cell is from a cancer selected from gastric cancer, small cell lung cancer, osteosarcoma, bladder cancer, and triple negative breast cancer.
• Some aspects relate to a method of inducing apoptosis in a cancer cell.
• the method includes contacting the cancer cell with an effective amount of plinabulin and no other chemotherapeutic agent, wherein the cancer is selected from gastric cancer, small cell lung cancer, osteosarcoma, bladder cancer, and triple negative breast cancer.
• FIG. 1 is a graph illustrating the efficacy of plinabulin monohydrate in a clonogenic assay.
• FIG. 2 is a heatmap illustrating the IC70 values of a study ranked to absolute
• FIG. 3 is a line graph illustrating the concentration-effect curves for plinabulin monohydrate and small cell lung cancer.
• FIG. 4 is a line graph illustrating the concentration-effect curves for plinabulin monohydrate and gastric cancer.
• FIG. 5 is a line graph illustrating the concentration-effect curves for plinabulin monohydrate and triple negative breast cancer.
• FIG. 6 is a graph illustrating the efficacy of plinabulin monohydrate in a clonogenic assay with IC50 values.
• FIG. 7 is a graph illustrating the efficacy of plinabulin monohydrate in a clonogenic assay with IC70 values.
• FIG. 8 is a heatmap illustrating the IC50 values of a study ranked to absolute
• FIG. 9 is a heatmap illustrating the IC70 values of a study ranked to absolute
• FIG. 10 is a line graph illustrating the concentration-effect curves for plinabulin monohydrate and small cell lung cancer.
• FIG. 11 is a line graph illustrating the concentration-effect curves for plinabulin monohydrate and gastric cancer.
• FIG. 12 is a line graph illustrating the concentration-effect curves for plinabulin monohydrate and triple negative breast cancer.
• FIG.13 A is a heatmap illustrating the IC50/IC70 values obtained for plinabulin;
• FIG. 13B is a continuation of the heatmap from FIG. 13 A.
• FIG. 14A is a heatmap illustrating T/C values obtained for plinabulin;
• FIG. 14B is a continuation of the heatmap from FIG. 14A.
• the present disclosure provides methods for treating a cancer or a tumor.
• Some embodiments relate to using Plinabulin to treat a cancer or a tumor, including but not limited to small cell lung cancer, gastric cancer, and triple negative breast cancer.
• methods provided herein are useful in treating, delaying the progression of, preventing relapse of, or alleviating a symptom of a cancer or a tumor, including but not limited to small cell lung cancer, gastric cancer, and triple negative breast cancer.
• the compound of Formula (I) is plinabulin.
• Plinabulin (3Z,6Z)-3-Benzylidene- 6- ⁇ [5-(2-methyl-2-propanyl)-l//-imidazol-4-yl]methylene ⁇ -2,5-piperazinedione, is a synthetic analog of the natural compound phenylahistin.
• plinabulin can be effective as a monotherapy against a cancer or a tumor, including but not limited to small cell lung cancer, gastric cancer, and triple negative breast cancer.
• Methods recited herein may be carried out in any order of the recited events, which is logically possible, as well as the recited order of events.
• agent is used herein to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials.
• ameliorate refers to any reduction in the extent, severity, frequency, and/or likelihood of a symptom or clinical sign characteristic of a particular condition.
• cancer neoplasm
• cancerma a malignant melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma mela, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma
• pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
• the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
• various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al.
• the pharmaceutically acceptable excipient can be a monosaccharide or monosaccharide derivative.
• subject means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
• mammal is used in its usual biological sense.
• primates including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, or the like.
• an effective amount or a “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and can include curing a disease or condition.
• the terms “treat,” “treatment,” or “treating,” as used herein refers to administering a compound or pharmaceutical composition to a subject for prophylactic and/or therapeutic purposes.
• prophylactic treatment refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition.
• therapeutic treatment refers to administering treatment to a subject already suffering from a disease or condition.
• chemotherapeutic agent refers to an agent that reduces, prevents, mitigates, limits, and/or delays the growth of metastases or neoplasms, or kills neoplastic cells directly by necrosis or apoptosis of neoplasms or any other mechanism, or that can be otherwise used, in a pharmaceutically-effective amount, to reduce, prevent, mitigate, limit, and/or delay the growth of metastases or neoplasms in a subject with neoplastic disease.
