Compositions and methods for treating cancer

Abstract

The present invention relates to methods of using herbal extracts in combination with anticancer agents for treating and preventing cancer.

Description

[0001] TITLE

[0002] Compositions and Methods for Treating Cancer

[0003] CROSS-REFERENCE TO RELATED APPLICATION

[0004] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 605,328 filed December 1, 2023, which is incorporated herein by reference in its entirety.

[0005] BACKGROUND

[0006] Many of the currently available anticancer drugs such as those used for treating metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST), and hepatocellular carcinoma (HCC) are known to cause major side effects in patients. These side effects (including diarrhea, nausea, vomiting) lead to further reduction in quality of a patients’ lives. Therefore, there is need in the art to develop therapeutic agents that have potential to ameliorate / inhibit the side effects of anticancer treatments. The present disclosure addresses this unmet need.

[0007] BRIEF SUMMARY OF THE INVENTION

[0008] Provided herein are methods and kits to treat or prevent a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of anticancer agent and a therapeutically effective amount of a herbal composition selected from the group consisting of a herbal extract of Scutellaria baicalensis (S), a herbal extract YIV-906 or YIV-906 GU, a herbal extract comprising an extract of S, or a herbal extract comprising a combination of S, G, P and Z, wherein the anticancer agent is regorafenib. The methods and kits are used to treat or prevent metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST) and hepatocellular carcinoma (HCC).

[0009] BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The following detailed description of specific embodiments of the invention will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, exemplary embodiments are shown in the drawings. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0011] FIG. 1 is a graph showing the combination effect of YIV906 and regorafenib on the growth of colon 38 tumor in BDF1 mice. YIV906 was orally feed to the mice (500 mg / kg bid at day 0-3 day & 7-10 day) with or without regorafenib (Img / kg bid, daily) or one group of mice was received regorafenib (lOmg / kg bid, daily) N=5. T-test for YIV-906+Regorafenib vs Regorafenib Img / kg = * P<0.05. Regorafenib lOmg / kg vs Regorafenib Img / kg = ** P<0.005.

[0012] FIGS. 2A-2B show interaction of (FIG. 2A) YIV-906 or (FIG. 2B) YIV-906GU with regorafenib on inhibiting Colon 38 cell growth. Isobologram plots were used to determine additive, synergistic, and antagonistic interactions of the combinations. Additive: Points lying on the diagonal line. Synergistic: Points located below the diagonal line. Antagonistic: Points situated above the diagonal line. YIV-906GU (P-glucuronidase treated YIV-906 or YIV-906 without glucuronide), demonstrate a distinct synergistic interaction (Points located below the diagonal line) between the agents. The combination of YIV-906 or YIV-906GU with regorafenib markedly enhanced the inhibitory effect on Colon 38 cell growth in culture compared to each agent alone.

[0013] DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention relates to method of using herbal compositions with an anticancer drug to enhance the antitumor activity of the anticancer drug. Regorafenib is approved for the treatment of metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST) and hepatocellular carcinoma (HCC). However, the major side effect is diarrhea. YIV-906 had been completed several clinical trial and showed to clear indication of decreased diarrhea, nausea, vomiting of cancer patients undergoing chemotherapy. In present disclosure it is demonstrated that YIV-906 enhanced the anti-tumor activity of regorafenib against the growth of colon 38 tumor in BDF1 mice indicating that YIV-906 has potential to enhance the anti-tumor activity of regorafenib for the treatment of cancers.

[0015] Definitions

[0016] As used herein, each of the following terms has the meaning associated with it in this section.

[0017] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in animal pharmacology, pharmaceutical science, separation science and organic chemistry are those well-known and commonly employed in the art. It should be understood that the order of steps or order for performing certain actions is immaterial, so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously or not.

[0018] As used herein, the articles “a” and “an” refer to one or to more than one (z.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0019] As used herein, the term “about” is understood by persons of ordinary skill in the art and varies to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0020] As used herein, the term “cancer” is defined as disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers include but are not limited to, bone cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer and the like.

