CA2658436A1 - A novel lactic acid formulation of mk-0457 useful for the treatment of cancer - Google Patents

Abstract

A lactic acid formulation, and a process to prepare that formulation, of MK-0457 is disclosed:. Such a formulation is useful in the treatment of cancer.

Description

TITLE OF THE INVENTION

OF CANCER

BACKGROUND OF THE INVENTION
The Aurora A, B, and C family of serine/threonine kinases is essential for entry into and progression through mitosis.. Aurora A regulates initiation of mitosis and plays a critical role in centrosome maturation, the establishment of bipolar spindles during cell division, and the attachment of chromosomes to the spindle. Aurora B is a chromosomal passenger protein with a more critical role in the latter stages of mitosis, being required for chromosome alignment, the mitotic checkpoint and cytokinesis. The function of Aurora C remains unclear.
MK-0457 is a potent and highly selective Aurora kinase inhibitor that is being developed for the treatment of cancer. MK-0457 causes delayed entry and progression through mitosis, exit from mitosis without cytokinesis, and induction of apoptosis. MK-0457 has potent activity in vitro and in vivo against a variety of solid tumors, leukemias, and lymphomas.
MK-0457 was initially formulated as a lyophilized sulfate salt product for Phase I
studies. The solubility of the initially prepared MK-0457 as a sulfate salt was 30 mg/mL.
However, during manufacture, a more thermodynamically stable polymorph was discovered and generated, which had a solubility of only 1 mg/mL. A salt screen was conducted to determine a.
more soluble formulation of MK-0457, which returned several crystalline pharmaceutically relevant salts, including but not limited to, phosphate, succinate, citrate, toysalate and besylate, all with a maximum solubility of approximately 2 mg/mL. Surprisingly, a novel formulation of MK-0457 utilizing lactic acid was identified having a solubility of 20 mg/mL.
MK-0457 is currently in Phase II clinical oncology studies.
It is an object of this invention to provide a novel lactic acid formulation and process thereof of MK-0457 which is characterized by properties that offer advantages in the delivery of MK-0457 to a patient in need of cancer treatment.

SUMMARY OF THE INVENTION
A lactic acid fonnulation, and a process to prepare that formulation, of MK-is disclosed:

Me NH
HN `N
H
yY
~N fLN N~SJ~ O

Me N MK-0457 Such a formulation is useful in the treatment of cancer. _ DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to the lactic acid formulation of MK-0457:
Me X'NH
HN
N
\N ~

O
N I N~S ~ I
~J

It has been surprisingly discovered that a lactic acid formulation of MK-0457 provided improved solubility (20 mg/mL).
The instant invention is also directed to the process for the preparation of the lactic acid formulation of MK-0457 which comprises the steps of: combining a lactic acid solution with an amount of MK-0457; and adding a sugar.
In an embodiment of the instant process, the process further comprises the step of mixing until all contents are dissolved.
In another embodiment of the instant process, the process further comprises the step of adjusting the pH.
In another embodiment of the instant process, the lactic acid solution has a concentration range from I mg/mL to 100 mg/mL.
In another embodiment of the instant process, the lactic acid solution has a concentration range from 5 mg/mL to 50 mg/mL.
In another embodiment of the instant process, the lactic acid solution has a concentration of 20 mg/mL.
In another embodiment of the instant process, the lactic acid solution has a concentration of 10 mg/mL.
In another embodiment of the instant process, the amount of MK-0457 ranges from 1 mg to 2000 mg.
In another embodiment of the instant process, the amount of MK-0457 ranges from 2 mg to 1000 mg.
In another embodiment of the instant process, the amount of MK-0457 ranges from 5 mg to 500 mg.
In another embodiment of the instant process, the amount of MK-0457 ranges from 100 mg to 500 mg.
In another embodiment of the instant process, the amount of MK-0457 is 200 mg.

In another embodiment of the instant process, the sugar is selected from mannitol or dextrose.
In another embodiment of the instant process, the sugar is added to reach tonicity.
In another embodiment of the instant process, the pH is adjusted to a range of about 2.5 to 4.5.
In another embodiment of the instant process, the pH is adjusted to a range of about 3 to 3.5.
The lactic acid formulation of MK-0457 may additionally comprise pharmaceutically acceptable carriers, excipients or diluents. In this regard, see, e.g. Remington's Pharmaceutical Sciences, 16th ed., 1980, Mack Publishing Company, edited by Osol et al. Such compositions may include proteins, such as serum proteins, for example, human serum albumin, and the like. Suitable diluents for reconstituting the lyophilized formulation prior to administration may include, for example, sterile water, isotonic saline, dilute aqueous dextrose, a polyhydric alcohol or mixtures of such alcohols, for example, glycerin, propylene glycol, polyethylene glycol and the like. As used, "pharmaceutically acceptable"
refers to those agents which are useful in the treatment or diagnosis of a warm-blooded animal including, for example, a human, equine, porcine, bovine, murine, canine, feline, or other manunal, as well as an avian or other warm-blooded animal. The preferred mode of administration of the reconstituted formulation is parenterally, particularly by the intravenous, intramuscular, subcutaneous, intraperitoneal, or intralymphatic route.
As used herein, the terms "composition" and "formulation" are intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combination of the specific ingredients.
The formulation of the instant invention may also be administered in combination with another anti-cancer agent(s).
For intravenous administration, the composition preferably will be prepared so that the amount administered to the patient will be from about 0.Olg to about lg of MK-0457.
Preferably, the amount administered will be in the range of about 0.2g to about 1 g of 1VIK-0457.
The salt of the invention is effective over a wide dosage range depending on factors such as the disease state to be treated or the biological effect to be modified, the manner in which the salt is administered, the age, weight and condition of the patient as well as other factors to be determined by the treating physician. Thus, the amount administered to any given patient must be determined on an individual basis.
One skilled in the art will appreciate that although specific reagents and reaction conditions are outlined in the following examples, modification can be made and are meant to be encompassed by the spirit and scope of the invention. The following preparations and examples, therefore, are provided to further illustrate the invention, and are not limiting.