• Chemotherapeutic agents include but are not limited to, for example, fluoropyrimidines; pyrimidine nucleosides; purine nucleosides; anti-folates, platinum-based agents; anthracyclines/anthracenediones; epipodophyllotoxins; camptothecins; hormones; hormonal complexes; antihormonals; enzymes, proteins, peptides and polyclonal and/or monoclonal antibodies; vinca alkaloids; taxanes; epothilones; antimicrotubule agents; alkylating agents; antimetabolites; topoisomerase inhibitors; antivirals; and various other cytotoxic and cytostatic agents.
• the compounds and therapeutic compositions for treating a cancer or tumor described herein include a compound represented by Formula (I):
• Ri, R4, and Re are each separately selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, and saturated Ci,-C24 alkyl, unsaturated Ci- C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, — CO — O — R7, cyano, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl — CH2CO — R7, wherein R7 is selected from a hydrogen atom, a halogen atom, and saturated C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalky
• Ri' and Ri" are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, and saturated C1-C24 alkyl, unsaturated Ci- C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, — CO — O — R7, cyano, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl — CH2CO — R7, wherein R7 is selected from a hydrogen atom, a halogen atom, and saturated C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl
• R, Ri' and Ri are either covalently bound to one another or are not covalently bound to one another;
• R2, R3, and R5 are each separately selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, and saturated C1-C12 alkyl, unsaturated Ci- C12 alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, and substituted nitro groups, sulfonyl and substituted sulfonyl groups;
• m is an integer equal to zero, one or two;
• Xi and X2 are separately selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, and
• Y is selected from the group consisting of NR5, an oxygen atom, a sulfur atom, a oxidized sulfur atom, a methylene group and a substituted methylene group;
• Z for each separate n, if non-zero, and Zi, Z2, Za and Z4 are each separately selected from a carbon atom, a sulfur atom, a nitrogen atom or an oxygen atom; and the dashed bonds may be either single or double bonds.
• a compound of Formula (I) can be readily prepared according to methods and procedures detailed in U.S. Patent Nos. 7,064,201 and 7,919,497, which are incorporated herein by reference in their entireties.
• the compounds described herein are a dehydrophenylahistin represented by Formula (II): wherein
• R2 and R3 are each separately selected from the group consisting of a hydrogen atom; a halogen atom; mono-substituted; poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C1-C12 alkyl, Ci-C 12 alkenyl, acyl, and alkoxy; and monosubstituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkoxy, aryl, heteroaryl, amino, nitro, and sulfonyl; or R2 is a bond to Ar; R4 and Re are each separately selected from the group consisting of hydrogen; halogen; hydroxyl; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alky
• Xi and X2 are separately selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom substituted with a R5 group;
• Rs is selected from the group consisting of a hydrogen atom, a halogen atom, and saturated C1-C12 alkyl, unsaturated C1-C12 alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, and substituted nitro groups, sulfonyl and substituted sulfonyl groups;
• Y is selected from the group consisting of NR5, an oxygen atom, a sulfur atom, an oxidized sulfur atom, a methylene group, and a substituted methylene group; n is 0, 1, 2, 3, or 4; and
• Ar is a cyclic or polycyclic aryl or heteroaryl ring system comprising between one and three rings, wherein: each ring in said system is separately a 5, 6, 7, or 8 membered ring; each ring in said system separately comprises 0, 1, 2, 3, or 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen; and each ring in said system is optionally substituted with one or more substituents selected from the group consisting of hydrogen; halogen; hydroxyl; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, alkoxy, acyl, arylalkyl, heteroarylalkyl, alkyloxycarbonyloxy, ester, arylalkoxy, alkoxy, and alkylthio; mono-substituted, poly-substituted or un
• a compound of Formula (II) can be readily prepared according to methods and procedures detailed in U.S. Patent Nos. 7,064,201 and 7,919,497, which are incorporated herein by reference in their entireties.
• a compound of Formula (I) is selected from plinabulin, (3Z,6Z)-3-(phenyl-2,3,4,5,6-d5)-methylene-6-((5-(tert-butyl)-lH-imidazol-4- yl)methylene)piperazine-2, 5-dione; (3Z, 6Z)-3-(phenyl-2, 3,4,5, 6-d5)-methylene-d-6-((5-(tert- butyl)-lH-imidazol-4-yl)methylene)piperazine-2, 5-dione; (3Z,6Z)-3-(phenylmethylene-d)-6- ((5-(tert-butyl)-lH-imidazol-4-yl)methylene-d)piperazine-2, 5-dione; (3Z,6Z)-3-(phenyl- 2,3,4,5,6-d5)-methylene-6-((5-(tert-butyl)-lH
• the compound of Formula (I) is plinabulin.