[0021] In one aspect, the terms “co-administered” and “co-administration” as relating to a subject refer to administering to the subject a compound and / or composition of the invention along with a compound and / or composition that may also treat or prevent a disease or disorder contemplated herein. In certain embodiments, the co-administered compounds and / or compositions are administered separately, or in any kind of combination as part of a single therapeutic approach. The co-administered compound and / or composition can be formulated in any kind of combinations as mixtures of solids and liquids under a variety of solid, gel, and liquid formulations, and as a solution.

[0022] As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, nasal, pulmonary and topical administration. A “disease” as used herein is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0023] A “disorder” as used herein in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[0024] As used herein, the term “extract” refers to a concentrated preparation or solution of a compound or drug derived from a naturally occurring source, such as an herb or other plant material. Extracts can be prepared by a number of processes including steeping an herb in solution or drying and grinding an herb into a powder and dissolving the powder in a solution. An extract can be further concentrated by removing a portion of the solvent after dissolving an amount of the desired compound in the solution. An extract may also be strained or centrifuged to remove any solid material from the solution.

[0025] The phrase “inhibit,” as used herein, means to reduce a molecule, a reaction, an interaction, a gene, an mRNA, and / or a protein’s expression, stability, function or activity by a measurable amount or to prevent entirely. Inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or downregulate a protein, a gene, and an mRNA stability, expression, function and activity, e.g., antagonists.

[0026] The terms “patient,” “subject” or “individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human. In other embodiments, the patient is a non-human mammal including, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. In yet other embodiments, the patient is an avian animal or bird. Preferably, the patient, individual or subject is human.

[0027] As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0028] As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof.

[0029] The term “prevent,” “preventing” or “prevention,” as used herein, means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences.

[0030] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.

[0031] As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient or effective to prevent or treat (delay or prevent the onset of, prevent the progression of, inhibit, decrease or reverse) a disease or condition described or contemplated herein, including alleviating symptoms of such disease or condition. As used herein, the term “treatment” or “treating” is defined as the application or administration of a therapeutic agent, z.e., a compound of the invention (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein, a symptom of a condition contemplated herein or the potential to develop a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a condition contemplated herein, the symptoms of a condition contemplated herein or the potential to develop a condition contemplated herein. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

[0032] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual and partial numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0033] Combination Therapies

[0034] In certain embodiments, the extracts of the invention are useful in the methods of present invention when used concurrently with at least one additional agent that has anticancer / antitumor activity.

[0035] In certain embodiments, the additional agent is regorafanib.

[0036] In certain embodiments, administration of the herbal extracts increases the efficacy of regorafenib. In certain embodiments, YIV-906 or YIV-906GU (P-glucuronidase treated YIV- 906 or YIV-906 without glucuronide) administered in combination with regorafenib synergistically inhibits cancer(s) in a subject.

[0037] A synergistic effect can be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55).

[0038] Methods

[0039] In one aspect, the invention provides a method of treating or preventing a cancer in a subject, the method comprises administering to the subject in need thereof a therapeutically effective amount of composition comprising at least one herbal extract or any active chemical present in the at least one herbal extract and an effective amount of an anticancer agent.

[0040] By the term “active chemical” as used herein is meant a chemical obtained from the at least one herbal extract where the chemical possesses a biological activity similar to that in the herbal extract, i.e., wherein the chemical inhibits tumor growth.

[0041] In certain embodiments, the at least one herbal extract is from an herb selected from the group consisting of : an herbal extract of Scutellaria baicalensis (S), a fraction thereof or any active chemical present in the herbal extract or fraction thereof; (b) the herbal extract YIV-906, which comprises herbal extracts of Scutellaria baicalensis (S), Glycyrrhiza uralensis (G), Paeonia lactiflora (P), and Ziziphus jujuba (Z), a fraction thereof or any active chemical present in the herbal extract or fraction thereof; (c) an herbal extract comprising an extract of S, a fraction thereof or any active chemical present in the herbal extract or fraction thereof; and (d) an herbal extract comprising a combination of S, G, P and Z, a fraction thereof or any active chemical present in the herbal extract or fraction thereof.