UTILITY
The formulations and methods provided herein are particularly deemed useful for the treatment of cancer. Cancers that may be treated by the formulations and methods of the invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;
Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non small cell;
Gastrointestinal:
esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, rectal ; Genitourinartract: kidney (adenocarcinoma, Wihn's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:
hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system:
skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);
Gvnecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;
and Adrenal glands: neuroblastoma. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above-identified conditions.
Cancers that may be treated by the formulations and methods of the invention include, but are not limited to: breast, prostate, colon, colorectal, lung, brain, testicular, stomach, ovarian, pancrease, skin, small intestine, large intestine, throat, head and neck, oral, bone, liver, bladder, kidney, thyroid and blood.
Cancers that may be treated by the formulations and methods of the invention include: breast, prostate, colon, ovarian, colorectal and lung.
Cancers that may be treated by the formulations and methods of the invention include: breast, colon, (colorectal) and lung (non small cell lung cancer).
Cancers that may be treated by the formulations and methods of the invention include: lymphoma and leukemia.
Cancers that may be treated by the formulations and methods of the invention include: myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodglcin's lymphoma [malignant lymphoma].
Cancers that may be treated by the formulations and methods of the invention include: myeloid leukemia [acute and.chronic], acute lymphoblastic leukemia, myeloproliferative diseases.
Cancers that may be treated by the formulations and methods of the invention include: chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL).
Cancers that may be treated by the formulations and methods of the invention include: chronic myeloid leukemia (CML).
The formulations of the invention are also useful in preparing a medicament that is useful in treating cancer.
MK-0457 may be synthesized according to the General Scheme and Examples herein (see also WO 04/000833, which is incorporated herein by reference).
Additionally, MK-0457 may be synthesized by methods known to skilled practitioners.

General Scheme:

cl cl H
N
+ N O (-' C ( CI N~S% MeHCI NS O

Me Me N ~ \N
HN ~I/ HN H
~L- ^ N 1~ H
N ~ ~ j ~ N
I

CI N~S ' \ I C N \NS \ 0 ~
D Me/-N J 1 EXAMPLES
Examples 1-4 refer to the General Scheme above.
Example 1 4,6-Dichloropyrimidine-2-methylsulfone (A): Prepared by methods substantially similar to those set forth in Koppell et al, JOC, 26, 1961, 792, in the following manner. To a stirred solution of 4,6-dichloro-2-(methylthio)pyrimidine (50 g, 0.26 mol) in dichloromethane (1 L) at 0 C was added meta-chloroperoxybenzoic acid (143.6 g, 0.64 mol) over a period of 20 minutes. The solution was allowed to warm to room temperature and was stirred for 4 hours.
The mixture was diluted with dichloromethane (1.5 L) and then treated sequentially with 50%
Na2S2O3 / NaHCO3 solution (2 x 200 ml), sat. NaHCO3 solution (4 x 300 ml), and brine (200 ml) then dried (MgSO4)= The solvent was removed in vacuo to afford an off-white solid, which was redissolved in EtOAc (1L) and treated sequentially with sat. NaHCO3 solution (3 x 300 ml), and brine (100 ml) then dried (MgSO4). The solvent was removed in vacuo to afford the title compound (A) as a white solid (55.6 g, 96% yield). ' H NMR CDC13 5 3.40 (3H, s, CH3), 7.75 (1 H. s. ArH).
Example 2 Cyclopropane carboxylic acid [4-(4,6-dichloro-pyrimidin-2-ylsulphanyl)-phenyl]-amide (C): A
suspension of compound A(lOg, 44.04 mmol) and cyclopropane carboxylic acid (4-mercapto-phenyl)-amide (B, 8.51 g, 44.04 nunol) in t-butanol (300 ml) was degassed by evacuation, then flushing with nitrogen. The mixture was stirred at 90 C under nitrogen atmosphere for 1 hour then the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (600 ml) and washed with an aqueous solution of potassium carbonate and sodium chloride.
The organic extract was dried over magnesium sulphate, concentrated to a low volume and allowed to crystallize. The product C was collected as colourless crystals, (11.15 e.
74%). IH-NMR

