WO2012135856A2

WO2012135856A2 - Very low dose vinorelbine for treatment of cancer

Info

Publication number: WO2012135856A2
Application number: PCT/US2012/031895
Authority: WO
Inventors: George F. TIDMARSH
Original assignee: Spectrum Pharmaceuticals, Inc.
Priority date: 2011-04-01
Filing date: 2012-04-02
Publication date: 2012-10-04
Also published as: WO2012135856A3

Abstract

The present specification discloses compositions comprising a vinca alkaloid and methods of treating a non-hematologic tumor using a daily administration of such compositions at a low non-toxic dose for an extended period of time.

Description

Very Low Dose Vinorelbine For Treatment of Cancer

George Tidmarsh

PRIORITY CLAIM

[01]This patent application claims priority pursuant to 35 U.S.C. § 1 19(e) to U. S. Provisional Patent Application Serial No. 61/471 ,031 , filed April 1 , 201 1 , which is hereby incorporated by reference in its entirety.

INTRODUCTION

[02]Cancer is a group of more than 100 diseases in which a group of cells display uncontrolled growth (cell division beyond the normal limits). In most cases, cancer cells form a clump of cells called a tumor, although in some cancers, like leukemia, the cells do not form solid tumors. Tumors may be malignant or benign. Besides, malignant tumors (or cancers) comprise cells with abnormal genetic material and usually undergo rapid uncontrolled cell growth, invade and destroy adjacent tissue, and sometimes spread to other locations in the body via lymph or blood (i.e., metastasis). Cancer is associated with a high incidence of mortality because if the invasion and metastasis of the cancer cells throughout the body are not stopped, cancer cells will invade vital organs and lead to the dysfunction of the organs and eventual death. The malignant properties of cancers differentiate them from benign tumors, which are usually slow-growing and self-limited, do not invade or metastasize, and as such, are generally not life- threatening. Cancers at the local, regional or distant stage are considered invasive. A very early cancer found in only a few layers of cells, called in situ cancer, is considered non-invasive.

[03]Cancer is a diverse class of diseases which differ widely in their causes and biology. Cancers are caused by a variety of factors working alone or in combination. Some cancers are caused by external factors such as tobacco, diet, certain chemicals, radiation, and viruses. Other cancers are caused by internal factors such as hormones, immune conditions, and inherited genetic mutations. Usually ten or more years pass between exposure to a factor that causes cancer and detectable disease.

[04]Cancers are generally classified by the type of cell that resembles the tumor and, therefore, the tissue presumed to be the origin of the tumor. Carcinomas are malignant tumors derived from epithelial cells. This group represents the most common cancers, including the common forms of breast, prostate, lung and colon cancer. Sarcomas are malignant tumors derived from connective tissue, or mesenchymal cells. Blastomas are usually malignant tumors which resembles an immature or embryonic tissue. Many of these tumors are most common in children. Lymphomas and leukemias are malignancies derived from hematopoietic (blood-forming) cells. Lastly, germ cell tumors are tumors derived from totipotent cells. In adults they are most often found in the testicle and ovary; in fetuses, babies, and young children they are most often found on the body midline, particularly at the tip of the tailbone. [05]Cancer is the second leading cause of death in the U.S., with 1 ,228,600 new cases and 564,800 deaths estimated for 1998. Over the past 50 years, the death rate from cancer has increased steadily, due mainly to a large rise in lung cancer death rates resulting from smoking. Cancer occurs in people of all ages, but its occurrence increases greatly in people over 45 years of age. However, cancer is the leading cause of death in the United States for people between the ages of 35 and 65 and it is also the leading cause of non-accidental death among U.S. children under age 15. Men have a higher mortality rate due to cancer than women, and blacks have the highest cancer mortality rate of any major racial group. In the U.S., men have about a 1 in 2 lifetime risk of developing cancer and women have about a 1 in 3 lifetime risk. With the continued decrease in deaths from heart disease and strokes, cancer has now become the overall leading cause of death for the entire American population.

[06]Diagnosis of cancer usually requires a histological examination of a tissue biopsy specimen by a pathologist, although the initial indication of malignancy can be symptoms or radiographic imaging abnormalities. Once diagnosed, cancer is commonly treated by surgery, chemotherapy, radiotherapy, or targeted therapies like immunotherapy, hormonal therapy, or angiogenesis inhibitor therapy. The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient (performance status). Furthermore, depending on the type and stage of the cancer, two or more of these types of cancer treatments may be combined at the same time or used after one another. Although complete removal of the cancer without damage to the rest of the body is the goal of treatment, current approaches to treating cancer have met with limited success. With respect to surgery, this is due, in part, to the propensity of individual or small numbers of cancer cells to invade adjacent tissue or metastasis to distant sites, thereby limiting the effectiveness of local surgical treatments. The effectiveness of chemotherapy and radiotherapy is often limited by toxicity to or damage of normal tissues in the body. Although targeted therapies are promising, as implied by their name, these treatments are usually specific for one particular type of cancer. Therefore, compounds and methods that can target all cancer cells, regardless of their location would be highly desirable for the treatment of cancer. In addition, compounds and methods that can target a particular type of cancer for which no current targeted therapy exists would also be highly desirable.

[07] For almost half a century, systemic treatment of cancer has been dominated by the use of cytotoxic chemotherapeutics typically administered in single doses or short courses of treatment at the highest doses that do not cause life-threatening levels of toxicity. This maximum tolerated dose therapy requires prolonged breaks (often 2-3 weeks in duration) between successive cycles of therapy due to the toxic side effects frequently associated with the dosing regimen. Unfortunately, maximum tolerated dose therapy has produced but modest benefits in terms of curing or significantly prolonging the lives of patients with cancer.

[08] For example, vinca alkaloids are used in the treatment of cancer for their ability to disrupt cellular division. The conventional dose of a vinca alkaloid is 25-30 mg/m², when intravenously administered once weekly, or 60-80 mg/m², when orally administered once weekly. However, vinca alkaloids have a number of side-effects that can limit its use, including bone marrow suppression (which is dose-limiting), gastrointestinal toxicity, potent vesicant (blister-forming) activity, and extravasation injury (forms deep ulcers), peripheral neuropathy, lowered resistance to infection, bruising or bleeding, anemia, constipation, diarrhea, nausea, tiredness and a general feeling of weakness (asthenia), inflammation of the vein into which it was injected (phlebitis), severe hyponatremia, hair loss and allergic reaction.

[09]lnstead of using short bursts of the maximum tolerated dose chemotherapy interspersed with long breaks to allow recovery from the harmful side effects, the present specification discloses a dose therapy involving the frequent, even daily, administration of chemotherapeutic agents at doses significantly below the maximum tolerated dose, without prolonged drug-free breaks. Such a low-dose therapy appears to be more effective than maximum tolerated dosing regimens in terms of both reducing toxicity and improving anti-tumor effects. For example, the present specification disclosure the utility of a dose therapy involving the daily administration a vinca alkaloid at about 1-10 mg/day. Thus, it has been discovered that daily administration of a very low dose of a vinca alkaloid for an extended period provides significant therapeutic benefit.

SUMMARY

[010] Aspects of the present specification disclose methods of treating a non-hematologic tumor in an individual in need thereof. The methods comprising the step of administering a vinca alkaloid at a daily dose significantly below the maximum tolerated dose for an extended period of time.

[011] Other aspects of the present specification disclose compositions comprising 10 mg or less of a vinca alkaloid, 100 mg or more of a polyol, and 5 mg or less of a fatty acid, wherein the total weight of the composition is about 125 mg.

[012] Yet other aspects of the present specification disclose compositions comprising between about 0.5% (w/w) to about 1 1 % (w/w) of a vinca alkaloid, between about 79%(w/w) to about 99% (w/w) of a polyol, and about 0.5%(w/w) to about 10%(w/w) of a fatty acid, wherein the composition comprises 10 mg or less of the vinca alkaloid.

[013] Still other aspects of the present specification disclose pharmaceutical kits comprising a) a composition comprising 10 mg or less of a vinca alkaloid, 100 mg or more of a polyol, and 5 mg or less of a fatty acid, wherein the total weight of the composition is about 125 mg; and b) instructions for daily administration over an extended period of time.

[014] Other aspects of the present specification disclose pharmaceutical kits comprising a) a composition comprising between about 0.5% (w/w) to about 1 1 % (w/w) of a vinca alkaloid, between about 79%(w/w) to about 99% (w/w) of a polyol, and about 0.5%(w/w) to about 10%(w/w) of a fatty acid, wherein the composition comprises 10 mg or less of the vinca alkaloid; and b) instructions for daily administration over an extended period of time. BREIF DESCRIPTION OF DRAWINGS

[015] FIG. 1 shows maximum percent increase in serum VEGF concentration of each subject from Study Day 1 to either Study Day 8 or Week 3.

[016] FIG. 2 shows maximum percent increase in CECs of each subject from Study Day 1 to either Study Day 8 or Week 3.

[017] FIG. 3 shows maximum percent increase in CTCs of each subject from Study Day 1 to either Study Day 8 or Week 3.

DESCRIPTION

[018] Aspects of the present specification disclose, in part, a vinca alkaloid. Vinca alkaloids are a set of anti-mitotic and anti-microtubule agents that were originally derived from the Periwinkle plant Catharanthus roseus. These compounds are a class of M phase cell cycle specific cytotoxic drugs that bind tubulin dimers and prevent their assembly of microtubules, a necessary component of the mitotic spindle and kinetochore which are essential for chromosomal separation during anaphase of mitosis. As such, vinca alkaloids prevent cell division by inhibiting microtubule polymerization, which causes mitotic cells to arrest in metaphase. As anti-mitotic and anti-microtubule drugs, vinca alkaloids affect all rapidly dividing cell types including cancer cells, but also those of intestinal epithelium and bone marrow cells.

[019] Vinca alkaloids may be produced synthetically and include, without limitation, vinblastine, vincristine, vindesine, vinflunine, and vinorelbine (Table 1 ). Vinca alkaloids useful in aspects of the present specification include the free base of a vinca alkaloid as well as any pharmaceutically-acceptable salt of a vinca alkaloid, such as, e.g. , a vinca alkaloid tartrate. In aspects of this embodiment, a vinca alkaloid is a vinblastine free base, a vincristine free base, a vindesine free base, a vinflunine free base, or a vinorelbine free base. In other aspects of this embodiment, a vinca alkaloid is a pharmaceutically- acceptable salt of a vinblastine, a pharmaceutically-acceptable salt of a vincristine, a pharmaceutically- acceptable salt of a vindesine, a pharmaceutically-acceptable salt of a vinflunine, or a pharmaceutically- acceptable salt of a vinorelbine. In other aspects of this embodiment, a vinca alkaloid is vinblastine tartrate, vincristine tartrate, vindesine tartrate, vinflunine tartrate, or vinorelbine tartrate.