[0042] In certain embodiments, the at least on herbal extract is YIV-906 or YIV-906GU extract.

[0043] In certain embodiments, (a) or (c) further comprises an herbal extract, a fraction thereof or any active chemical present in the herbal extract or fraction thereof, which is derived from at least one herb selected from the group consisting of Glycyrrhiza uralensis (G), Paeonia lactiflora (P), and Ziziphus jujuba (Z).

[0044] In certain embodiments, the anticancer agent is regorafenib.

[0045] In certain embodiments, administering the therapeutically effective amount of the herbal composition minimizes or eliminates one or more of side effects of administering regorafenib to the subject. In certain embodiments, the one or more side effects are gastrointestinal related side effects. In certain embodiments, the side effects are selected from the group consisting of nausea, vomiting, fatigue, colitis and diarrhea. In certain embodiments, administering the therapeutically effective amount of anticancer agent and the therapeutically effective amount of herbal composition increases therapeutic efficacy of and reduces the toxicity caused due to administering the anticancer agent alone to the subject. In certain embodiments, administering the therapeutically effective amount of anticancer agent and the therapeutically effective amount of herbal composition increases therapeutic efficacy of and reduces the toxicity caused due to administering the regorafenib alone to the subject.

[0046] In certain embodiments, the composition is administered to the subject by at least one route selected from the group consisting of oral, nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, intra-peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, optic, intraocular, intrathecal, and intravenous routes. In certain embodiments, the herbal composition is administered to the subject orally.

[0047] In certain embodiments, the herbal composition is administered to the subject in a form selected from the group consisting of a pill, a tablet, a capsule, a soup, a tea, a concentrate, a dragee, a liquid, a drop, and a gelcap.

[0048] In certain embodiments, the therapeutically effective amount of the herbal composition is about 20 mg / day to about 6 g / day. In certain embodiments, the therapeutically effective amount of the herbal composition is about 20, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900,1950, 2000, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650,

[0049] 2700, 2750, 2800, 2850, 2900, 2950. 3000, 3050, 3100, 3150, 3200, 3250, 3300, 3350, 3400,

[0050] 3450, 3500, 3550, 3600, 3650, 3700, 3750, 3800, 3850, 3900, 3950, 4000, 4050, 4100, 4150,

[0051] 4200, 4250, 4300, 4350, 4400, 4450, 4500, 4550, 4600, 4650, 4700, 4750, 4800, 4850, 4900,

[0052] 4950, 5000, 5050, 5100, 5150, 5200, 5250, 5300, 5350, 5400, 5450, 5500, 5550, 5600, 5650,

[0053] 5700, 5750, 5800, 5850, 5900, 5950, or about 6000 mg / day. In certain embodiments, the therapeutically effective amount of the herbal composition is about 4800mg / day.

[0054] In certain embodiments, the therapeutically effective amount of the herbal composition is about 500 mg / kg bid (two times a day) i.e., 1 g / kg of body weight per day.

[0055] In certain embodiments, the therapeutically effective amount of regorafenib is about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5. 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 mg / kg of body weight per day.

[0056] In certain embodiments, the herbal composition is administered twice daily. In certain embodiments, the herbal composition is administered at a time selected from prior to, simultaneously with and after administration of regorafenib to the subject.

[0057] In certain embodiments, the cancer is at least one selected from the group consisting of metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST) and hepatocellular carcinoma (HCC).

[0058] In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human.