DMSO-d6, S 0.82-0.89 (4H, m), 1.80-1.88 (IH, m), 7.55 (2H, d), 7.70-7.76 (3H, m), 10.49 (IH, s); M+H, 340.
ExamQle 3 Cyclopropane carboxylic acid{4-[4-chloro-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulphanyl]-phenyl} amide (D): A mixture of compound C (1.0 g, 2.94 mmol)and 3-amino-5-methylpyrazole (314 mg, 3.23 mmol) in dimethylformamide (6 ml) was treated with diisopropylethylamine (0.614 ml, 3.53 mmol) and sodium iodide (530 mg, 3.53 mmol). The mixture was stirred under nitrogen at 85 for 4 hours, cooled to room temperature and diluted with ethyl acetate. The solution was washed with water (x 4), dried over magnesium sulphate and concentrated to 5 ml to afford, upon crystallization and harvesting of colourless crystals, the title compound D (920 mg, 78%). 'H-NMR DMSO-d6, S 0.80-0.87 (4H, m), 1.77-1.85 (1H, m), 1.92 (1 H, s), 5.24 (IH, br s), 6.47 (1 H, br s), 7.55 (2H, d), 7.70-7.80 (2H, m), 10.24 (1 H, s), 10.47 (1H, s), 11.92 (1H, s).
Example 4 Cyclopropane carboxylic acid {4-[4-(4-methyl-piperazin-1-yl)-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulphanyl]-phenyl}-amide (I): Compound D (2.373 g, 5.92 mmol) was treated with N-methylpiperazine (10 ml) and the mixture stirred at 110 for 2 hours. The excess N-methylpiperazine was removed in vacuo then the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried over magnesium sulphate, and concentrated. The residue was crystallised from methanol to give colourless crystals of desired product I(MK-0457) (1.82 g, 66%), 'H-NMR DMSO-d6, S 0.81 (4H, d), 1.79 (1H, m), 2.01 (3H, s), 2.18 (3H, s), 2.30 (4H, m), 3.35 (masked signal), 5.42 (1H, s), 6.02 (1H, br s), 7.47 (2H, d), 7.69 (2H, d), 9.22 (IH, s), 10.39 (1 H, s), 11.69 (1 H, s).
The formulations of this invention may be administered to mammals, including humans, either alone or, in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, and subcutaneous routes of administration.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents/fillers, such as calcium carbonate, sodium carbonate, lactose, mannitol, sucrose, starch, kaolin, dicalcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, crospovidone, sodium starch glycolate, or alginic acid; binding agents, for example starch, cellulose polymers (hydroxypropyl cellulose, HPMC, hydroxyethyl cellulose, methyl cellulose), gelatin, polyvinyl-pyrrolidone or synthetic gums (acacia, guar gum, xanthan gum, pectin, sodium alginate, carageenan) and lubricating agents, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, colloidal silicon dioxide or talc. The tablets may. be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug, improve physical appearance, or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, any water soluble taste masking material such as but not limited to hydroxypropylmethyl-cellulose, shellac, Eudragit, cellulose acetate phthalate, or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate, cellulose acetate, or Eudragits may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate or nonionic surfactants (tween or TPGS) or others such as sodium lauryl sulfate, docusate sodium, polyethylene-polypropylene block co-polymers (poloxamer). The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable.oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring agents, preservatives and antioxidants.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
The pharmaceutical compositions may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulsion.
The injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspensioin may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
In addition, sterile, fixed oils.are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil composed of different chain length triglycerides (e.g. soybean oil, coconut oil, and safflower oil) may be employed including synthetic mono- or diglycerides.
In addition, fatty acids such as oleic acid, linoleic acid, palmitic acid, stearic acid fmd use in the preparation of injectables.
When a composition according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
The dosage regimen utilizing the formulations of the instant invention can be selected in accordance with a variety of factors including type, species, age, weight, sex and the type of cancer being treated; the severity (i.e., stage) of the cancer to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to treat, for example, to prevent, inhibit (fully or partially) or arrest the progress of the disease. For example, formulations of the instant invention can be administered in a total daily dose of up to 1000 mg.
Formulations of the instant invention can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), and three times daily (TID). Formulations of the instant invention can be administered at a total daily dosage of up to 1000 mg, e.g., 200 mg, 300 mg, 400 mg, 600 mg, 800 mg or 1000 mg, which can be administered in one daily dose or can be divided into multiple daily doses as described above.
In addition, the administration can be continuous, i.e., every day, or intermittently.
The terms "intemzittent" or "intermittently" as used herein means stopping and starting at either regular or irregular intervals. For example, intermittent administration of a formulation of the instant invention may be administration one to six days per week or it may mean administration in cycles (e.g. daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week) or it may mean administration on alternate days.
In addition, the formulations of the instant invention may be administered according to any of the schedules described above, consecutively for a few weeks, followed by a rest period. For example, the formulations of the instant invention may be administered according to any one of the schedules described above from two to eight weeks, followed by a rest period of one week, or twice daily at a dose of 100 - 500 mg for three to five days a week. In another particular embodiment, the formulations of the instant invention may be administered three times daily for two consecutive weeks, followed by one week of rest.
In another embodiment, the formulations of the instant invention can be administered intravenously for a 5-day continuous infusion at 24-64 mg/m2/hr with a cycle duration every 14-28 days. In another embodiment, the formulation can be administered intravenously for a 5-day continuous infusion at 6-12 mg/m2/hr with a cycle duration every 14-28 days. In another embodiment, the formulation can be administered intravenously for a 5-day continuous infusion at 8-10 mg/m2/hr with a cycle duration every 14-28 days.
In another embodiment, the formulation can be administered intravenously for a 24 hr infusion every 14-21 days at 32-200 mg/m2/hr. In another embodiment, the formulation can be administered intravenously for a 24 hr infusion every 14-21 days at 32-64 mg/m2/hr. In another embodiment, the formulation can be administered intravenously for a 48 hr infusion every 21-28 days at 8-12 mg/mZ/hr. In another embodiment, the formulation can be administered intravenously for a 6 hr infusion every 14-21 days at 32-200 mg/m2/hr. In another embodiment, the formulation can be administered intravenously for a 6 hr infusion every 14-21 days at 32-64 mg/mZ/hr. In another embodiment, the formulation can be administered intravenously for a 3 hr infusion every 14-21 days at 32-200 mg/m2/hr. In another embodiment, the formulation can be administered intravenously for a 3 hr infusion every 14-21 days at 32-64 mg/m2/hr.
In another embodiment, the formulation can be administered intravenously for a 5-day continuous infusion at 24-64 mg/m2/hr with a cycle duration every 14-28 days. In another embodiment, the formulation can be administered intravenously for a 5-day continuous infusion at 8-10 mg/m2/hr with a cycle duration every 21 days. In another embodiment, the formulation can be administered intravenously for a 24 hr infusion every 21 days at 64-96 mg/m2/hr. In another embodiment, the formulation can be administered intravenously for a 24 hr infusion every 21 days at 32-64 mg/m2/hr. In another embodiment, the formulation can be administered intravenously for a 6 hr infusion every 14-21 days at 32-200 mg/m2/hr. In another embodiment, the formulation can be administered intravenously for a 3 hr infusion every 14-21 days at 32-200 mg/m2/hr.
Any one or more of the specific dosages and dosage schedules of the formulations of the instant invention, may also be applicable to any one or more of the therapeutic agents to be used in the combination treatinent (hereinafter refered to as the "second therapeutic agent").
Moreover, the specific dosage and dosage schedule of this second therapeutic agent can further vary, and the optimal dose, dosing schedule and route of administration will be determined based upon the specific second therapeutic agent that is being used.
Of course, the route of administration of the formulations of the instant invention is independent of the route of administration of the second therapeutic agent.
In an embodiment, the administration for a formulation of the instant invention is oral administration. In another embodiment, the administration for a formulation of the instant invention is intravenous administration. Thus, in accordance with these embodiments, a formulation of the instant invention is administered orally or intravenously, and the second therapeutic agent can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
In addition, a formulation of the instant invention and second therapeutic agent may be administered by the same mode of administration, i.e. both agents administered e.g.
orally, by IV. However; it is also within the scope of the present invention to administer a formulation of the instant invention by one mode of administration, e.g. IV, and to administer the second therapeutic agent by another mode of administration, e.g. oral or any other ones of the administration modes described hereinabove.
The first treatment procedure, administration of afonnulation of the instant invention, can take place prior to the second treatment procedure, i.e., the second therapeutic agent, after the treatment with the second therapeutic agent, at the same time as the treatment with the second therapeutic agent, or a combination thereof. For example, a total treatment period can be decided for a formulation of the instant invention. The second therapeutic agent can be administered prior to onset of treatment with a fonnulation of the instant invention or following treatment with a formulation of the instant invention. In addition, anti-cancer treatment can be administered during the period of administration of a formulation of the instant invention but does not need to occur over the entire treatment period of a formulation of the instant invention.
The instant formulations are also useful in combination with therapeutic, chemotherapeutic and anti-cancer agents. Combinations of the presently disclosed formulations with therapeutic, chemotherapeutic and anti-cancer agents are within the scope of the invention.
Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T.
Devita and S. Hellman (editors), 6h edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Such agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA
therapeutics, -y-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and agents that interfere with cell cycle checkpoints. The instant compounds are particularly useful when co-administered with radiation therapy.
"Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.
"Androgen receptor modulators" refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5ac reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
"Retinoid receptor modulators" refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, a-. 10 difluoromethylomithine, ILX23-7553, trans-N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
"Cytotoxic%ytostatic agents" refer to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins,histone deacetylase inhibitors, inhibitors of kinases involved in mitotic progression, inhibitors of kinases involved in growth factor and cytokine signal transduction pathways, antimetabolites, biological response modifiers, hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteosome inhibitors, ubiquitin ligase inhibitors, and aurora kinase inhibitors.
Examples of cytotoxic/cytostatic agents include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum (II)]tetrachloride, diarizidinylspermine, arsenic trioxide, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755, 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (see WO 00/50032), Raf kinase inhibitors (such as Bay43-9006) and mTOR inhibitors (such as Wyeth's CCI-779).
An example of a hypoxia activatable compound is tirapazamine.
Examples of proteosome inhibitors include but are not limited to lactacystin and MLN-341 (Velcade).