Table 1. Vinca Alkaloid Compounds

vinblastine

[020] Aspects of the present specification disclose, in part, a composition. A composition disclosed herein may comprise a single vinca alkaloid or a plurality of vinca alkaloids. In aspects of this embodiment, a composition can comprise, e.g., two or more vinca alkaloids disclosed herein, three or more vinca alkaloids disclosed herein, four or more vinca alkaloids disclosed herein, or five or more vinca alkaloids disclosed herein.

[021] A composition comprising a vinca alkaloid is generally administered to an individual as a pharmaceutical composition. Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one vinca alkaloid as disclosed herein as an active ingredient, with conventional acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for therapeutic use. As used herein, the term "pharmaceutical composition" refers to a therapeutically effective concentration of an active compound, such as, e.g., any of the vinca alkaloids disclosed herein. Preferably, the pharmaceutical composition does not produce an adverse, allergic, or other untoward or unwanted reaction when administered to an individual. A pharmaceutical composition disclosed herein is useful for medical and veterinary applications. A pharmaceutical composition may be administered to an individual alone, or in combination with other supplementary active compounds, agents, drugs or hormones. The pharmaceutical compositions may be manufactured using any of a variety of processes, including, without limitation, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, and lyophilizing. The pharmaceutical composition can take any of a variety of forms including, without limitation, a sterile solution, suspension, emulsion, lyophilizate, tablet, pill, pellet, capsule, powder, syrup, elixir, or any other dosage form suitable for administration.

[022] A pharmaceutical composition disclosed herein can optionally include a pharmaceutically acceptable carrier that facilitates processing of an active compound into pharmaceutically acceptable compositions. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio. As used herein, the term "pharmacologically acceptable carrier" is synonymous with "pharmacological carrier" and refers to any carrier that has substantially no long term or permanent detrimental effect when administered and encompasses terms such as "pharmacologically acceptable vehicle, stabilizer, diluent, additive, auxiliary, or excipient." Such a carrier generally is mixed with an active compound or permitted to dilute or enclose the active compound and can be a solid, semi-solid, or liquid agent. It is understood that the active compounds can be soluble or can be delivered as a suspension in the desired carrier or diluent. Any of a variety of pharmaceutically acceptable carriers can be used including, without limitation, aqueous media such as, e.g., water, saline, glycine, hyaluronic acid and the like; solid carriers such as, e.g., starch, magnesium stearate, mannitol, sodium saccharin, talcum, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, and the like; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient. Selection of a pharmacologically acceptable carrier can depend on the mode of administration. Except insofar as any pharmacologically acceptable carrier is incompatible with the active compound, its use in pharmaceutically acceptable compositions is contemplated. Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7^th ed. 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20^th ed. 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional, 10^th ed. 2001 ); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4^th edition 2003). These protocols are routine and any modifications are well within the scope of one skilled in the art and from the teaching herein.

[023] A pharmaceutical composition disclosed herein can optionally include, without limitation, other pharmaceutically acceptable components (or pharmaceutical components), including, without limitation, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like. Various buffers and means for adjusting pH can be used to prepare a pharmaceutical composition disclosed herein, provided that the resulting preparation is pharmaceutically acceptable. Such buffers include, without limitation, acetate buffers, borate buffers, citrate buffers, phosphate buffers, neutral buffered saline, and phosphate buffered saline. It is understood that acids or bases can be used to adjust the pH of a composition as needed. Pharmaceutically acceptable antioxidants include, without limitation, sodium m eta bisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Useful preservatives include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilized oxy chloro composition, such as, e.g. , sodium chlorite and chelants, such as, e.g., DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity adjustors useful in a pharmaceutical composition include, without limitation, salts such as, e.g., sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity adjustor. The pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. It is understood that these and other substances known in the art of pharmacology can be included in a pharmaceutical composition useful in the invention. [024] Liquid dosage forms suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethyleneglycol (PEG), glycerol, and the like), suitable mixtures thereof, vegetable oils (such as. e.g., rapeseed oil and olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. In liquid formulations, a therapeutically effective amount of a vinca alkaloid disclosed herein typically is between about 0.0001 % (w/v) to about 50% (w/v), about 0.001 % (w/v) to about 10.0% (w/v), or about 0.01 % (w/v) to about 1.0% (w/v).

[025] Solid dosage forms suitable for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, as for example, paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. In solid formulations, a therapeutically effective amount of a vinca alkaloid disclosed herein is typically is between about 0.001 mg/kg to about 0.200 mg/kg, about 0.01 mg/kg to about 0.150 mg/kg, or about 0.1 mg/kg to about 0.100 mg/kg. Additionally, in solid formulations, a therapeutically effective amount of a compound disclosed herein is typically is between about 0.01 mg/m²/day to about 5 mg/m²/day, about 0.1 mg/m²/day to about 2.5 mg/m²/day, or about 0.25 mg/m²/day to about 2 mg/m²/day.

[026] In one embodiment, a solid dosage forms suitable for oral administration comprises a vinca alkaloid, a sugar, and a fatty acid. As used herein, the term "sugar" refers to a compound comprising one to 10 monosaccharide units, e.g. , a monosaccharide, a disaccharide, a trisaccharide, and an oligosaccharide comprising four to ten monosaccharide units. It is envisioned that any sugar is useful in formulating a vinca alkaloid pharmaceutical compositions disclosed in the present specification, with the proviso that a therapeutically effective amount of the vinca alkaloid active ingredient is recovered using this sugar. Monosaccharides are polyhydroxy aldehydes or polyhydroxy ketones with three or more carbon atoms, including aldoses, dialdoses, aldoketoses, ketoses and diketoses, as well as cyclic forms, deoxy sugars and amino sugars, and their derivatives, provided that the parent monosaccharide has a (potential) carbonyl group. Monosacchrides include trioses, like glyceraldehyde and dihydroxyacetone; tetroses, like erythrose, threose and erythrulose; pentoses, like arabinose, lyxose, ribose, xylose, ribulose, xylulose; hexoses, like allose, altrose, galactose, glucose, gulose, idose, mannose, talose, fructose, psicose, sorbose, tagatose, fucose, rhamnose; heptoses, like sedoheptulose and mannoheptulose; octooses, like octulose and 2-keto-3-deoxy-manno-octonate; nonoses like sialose; and decose. Oligosaccharides are compounds in which at least two monosaccharide units are joined by glycosidic linkages. According to the number of units, they are called disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, hexoaccharides, heptoaccharides, octoaccharides, nonoaccharides, decoaccharides, etc. An oligosaccharide can be unbranched, branched or cyclic. Common disaccharides include, without limitation, sucrose, lactose, maltose, trehalose, cellobiose, gentiobiose, kojibiose, laminaribiose, mannobiose, melibiose, nigerose, rutinose, and xylobiose. Common trisaccharides include, without limitation, raffinose, acarbose, maltotriose, and melezitose. Other non- limiting examples of specific uses of sugar excipients can be found in, e.g. , Ansel, supra, (1999); Gennaro, supra, (2000); Hardman, supra, (2001 ); and Rowe, supra, (2003), each of which is hereby incorporated by reference in its entirety.

[027] In aspects of this embodiment, the amount of sugar added to a solid dosage form may be, e.g. , at least 60% (w/w), at least 70% (w/w), at least 80% (w/w), at least 85% (w/w), at least 90% (w/w), at least 93% (w/w), at least 95% (w/w), at least 97% (w/w), at least 98% (w/w), or at least 99% (w/w). In other aspects of this embodiment, the amount of sugar added to a solid dosage form may be between, e.g., about 60% (w/w) to about 99% (w/w), about 70% (w/w) to about 99% (w/w), about 80% (w/w) to about 99% (w/w), about 85% (w/w) to about 99% (w/w), about 90% (w/w) to about 99% (w/w), about 93% (w/w) to about 99% (w/w), about 95% (w/w) to about 99% (w/w), about 60% (w/w) to about 98% (w/w), about 70% (w/w) to about 98% (w/w), about 80% (w/w) to about 98% (w/w), about 85% (w/w) to about 98% (w/w), about 90% (w/w) to about 98% (w/w), about 93% (w/w) to about 98% (w/w), or about 95% (w/w) to about 98% (w/w).

[028] As used herein, the term "fatty acid" refers to a molecule comprising a carboxylic acid with a long unbranched hydrocarbon chain which may be either saturated or unsaturated. This arrangement confers a fatty acid with a polar, hydrophilic end, and a nonpolar, hydrophobic end that is insoluble in water. Most naturally occurring fatty acids have a hydrocarbon chain of an even number of carbon atoms, typically between 4 and 24 carbons, and may be attached to functional groups containing oxygen, halogens, nitrogen, and sulfur. Synthetic or non-natural fatty acids may have a hydrocarbon chain of any number of carbon atoms from between 3 and 40 carbons. Where a double bond exists, there is the possibility of either a cis or a trans geometric isomerism, which significantly affects the molecule's molecular configuration. Cis-double bonds cause the fatty acid chain to bend, an effect that is more pronounced the more double bonds there are in a chain. Most naturally occurring fatty acids are of the cis configuration, although the trans form does exist in some natural and partially hydrogenated fats and oils. Examples of fatty acids include, without limitation, Capryllic acid (8:0), Pelargonic acid (9:0), Capric acid (10:0), Undecylic acid (1 1 :0), Laurie acid (12:0), Tridecylic acid (13:0), Myristic acid (14:0), Myristoleic acid (14:1 ), Pentadecyclic acid (15:0), Palmitic acid (16:0), Palmitoleic acid (16: 1 ), Sapienic acid (16: 1 ), Margaric acid (17:0), Stearic acid (18:0), Oleic acid (18: 1 ), Elaidic acid (18:1 ), Vaccenic acid (18:1 ), Linoleic acid (18:2), Linoelaidic acid (18:2), oLinolenic acid (18:3), γ-Linolenic acid (18:3), Stearidonic acid (18:4), Nonadecylic acid (19:0), Arachidic acid (20:0), Eicosenoic acid (20:1 ), Dihomo-Y-linolenic acid (20:3), Mead acid (20:3), Arachidonic acid (20:4), Eicosapentaenoic acid (20:5), Heneicosylic acid (21 :0), Behenic acid (22:0), Erucic acid (22: 1 ), Docosahexaenoic acid (22:6), Tricosylic acid (23:0), Lignoceric acid (24:0), Nervonic acid (24:1 ), Pentacosylic acid (25:0), Cerotic acid (26:0), Heptacosylic acid (27:0), Montanic acid (28:0), Nonacosylic acid (29:0), Melissic acid (30:0), Henatriacontylic acid (31 :0), Lacceroic acid (32:0), Psyllic acid (33:0), Geddic acid (34:0), Ceroplastic acid (35:0), and Hexatriacontylic acid (36:0).