• the compound of Formula (I) is plinabulin monohydrate.
• the compound of Formula (I) is a salt form of plinabulin.
• Plinabulin can be readily prepared according to methods and procedures detailed in U.S. Pat. Nos. 7,064,201 and 7,919,497, which are incorporated herein by reference in their entireties. Use and Method of Treatment
• the present disclosure provides methods and therapeutic compositions for treating, preventing, or ameliorating a cancer or tumor in a subject by administering a compound of Formula (I) (e.g., plinabulin), or a pharmaceutically acceptable salt thereof, as a monotherapy.
• a compound of Formula (I) e.g., plinabulin
• the cancer or tumor is selected from gastric cancer, small cell lung cancer, osteosarcoma, bladder cancer, and triple negative breast cancer.
• the cancer or tumor is gastric cancer.
• the cancer or tumor is small cell lung cancer.
• the cancer or tumor is triple negative breast cancer.
• the method comprises administering the compound of Formula (I) (e.g., plinabulin) at a dose from about 5 mg/m 2 to 150 mg/m 2 . In some embodiments, the method comprises administering the compound of Formula (I) (e.g., plinabulin) at a dose from about 10 mg/m 2 to 50 mg/m 2 . In some embodiments, the method comprises administering the compound of Formula (I) (e.g., plinabulin) at a dose from about 20 mg/m 2 to 30 mg/m 2 . In some embodiments, the compound of Formula (I) (e.g., plinabulin) is administered at a dose that is greater than 20 mg/m 2 .
• the compound of Formula (I) e.g., plinabulin
• the compound of Formula (I) (e.g., plinabulin) is administered at a dose that is greater than 30 mg/m 2 . In some embodiments, the compound of Formula (I) (e.g., plinabulin) is administered at a dose of about 40 mg/m 2 . In some embodiments, plinabulin is administered at a dose of from about 30 mg to about 40 mg. In some embodiments, plinabulin is administered at a dose of about 40 mg.
• the compound of Formula (I) (e.g., plinabulin) is administered on day 1 of a 14 day dosing cycle. In some embodiments, the compound of Formula (I) (e.g., plinabulin) is administered on day 1 of a 21 day dosing cycle.
• Some embodiments relate to a method of halting or reversing a progressive cancer in a subject.
• the method comprises administering a compound of Formula (I) to the subject.
• the cancer cell is from a cancer selected from gastric cancer, small cell lung cancer, osteosarcoma, bladder cancer, and triple negative breast cancer.
• the compound of Formula (I) is plinabulin or a pharmaceutically acceptable salt thereof.
• Some embodiments relate to a method of inhibiting the proliferation of a cancer cell.
• the method comprises contacting the cancer cell with a compound of Formula (I) to the subject.
• the cancer cell is from a cancer selected from gastric cancer, small cell lung cancer, osteosarcoma, bladder cancer, and triple negative breast cancer.
• the compound of Formula (I) is plinabulin or a pharmaceutically acceptable salt thereof.
• Some embodiments relate to a method of inducing apoptosis in a cancer cell.
• the method comprises contacting the cancer cell with a compound of Formula (I) to the subject.
• the cancer cell is from a cancer selected from gastric cancer, small cell lung cancer, osteosarcoma, bladder cancer, and triple negative breast cancer.
• the compound of Formula (I) is plinabulin or a pharmaceutically acceptable salt thereof.
• Some embodiments relate to a method of inhibiting the progression of a cancer.
• the method comprises administering an effective amount of Plinabulin to a subject in need thereof.
• Administration of the pharmaceutical compositions described herein can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, sublingually, buccally, subcutaneously, intravenously, intranasally, intratumorally, topically, transdermally, intradermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly.
• Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.
• compositions described herein may be provided in unit dosage form.
• a "unit dosage form” is a composition containing an amount of a compound or composition that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice.
• the preparation of a single or unit dosage form does not imply that the dosage form is administered once per day or once per course of therapy.
• Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, although a single administration is not specifically excluded.
• the skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.
• compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, sublingual, buccal, nasal, rectal, topical (including transdermal and intradermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration.