Examples of microtubule inhibitors/microtubule-stabilising agents include.
paclitaxel, vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS 184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258, the epothilones (see for example U.S. Pat. Nos.
6,284,781 and 6,288,237) and BMS 188797. In an embodiment the epothilones are not included in the microtubule inhibitors/microtubule-stabilising agents.
Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-O-exo-benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, 1-amino-9-ethyl=5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1 H,12H-benzo[de]pyrano[3',4':b,7]-indolizino[
1,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'-.
dimethylamino-2'-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-I-carboxamide, asulacrine, (5a, 5aB, 8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydro0xy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofiuo(3',4':6,7)naphtho(2,3-d)-1,3-dioxol-6-one, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium, 6,9-bis[(2-aminoethyl)amino]benzo[g]isoguinoline-5,10-dione, 5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one, N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c] quinolin-7-one, and dimesna.
Examples of inhibitors of mitotic kinesins, and in particular the human mitotic kinesin KSP, are described in Publications W003/039460, W003/050064, W003/050122, -W003/049527, W003/049679, W003/049678, W004/039774, W003/079973, W003/09921 1, W003/105855, W003/106417, W004/037171, W004/058148; W004/058700, W004/126699, W005/018638, W005/019206, W005/019205, W005/018547, W005/017190, US2005/0176776. In an embodiment inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E, inhibitors of MCAK and inhibitors of Rab6-KIFL.
Examples of "histone deacetylase inhibitors" include, but are not limited to, SAHA, TSA, oxamflatin, PXD101, MG98 and scriptaid. Further reference to other histone deacetylase inhibitors may be found in the following manuscript; Miller, T.A.
et al. J. Med.
Chem. 46(24):5097-5116 (2003).
"Inhibitors of kinases involved in mitotic progression" include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub-1 and inhibitors of bub-Rl. An example of an "aurora kinase inhibitor" is VX-680.
."Antiproliferative agents" includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][ 1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamic acid, aminopterin, 5-flurouracil, alanosine, 11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1Ø0)-tetradeca-2,4,6-trien-9-yl acetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-l-B-D-arabino furanosyl cytosine, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone and trastuzumab.
Examples of monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar.
"HMG-CoA rediuctase inhibitors" refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR ; see U.S. Patent Nos.
4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR ; see U.S. Patent Nos. 4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL ; see U.S. Patent Nos.
4,346,227,4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL ; see U.S. Patent Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896), atorvastatin (LIPITOR ;
see U.S. Patent Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL ; see US Patent No. 5,177,080). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry &
Industry, pp.
85-89 (5 February 1996) and US Patent Nos. 4,782,084 and 4,885,314. The term HMG-CoA
reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
"Prenyl-protein transferase inhibitor" refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including famesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I(GGPTase-I), and geranylgeranyl-protein transferase type-H (GGPTase-II, also called Rab GGPTase).
Examples of prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO
97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Patent No. 5,420,245, U.S. Patent No. 5,523,430, U.S. Patent No. 5,532,359, U.S. Patent No. 5,510,510, U.S.
Patent No. 5,589,485, U.S. Patent No. 5,602,098, European Patent Publ. 0 618 221, European Patent Publ. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ. 0 696 593, WO 94/19357, WO
95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Patent No.
5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO
96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO
96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S.
Patent No. 5,571,792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO
96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO
97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO
98/02436, and U.S. Patent No. 5,532,359. For an example of the role of a prenyl-protein transferase inhibitor on angiogenesis see European J. of Cancer, Vol. 35, No.
9, pp.1394-1401 (1999).
"Angiogenesis inhibitors" refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFRI) and Flk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-a, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib (PNAS, Vol. 89, p.
7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch. Opthalmol., Vol. 108, p.573 (1990); Anat. Rec., Vol. 238, p. 68 (1994); FEBSLetters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76 (1995); J. Mol.
Endocrinol., Vol. 16, p.107 (1996); Jpn. J. Pharmacol., Vol. 75, p. 105 (1997); CancerRes., Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J.
Biol. Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab.
Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, Nature Biotechnology, Vol. 17, pp.963-968 (October 1999); Kim et al., Nature, 362, 841-844 (1993); WO
00/44777; and WO
00/61186).