[029] In an embodiment, a solid dosage forms suitable for oral administration comprises a pharmaceutically-acceptable saturated or unsaturated fatty acid. In aspects of this embodiment, a saturated or unsaturated fatty acid comprises, e.g., at least 8, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 22, at least 24, at least 26, at least 28, or at least 30 carbon atoms, In other aspects of this embodiment, a saturated or unsaturated fatty acid comprises, e.g., between 4 and 24 carbon atoms, between 6 and 24 carbon atoms, between 8 and 24 carbon atoms, between 10 and 24 carbon atoms, between 12 and 24 carbon atoms, between 14 and 24 carbon atoms, or between 16 and 24 carbon atoms, between 4 and 22 carbon atoms, between 6 and 22 carbon atoms, between 8 and 22 carbon atoms, between 10 and 22 carbon atoms, between 12 and 22 carbon atoms, between 14 and 22 carbon atoms, or between 16 and 22 carbon atoms, between 4 and 20 carbon atoms, between 6 and 20 carbon atoms, between 8 and 20 carbon atoms, between 10 and 20 carbon atoms, between 12 and 20 carbon atoms, between 14 and 20 carbon atoms, or between 16 and 20 carbon atoms. If unsaturated, the fatty acid may have, e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more double bonds.

[030] In other aspects of this embodiment, the amount of fatty acid added to a solid dosage form may be, e.g., at most 0.5% (w/w), at most 1.0% (w/w), at most 2.0% (w/w), at most 3.0% (w/w), at most 4.0% (w/w), at most 5.0% (w/w), at most 6.0% (w/w), at most 7.0% (w/w), at most 8.0% (w/w), at most 9.0% (w/w), or at most 10% (w/w). In yet other aspects of this embodiment, the amount of fatty acid added to a solid dosage form may be between, e.g., about 0.5% (w/w) to about 10% (w/w), about 0.5% (w/w) to about 9% (w/w), about 0.5% (w/w) to about 8% (w/w), about 0.5% (w/w) to about 7% (w/w), about 0.5% (w/w) to about 6% (w/w), about 0.5% (w/w) to about 5% (w/w), about 0.5% (w/w) to about 4% (w/w), about 0.5% (w/w) to about 3% (w/w), about 0.5% (w/w) to about 2% (w/w), or about 0.5% (w/w) to about 1 % (w/w).

[031] In another embodiment, a solid dosage form suitable for oral administration comprises a vinca alkaloid, a polyol, and a lubricant. As used herein, the term "polyol" is synonymous with "sugar alcohol," "polyhydric alcohol," and "polyalcohol" and refers to a sugar derivative having an alcohol group (CH₂OH) instead of the aldehyde group (CHO), such as, e.g., mannitol from mannose, xylitol from xylose, and lactitol from lactulose. It is envisioned that any polyol is useful in formulating a vinca alkaloid pharmaceutical compositions disclosed in the present specification, with the proviso that a therapeutically effective amount of the vinca alkaloid active ingredient is recovered using this polyol. Non-limiting examples of polyols include, glycol, glycerol, arabitol, erythritol, xylitol, maltitol, sorbitol (gluctiol), mannitol, inositol, lactitol, galactitol (iditol), isomalt. Other non-limiting examples of sugar excipients can be found in, e.g. , Ansel, supra, (1999); Gennaro, supra, (2000); Hardman, supra, (2001 ); and Rowe, supra, (2003), each of which is hereby incorporated by reference in its entirety.

[032] In aspects of this embodiment, the amount of polyol added to a solid dosage form may be, e.g., at least 60% (w/w), at least 70% (w/w), at least 80% (w/w), at least 85% (w/w), at least 90% (w/w), at least 93% (w/w), at least 95% (w/w), at least 97% (w/w), at least 98% (w/w), or at least 99% (w/w). In other aspects of this embodiment, the amount of polyol added to a solid dosage form may be between, e.g., about 60% (w/w) to about 99% (w/w), about 70% (w/w) to about 99% (w/w), about 80% (w/w) to about 99% (w/w), about 85% (w/w) to about 99% (w/w), about 90% (w/w) to about 99% (w/w), about 93% (w/w) to about 99% (w/w), about 95% (w/w) to about 99% (w/w), about 60% (w/w) to about 98% (w/w), about 70% (w/w) to about 98% (w/w), about 80% (w/w) to about 98% (w/w), about 85% (w/w) to about 98% (w/w), about 90% (w/w) to about 98% (w/w), about 93% (w/w) to about 98% (w/w), or about 95% (w/w) to about 98% (w/w).

[033] In another embodiment, a solid dosage form suitable for oral administration comprises about 10 mg or less of a vinca alkaloid, about 100 mg or more of polyol, and about 5 mg or less of a fatty acid between 16 and 24 carbons, wherein the total weight of the composition is about 125 mg. In aspects of this embodiment, a solid dosage form suitable for oral administration comprises between about 0.5 mg to about 10 mg of a vinca alkaloid, between about 100 mg to about 124 mg of a polyol, and between 0.5 mg to about 5 mg of a fatty acid between 16 and 24 carbons, wherein the total weight of the composition is about 125 mg. In other aspects of this embodiment, a solid dosage forms suitable for oral administration comprises between about 1 mg to about 5 mg of a vinca alkaloid, between about 100 mg to about 123.5 mg of a polyol, and between 0.5 mg to about 3 mg of a fatty acid between 16 and 24 carbons, wherein the total weight of the composition is about 125 mg. In yet other aspects of this embodiment, a solid dosage form suitable for oral administration comprises between about 1 mg to about 3 mg of a vinca alkaloid, between about 100 mg to about 123.5 mg of a polyol, and between 0.5 mg to about 1.5 mg of a fatty acid between 16 and 24 carbons, wherein the total weight of the composition is about 125 mg. In another aspect of this embodiment, the solid dosage form is alcohol-free.

[034] In yet another embodiment, a solid dosage form suitable for oral administration comprises about 10 mg or less of a vinorelbine, about 100 mg or more of an isomalt, and about 5 mg or less a magnesium stearate, wherein the total weight of the composition is about 125 mg. In aspects of this embodiment, a solid dosage form suitable for oral administration comprises between about 0.5 mg to about 10 mg of a vinorelbine, between about 100 mg to about 124 mg of an isomalt, and between 0.5 mg to about 5 mg of a magnesium stearate, wherein the total weight of the composition is about 125 mg. In other aspects of this embodiment, a solid dosage form suitable for oral administration comprises between about 1 mg to about 5 mg of a vinorelbine, between about 100 mg to about 123.5 mg of an isomalt, and between 0.5 mg to about 3 mg of a magnesium stearate, wherein the total weight of the composition is about 125 mg. In yet other aspects of this embodiment, a solid dosage form suitable for oral administration comprises between about 1 mg to about 3 mg of a vinorelbine, between about 100 mg to about 123.5 mg of an isomalt, and between 0.5 mg to about 1 .5 mg of a magnesium stearate, wherein the total weight of the composition is about 125 mg. In another aspect of this embodiment, the solid dosage form is alcohol- free.

[035] In another embodiment, a solid dosage form suitable for oral administration comprises about 1 1 % (w/w) or less of a vinca alkaloid, about 79% (w/w) or more of a polyol, about 10% (w/w) or less of a fatty acid between 16 and 24 carbons, wherein the composition comprises 10 mg or less of the vinca alkaloid. In aspects of this embodiment, a solid dosage form suitable for oral administration comprises between about 0.5% (w/w) to about 1 1 % (w/w) of a vinca alkaloid, between about 79% (w/w) to about 99% (w/w) of a polyol, and about 0.5% (w/w) to about 10% (w/w) of a fatty acid between 16 and 24 carbons, wherein the composition comprises 10 mg or less of the vinca alkaloid. In other aspects of this embodiment, a solid dosage form suitable for oral administration comprises between about 0.5% (w/w) to about 5.5% (w/w) of a vinca alkaloid, between about 89.5% (w/w) to about 99% (w/w) of a polyol, and about 0.5% (w/w) to about 5% (w/w) of a fatty acid between 16 and 24 carbons, wherein the composition comprises 5 mg or less of the vinca alkaloid. In yet other aspects of this embodiment, a solid dosage form suitable for oral administration comprises between about 0.5% (w/w) to about 3.3% (w/w) of a vinca alkaloid, between about 94.7% (w/w) to about 99% (w/w) of a polyol, and about 0.5% (w/w) to about 2% (w/w) of a fatty acid between 16 and 24 carbons, wherein the composition comprises 3 mg or less of the vinca alkaloid. In another aspect of this embodiment, the solid dosage form is alcohol-free.

[036] In yet another embodiment, a solid dosage form suitable for oral administration comprises about 1 1 % (w/w) or less of a vinorelbine, about 79% (w/w) or more of an isomalt, about 10% (w/w) or less of a magnesium stearate, wherein the composition comprises 10 mg or less of the vinorelbine. In aspects of this embodiment, a solid dosage form suitable for oral administration comprises between about 0.5% (w/w) to about 1 1 % (w/w) of a vinorelbine, between about 79% (w/w) to about 99% (w/w) of an isomalt, and about 0.5% (w/w) to about 10% (w/w) of a magnesium stearate, wherein the composition comprises 10 mg or less of the vinorelbine. In other aspects of this embodiment, a solid dosage form suitable for oral administration comprises between about 0.5% (w/w) to about 5.5% (w/w) of a vinorelbine, between about 89.5% (w/w) to about 99% (w/w) of an isomalt, and about 0.5% (w/w) to about 5% (w/w) of a magnesium stearate, wherein the composition comprises 5 mg or less of the vinorelbine. In yet other aspects of this embodiment, a solid dosage form suitable for oral administration comprises between about 0.5% (w/w) to about 3.3% (w/w) of a vinorelbine, between about 94.7% (w/w) to about 99% (w/w) of an isomalt, and about 0.5% (w/w) to about 2% (w/w) of a magnesium stearate, wherein the composition comprises 3 mg or less of the vinorelbine. In another aspect of this embodiment, the solid dosage form is alcohol-free.

[037] A vinca alkaloid disclosed herein, or a composition comprising such a vinca alkaloid, may also be incorporated into a drug delivery platform in order to achieve a controlled release profile over time. Such a drug delivery platform comprises a vinca alkaloid disclosed herein dispersed within a polymer matrix, typically a biodegradable, bioerodible, and/or bioresorbable polymer matrix. As used herein, the term "polymer" refers to synthetic homo- or copolymers, naturally occurring homo- or copolymers, as well as synthetic modifications or derivatives thereof having a linear, branched or star structure. Copolymers can be arranged in any form, such as, e.g., random, block, segmented, tapered blocks, graft, or triblock. Polymers are generally condensation polymers. Polymers can be further modified to enhance their mechanical or degradation properties by introducing cross-linking agents or changing the hydrophobicity of the side residues. If crosslinked, polymers are usually less than 5% crosslinked, usually less than 1 % crosslinked.