[0059] Kit

[0060] In another aspect, the invention provides a kit for treating or preventing a cancer in a subject, wherein the kit comprises a therapeutically effective amount of anticancer agent and a therapeutically effective amount of herbal composition wherein the herbal composition is selected from the group consisting of : (a) an herbal extract of Scutellaria baicalensis (S), a fraction thereof or any active chemical present in the herbal extract or fraction thereof; (b) the herbal extract YIV-906, which comprises herbal extracts of Scutellaria baicalensis (S), Glycyrrhiza uralensis (G), Paeonia lactiflora (P), and Ziziphus jujuba (Z), a fraction thereof or any active chemical present in the herbal extract or fraction thereof; (c) an herbal extract comprising an extract of S, a fraction thereof or any active chemical present in the herbal extract or fraction thereof; and (d) an herbal extract comprising a combination of S, G, P and Z, a fraction thereof or any active chemical present in the herbal extract or fraction thereof. In certain embodiments, the anticancer agent is regorafenib. In certain embodiments, the herbal composition comprises YIV-906GU extract. In certain embodiments, the kit further comprises an instruction material regarding using the kit for treatment of at least one cancers selected from the group consisting of bone cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer and the like.

[0061] Administration / Dosage / Formulations

[0062] The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of disease or disorder contemplated in the invention. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0063] Administration of the compositions of the present invention to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder contemplated in the invention. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease or disorder contemplated in the invention. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 and 1,000 mg / kg of body weight / per day. The pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of from 1 ng / kg / day and 100 mg / kg / day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0064] In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0065] A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0066] In particular embodiments, it is advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound for the treatment of a disease or disorder contemplated in the invention.

[0067] In certain embodiments, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In other embodiments, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. In yet other embodiments, the compound of the invention is the only biologically active agent (z.e., capable of treating cancer) in the composition. In yet other embodiments, the compound of the invention is the only biologically active agent (z.e., capable of treating cancer) in therapeutically effective amounts in the composition.

[0068] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may 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 dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

[0069] In certain embodiments, the compositions of the invention are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions of the invention are administered to the patient in range of dosages that include, but are not limited to, once every day, every two days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physical taking all other factors about the patient into account.

[0070] Compounds and / or compositions of the invention for administration may be in the range of from about 1 mg to about 10,000 mg, about 20 mg to about 9,500 mg, about 40 mg to about 9,000 mg, about 75 mg to about 8,500 mg, about 150 mg to about 7,500 mg, about 200 mg to about 7,000 mg, about 400 mg to about 6,000 mg, about 500 mg to about 5,000 mg, about 750 mg to about 4,000 mg, about 1,000 mg to about 3,000 mg, about 1,000 mg to about 2,500 mg, about 20 mg to about 2,000 mg and any and all whole or partial increments therebetween. In certain embodiments, the dose of the compounds and / or compositions of the invention is about 800 mg.

[0071] In certain embodiments, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder contemplated in the invention.

[0072] Formulations may be employed in admixtures with conventional excipients, ie., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents. Routes of administration of any of the compositions of the invention include oral nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. The compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-peritoneal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0073] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.

[0074] Oral Administration

[0075] For oral application, particularly suitable are soups, teas, concentrates, tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

[0076] For oral administration, the compounds of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OP ADR Y™ film coating systems available from Colorcon, West Point, Pa. (e.g., OP ADR Y™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OP ADR Y™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).

[0077] Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient. The powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a “granulation”. For example, solvent-using “wet” granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.

[0078] Melt granulation generally consists in the use of materials that are solid or semi-solid at room temperature (i.e., having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents. The low melting solids, when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium. The liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together. The resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form. Melt granulation improves the dissolution rate and bioavailability of an active (i.e., drug) by forming a solid dispersion or solid solution.

[0079] U.S. Patent No. 5,169,645 discloses directly compressible wax-containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) melt.

[0080] The present invention also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the invention, and a further layer providing for the immediate release of a medication for treatment of a disease or disorder contemplated in the invention. Using a wax / pH-sensitive polymer mix, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.

[0081] Parenteral Administration

[0082] As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intravenous, intra-peritoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.