Other.therapeutic agents that modulate or inhibit angiogenesis and may also be used in combination with the formulations of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem.
La. Med. 38:679-692 (2000)). Examples of such agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost. 80:10-23 (1998)), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res.
101:329-354 (2001)).
TAFIa inhibitors have been described in U.S. Ser. Nos. 60/310,927 (filed August 8, 2001) and 60/349,925 (filed January 18, 2002).
"Agents that interfere with cell cycle checkpoints" refer to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents. Such agents include inhibitors of ATR, ATM, the CHKI and kinases and cdk and cdc kinase inhibitors and are specifically exemplified by hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
"Agents that interfere with'receptor tyrosine kinases (RTKs)" refer to compounds that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor progression.
Such agents include inhibitors of c-Kit, Eph, PDGF, F1t3 and c-Met. Further agents include inhibitors of RTKs as described by Bume-Jensen and Hunter, Nature, 411:355-365, 2001.
."Inhibitors of cell proliferation and survival signalling pathway" refer to compounds that inhibit signal transduction cascades downstream of cell surface receptors. Such agents include inhibitors of serine/threonine kinases (including but not limited to inhibitors of Akt such as described in WO 02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US 2004-0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO
03/084473, WO 03/086403, WO 2004/04 1 1 62, WO 2004/096131, WO 2004/096129, WO
2004/096135, WO 2004/096130, WO 2005/100356, WO 2005/100344, US 2005/029941, US
2005/44294, US 2005/43361, 60/734188, 60/652737, 60/670469), inhibitors of Raf kinase (for example BAY-43-9006 ), inhibitors of MEK (for example CI-1040 and PD-098059), inhibitors of mTOR (for example Wyeth CCI-779), and inhibitors of P13K (for example LY294002).
As described above, the combinations with NSAID's are directed to the use of NSAID's which are potent COX-2 inhibiting agents. For purposes of this specification an NSAID is potent if it possesses an IC50 for the inhibition of COX-2 of 1 M or less as measured by cell or microsomal assays.
The invention also encompasses combinations with NSAID's which are selective COX-2 inhibitors. For purposes of this specification NSAID's which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays. Such compounds include, but are not limited to those disclosed in U.S. Patent 5,474,995, U.S. Patent 5,861,419, U.S. Patent 6,001,843, U.S.
Patent 6,020,343, U.S.

Patent 5,409,944, U.S. Patent 5,436,265, U.S. Patent 5,536,752, U.S. Patent 5,550,142, U.S.
Patent 5,604,260, U.S. 5,698,584, U.S. Patent 5,710,140, WO 94/15932, U.S.
Patent 5,344,991, U.S. Patent 5,134,142, U.S. Patent 5,380,738, U.S. Patent 5,393,790, U.S.
Patent 5,466,823, U.S.
Patent 5,633,272 and U.S. Patent 5,932,598, all of which are hereby incorporated by reference.
Inhibitors of COX-2 that are particularly useful in the instant method of treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof.
Compounds that have been described as specific inhibitors of COX-2 and are therefore useful in the present invention include, but are not limited to, the following: parecoxib, BEXTRA and CELEBREX or a pharmaceutically acceptable salt thereof.
Other examples of angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-l-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bi s[imino-N-methyl-4,2-pyrrolocarbonylimino [N-methyl-4,2-pyrrole]-carbonylimino]-bi s-(1, 3-naphthalene disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416).
As used above, "integrin blockers" refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the av[i3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the av(35 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the av(33 integrin and the a05 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the avR6, avR8, aiRl, a201, a01, a6(31 and a6[34 integrins. The term also refers to antagonists of any combination of avR3, a05, avR6, avP8, a1R1, a2R1, a5R1, a601 and a6[34 integrins.
Some specific examples of tyrosine kinase inhibitors include N-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-yl)methylidenyl)indolin-2-one, 17-(allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1 H-diindolo[ 1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocin-l-one, SH268, genistein, ST1571, CEP2563, 4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethane sulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