[038] Suitable polymers include, without limitation, alginates, aliphatic polyesters, polyalkylene oxalates, polyamides, polyamidoesters, polyanhydrides, polycarbonates, polyesters, polyethylene glycol, polyhydroxyaliphatic carboxylic acids, polyorthoesters, polyoxaesters, polypeptides, polyphosphazenes, polysaccharides, and polyurethanes. The polymer usually comprises at least about 10% (w/w), at least about 20% (w/w), at least about 30% (w/w), at least about 40% (w/w), at least about 50% (w/w), at least about 60% (w/w), at least about 70% (w/w), at least about 80% (w/w), or at least about 90% (w/w) of the drug delivery platform. Examples of biodegradable, bioerodible, and/or bioresorbable polymers and methods useful to make a drug delivery platform are described in, e.g., Drost, et. al., Controlled Release Formulation, U.S. Patent 4,756,91 1 ; Smith, et. al., Sustained Release Drug Delivery Devices, U.S. Patent 5,378,475; Wong and Kochinke, Formulation for Controlled Release of Drugs by Combining Hyrophilic and Hydrophobic Agents, U.S. Patent 7,048,946; Hughes, et. al., Compositions and Methods for Localized Therapy of the Eye, U.S. Patent Publication 2005/0181017; Hughes, Hypotensive Lipid- Containing Biodegradable Intraocular Implants and Related Methods, U.S. Patent Publication 2005/0244464; Altman, et al., Silk Fibroin Hydrogels and Uses Thereof, U.S. Patent Publication 201 1/0008437; each of which is incorporated by reference in its entirety.

[039] In aspects of this embodiment, a polymer composing the matrix is a polypeptide such as, e.g. , silk fibroin, keratin, or collagen. In other aspects of this embodiment, a polymer composing the matrix is a polysaccharide such as, e.g., cellulose, agarose, elastin, chitosan, chitin, or a glycosaminoglycan like chondroitin sulfate, dermatan sulfate, keratan sulfate, or hyaluronic acid. In yet other aspects of this embodiment, a polymer composing the matrix is a polyester such as, e.g. , D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, caprolactone, and combinations thereof.

[040] One of ordinary skill in the art appreciates that the selection of a suitable polymer for forming a suitable disclosed drug delivery platform depends on several factors. The more relevant factors in the selection of the appropriate polymer(s), include, without limitation, compatibility of polymer with drug, desired release kinetics of drug, desired biodegradation kinetics of platform at implantation site, desired bioerodible kinetics of platform at implantation site, desired bioresorbable kinetics of platform at implantation site, in vivo mechanical performance of platform, processing temperatures, biocompatibility of platform, and patient tolerance. Other relevant factors that, to some extent, dictate the in vitro and in vivo behavior of the polymer include the chemical composition, spatial distribution of the constituents, the molecular weight of the polymer and the degree of crystallinity. [041] A drug delivery platform includes both a sustained release drug delivery platform and an extended release drug delivery platform. As used herein, the term "sustained release" refers to the release of a compound disclosed herein over a period of about seven days or more. As used herein, the term "extended release" refers to the release of a compound disclosed herein over a period of time of less than about seven days.

[042] In aspects of this embodiment, a sustained release drug delivery platform releases a compound disclosed herein with substantially zero order release kinetics over a period of, e.g., about 7 days after administration, about 15 days after administration, about 30 days after administration, about 45 days after administration, about 60 days after administration, about 75 days after administration, or about 90 days after administration. In other aspects of this embodiment, a sustained release drug delivery platform releases a compound disclosed herein with substantially zero order release kinetics over a period of, e.g., at least 7 days after administration, at least 15 days after administration, at least 30 days after administration, at least 45 days after administration, at least 60 days after administration, at least 75 days after administration, or at least 90 days after administration.

[043] In aspects of this embodiment, a sustained release drug delivery platform releases a compound disclosed herein with substantially first order release kinetics over a period of, e.g., about 7 days after administration, about 15 days after administration, about 30 days after administration, about 45 days after administration, about 60 days after administration, about 75 days after administration, or about 90 days after administration. In other aspects of this embodiment, a sustained release drug delivery platform releases a compound disclosed herein with substantially first order release kinetics over a period of, e.g., at least 7 days after administration, at least 15 days after administration, at least 30 days after administration, at least 45 days after administration, at least 60 days after administration, at least 75 days after administration, or at least 90 days after administration.

[044] In aspects of this embodiment, a drug delivery platform releases a compound disclosed herein with substantially zero order release kinetics over a period of, e.g., about 1 day after administration, about 2 days after administration, about 3 days after administration, about 4 days after administration, about 5 days after administration, or about 6 days after administration. In other aspects of this embodiment, a drug delivery platform releases a compound disclosed herein with substantially zero order release kinetics over a period of, e.g., at most 1 day after administration, at most 2 days after administration, at most 3 days after administration, at most 4 days after administration, at most 5 days after administration, or at most 6 days after administration.

[045] In aspects of this embodiment, a drug delivery platform releases a compound disclosed herein with substantially first order release kinetics over a period of, e.g., about 1 day after administration, about 2 days after administration, about 3 days after administration, about 4 days after administration, about 5 days after administration, or about 6 days after administration. In other aspects of this embodiment, a drug delivery platform releases a compound disclosed herein with substantially first order release kinetics over a period of, e.g., at most 1 day after administration, at most 2 days after administration, at most 3 days after administration, at most 4 days after administration, at most 5 days after administration, or at most 6 days after administration.

[046] Aspects of the present specification provide, in part, a pharmaceutical kit. A pharmaceutical kit disclosed herein comprises a composition disclosed herein. Additionally such kits contain instructions providing guidance on the daily administration of the disclosed compositions over an extended period of time as disclosed herein. The components of the kit may be contained in a single container.

[047] In one embodiment, a pharmaceutical kit is provided comprising a) a composition comprising 10 mg or less of a vinca alkaloid, 100 mg or more of a polyol, and 5 mg or less of a fatty acid, wherein the total weight of the composition is about 125 mg; and b) instructions for daily administration over an extended period of time. In an aspect of this embodiment, a pharmaceutical kit is provided comprising a) a composition comprising 10 mg or less of a vinorelbine, 100 mg or more of an isomalt, and 5 mg or less of a magnesium stearate, wherein the total weight of the composition is about 125 mg; and b) instructions for daily administration over an extended period of time.

[048] In another embodiment, a pharmaceutical kit is provided comprising a) a composition comprising between about 0.5% (w/w) to about 1 1 % (w/w) of a vinca alkaloid, between about 79% (w/w) to about 99% (w/w) of a polyol, and about 0.5% (w/w) to about 10% (w/w) of a fatty acid, wherein the composition comprises 10 mg or less of the vinca alkaloid; and b) instructions for daily administration over an extended period of time. In an aspect of this embodiment, a pharmaceutical kit is provided comprising a) a composition comprising between about 0.5% (w/w) to about 1 1 % (w/w) of a vinorelbine, between about 79% (w/w) to about 99% (w/w) of an isomalt, and about 0.5% (w/w) to about 10% (w/w) of a magnesium stearate, wherein the composition comprises 10 mg or less of the vinca alkaloid; and b) instructions for daily administration over an extended period of time.

[049] Aspects of the present invention provide, in part, a non-hematologic tumor. As used herein, the term "non-hematologic tumor" refers to cells exhibiting uncontrolled or abnormal growth having a pathophysiology effect with the proviso that the tumor cells are not hematopoietic (blood-forming) cells. As such, a non-hematologic tumor includes all tumors except lymphomas and leukemias.

[050] In one embodiment, a non-hematologic tumor is a non-hematologic carcinoma. In aspects of this embodiment, a carcinoma includes, without limitation, an adrenal gland tumor, a bone tumor, a brain tumor, a breast tumor, a bronchi tumor, a colon tumor, a gallbladder tumor, a kidney tumor, a larynx tumor, a liver tumor, a lung tumor, a neural tumor, a pancreatic tumor, a prostate tumor, a parathyroid tumor, a skin tumor, a stomach tumor, and a thyroid tumor. In other aspects of this embodiment, a carcinoma includes, without limitation, an adenocarcinoma, an adenosquamous carcinoma, an anaplastic carcinoma, a large cell carcinoma, a small cell carcinoma, and a squamous cell carcinoma. In other aspects of this embodiment, a carcinoma includes, without limitation, a small cell carcinoma, a combined small cell carcinoma, a verrucous carcinoma, a squamous cell carcinoma, a basal cell carcinoma, a transitional cell carcinoma, an inverted papilloma, a linitis plastica, a familial adenomatous polyposis, an insulinoma, a glucagonoma, a gastrinoma, a VIPoma, a somatostatinoma, a cholangiocarcinoma, a Klatskin tumor, a hepatocellular adenoma, a hepatocellular carcinoma, a renal cell carcinoma, a endometrioid tumor, a renal oncocytoma, a prolactinoma, a multiple endocrine neoplasia, an adrenocortical adenoma, an adrenocortical carcinoma, a Hurthle cell, a neuroendocrine tumor, an adenoid cystic carcinoma, an oncocytoma, a clear cell adenocarcinoma, an apudoma, a cylindroma, a papillary hidradenoma, a hidrocystoma, a syringoma, a syringocystadenoma papilliferum, a cystadenoma, a cystadenocarcinoma, signet ring cell carcinoma, a mucinous cystadenoma, a mucinous cystadenocarcinoma, a mucoepidermoid carcinoma, an ovarian serous cystadenoma, a pancreatic serous cystadenoma, a serous cystadenocarcinoma, a papillary serous cystadenocarcinoma, a mammary ductal carcinoma, a pancreatic ductal carcinoma, a comedocarcinoma, a Paget's disease of the breast, an extramammary Paget's disease, a lobular carcinoma in situ, an invasive lobular carcinoma, a medullary carcinoma of the breast, a medullary thyroid cancer, an acinic cell carcinoma, a Warthin's tumor, and a thymoma.

[051] In another embodiment, a non-hematologic tumor is a non-hematologic sarcoma. In aspects of this embodiment, a non-hematologic sarcoma includes, without limitation, a soft tissue sarcoma, a connective tissue sarcoma, a lipomatous sarcoma, a myomatous sarcoma, a complex mixed and stromal sarcoma, and a mesothelial. In aspects of this embodiment, a non-hematologic sarcoma includes, without limitation, an adenomatoid tumor, an adenomyoma, an aggressive infantile fibromatosis, an alveolar rhabdomyosarcoma, an angiolipoleiomyoma, an angiomyolipoma, an angioleiomyoma, an angiomyxoma, an angiosarcoma, an aponeurotic fibroma, an Askin's tumor, an atypical fibroxanthoma, a benign lipoblastomatosis, a Brenner tumor, a carcinosarcoma, a chondroid lipoma, a chondrosarcoma, a clear-cell sarcoma, a clear-cell sarcoma of the kidney, a collagenous fibroma, a cystosarcoma phyllodes, a dermatofibrosarcoma, a dermatofibrosarcoma protuberans (DFSP), a desmoplastic fibroma, a desmoplastic small round cell tumor, a diffuse infantile fibromatosis, an Ewing's/PNET sarcoma, a familial myxovascular fibroma, a fibroadenoma, a fibroma of tendon sheath, a fibromatosis colli, a fibrous histiocytoma, a fibrosarcoma, a gastrointestinal stromal tumor (GIST), a genital leiomyoma, a hemangioendothelioma, a hepatoblastoma, a hibernoma, a histiocytoma, an infantile digital fibromatosis, an intradermal spindle cell lipoma, a juvenile hyaline fibromatosis, a Kaposi's sarcoma, a leiomyosarcoma, a liposarcoma, a mesoblastic nephroma, a mesothelioma, a mixed Mullerian tumor, a multiple cutaneous leiomyoma, a multiple cutaneous and uterine leiomyomatosis syndrome, a myelolipoma, a myosarcoma, a myxoid liposarcoma, a myxosarcoma, a neural fibrolipoma, a neurofibrosarcoma, an oral submucous fibrosis, an ossifying fibromyxoid tumor, an osteosarcoma, a pancreatoblastoma, a phyllodes tumor, a plantar fibromatosis, a pleomorphic adenoma, a pleomorphic fibroma, a pleomorphic lipoma, a rhabdomyosarcoma, a sarcoma botryoides, a schwannoma sarcoma, a solitary cutaneous leiomyoma, a solitary fibrous tumor, a spindle cell lipoma, a stromal tumor of undetermined malignant potential (STUMP), a synovial sarcoma, a vascular sarcoma, and a Wilms' tumor.