[0083] Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multidose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (z.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0084] The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a nontoxic parenterally-acceptable diluent or solvent, such as water or 1, 3 -butanediol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer’s solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or diglycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.

[0085] Controlled Release Formulations and Drug Delivery Systems

[0086] In certain embodiments, the formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.

[0087] The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.

[0088] For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material that provides sustained release properties to the compounds. As such, the compounds useful within the methods of the invention may be administered in the form of microparticles, for example by injection, or in the form of wafers or discs by implantation.

[0089] In one embodiment of the invention, the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

[0090] The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that may, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

[0091] The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.

[0092] The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.

[0093] As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, about 10 minutes, or about 1 minute and any or all whole or partial increments thereof after drug administration after drug administration. As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, about 10 minutes, or about 1 minute and any and all whole or partial increments thereof after drug administration.

[0094] Dosing

[0095] The therapeutically effective amount or dose of a compound of the present invention depends on the age and weight of the patient, the current medical condition of the patient and the progression of a disease or disorder contemplated in the invention. The skilled artisan is able to determine appropriate dosages depending on these and other factors.

[0096] A suitable dose of a compound of the present invention may be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 5 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.

[0097] It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.

[0098] In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the inhibitor of the invention is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (z.e., a “drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%- 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0099] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of the disease or disorder, to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a longterm basis upon any recurrence of symptoms and / or infection.

[0100] The compounds for use in the method of the invention may be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 5 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0101] Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in experimental animals, including, but not limited to, the determination of the LDso (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. The data obtained from animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0102] The practice of the present invention employs, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are well within the purview of the skilled artisan. Such techniques are explained fully in the literature, such as, “Molecular Cloning: A Laboratory Manual”, second edition (Sambrook, 1989); “Oligonucleotide Synthesis” (Gait, 1984); “Animal Cell Culture” (Freshney, 1987); “Methods in Enzymology” “Handbook of Experimental Immunology” (Weir, 1996); “Gene Transfer Vectors for Mammalian Cells” (Miller and Calos, 1987); “Current Protocols in Molecular Biology” (Ausubel, 1987); “PCR: The Polymerase Chain Reaction”, (Mullis, 1994); “Current Protocols in Immunology” (Coligan, 1991). These techniques are applicable to the production of the polynucleotides and polypeptides of the invention, and, as such, may be considered in making and practicing the invention. Particularly useful techniques for particular embodiments will be discussed in the sections that follow.

[0103] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

[0104] It is to be understood that, wherever values and ranges are provided herein, the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, all values and ranges encompassed by these values and ranges are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range and, when appropriate, partial integers of the numerical values within ranges. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0105] EXPERIMENTAL EXAMPLES

[0106] The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0107] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples therefore, specifically point out the preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

[0108] Materials and Methods:

[0109] Regorafenib (STIVARGA) is approved for the treatment of metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST), and hepatocellular carcinoma (HCC). A predominant side effect is diarrhea, affecting 41%-47% of treated patients. There is also a risk of gastrointestinal perforation or fistula during its use.

[0110] YIV-906, rooted in the ancient Chinese formulation "Huang Qin Tang," has been historically used to address gastrointestinal symptoms. Comprising Glycyrrhiza uralensis Fisch (G), Pae onia lactiflora Pall (P), Scutellaria baicalensis Georgi (S), and Ziziphus jujubaMill (Z), YIV-906 has been consistently manufactured following cGMP standards. Clinical trials indicate its potential in reducing gastrointestinal symptoms from cancer treatments and possible synergy in anticancer activity.

[0111] As used herein, the term “YIV-906” refers to an herbal composition comprising Glycyrrhiza uralensis Fisch (G), Paeonia lactiflora Pall (P), Scutellaria baicalensis Georgi (S), and Ziziphus jujuba Mill (Z). YIV-906 can refer to, for example, to a specific composition comprising S, G, P and Z in a 3: 2: 2: 2 ratio prepared under standard operational procedures, including, in some embodiments, hot water extraction of S, P, G, and Z. YIV-906 was dissolved in HPLC water at 50mg / ml and heated at 80°C water bath for 30 minutes. Regorafenib was dissolved in HPLC water as water suspension.