. Combinations with compounds other than anti-cancer compounds are also encompassed in the instant methods. For example, combinations of the instantly claimed formulations with PPAR-y (i.e., PPAR-gamma) agonists and PPAR-S (i.e., PPAR-delta) agonists are useful in the treatment of certain malingnancies. PPAR-y and PPAR-S are the nuclear peroxisome proliferator-activated receptors y and S. The expression of PPAR-y on endothelial cells and its involvement in angiogenesis has been reported in the. literature (see J. Cardiovasc.
Pharmacol. 1998; 31:909-913; J. Biol. Chem. 1999;274.:9116-9121; Invest.
Ophthalmol Vis. Sci.
2000; 41:2309-2317). More recently, PPAR-y agonists have been shown to inhibit the angiogenic response to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice. (Arch. Ophthamol. 2001;
119:709-717).
Examples of PPAR-y agonists and PPAR- y/a agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NPOI 10, DRF4158, NN622, G1262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionic acid (disclosed in USSN 09/782,856), and 2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy) phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid (disclosed in USSN
60/235,708 and 60/244,697).
Another embodiment of the instant invention is the use of the presently disclosed fonnulations in combination with gene therapy for the treatment of cancer. For an overview of genetic strategies to treating cancer see Hall et al (Am. J. Hum. Genet.
61:785-789, 1997) and Kufe et al (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000).
Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S.
Patent No. 6,069,134, for example), a uPA/uPAR antagonist ("Adenovirus-Mediated Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August 1998;5(8):1105-13), and interferon gamma (J.
Immunol.
2000;164:217-222).
The formulation of the instant invention may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR
associated with high levels of expression of transporter proteins. Such MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and (valspodar).
A formulation of the present invention may be employed in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a formulation of the present invention, alone or with radiation therapy. For the prevention or treatment of emesis, a formulation of the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists, such as.ondansetron, granisetron, xropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.Patent Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, an antidopaminergic, such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol. In another embodiment, conjunctive therapy with an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosed for the treatment or prevention of emesis that may result upon administration of the instant compounds.
Neurokinin-1 receptor antagonists of use in conjunction with the formulations of the present invention are fully described, for example, in U.S. Patent Nos.
5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147;
European Patent Publication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394,0 585 913,0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 709 375, 0 709 376,0 714 891, 0 723 959, 0 733 632 and 0 776 893; PCT
International Patent Publication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/1215 1, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320; 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689. The preparation of such compounds is fully described in the aforementioned patents and publications, which are incorporated herein by reference.
In an embodiment, the neurokinin-1 receptor antagonist for use in conjunction with the formulations of the present invention is selected from: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxb-1 H,4H-1,2,4-triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Patent No. 5,719,147.
A formulation of the instant invention may also be administered with an agent useful in the treatment of anemia. Such an anemia treatment agent is, for example, a continuous erythropoiesis receptor activator (such as epoetin alfa).
A formulation of the instant invention may also be administered with an agent useful in the treatment of neutropenia. Such a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF). Examples of a G-CSF
include filgrastim.
A formulation of the instant invention may also be administered with an immunologic-enhancing drug, such as levamisole, isoprinosine and Zadaxin.
A formulation of the instant invention may also be useful for treating or preventing cancer in combination with P450 inhibitors including: xenobiotics, quinidine, tyrarnine, ketoconazole, testosterone, quinine, methyrapone, caffeine, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafyline, cimetidine, dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem, terfenadine, verapamil, cortisol, itraconazole, mibefradil, nefazodone and nelfinavir.
A formulation of the instant invention may also be useful for treating or preventing cancer in combination with Pgp and/or BCRP inhibitors including:
cyclosporin A, PSC833, GF120918, cremophorEL, fumitremorgin C, Ko132, Ko134, Iressa, Imatnib mesylate, EKI-785, C11033, novobiocin, diethylstilbestrol, tamoxifen, resperpine, VX-710, tryprostatin A, flavonoids, ritonavir, saquinavir, nelfinavir, omeprazole, quinidine, verapamil, terfenadine, ketoconazole, nifidepine, FK506, amiodarone, XR9576, indinavir, amprenavir, cortisol, testosterone, LY335979, OC144-093, erythromycin, vincristine, digoxin and talinolol.
A formulation of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids).
Examples of bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
A formulation of the instant invention may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors. Examples of aromatase inhibitors include but are not limited to: anastrozole, letrozole and exemestane.
A formulation of the instant invention may also be useful for treating or.
preventing cancer in combination with siRNA therapeutics.