[052] In another embodiment, a non-hematologic tumor is a non-hematologic blastoma. In aspects of this embodiment, a non-hematologic blastoma includes, without limitation, a chondroblastoma, a hepatoblastoma, a medulloblastoma, a nephroblastoma, a neuroblastoma, a pancreatoblastoma, a pleuropulmonary blastoma, a retinoblastoma, and a lioblastoma multiforme.

[053] In another embodiment, a non-hematologic tumor is a germ cell tumor. In aspects of this embodiment, a germ cell tumor is a testicular tumor or an ovarian tumor.

[054] Aspects of the present specification disclose, in part, treating an individual suffering from a non- hematologic tumor. As used herein, the term "treating," refers to reducing or eliminating in an individual a clinical symptom of a non-hematologic tumor; or delaying or preventing in an individual the onset of a clinical symptom of a non-hematologic tumor. For example, the term "treating" can mean reducing a symptom of a condition characterized by a non-hematologic tumor by, e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95%. The actual symptoms associated with a non-hematologic tumor are well known and can be determined by a person of ordinary skill in the art by taking into account factors, including, without limitation, the location of the non-hematologic tumor, the cause of the non-hematologic tumor, the severity of the non-hematologic tumor, and/or the tissue or organ affected by the non-hematologic tumor. Those of skill in the art will know the appropriate symptoms or indicators associated with a specific non-hematologic tumor and will know how to determine if an individual is a candidate for treatment as disclosed herein.

[055] Aspects of the present specification provides, in part, reducing or eliminating a clinical symptom associated with a non-hematologic tumor. In an aspect of this embodiment, the symptom reduced is an increase in the growth rate of non-hematologic tumor cells. In another aspect of this embodiment, the symptom reduced is an increase in the cell division rate of non-hematologic tumor cells. In yet another aspect of this embodiment, the symptom reduced is an increase in the extent of invasion of non- hematologic tumor cells into adjacent tissue or organs. In still another aspect of this embodiment, the symptom reduced is an increase in the extent of metastasis of a non-hematologic tumor. In a further aspect of this embodiment, the symptom reduced is an increase in angiogenesis associated with a non- hematologic tumor. In a yet further aspect of this embodiment, the symptom reduced is a decrease in apoptosis of non-hematologic tumor cells. In a still further aspect of this embodiment, the symptom reduced is a decrease in cell death or cell necrosis of non-hematologic tumor cells. Thus, a treatment disclosed herein will decrease the growth rate of non-hematologic tumor cells, decrease the cell division rate of non-hematologic tumor cells, decrease the extent of invasion of non-hematologic tumor cells into adjacent tissue or organs, decrease the extent of metastasis of a non-hematologic tumor, decrease angiogenesis associated with a non-hematologic tumor, increase apoptosis of non-hematologic tumor cells, and/or increase cell death and/or cell necrosis of non-hematologic tumor cells.

[056] A composition or compound is administered to an individual. An individual comprises all mammals including a human being. Typically, any individual who is a candidate for a conventional non- hematologic tumor treatment is a candidate for a non-hematologic tumor treatment disclosed herein. Pre- treatment evaluation typically includes routine history and physical examination in addition to thorough informed consent disclosing all relevant risks and benefits of the procedure. [057] A vinca alkaloid disclosed herein is frequently administered to an individual at doses significantly below the maximum tolerated dose for an extended period of time. As used herein, the term "maximum tolerated dose" refers to the highest dose of a drug or treatment that does not cause unacceptable side effects. Typically, the maximum tolerated dose is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found. A therapy based on a maximum tolerated dose requires prolonged breaks (often 2-3 weeks in duration) between successive cycles of chemotherapeiutic agent administration due to the toxic side effects frequently associated with the dosing regimen. For example, the maximum tolerated dose of a vinca alkaloid is 25- 30 mg/m², when intravenously administered once weekly, or 60-80 mg/m², when orally administered once weekly. However, the methods disclosed herein rely on a therapy involving the frequent, even daily, administration of chemotherapeutic agents, without prolonged drug-free breaks. For example, a dose therapy disclosed herein involves the daily administration a vinca alkaloid of about 1-10 mg over the course of about 1 month to about 12 months.

[058] An extended period of time, when made in reference to the length of time a vinca alkaloid is administered to an individual, refers to any time period that is longer than the conventional time period used for a maximum tolerable dose therapy. For example, typically a vinca alkaloid is administered no more than once a week when the dose is the maximum tolerable dose. Thus a vinca alkaloid administration that occurs at least twice in one week would be considered longer than the conventional time period used for a maximum tolerable dose therapy. In addition, it will be recognized that in daily administration over an extended period of time there will be occasions in which a vinca alkaloid or a composition comprising a vinca alkaloid will not be taken by an individual. For example, the individual may forget occasionally to take the dose for that day, or suffer from a gastrointestinal condition that prevents administration of the dose for that day. But in general, the drug is administered substantially every day over the time period.

[059] An amount of a vinca alkaloid disclosed herein will typically be an effective amount. As used herein, the term "effective amount" is synonymous with "therapeutically effective amount", "effective dose", or "therapeutically effective dose" and when used in reference to treating a non-hematologic tumor refers to the minimum dose of a vinca alkaloid alone necessary to achieve the desired therapeutic effect and includes a dose sufficient to reduce a symptom associated with a non-hematologic tumor. An effective amount refers to the total amount of a vinca alkaloid administered to an individual in one setting. The effectiveness of a vinca alkaloid disclosed herein in treating a non-hematologic tumor can be determined by observing an improvement in an individual based upon one or more clinical symptoms, and/or physiological indicators associated with the condition. An improvement in a non-hematologic tumor also can be indicated by a reduced need for a concurrent therapy.

[060] The appropriate effective amount of a vinca alkaloid administered to an individual for a particular non-hematologic tumor can be determined by a person of ordinary skill in the art by taking into account factors, including, without limitation, the type of non-hematologic tumor, the location of the non- hematologic tumor, the cause of the non-hematologic tumor, the severity of the non-hematologic tumor, the degree of relief desired, the duration of relief desired, the particular vinca alkaloid used, the rate of excretion of the particular vinca alkaloid used, the pharmacodynamics of the particular vinca alkaloid used, the nature of the other compounds to be included in the composition, the particular route of administration, the particular characteristics, history and risk factors of the individual, such as, e.g. , age, weight, general health and the like, or any combination thereof. Additionally, where repeated administration of a composition disclosed herein is used, an effective amount of a vinca alkaloid will further depend upon factors, including, without limitation, the frequency of administration, the half-life of the particular vinca alkaloid used, or any combination thereof. In is known by a person of ordinary skill in the art that an effective amount of a composition comprising a vinca alkaloid can be extrapolated from in vitro assays and in vivo administration studies using animal models prior to administration to humans.

[061] Wide variations in the necessary effective amount are to be expected in view of the differing efficiencies of the various routes of administration. For instance, oral administration of a vinca alkaloid disclosed herein generally would be expected to require higher dosage levels than administration by intravenous or intravitreal injection. Similarly, systemic administration of a vinca alkaloid disclosed herein would be expected to require higher dosage levels than a local administration. Variations in these dosage levels can be adjusted using standard empirical routines of optimization, which are well-known to a person of ordinary skill in the art. The precise therapeutically effective dosage levels and patterns are preferably determined by the attending physician in consideration of the above-identified factors. One skilled in the art will recognize that the condition of the individual can be monitored throughout the course of therapy and that the effective amount of a vinca alkaloid disclosed herein that is administered can be adjusted accordingly.

[062] In one embodiment, a vinca alkaloid is administered to an individual suffering from a non- hematologic tumor in a therapeutically effective amount at a dose significantly below the maximum tolerated dose. In an aspect of this embodiment, a vinca alkaloid is administered to an individual suffering from a non-hematologic tumor in a therapeutically effective amount at a dose significantly below 25-30 mg/m², when intravenously administered. In another aspect of this embodiment, a vinca alkaloid is administered to an individual suffering from a non-hematologic tumor in a therapeutically effective amount at a dose significantly below 60-80 mg/m² when orally administered.

[063] In aspects of this embodiment, a therapeutically effective amount of a vinca alkaloid reduces a symptom associated with a non-hematologic tumor by, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95%. In other aspects of this embodiment, a therapeutically effective amount of a vinca alkaloid reduces a symptom associated with a non-hematologic tumor by, e.g., at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90% or at most 100%. In yet other aspects of this embodiment, a therapeutically effective amount of a vinca alkaloid reduces a symptom associated with a non-hematologic tumor by, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%. In still other aspects of this embodiment, a therapeutically effective amount of a vinca alkaloid is the dosage sufficient to reduce a symptom associated with a non-hematologic tumor for, e.g., at least one week, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months.

[064] In aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is, e.g., about 0.5 mg/day, about 1 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, or about 10 mg/day and this daily dose is administered for an extended period of time. In other aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is, e.g., about 0.5 mg/day, about 1 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, or about 10 mg/day and this daily dose is administered for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 1 weeks, or at least 12 weeks. In yet other aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is, e.g., about 0.5 mg/day, about 1 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, or about 10 mg/day and this daily dose is administered for at least five days each week for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 1 weeks, or at least 12 weeks.

[065] In other aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is, e.g., about 0.5 mg/day, about 1 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, or about 10 mg/day and this daily dose is administered for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months. In yet other aspects of this embodiment, a therapeutically- effective amount of a vinca alkaloid is, e.g., about 0.5 mg/day, about 1 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, or about 10 mg/day and this daily dose is administered for at least five days each week for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months.