[0112] Colon 38 cells were subcutaneously implanted into 10-week-old BDF1 mice. Upon tumors reaching a size of 5mm x 5 mm x 5mm, the mice were treated with varying regimens: YIV-906 orally (50mg / ml water, 500 mg / kg bid@day 0-3 & 7-10), regorafenib (Img / kg bid, daily), regorafenib (lOmg / kg bid, daily), and a combination of YIV-906 with regorafenib (Img / kg bid, daily). All treatments were administered by oral gavage. Tumor volume was measured by using the formula length x width2 x K / 6.

[0113] Example 1:

[0114] As depicted in FIG. 1, YIV-906, when used alone, had a minimal non-significant impact on tumor growth. Regorafenib displayed dose-dependent antitumor activity. Img / kg regorafenib produced a non-significant inhibitory effect on tumor growth. lOmg / kg regorafenib halted tumor growth. The combination of YIV-906 and Img / kg regorafenib markedly inhibited tumor growth. These results clearly demonstrated that YIV-906 has potential to enhance antitumor activity of regorafenib.

[0115] Example 2: Cell growth assay and drug-drug interaction analysis

[0116] Colon 38 cells were seeded at a density of 5,000 cells / well in a 96-well plate. Cells were cultured in RPMI1640 medium, supplemented with 5% FBS and 50 pg / ml Kanamycin, and incubated at 37 °C in a 5% CO2 atmosphere. Cells were treated for 72 hours with the following: YIV-906 or YIV-906GU (post E.coli beta-glucuronidase treatment) ranging from 50 pg / ml to 800 pg / ml. Regorafenib ranging from 0.5 pM to 20 pM. For combination treatments, YIV-906 or YIV-906GU was mixed with regorafenib in various ratios. This mixture was subsequently diluted before being applied to the Colon 38 cells.

[0117] Post-treatment: The cell medium was carefully aspirated. Cells were stained with methylene blue prepared in 50% ethanol for 2 hours. Excess, unstained methylene blue was gently washed away using tap water. After allowing the plates to air dry, 1% sarkosyl was added to solubilize the retained methylene blue. Absorbance (optical density or OD) was then measured at 590 nm using a microplate reader. The IC50, representing the concentration at which there is a 50% reduction in the OD, was determined employing the median-effect equation as described earlier.

[0118] Isobologram plots based on combination index were used to determine additive, synergistic, and antagonistic interactions of the combinations. Isobologram plots: (D)l / (D / ) l against (D)2 / (D / )2 in which (D / ) l and (D%)2 represented concentrations of each drug alone to exert 50 % inhibition, while (D)l and (D)2 were concentrations of drugs in combination to achieve 50 % inhibition. Different ratio of two herbs were used to determine their combination effects. Additive: Points lying on the diagonal line. Synergistic: Points located below the diagonal line. Antagonistic: Points situated above the diagonal line. Different ratios of the two treatment agents were employed to determine their combined effects.

[0119] To assess the potential synergistic effect of YIV-906 or YIV-906GU (following E.coli beta-glucuronidase treatment) with regorafenib on Colon 38 cell growth inhibition, the isobologram plots based on the combination index were employed. The findings, as illustrated in FIG. 2 A for YIV-906 and FIG. 2B for YIV-906GU, demonstrate a distinct synergistic interaction (Points located below the diagonal line) between the agents. The combination of YIV-906 or YIV-906GU with regorafenib markedly enhanced the inhibitory effect on Colon 38 cell growth in culture compared to each agent alone.