The formulations of the instant invention may also be administered in combination with ry-secretase inhibitors and/or inhibitors of NOTCH signaling.
Such inhibitors include compounds described in WO 01/90084, WO 02/30912, WO 01/70677, WO
03/013506, WO 02/36555, WO 03/093252, WO 03/093264; WO 03/09325 1, WO 03/093253, WO.
2004/039800, WO 2004/039370, WO 2005/030731, WO 2005/014553, USSN 10/957,251, WO
2004/089911, WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137, WO
2004/03 1 1 39, WO 2004/031138, WO 2004/101538, WO 2004/101539 and WO 02/47671 (including LY-450139).
A formulation of the instant invention may also be useful for treating or preventing cancer in combination with PARP inhibitors.
A formulation of the instant invention may also be useful for treating cancer in combination with the following therapeutic agents: abarelix (Plenaxis depot(&); aldesleukin (Prokine ); Aldesleukin (Proleukin(&); Alemtuzumabb (Campath ); alitretinoin (Panretin );
allopurinol (Zyloprim ); altretamine (Hexalen ); amifostine (Ethyol );
anastrozole (Arimidex ); arsenic trioxide (Trisenox ); asparaginase (Elspar ); azacitidine (Vidaza );
bevacuzimab (Avastin ); bexarotene capsules (Targretin ); bexarotene gel (Targretin );
bleomycin (Blenoxane ); bortezomib (Velcade ); busulfan intravenous (Busulfex ); busulfan oral (Myleran(&); calusterone (Methosarb ); capecitabine (Xeloda );
carboplatin (Paraplatin(&);
carmustine (BCNU , BiCNU(&); carmustine (Gliadel ); carmustine with Polifeprosan 20 Implant (Gliadel Wafer ); celecoxib (Celebrex(D); cetuximab (Erbitux );
chlorambucil (Leukeran ); cisplatin (Platinol ); cladribine (Leustatin , 2-CdA );
clofarabine (Clolar );
cyclophosphamide (Cytoxan , Neosar ); cyclophosphamide (Cytoxan Injection );
cyclophosphamide (Cytoxan Tablet ); cytarabine (Cytosar-U ); cytarabine liposomal (DepoCyt(D); dacarbazine (DTIC-Dome ); dactinomycin, actinomycin D (Cosmegen );
Darbepoetin alfa (Aranesp(&); daunorubicin liposomal (DanuoXome );
daunorubicin, daunomycin (Daunorubicin ); daunorubicin, daunomycin (Cerubidine ); Denileukin difftitox (Ontak ); dexrazoxane (Zinecard ); docetaxel (Taxotere ); doxorubicin (Adriamycin PFS );
doxorubicin (Adriamycin , Rubex ); doxorubicin (Adriamycin PFS Injection );
doxorubicin liposomal (Doxil ); dromostanolone propionate (dromostanolone );
dromostanolone propionate (masterone injection ); Elliott's B Solution (Elliott's B Solution ); epirubicin (Ellence ); Epoetin alfa (epogen ); erlotinib (Tarceva ); estramustine (Emcyt ); etoposide phosphate (Etopophos ); etoposide, VP-16 (Vepesid ); exemestane (Aromasin );
Filgrastim (Neupogen ); floxuridine (intraarterial) (FUDR ); fludarabine (Fludara(&);
fluorouracil, 5-FU
(Adrucil ); fulvestrant (Faslodex ); gefitinib (Iressa ); gemcitabine (Gemzar ); gemtuzumab ozogamicin (Mylotarg ); goserelin acetate (Zoladex Implant ); goserelin acetate (Zoladex );
histrelin acetate (Histrelin implant ); hydroxyurea (Hydrea ); Ibritumomab Tiuxetan (Zevalin ); idarubicin (Idamycin ); ifosfamide (IFEX ); imatinib mesylate (Gleevec );
interferon alfa 2a (Roferon A ); Interferon alfa-2b (Intron A ); irinotecan (Camptosar );

lenalidomide (Revlimid ); letrozole (Femara ); leucovorin (Wellcovorin(D, Leucovorin );
Leuprolide Acetate (Eligard ); levamisole (Ergamisol ); lomustine, CCNU (CeeBU
);
meclorethamine, nitrogen mustard (Mustargen ); megestrol acetate (Megace );
melphalan, L-PAM (Alkeran ); mercaptopurine, 6-MP (Purinethol ); mesna (Mesnex(D); mesna (Mesnex tabs ); methotrexate (Methotrexate ); methoxsalen (Uvadex ); mitomycin C(Mutamycin );
mitotane (Lysodren ); mitoxantrone (Novantrone ); nandrolone phenpropionate (Durabolin-50 ); nelarabine (Arranon ); Nofetumomab (Verluma(D); Oprelvekin (Neumega );
oxaliplatin (Eloxatin ); paclitaxel (Paxene(g); paclitaxel (Taxol ); paclitaxel protein-bound particles (Abraxane(D); palifermin (Kepivance ); pamidronate (Aredia(D); pegademase (Adagen (Pegademase Bovine) ); pegaspargase (Oncaspar ); Pegfilgrastim (Neulasta );
pemetrexed disodium (Alimta ); pentostatin (Nipent ); pipobroman (Vercyte ); plicamycin, mithramycin (Mithracin ); porfimer sodium (Photofrin ); procarbazine (Matulane );
quinacrine (Atabrine ); Rasburicase (Elitek ); Rituximab (Rituxan ); sargramostim (Leukine(&);
Sargramostim (Prokine ); sorafenib (Nexavar ); streptozocin (Zanosar );
sunitinib maleate (Sutent ); talc (Sclerosol ); tamoxifen (Nolvadex ); temozolomide (Temodar );
teniposide, VM-26 (Vumon ); testolactone (Teslac(&); thioguanine, 6-TG (Thioguanine );
thiotepa (Thioplex ); topotecan (Hycanitin ); toremifene (Fareston ); Tositumomab (Bexxar(&);
Tositumomab/I-131 tositumomab (Bexxar ); Trastuzumab (Herceptin ); tretinoin, ATRA
(Vesanoid ); Uracil Mustard (Uracil Mustard Capsules ); valrubicin (Valstar );
vinblastine (Velban ); vincristine (Oncovin(D); vinorelbine (Navelbine ); vorinostat (Zolinza ) and zoledronate (Zometa ).
In another embodiment, the formulation may also be useful for treating cancer in combination with dasatinib or nilotinib.
In another embodiment, the formulation may be useful for treating cancer in combination with radioactive iodine (usually 1131) and thyroid hormone (levothyroxine and/or triiodothyronin).
In another embodiment, the formulation may be useful for treating cancer in combination with somatostatin analogs (e.g. sandostatin and octreotide).
In another embodiment, the formulation may be useful for treating cancer in combination with radiolabeled CEA antibodies.
Thus, the scope of the instant invention encompasses the use of the instantly claimed formulations in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR-y agonists, PPAR-8 agonists, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA
therapeutic, -i-secretase and/or NOTCH inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint, and any of the therapeutic agents listed above.
In an embodiment, the angiogenesis inhibitor to be used as the second compound is selected from a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an 1VIMP (matrix metalloprotease) inhibitor, an integrin blocker, interferon-a, interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, or an antibody to VEGF. In an embodiment, the estrogen receptor modulator is tamoxifen or raloxifene.
The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a formulation of the invention means introducing the formulation or a prodrug of the formulation into the system of the animal in need of treatment. When a formulation of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), "administration" and its variants are each understood to include concurrent and sequential introduction of the formulation or prodrug thereof and other agents.
As used herein, the term "composition" or "formulation" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent in the insant formulation that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
The term "treating cancer" or "treatment of cancer" refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.
Also included in the scope of the claims is a method of treating cancer that comprises administering a therapeutically effective amount of a formulation of the instant invention in combination with radiation therapy and/or in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxiccytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR-y agonists, PPAR-S
agonists, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, -t-secretase and/or NOTCH inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint, and any of the therapeutic agents listed above.
And yet another embodiment of the invention is a method of treating cancer that comprises administering a therapeutically effective amount of a formulation of the instant invention in combination with paclitaxel or trastuzumab.
The invention further encompasses a method of treating or preventing cancer that comprises administering a therapeutically effective amount of a formulation of the instant invention in combination with a COX-2 inhibitor.
The instant invention also includes a pharmaceutical composition useful for treating or preventing cancer that comprises a therapeutically effective amount of a formulation of the instant invention and a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA
reductase inhibitor, an HN protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR-y agonist, a PPAR-S agonist, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, -)-secretase and/or NOTCH
inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint, and any of the therapeutic agents listed above.