[066] In aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is, e.g., about 10 mg/day or less, about 9 mg/day or less, about 8 mg/day or less, about 7 mg/day or less, about 6 mg/day or less, about 5 mg/day or less, about 4 mg/day or less, about 3 mg/day or less, about 2 mg/day or less, or about 1 mg/day or less and this daily dose is administered for an extended period of time. In other aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is, e.g., about 10 mg/day or less, about 9 mg/day or less, about 8 mg/day or less, about 7 mg/day or less, about 6 mg/day or less, about 5 mg/day or less, about 4 mg/day or less, about 3 mg/day or less, about 2 mg/day or less, or about 1 mg/day or less and this daily dose is administered for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 1 weeks, or at least 12 weeks. In yet other aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is, e.g., about 10 mg/day or less, about 9 mg/day or less, about 8 mg/day or less, about 7 mg/day or less, about 6 mg/day or less, about 5 mg/day or less, about 4 mg/day or less, about 3 mg/day or less, about 2 mg/day or less, or about 1 mg/day or less and this daily dose is administered for at least five days each week for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 1 weeks, or at least 12 weeks.

[067] In other aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is, e.g., about 10 mg/day or less, about 9 mg/day or less, about 8 mg/day or less, about 7 mg/day or less, about 6 mg/day or less, about 5 mg/day or less, about 4 mg/day or less, about 3 mg/day or less, about 2 mg/day or less, or about 1 mg/day or less and this daily dose is administered for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months. In yet other aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is, e.g., about 10 mg/day or less, about 9 mg/day or less, about 8 mg/day or less, about 7 mg/day or less, about 6 mg/day or less, about 5 mg/day or less, about 4 mg/day or less, about 3 mg/day or less, about 2 mg/day or less, or about 1 mg/day or less and this daily dose is administered for at least five days each week for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months.

[068] In aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is, e.g., at most 1 mg/day, at most 2 mg/day, at most 3 mg/day, at most 4 mg/day, at most 5 mg/day, at most 6 mg/day, at most 7 mg/day, at most 8 mg/day, at most 9 mg/day, or at most 10 mg/day and this daily dose is administered for an extended period of time. In other aspects of this embodiment, a therapeutically- effective amount of a vinca alkaloid is, e.g., at most 1 mg/day, at most 2 mg/day, at most 3 mg/day, at most 4 mg/day, at most 5 mg/day, at most 6 mg/day, at most 7 mg/day, at most 8 mg/day, at most 9 mg/day, or at most 10 mg/day and this daily dose is administered for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 1 weeks, or at least 12 weeks. In yet other aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is, e.g., at most 1 mg/day, at most 2 mg/day, at most 3 mg/day, at most 4 mg/day, at most 5 mg/day, at most 6 mg/day, at most 7 mg/day, at most 8 mg/day, at most 9 mg/day, or at most 10 mg/day and this daily dose is administered for at least five days each week for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 1 weeks, or at least 12 weeks.

[069] In other aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is, e.g., at most 1 mg/day, at most 2 mg/day, at most 3 mg/day, at most 4 mg/day, at most 5 mg/day, at most 6 mg/day, at most 7 mg/day, at most 8 mg/day, at most 9 mg/day, or at most 10 mg/day and this daily dose is administered for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months. In yet other aspects of this embodiment, a therapeutically- effective amount of a vinca alkaloid is, e.g., at most 1 mg/day, at most 2 mg/day, at most 3 mg/day, at most 4 mg/day, at most 5 mg/day, at most 6 mg/day, at most 7 mg/day, at most 8 mg/day, at most 9 mg/day, or at most 10 mg/day and this daily dose is administered for at least five days each week for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months.

[070] In aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is between, e.g., about 0.5 mg/day to about 10 mg/day, about 0.5 mg/day to about 7 mg/day, about 0.5 mg/day to about 5 mg/day, about 0.5 mg/day to about 4 mg/day, about 0.5 mg/day to about 3 mg/day, about 0.5 mg/day to about 2 mg/day, about 0.5 mg/day to about 1 mg/day, about 1 mg/day to about 10 mg/day, about 1 mg/day to about 7 mg/day, about 1 mg/day to about 5 mg/day, about 1 mg/day to about 4 mg/day, about 1 mg/day to about 3 mg/day, about 1 mg/day to about 2 mg/day, about 2 mg/day to about 10 mg/day, about 2 mg/day to about 7 mg/day, about 2 mg/day to about 5 mg/day, about 2 mg/day to about 4 mg/day, about 2 mg/day to about 3 mg/day, about 3 mg/day to about 10 mg/day, about 3 mg/day to about 7 mg/day, about 3 mg/day to about 5 mg/day, about 3 mg/day to about 4 mg/day and this daily dose is administered for an extended period of time. In other aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is between, e.g., about 0.5 mg/day to about 10 mg/day, about 0.5 mg/day to about 7 mg/day, about 0.5 mg/day to about 5 mg/day, about 0.5 mg/day to about 4 mg/day, about 0.5 mg/day to about 3 mg/day, about 0.5 mg/day to about 2 mg/day, about 0.5 mg/day to about 1 mg/day, about 1 mg/day to about 10 mg/day, about 1 mg/day to about 7 mg/day, about 1 mg/day to about 5 mg/day, about 1 mg/day to about 4 mg/day, about 1 mg/day to about 3 mg/day, about 1 mg/day to about 2 mg/day, about 2 mg/day to about 10 mg/day, about 2 mg/day to about 7 mg/day, about 2 mg/day to about 5 mg/day, about 2 mg/day to about 4 mg/day, about 2 mg/day to about 3 mg/day, about 3 mg/day to about 10 mg/day, about 3 mg/day to about 7 mg/day, about 3 mg/day to about 5 mg/day, about 3 mg/day to about 4 mg/day and this daily dose is administered for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 1 weeks, or at least 12 weeks. In yet other aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is between, e.g., about 0.5 mg/day to about 10 mg/day, about 0.5 mg/day to about 7 mg/day, about 0.5 mg/day to about 5 mg/day, about 0.5 mg/day to about 4 mg/day, about 0.5 mg/day to about 3 mg/day, about 0.5 mg/day to about 2 mg/day, about 0.5 mg/day to about 1 mg/day, about 1 mg/day to about 10 mg/day, about 1 mg/day to about 7 mg/day, about 1 mg/day to about 5 mg/day, about 1 mg/day to about 4 mg/day, about 1 mg/day to about 3 mg/day, about 1 mg/day to about 2 mg/day, about 2 mg/day to about 10 mg/day, about 2 mg/day to about 7 mg/day, about 2 mg/day to about 5 mg/day, about 2 mg/day to about 4 mg/day, about 2 mg/day to about 3 mg/day, about 3 mg/day to about 10 mg/day, about 3 mg/day to about 7 mg/day, about 3 mg/day to about 5 mg/day, about 3 mg/day to about 4 mg/day and this daily dose is administered for at least five days each week for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 1 weeks, or at least 12 weeks.

[071] In other aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is between, e.g. , about 0.5 mg/day to about 10 mg/day, about 0.5 mg/day to about 7 mg/day, about 0.5 mg/day to about 5 mg/day, about 0.5 mg/day to about 4 mg/day, about 0.5 mg/day to about 3 mg/day, about 0.5 mg/day to about 2 mg/day, about 0.5 mg/day to about 1 mg/day, about 1 mg/day to about 10 mg/day, about 1 mg/day to about 7 mg/day, about 1 mg/day to about 5 mg/day, about 1 mg/day to about 4 mg/day, about 1 mg/day to about 3 mg/day, about 1 mg/day to about 2 mg/day, about 2 mg/day to about 10 mg/day, about 2 mg/day to about 7 mg/day, about 2 mg/day to about 5 mg/day, about 2 mg/day to about 4 mg/day, about 2 mg/day to about 3 mg/day, about 3 mg/day to about 10 mg/day, about 3 mg/day to about 7 mg/day, about 3 mg/day to about 5 mg/day, about 3 mg/day to about 4 mg/day and this daily dose is administered for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months. In yet other aspects of this embodiment, a therapeutically-effective amount of a vinca alkaloid is between, e.g., about 0.5 mg/day to about 10 mg/day, about 0.5 mg/day to about 7 mg/day, about 0.5 mg/day to about 5 mg/day, about 0.5 mg/day to about 4 mg/day, about 0.5 mg/day to about 3 mg/day, about 0.5 mg/day to about 2 mg/day, about 0.5 mg/day to about 1 mg/day, about 1 mg/day to about 10 mg/day, about 1 mg/day to about 7 mg/day, about 1 mg/day to about 5 mg/day, about 1 mg/day to about 4 mg/day, about 1 mg/day to about 3 mg/day, about 1 mg/day to about 2 mg/day, about 2 mg/day to about 10 mg/day, about 2 mg/day to about 7 mg/day, about 2 mg/day to about 5 mg/day, about 2 mg/day to about 4 mg/day, about 2 mg/day to about 3 mg/day, about 3 mg/day to about 10 mg/day, about 3 mg/day to about 7 mg/day, about 3 mg/day to about 5 mg/day, about 3 mg/day to about 4 mg/day and this daily dose is administered for at least five days each week for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months.

[072] In another embodiment, administration of the therapeutically-effective amount of the vinca alkaloid results in an amount of the vinca alkaloid in blood serum that is less then 5.0 ng/mL. In aspects of this embodiment, administration of the therapeutically-effective amount of the vinca alkaloid results in an amount of the vinca alkaloid in blood serum that is, e.g., about 5 ng/mL, about 4 ng/mL, about 3 ng/mL, about 2 ng/mL, about 1 ng/mL. about 0.9 ng/mL, about 0.8 ng/mL, about 0.7 ng/mL, about 0.6 ng/mL, about 0.5 ng/mL, about 0.4 ng/mL, about 0.3 ng/mL, about 0.2 ng/mL, or about 0.1 ng/mL. In other aspects of this embodiment, administration of the therapeutically-effective amount of the vinca alkaloid results in an amount of the vinca alkaloid in blood serum that is, e.g. , about 5 ng/mL or less, about 4 ng/mL or less, about 3 ng/mL or less, about 2 ng/mL or less, about 1 ng/mL or less, about 0.9 ng/mL or less, about 0.8 ng/mL or less, about 0.7 ng/mL or less, about 0.6 ng/mL or less, about 0.5 ng/mL or less, about 0.4 ng/mL or less, about 0.3 ng/mL or less, about 0.2 ng/mL or less, or about 0.1 ng/mL or less. In yet other aspects of this embodiment, administration of the therapeutically-effective amount of the vinca alkaloid results in an amount of the vinca alkaloid in blood serum that is, e.g. , at most 5 ng/mL, at most 4 ng/mL, at most 3 ng/mL, at most 2 ng/mL, at most 1 ng/mL. at most 0.9 ng/mL, at most 0.8 ng/mL, at most 0.7 ng/mL, at most 0.6 ng/mL, at most 0.5 ng/mL, at most 0.4 ng/mL, at most 0.3 ng/mL, at most 0.2 ng.mL, or at most 0.1 ng/mL.