• routes for administration for example, for oral, sublingual, buccal, nasal, rectal, topical (including transdermal and intradermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration.
• oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies.
• a variety of pharmaceutically- acceptable carriers well-known in the art may be used.
• Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances.
• Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound or composition.
• the amount of carrier employed in conjunction with the compound or composition is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
• Various oral dosage forms can be used, including such solid forms as tablets, capsules (e.g. solid gel capsules and liquid gel capsules), granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
• Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
• suitable solvents preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
• Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.
• Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
• the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
• Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
• typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate;
• typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
• Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
• compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject composition is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
• dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
• compositions described herein may optionally include additional drug actives.
• compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms.
• Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
• a liquid composition which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye.
• the comfort may be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort.
• the liquid may be formulated such that the liquid is tolerable to the patient for topical ophthalmic use.
• an ophthalmically acceptable liquid may either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
• solutions or medicaments are often prepared using a physiological saline solution as a major vehicle.
• Ophthalmic solutions may preferably be maintained at a comfortable pH with an appropriate buffer system.
• the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
• Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate.
• a useful surfactant is, for example, Tween 80.
• various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
• Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
• buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
• Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxy toluene.
• excipient components which may be included in the ophthalmic preparations, are chelating agents.
• a useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
• Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.
• compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution.
• a pharmaceutically acceptable diluent such as a saline or dextrose solution.
• Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid.
• the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.
• Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA.
• excipients utilized for intravenous delivery may include Kolliphor HS 15 (polyoxyl 15 hydroxy stearate or Solutol HS-15), propylene glycol and 5% dextrose in water (D5W).
• Kolliphor HS 15 polyoxyl 15 hydroxy stearate or Solutol HS-15
• propylene glycol propylene glycol
• 5% dextrose in water D5W
• suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran.
• Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
• plinabulin is added to a light protected bag containing at least 200 ml D5W to achieve 0.08 mg/ml-0.2 mg/ml plinabulin.
• 40 mg of plinabulin crude drug was taken and was added to 6.0 g of propylene glycol, which was then added to 200 ml of D5W.
• plinabulin is a concentrated solution (4mg/ml plinabulin in propylene glycol/polyoxyl 15 hydroxy stearates, 60:40 (wt:wt)).
• the plinabulin in a concentrated solution is added to a D5W injection (e.g., a 1:10 dilution level or a 1:20 dilution level).
• compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
• a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
• the compositions are provided in solution ready to administer parenterally.
• the compositions are provided in a solution that is further diluted prior to administration.
• the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.
• a compound of Formula (I) may be administered at a dose in the range of about 1 mg/m 2 to about 50 mg/m 2 . In some embodiments, a compound of Formula (I) is administered at a dose in the range of about 1-50 mg/m 2 of the body surface area.
• a compound of Formula (I) is administered at a dose in the range of about 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-13.75, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-22.5, 1-25, 1-27.5, 1-30, 1.5-2,
• a compound of Formula (I) is administered at a dose of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16,
• a compound of Formula (I) is administered at a dose less than about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10,
• a compound of Formula (I) is administered at a dose greater than about 0.5, 1,
• a compound of Formula (I) is administered at a dose of about 40 mg/m 2 of the body surface area.
• a compound of Formula (I) dose is about 5 mg - 300 mg, 5 mg -200 mg, 7.5 mg - 200 mg, 10 mg - 100 mg, 15 mg - 100 mg, 20 mg - 100 mg, 30 mg - 100 mg, 40 mg - 100 mg, 10 mg - 80 mg, 15 mg - 80 mg, 20 mg - 80 mg, 30 mg - 80 mg, 40 mg - 80 mg, 10 mg - 60 mg, 15 mg - 60 mg, 20 mg - 60 mg, 30 mg - 60 mg, or about 40 mg - 60 mg.
• a compound of Formula (I) administered is about 20 mg - 60 mg, 27 mg - 60 mg, 20 mg - 45 mg, or 27 mg - 45 mg. In some embodiments, a compound of Formula (I) administered is about 5 mg-7.5 mg, 5 mg-9 mg, 5 mg-10 mg, 5 mg-12mg, 5mg- 14mg, 5mg-15 mg, 5 mg-16 mg, 5 mg-18 mg, 5 mg-20 mg, 5 mg-22 mg, 5 mg-24 mg, 5 mg- 26 mg, 5 mg-28mg, 5mg-30mg, 5mg-32mg, 5mg-34mg, 5mg-36mg, 5mg-38mg, 5mg-40mg, 5mg-42mg, 5mg-44mg, 5mg-46mg, 5mg-48mg, 5mg-50mg, 5mg-52mg, 5mg-54mg, 5mg- 56mg, 5mg-58mg, 5mg
• a compound of Formula (I) dose is greater than about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150mg, or about 200 mg.