[0120] Ennumerated Embodiments Embodiment 1 provides a method of treating or preventing a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of anticancer agent and a therapeutically effective amount of a herbal composition selected from the group consisting of a) a herbal extract of Scutellaria baicalensis (S), a fraction thereof or any active chemical present in the herbal extract or fraction thereof;

[0121] (b) a herbal extract YIV-906 or YIV-906 GU, which comprises herbal extracts of Scutellaria baicalensis (S), Glycyrrhiza uralensis (G), Paeonia lactiflora (P), and Ziziphus jujuba (Z), a fraction thereof or any active chemical present in the herbal extract or fraction thereof;

[0122] (c) a herbal extract comprising an extract of S, a fraction thereof or any active chemical present in the herbal extract or fraction thereof; and (d) a herbal extract comprising a combination of S, G, P and Z, a fraction thereof or any active chemical present in the herbal extract or fraction thereof, wherein the anticancer agent is regorafenib.

[0123] Embodiment 2 provides the method of embodiment 1 wherein (a) or (c) further comprises a herbal extract, a fraction thereof or any active chemical present in the herbal extract or fraction thereof, which is derived from at least one herb selected from the group consisting of Glycyrrhiza uralensis (G), Paeonia lactiflora (P), and Ziziphus jujuba (Z).

[0124] Embodiment 3 provides the method of embodiment 1, wherein administering the therapeutically effective amount of the herbal composition minimizes or eliminates one or more of gastro-intestinal side effects of administering regorafenib to the subject, wherein the side effects are selected from the group consisting of nausea, vomiting, fatigue, colitis and diarrhea.

[0125] Embodiment 4 provides the method of embodiment 1, wherein the herbal composition is administered to the subject orally.

[0126] Embodiment 5 provides the method of embodiment 4, wherein the herbal composition is administered to the subject in a form selected from the group consisting of a pill, a tablet, a capsule, a soup, a tea, a concentrate, a dragee, a liquid, a drop, and a gelcap.

[0127] Embodiment 6 provides the method of embodiment 1, wherein the therapeutically effective amount of the herbal composition is about 20 mg / day to about 6 g / day.

[0128] Embodiment 7 provides the method of embodiment 1, wherein the therapeutically effective amount of the herbal composition is about 500 mg / kg of body weight bid (i.e., twice a day).

[0129] Embodiment 8 provides the method of embodiment 1, wherein wherein the herbal composition is administered twice daily. Embodiment 9 provides the method of embodiment 8, wherein the herbal composition is administered at a time selected from prior to, simultaneously with and after administration of regorafenib to the subject.

[0130] Embodiment 10 provides the method of embodiment 1, wherein the cancer is at least one selected from the group consisting of metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST) and hepatocellular carcinoma (HCC).

[0131] Embodiment 11 provides the method of embodiment 1, wherein administering the therapeutically effective amount of anticancer agent and the therapeutically effective amount of herbal composition increases therapeutic efficacy of and reduces toxicity caused due to administering the anticancer agent alone to the subject.

[0132] Embodiment 12 provides the method of embodiment 1, wherein the subject is a mammal.

[0133] Embodiment 13 provides the method of embodiment 1, wherein the mammal is a human.

[0134] Embodiment 14 provides a kit for treating or preventing a cancer in a subject, wherein the kit comprises a therapeutically effective amount of anticancer agent and a therapeutically effective amount of a herbal composition wherein the herbal composition is selected from the group consisting of: (a) a herbal extract of Scutellaria baicalensis (S), a fraction thereof or any active chemical present in the herbal extract or fraction thereof; (b) a herbal extract YIV-906 or YIV-906GU, which comprises herbal extracts of Scutellaria baicalensis (S), Glycyrrhiza uralensis (G), Paeonia lactiflora (P), and Ziziphus jujuba (Z), a fraction thereof or any active chemical present in the herbal extract or fraction thereof; (c) a herbal extract comprising an extract of S, a fraction thereof or any active chemical present in the herbal extract or fraction thereof; and (d) a herbal extract comprising a combination of S, G, P and Z, a fraction thereof or any active chemical present in the herbal extract or fraction thereof; and wherein the anticancer agent is regorafenib.