Lactic Acid Formulation (20mg/mL) of MK-0457 Prepare a 20mg/mL concentration of lactic acid in water by weighing 2.Og of lactic acid (either, L-lactic acid, D-lactic acid or a racemic mixture) into a 100mL volumetric flask. Next, weigh out 200mg of MK-0457 into a lOmL volumetric flask. Next, add approximately 8mL of the 20mg/mL lactic acid solution to the l OmL volumetric flask. Next, add the appropriate amount of sugar (for example, 15mg/mL, 50mg/mL and 100mg/mL, depending on the desired tonicity). Stir the solution until all the drug contents are dissolved. Qs'd the solution to l OmL with the 20mg/mL lactic acid solution and adjust the pH as needed to aid in solublization.

Lactic Acid Formulation (20mg/mL) of MK-0457 (large scale manufacture) Add water for injection equal to 80 percent of batch weight to a suitable mixing vessel. Add the necessary amount of compendial lactic acid (either, L-lactic acid, D-lactic acid or a racemic mixture) equaling to 20mg/mL and mix to insure homogeneity. Add equal to 20mg/mL free base to the vessel and mix to dissolve. Add the appropriate amount of sugar (for example, 15mg/mL, 50mg/mI, and 100mg/mL, depending on the desired tonicity) to the vessel and mix to dissolve. Adjust the pH as needed. Qs'd the batch to final weight with water for injection. Sterile filter and collect the filtered formulation in an appropriate sterile receiving vessel. Fill and stopper the formulation in appropriate vials using aseptic technique in a properly classified area. Cap and terminally sterilize product as required.
Store the formulation at the appropriate temperature conditions.

Lactic Acid Formulation (20mg/mL) of MK-0457 (large scale manufacture) In another embodiment, a 20mg/mL lactic acid formulation of Compound I (large scale manufacture) may be prepared according to the following steps: Add water for injection equal to 80 percent of batch weight to a suitable mixing vessel. Add the necessary amount of compendial lactic acid (either L-lactic acid, D-lactic acid.or a racemic mixture) equaling to 20mg/mL and mix to insure homogeneity. Add MK-0457 equal to 20mg/mL free base to the vessel and mix to dissolve. Add the appropriate amount of sugar (for example, 15mg/mL, 50mg/mL or 100mg/mL, depending on the desired tonicity) and 0.05mg/ml EDTA
(edetate disodium dihydrate) to the vessel and mix to dissolve. Adjust the pH as needed. Qs'd the batch to final weight with water for injection. Sterile filter and collect the filtered fonmulation in an appropriate sterile receiving vessel. Fill and stopper the formulation in appropriate vials using aseptic technique in a properly classified area. Cap and terminally sterilize product as required.
Store the formulation at the appropriate temperature conditions.

Claims (16)

1. A process for the preparation of the lactic acid formulation of MK-0457 which comprises the steps of: combining a lactic acid solution with an amount of MK-0457; and adding a sugar.

2. The process according to Claim 1 wherein an additional step is added comprising, mixing until all contents are dissolved.

3. The process according to Claim 2 wherein an additional step is added comprising, adjusting the pH.

4. The process according to any Claims 1-3 wherein the lactic acid solution has a concentration range from 1 mg/mL to 100 mg/mL.

5. The process according to any Claims 1-3 wherein the lactic acid solution has a concentration range from 5 mg/mL to 50 mg/mL.

6. The process according to any Claims 1-3 wherein the lactic acid solution has a concentration of 20 mg/mL.

7. The process according to any Claims 1-6 wherein the amount of MK-0457 ranges from 1 mg to 2000 mg.

8. The process according to any Claims 1-6 wherein the amount of MK-0457 ranges from 2 mg to 1000 mg.

9. The process according to any Claims 1-6 wherein the amount of MK-0457 ranges from 5 mg to 500 mg.

10. The process according to any Claims 1-6 wherein the amount of MK-0457 ranges from 100 mg to 500 mg.

11. The process according to any Claims 1-6 wherein the amount of MK-0457 is 200 mg.

12. The process according to any Claims 1-11 wherein the sugar is selected from mannitol or dextrose.

13. The process according to any Claims 1-11 wherein the sugar is added to reach tonicity.

14. A lactic acid formulation of MK-0457.

15. A method of treating cancer in a mammal utilizing the lactic acid formulation of MK-0457 according to Claim 14.

16. A method of treating cancer in a mammal utilizing the lactic acid formulation of MK-0457 according to Claim 14 in combination with another anti-cancer agent.