[073] In further aspects of this embodiment, administration of the therapeutically-effective amount of the vinca alkaloid results in an amount of the vinca alkaloid in blood serum that is between , e.g. , about 0.1 ng/mL to about 5 ng/mL, about 0.1 ng/mL to about 4 ng/mL, about 0.1 ng/mL to about 3 ng/mL, about 0.1 ng/mL to about 2 ng/mL, about 0.1 ng/mL to about 1 ng/mL, about 0.1 ng/mL to about 0.9 ng/mL, about 0.1 ng/mL to about 0.8 ng/mL, about 0.1 ng/mL to about 0.7 ng/mL, about 0.1 ng/mL to about 0.6 ng/mL, about 0.1 ng/mL to about 0.5 ng/mL, about 0.1 ng/mL to about 0.4 ng/mL, about 0.1 ng/mL to about 0.3 ng/mL, about 0.1 ng/mL to about 0.2 ng/mL, about 0.2 ng/mL to about 5 ng/mL, about 0.2 ng/mL to about 4 ng/mL, about 0.2 ng/mL to about 3 ng/mL, about 0.2 ng/mL to about 2 ng/mL, about 0.2 ng/mL to about 1 ng/mL, about 0.2 ng/mL to about 0.9 ng/mL, about 0.2 ng/mL to about 0.8 ng/mL, about 0.2 ng/mL to about 0.7 ng/mL, about 0.2 ng/mL to about 0.6 ng/mL, about 0.2 ng/mL to about 0.5 ng/mL, about 0.2 ng/mL to about 0.4 ng/mL, about 0.2 ng/mL to about 0.3 ng/mL, about 0.3 ng/mL to about 5 ng/mL, about 0.3 ng/mL to about 4 ng/mL, about 0.3 ng/mL to about 3 ng/mL, about 0.3 ng/mL to about 2 ng/mL, about 0.3 ng/mL to about 1 ng/mL, about 0.3 ng/mL to about 0.9 ng/mL, about 0.3 ng/mL to about 0.8 ng/mL, about 0.3 ng/mL to about 0.7 ng/mL, about 0.3 ng/mL to about 0.6 ng/mL, about 0.3 ng/mL to about 0.5 ng/mL, about 0.3 ng/mL to about 0.4 ng/mL, about 0.5 ng/mL to about 5 ng/mL, about 0.5 ng/mL to about 4 ng/mL, about 0.5 ng/mL to about 3 ng/mL, about 0.5 ng/mL to about 2 ng/mL, about 0.5 ng/mL to about 1 ng/mL, about 0.5 ng/mL to about 0.9 ng/mL, about 0.5 ng/mL to about 0.8 ng/mL, about 0.5 ng/mL to about 0.7 ng/mL, or about 0.5 ng/mL to about 0.6 ng/mL.

[074] In another embodiment, administration of a daily dose of the vinca alkaloid over an extended period of time does not result in an onset of a severe side effect. Non-limiting examples of a severe side- effect of vinca alkaloid administrations include bone marrow suppression, gastrointestinal toxicity, potent vesicant (blister-forming) activity, extravasation injury (deep ulcer formation), peripheral neuropathy, lowered resistance to infection, bruising, bleeding, anemia, constipation, diarrhea, nausea, tiredness and a general feeling of weakness (asthenia), inflammation of the vein into which vinca alkaloid was administered (phlebitis), severe hyponatremia, hair loss and an allergic reaction.

[075] In aspects of this embodiment, administration of a daily dose of the vinca alkaloid for an extended period of time does not result in an onset of a severe side effect from the vinca alkaloid administration. In other aspects of this embodiment, administration of a daily dose of the vinca alkaloid for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 1 weeks, or at least 12 weeks does not result in an onset of a severe side effect from the vinca alkaloid administration. In yet other aspects of this embodiment, administration of a daily dose of the vinca alkaloid for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 1 weeks, or at least 12 weeks does not result in an onset of bone marrow suppression, gastrointestinal toxicity, potent vesicant (blister-forming) activity, extravasation injury (deep ulcer formation), peripheral neuropathy, lowered resistance to infection, bruising, bleeding, anemia, constipation, diarrhea, nausea, tiredness and a general feeling of weakness (asthenia), inflammation of the vein into which vinca alkaloid was administered (phlebitis), severe hyponatremia, hair loss and/or an allergic reaction, or any combination thereof.

[076] In aspects of this embodiment, administration of a daily dose of the vinca alkaloid for at least five days each week for an extended period of time does not result in an onset of a severe side effect from the vinca alkaloid administration. In other aspects of this embodiment, administration of a daily dose of the vinca alkaloid for at least five days each week for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 1 weeks, or at least 12 weeks does not result in an onset of a severe side effect from the vinca alkaloid administration. In yet other aspects of this embodiment, administration of a daily dose of the vinca alkaloid for at least five days each week for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 1 weeks, or at least 12 weeks does not result in an onset of bone marrow suppression, gastrointestinal toxicity, potent vesicant (blister-forming) activity, extravasation injury (deep ulcer formation), peripheral neuropathy, lowered resistance to infection, bruising, bleeding, anemia, constipation, diarrhea, nausea, tiredness and a general feeling of weakness (asthenia), inflammation of the vein into which vinca alkaloid was administered (phlebitis), severe hyponatremia, hair loss and/or an allergic reaction, or any combination thereof.

[077] In other aspects of this embodiment, administration of a daily dose of the vinca alkaloid for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months does not result in an onset of a severe side effect from the vinca alkaloid administration. In yet other aspects of this embodiment, administration of a daily dose of the vinca alkaloid for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months does not result in an onset of bone marrow suppression, gastrointestinal toxicity, potent vesicant (blister-forming) activity, extravasation injury (deep ulcer formation), peripheral neuropathy, lowered resistance to infection, bruising, bleeding, anemia, constipation, diarrhea, nausea, tiredness and a general feeling of weakness (asthenia), inflammation of the vein into which vinca alkaloid was administered (phlebitis), severe hyponatremia, hair loss and/or an allergic reaction, or any combination thereof. [078] In other aspects of this embodiment, administration of a daily dose of the vinca alkaloid for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months does not result in an onset of a severe side effect from the vinca alkaloid administration. In yet other aspects of this embodiment, administration of a daily dose of the vinca alkaloid for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months does not result in an onset of bone marrow suppression, gastrointestinal toxicity, potent vesicant (blister-forming) activity, extravasation injury (deep ulcer formation), peripheral neuropathy, lowered resistance to infection, bruising, bleeding, anemia, constipation, diarrhea, nausea, tiredness and a general feeling of weakness (asthenia), inflammation of the vein into which vinca alkaloid was administered (phlebitis), severe hyponatremia, hair loss and/or an allergic reaction, or any combination thereof.

[079] A composition and/or vinca alkaloid disclosed herein can be administered to an individual using a variety of routes. Routes of administration suitable for a method of treating a non-hematologic tumor disclosed herein include both local and systemic administration. Local administration results in significantly more delivery of a composition and/or vinca alkaloid to a specific location as compared to the entire body of the individual, whereas, systemic administration results in delivery of a composition to essentially the entire body of the individual. The actual route of administration of a composition and/or vinca alkaloid disclosed herein used can be determined by a person of ordinary skill in the art by taking into account factors, including, without limitation, the type of non-hematologic tumor, the location of the non-hematologic tumor, the cause of the non-hematologic tumor, the severity of the non-hematologic tumor, the degree of relief desired, the duration of relief desired, the particular vinca alkaloid used, the rate of excretion of the vinca alkaloid used, the pharmacodynamics of the vinca alkaloid used, the nature of the other compounds to be included in the composition, the particular route of administration, the particular characteristics, history and risk factors of the individual, such as, e.g. , age, weight, general health and the like, or any combination thereof.

[080] In an embodiment, a composition and/or vinca alkaloid disclosed herein is administered by injection. In aspects of this embodiment, administration of a composition disclosed herein is by, e.g. , intravenous injection, intraarterial injection, intramuscular injection, intraorgan injection, subdermal injection, dermal injection, intracranical injection, spinal injection, or injection into any other body area for the effective administration of a composition disclosed herein.

[081] In another embodiment, a composition and/or vinca alkaloid disclosed herein is administered by catheter. In aspects of this embodiment, administration of a composition disclosed herein is by, e.g. , a catheter placed in an epidural space. [082] A composition and/or vinca alkaloid disclosed herein can also be administered to an individual in combination with other therapeutic compounds to increase the overall therapeutic effect of the treatment. The use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.

EXAMPLES

[083] The following non-limiting examples are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments now contemplated. These examples should not be construed to limit any of the embodiments described in the present specification, including those pertaining to the compounds, pharmaceutical compositions, pharmaceutical kits, or methods of treating cancer.

Example 1

Preparation of a solid dose form

[084] To make a composition disclosed herein, the components listed in Table 2 were weighed and passed through a 30 mesh screen. The sieved components were then blended together for ten minutes prior to compression. Tablets were formed by compressing the blended components using a ¼ inch tool. Tablets were packaged in foil pouches with 20 tablets per pouch.

Example 2

Evaluation of low dose administration of a vinca alkaloid

[085] Approximately 10 male or female adult subjects were enrolled into the seven day trial (Table 3). These subjects were diagnosed with a non-hematologic tumor for which there were no currently accepted therapy. Subjects were entered sequentially into 1 of 2 cohorts. Cohort 1 was made up of three subjects that received a daily dosing of 1 mg of vinorelbine (1 mg/day). Cohort 2 was made up of seven subjects that received a daily dosing of 3 mg of vinorelbine (3 mg/day).

[086] On Study Day 1 subjects visit the study center for enrollment into the study, collection of a blood sample for baseline measurement of circulating endothelial cells (CECs), circulating tumor cells (CTCs), and serum concentration of vascular endothelial growth factor (VEGF), administration of their first dose of vinorelbine, safety monitoring, and collection of blood samples for pharmacokinetics analysis. Subjects visit the study center on Study Day 2 for safety monitoring and collection of an additional blood sample for pharmacokinetics analysis, followed by administration of vinorelbine. Subjects self-administer vinorelbine on Study Days 3-7. Subjects visit the study center on Study Day 8 for safety monitoring, collection of a blood sample for measurement of CECs, CTC, and serum concentration of VEGF, and for collection of an additional blood sample for pharmacokinetics analysis.

[087] After completing the initial seven-day treatment period, subjects may, at the discretion of the Principal Investigator, continue to receive their assigned daily dose of vinorelbine until they exhibit disease progression and/or they experience unacceptable toxicity. Subjects who continue to receive vinorelbine after Study Day 7 visit the study center for safety monitoring and collection of a blood sample for measurement of CECs, CTCs, and serum concentration of VEGF during Study Week 3, and at six week intervals thereafter, while they continue to receive vinorelbine. Subjects are followed up for safety one week after receiving their final dose of vinorelbine.