• a compound of Formula (I) dose is about less than about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150mg, or about 200 mg.
• the treatment schedule includes administration of a compound of Formula (I) once every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes administration of a compound of Formula (I) two times every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes administration of a compound of Formula (I) once every 1 week in a treatment cycle of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.
• the treatment schedule includes administration of a compound of Formula (I) twice every 1 week in a treatment cycle of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes the administration of a compound of Formula (I) on day 1, day 8, and day 15 of a 21-day treatment cycle.
• the treatment cycle can be repeated as long as the regimen is clinically tolerated.
• the treatment cycle for a compound of Formula (I) is repeated for n times, wherein n is an integer in the range of 2 to 30.
• n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• a new treatment cycle can occur immediately after the completion of the previous treatment cycle.
• a new treatment cycle can occur a period of time after the completion of the previous treatment cycle.
• a new treatment cycle can occur after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 7 weeks after the completion of the previous treatment cycle.
• plinabulin was characterized for its ability to inhibit anchorage independent growth and ex vivo colony formation of tumor cells in semi- solid medium.
• the compound was investigated in 87 out of 93 originally planned tumor xenografts representing all major cancer types using a 3D clonogenic assay in a 96-well format with colony count based on image analysis as read-out. By using this assay, the investigational compound was assessed for the ability to inhibit anchorage independent growth and ex vivo colony formation of tumor cells in semi-solid medium.
• a master stock solution of plinabulin was prepared by dissolving the compound in DMSO at a concentration of 9.9 mM.
• Working stock solutions were prepared by diluting the master stock solution with DMSO to a concentration of 0.99 mM (330-fold the highest test concentration). Small aliquots of the master and working stock were stored at -20 °C. On each day of an experiment, an aliquot of the working stock was used and stored at room temperature prior to and during treatment. All liquid handling steps were performed using a Tecan Freedom EVO 200 robotic platform. First, serial dilutions of the working stock solution were done in DMSO. The DMSO dilutions were then diluted 1:22 into cell culture medium (IMDM, supplemented with 20% (v/v) fetal calf serum, and 50 pg/ml gentamicin) in an intermediate dilution plate.
• IMDM cell culture medium
• Plinabulin was investigated in 87 PDX models representing a number of cancer types. Tumors were passaged as subcutaneous xenografts in NMRI nu/nu mice. At a tumor volume of 400-1000 mm 3 tumor-bearing mice were euthanized and tumors were collected under sterile conditions without delay according to relevant SOPs and the relevant animal welfare guidelines published by the FEEASA and the GV-SOEAS.
• Tumors were mechanically disaggregated and subsequently incubated with an enzyme cocktail consisting of collagenase type IV (41 U/ml), DNase I (125 U/ml), hyaluronidase type III (100 U/ml), and dispase II (1 U/ml) in RPMI 1640 medium (Life Technologies) at 37°C for 60 - 120 minutes.
• Cells were passed through sieves of 100 pm and 40 pm mesh size (Cell Strainer, BD FalconTM), and washed with RPMI 1640 medium (Biochrom). The percentage of viable cells was determined in a Neubauer-hemocytometer using trypan blue exclusion. Aliquots of the cells were frozen down and stored in a liquid nitrogen vapor phase. On each day of an experiment, a frozen aliquot of tumor cells was thawed and used for the preparation of assay plates.
• each test well contained a layer of semi-solid medium with tumor cells (50 pl), and a second layer of medium supernatant with or without test compound (100 pl).
• the cell layer consisted of 2.5-12.5 x 10 3 tumor cells per well, which were seeded on day 0 (dO) in 50 p 1/well cell culture medium (IMDM, supplemented with 20% (v/v) fetal calf serum, 50 pg/ml gentamicin, and 0.4% (w/v) agar).