[088] Nonclinical studies have shown that CECs and CTCs correlate well with several standard laboratory angiogenesis assays, and emerging clinical evidence indicates that the viability and kinetics of CECs and CTCs may correlate with clinical outcomes in cancer patients who undergo anti-angiogenic treatment. For the CEC assay, 4.0 mL of whole blood was incubated with magnetically labeled beads which pull out CD146-positive cells. This enriched population was analyzed with three additional markers to identify the presence of CECs. For the CTC assay, 7.5 mL of whole blood was incubated with magnetically labeled beads which pull out EpCAM-positive cells. This enriched population was analyzed with three additional markers to identify the presence of CTCs. Measurements of serum VEGF concentrations were performed using the R&D Systems Quantikine Human VEGF ELISA System. Measurements of plasma concentrations of vinorelbine were being performed using a validated LC- API/MS/MS bioassay method with a lower limit of quantification of 0.2 mg/mL.

[089] Serum VEGF concentrations collected by subject for Study Day 1 , Study Day 8, and Week 3 are listed in Table 4. For most subjects, although higher than on Study Day 1 , serum VEGF concentrations were similar on Study Day 8 and at Week 3. The maximum on-study percent increase in serum VEGF concentration from Study Day 1 to either Study Day 8 or Week 3 (Subjects 101 -106), or the on-study percent increase in serum VEGF concentration from Study Day 1 to Study Day 8 (Subject 107), is summarized by subject in Figure 1. All subjects had an increase in serum VEGF concentration while on study, although there were large differences among subjects (range 15% to 2700%) in the magnitude of this increase.

[090] Circulating Endothelial Cell (CEC) values collected by subject for Study Day 1 , Study Day 8, and Week 3 are listed in Table 5. Five of seven subjects had higher numbers of CECs on Study Day 8 than they did at Week 3. The maximum on-study percent increase in CECs from Study Day 1 to either Study Day 8 or Week 3 is summarized by subject in Figure 2. All subjects had an increased number of CECs while on study, although there were large differences among subjects (range 16% to 1940%) in the magnitude of this increase.

[091] Circulating Tumor Cell (CTC) values collected by subject for Study Day 1 , Study Day 8, and Week 3 are listed in Table 6. The maximum on-study percent increase or decrease in CTCs from Study Day 1 to either Study Day 8 or Week 3 is summarized by subject in Figure 3. Four subjects had a decrease (40% to 71 %) in CTCs while on study, one subject had an increase (4100%) in CTCs while on study, and two subjects had no detectable CTCs on Study Day 1 , Study Day 8, and Week 3. Subject 102 and Subject 106 did not have detectable CTCs at any sampling timepoints and hence are not included in Figure 3. The maximum % increase for Subject 103 was 4100%.

Table 6. CTC Assay

Subject Day 1 Day 8 Day 21

101 15 12 1 1

102 0 0 0 103 3 0 37

104 5 5 3

105 28 6 8

106 0 0 0

107 14 8 4

[092] Plasma vinorelbine concentrations were below the lower limit of detection (0.2 ng/mL) at all sampling timepoints for all subjects in Cohort 1 (vinorelbine 1 mg/day).

[093] This study indicates that both vinorelbine dose levels were well tolerated by all subjects for an extended period of time (at least 8 weeks), and that no clinically significant adverse events related to vinorelbine treatment were observed. As noted in Table 3, two subjects were terminated early from the study; however this termination was due to disease progression and not because of a severe adverse side-effect from vinorelbine administration. In addition, results from the assays conducted indicate that there was anti-angiogenesis activity at both vinorelbine doses used in this study.

[094] Furthermore, Subject 102, who has adenocarcinoma of the colon, had a palpable supraclavicular mass at study entry which measured 10 cm. After approximately four weeks on study in Cohort 1 (vinorelbine 1 mg/day), the mass had decreased to 5 cm by physical examination measurement. A CT scan indicated that the mass measured 6.5 cm, therefore a formal PR confirmation is pending (>30% diameter reduction by Response Evaluation Criteria In Solid Tumors [RECIST]).

[095] In addition, Subject 104, who has adenocarcinoma of the colon and a history of minimal response to six prior courses of therapy, had a stable scan (stable disease) after approximately six weeks on study in Cohort 2 (vinorelbine 3 mg/day).

[096] In closing, it is to be understood that although aspects of the present specification are highlighted by referring to specific embodiments, one skilled in the art will readily appreciate that these disclosed embodiments are only illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to a particular methodology, protocol, and/or reagent, etc., described herein. As such, various modifications or changes to or alternative configurations of the disclosed subject matter can be made in accordance with the teachings herein without departing from the spirit of the present specification. Lastly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. Accordingly, the present invention is not limited to that precisely as shown and described.

[097] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above- described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[098] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[099] Unless otherwise indicated, all numbers expressing a characteristic, item, quantity, parameter, property, term, and so forth used in the present specification and claims are to be understood as being modified in all instances by the term "about." As used herein, the term "about" means that the characteristic, item, quantity, parameter, property, or term so qualified encompasses a range of plus or minus ten percent above and below the value of the stated characteristic, item, quantity, parameter, property, or term. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values setting forth the broad scope of the invention are approximations, the numerical ranges and values set forth in the specific examples are reported as precisely as possible. Any numerical range or value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Recitation of numerical ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the present specification as if it were individually recited herein.

[0100] The terms "a," "an," "the" and similar referents used in the context of describing the present invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. , "such as") provided herein is intended merely to better illuminate the present invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the present specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0101] Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term "consisting of" excludes any element, step, or ingredient not specified in the claims. The transition term "consisting essentially of limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the present invention so claimed are inherently or expressly described and enabled herein.

[0102] All patents, patent publications, and other publications referenced and identified in the present specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

Claims

1. A method of treating a non-hematologic tumor in an individual in need thereof, the method comprising the step of administering a daily dose of 10 mg/day or less of a vinca alkaloid to the individual, wherein the daily dose of the vinca alkaloid is administered for at least five day each week for at least one week, and wherein a reduction in a symptom associated with the non-hematologic tumor is indicative of treating the non-hematologic tumor.

2. The method of Claim 1 , wherein the daily dose of the vinca alkaloid administered is 5 mg/day or less, 3 mg/day or less, 2 mg/day or less, or 1 mg/day or less.

3. The method of Claim 1 , wherein the daily dose of the vinca alkaloid is administered for at least five day each week for at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 1 weeks, or at least 12 weeks.

4. The method of Claim 1 , wherein the daily dose of the vinca alkaloid is administered for at least five day each week for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 1 1 months, or at least 12 months.

5. The method of Claim 1 , wherein administration of the the daily dose of the vinca alkaloid results in an amount of the vinca alkaloid in blood serum that is less than 1.0 ng/mL, less than 0.5 ng/mL, less than 0.3 ng/mL, less than 0.2 ng/mL, or less than 0.1 ng/mL.

6. The method of Claim 1 , wherein the administration of the daily dose of the vinca alkaloid does not result in a severe side effect.

7. The method of Claim 1 , wherein the severe side effect incldues bone marrow suppression, gastrointestinal toxicity, potent vesicant (blister-forming) activity, extravasation injury (deep ulcer formation), peripheral neuropathy, lowered resistance to infection, bruising, bleeding, anemia, constipation, diarrhea, nausea, tiredness and a general feeling of weakness (asthenia), inflammation of the vein into which vinca alkaloid was administered (phlebitis), severe hyponatremia, hair loss, an allergic reaction, or any combination thereof.

8. The method of Claim 1 , wherein the vinca alkaloid includes vinca alkaloid free base.

9. The method of Claim 1 , wherein the vinca alkaloid free base includes a vinblastine free base, a vincristine free base, a vindesine free base, a vinflunine free base, or a vinorelbine free base.

10. The method of Claim 1 , wherein the vinca alkaloid includes pharmaceutically-acceptable salt of a vinca alkaloid.

1 1. The method of Claim 1 , wherein the pharmaceutically-acceptable salt of a vinca alkaloid includes a pharmaceutically-acceptable salt of a vinblastine, a pharmaceutically-acceptable salt of a vincristine, a pharmaceutically-acceptable salt of a vindesine, a pharmaceutically-acceptable salt of a vinflunine, or a pharmaceutically-acceptable salt of a vinorelbine.

12. The method of Claim 1 , wherein the pharmaceutically-acceptable salt of a vinca alkaloid includes a vinblastine tartrate, a vincristine tartrate, a vindesine tartrate, a vinflunin tartrate, or a vinorelbine tartrate.

13. The method of Claim 1 , wherein the vinca alkaloid includes a vinorelbine free base or a vinorelbine tartrate.

14. The method of Claim 1 , wherein the administration is an oral administration.

15. The method of Claim 1 , wherein the administration is by an intravenous injection.

16. The method of Claim 1 , wherein the non-hematologic tumor is a carcinoma, a sarcoma, a blastoma, or a germ cell tumor.

17. A composition comprising 10 mg or less of a vinca alkaloid, 100 mg or more of a polyol, and 5 mg or less of a fatty acid, wherein the total weight of the composition is about 125 mg.

18. The composition of Claim 17, wherein the vinca alkaloid includes a vinorelbine.

19. The composition of Claim 18, wherein the vinca alkaloid includes a vinorelbine free base or a vinorelbine tartrate.

20. The composition of Claim 17, wherein the polyol is a disaccharide polyol.

21. The composition of Claim 20, wherein the disaccharide polyol includes isomalt.

22. The composition of Claim 17, wherein the fatty acid comprises between 16 and 24 carbon atoms.

23. The composition of Claim 22, wherein the fatty acid includes stearate.

24. The composition of Claim 17, wherein the composition is alcohol-free.

25. A composition comprising between about 0.5% (w/w) to about 1 1 % (w/w) of a vinca alkaloid, between about 79% (w/w) to about 99% (w/w) of a polyol, and about 0.5% (w/w) to about 10% (w/w) of a fatty acid, wherein the composition comprises 10 mg or less of the vinca alkaloid.

26. The composition of Claim 25, wherein the vinca alkaloid includes a vinorelbine.

27. The composition of Claim 26, wherein the vinca alkaloid includes a vinorelbine free base or a vinorelbine tartrate.

28. The composition of Claim 25, wherein the polyol is a disaccharide polyol.

29. The composition of Claim 28, wherein the disaccharide polyol includes isomalt.

30. The composition of Claim 25, wherein the fatty acid comprises between 16 and 24 carbon atoms.

31. The composition of Claim 31 , wherein the fatty acid includes stearate.

32. The composition of Claim 25, wherein the composition is alcohol-free.

33. A pharmaceutical kit comprising a) a composition comprising 10 mg or less of a vinca alkaloid, 100 mg or more of a polyol, and 5 mg or less of a fatty acid, wherein the total weight of the composition is about 125 mg; and b) instructions for daily administration over an extended period of time.

34. A pharmaceutical kit comprising a) a composition comprising between about 0.5% (w/w) to about 1 1 % (w/w) of a vinca alkaloid, between about 79% (w/w) to about 99% (w/w) of a polyol, and about 0.5% (w/w) to about 10% (w/w) of a fatty acid, wherein the composition comprises 10 mg or less of the vinca alkaloid; and b) instructions for daily administration over an extended period of time.