• IMDM 50 p 1/well cell culture medium
• the soft-agar layer was covered with 90 pl of the same culture medium without agar. Seven days after seeding 10 pl of test compound or control medium was added, and left on the cells for 24 h. Every 96 well plate included six DMSO-treated control wells and drug-treated wells in duplicate at 9 concentrations. After the incubation time of 24 h the supernatant (90 pl medium without agar + 10 pl compound/control) was changed against drug free medium and incubated until the end of the study. Cultures were incubated at 37 °C and 7.5 % CO2 in a humidified atmosphere 13 days in total and monitored closely for colony growth using an inverted microscope.
• the present study investigated plinabulin for anticancer activity ex vivo in 68 out of 71 originally planned patient-derived xenograft (PDX) models representing major cancer types. Experiments were performed using a 3D clonogenic assay in a 96-well format with colony count based on image analysis as a read-out. By using this assay, the investigational compound was assessed for the ability to inhibit anchorage independent growth and ex vivo colony formation of tumor cells in semi-solid medium.
• PDX patient-derived xenograft
• a master stock solution of plinabulin was prepared by dissolving the compound in DMSO at a concentration of 9.9 mM.
• Working stock solutions were prepared by diluting the master stock solution with DMSO to a concentration of 0.99 mM (330-fold the highest test concentration). Small aliquots of the master and working stock were stored at - 20 °C. On each day of an experiment, an aliquot of the working stock was used and stored at room temperature prior to and during treatment. All liquid handling steps were performed using a Tecan Freedom EVO 200 robotic platform. First, serial dilutions of the working stock solution were done in DMSO.
• DMSO dilutions were then diluted 1:22 into the cell culture medium (IMDM, supplemented with 20% (v/v) fetal calf serum, and 50 pg/ml gentamicin) in an intermediate dilution plate. Finally, 10 pl taken from the intermediate dilution plate were transferred to 140 pl/well of the final assay plate. Thus, the DMSO working stock was diluted at 1:330, and the DMSO concentration in the assay was 0.3% v/v in all wells. [0093] Plinabulin was investigated in 68 PDX models representing a number of cancer types. Tumors were passaged as subcutaneous xenografts in NMRI nu/nu mice.
• tumor-bearing mice were euthanized and tumors were collected under sterile conditions without delay according to relevant SOPs and the relevant animal welfare guidelines published by the FELASA and the GV-SOLAS.
• Tumors were mechanically disaggregated and subsequently incubated with an enzyme cocktail consisting of collagenase type IV (41 U/ml), DNase I (125 U/ml), hyaluronidase type III (100 U/ml), and dispase II (1 U/ml) in RPMI 1640 medium (Life Technologies) at 37°C for 60 - 120 minutes.
• Cells were passed through sieves of 100 pm and 40 pm mesh size (Cell Strainer, BD FalconTM), and washed with RPMI 1640 medium (Biochrom). The percentage of viable cells was determined in a Neubauer-hemocytometer using trypan blue exclusion. Aliquots of the cells were frozen down and stored in a liquid nitrogen vapor phase. On each day of an experiment, a frozen aliquot of tumor cells was thawed and used for the preparation of assay plates.
• each test well contained a layer of semi-solid medium with tumor cells (50 pl), and a second layer of medium supernatant with or without test compound (100 pl).
• the cell layer consisted of 2.5-12.5- 10 3 tumor cells per well, which were seeded on day 0 (dO) in 50 pl/well cell culture medium (IMDM, supplemented with 20% (v/v) fetal calf serum, 50 pg/ml gentamicin, and 0.4% (w/v) agar).
• the soft- agar layer was covered with 90 pl of the same culture medium without agar. Seven days after seeding 10 pl of test compound or control medium was added, and left on the cells for 24 h. Every 96 well plate included six DMSO-treated control wells and drug-treated wells in duplicate at 9 concentrations. After the incubation time of 24 h the supernatant (90 pl medium without agar + 10 pl compound/control) was changed against drug free medium and incubated until the end of the study. Cultures were incubated at 37 °C and 7.5 % CO2 in a humidified atmosphere 13 days in total and monitored closely for colony growth using an inverted microscope.
• Plinabulin inhibited tumor colony formation with a geometric mean absolute IC50 value of 0.6 pM (FIG. 6 and FIG. 9). Based on absolute IC50 24 out of 68 tumor models were sensitive toward plinabulin with a 10.7-fold difference of absolute IC50 of sensitive versus all models (Table 2).
• the most responsive models based on abs. IC70 were the small cell lung cancer models LXFS 2156 (abs.

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