[0135] Other Embodiments

[0136] The recitation of a listing of elements in any definition of a variable herein includes definitions of that variable as any single element or combination (or subcombination) of listed elements. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0137] The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this disclosure has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this disclosure may be devised by others skilled in the art without departing from the true spirit and scope of the disclosure. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

CLAIMSWhat is claimed is:

1. A method of treating or preventing a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of anticancer agent and a therapeutically effective amount of a herbal composition selected from the group consisting of : a) a herbal extract of Scutellaria baicalensis (S), a fraction thereof or any active chemical present in the herbal extract or fraction thereof;(b) a herbal extract YIV-906 or YIV-906 GU, which comprises herbal extracts of Scutellaria baicalensis (S), Glycyrrhiza uralensis (G), Paeonia lactiflora (P), and Ziziphus jujuba (Z), a fraction thereof or any active chemical present in the herbal extract or fraction thereof;(c) a herbal extract comprising an extract of S, a fraction thereof or any active chemical present in the herbal extract or fraction thereof; and(d) a herbal extract comprising a combination of S, G, P and Z, a fraction thereof or any active chemical present in the herbal extract or fraction thereof, wherein the anticancer agent is regorafenib.

2. The method of claim 1, wherein (a) or (c) further comprises a herbal extract, a fraction thereof or any active chemical present in the herbal extract or fraction thereof, which is derived from at least one herb selected from the group consisting of Glycyrrhiza uralensis (G), Paeonia lactiflora (P), and Ziziphus jujuba (Z).

3. The method of claim 1, wherein administering the therapeutically effective amount of the herbal composition minimizes or eliminates one or more of gastro-intestinal side effects of administering regorafenib to the subject, wherein the side effects are selected from the group consisting of nausea, vomiting, fatigue, colitis and diarrhea.

4. The method of claim 1, wherein the herbal composition is administered to the subject orally.

5. The method of claim 4, wherein the herbal composition is administered to the subject in a form selected from the group consisting of a pill, a tablet, a capsule, a soup, a tea, a concentrate, a dragee, a liquid, a drop, and a gelcap.

6. The method of claim 1, wherein the therapeutically effective amount of the herbal composition is about 20 mg / day to about 6 g / day.

7. The method of claim 1, wherein the therapeutically effective amount of the herbal composition is about 500 mg / kg of body weight bid (i .e., twice a day).

8. The method of claim 1, wherein the herbal composition is administered twice daily.

9. The method of claim 8, wherein the herbal composition is administered at a time selected from prior to, simultaneously with and after administration of regorafenib to the subject.

10. The method of claim 1, wherein the cancer is at least one selected from the group consisting of metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST) and hepatocellular carcinoma (HCC).

11. The method of claim 1, wherein administering the therapeutically effective amount of anticancer agent and the therapeutically effective amount of herbal composition increases therapeutic efficacy of and reduces toxicity caused due to administering the anticancer agent alone to the subject.

12. The method of claim 1, wherein the subject is a mammal.

13. The method of claim 12, wherein the mammal is a human.

14. A kit for treating or preventing a cancer in a subject, wherein the kit comprises a therapeutically effective amount of anticancer agent and a therapeutically effective amount of a herbal composition wherein the herbal composition is selected from the group consisting of(a) a herbal extract of Scutellaria baicalensis (S), a fraction thereof or any active chemical present in the herbal extract or fraction thereof;(b) a herbal extract YIV-906 or YIV-906GU, which comprises herbal extracts of Scutellaria baicalensis (S), Glycyrrhiza uralensis (G), Paeonia lactiflora (P), and Ziziphus jujuba (Z), a fraction thereof or any active chemical present in the herbal extract or fraction thereof;(c) a herbal extract comprising an extract of S, a fraction thereof or any active chemical present in the herbal extract or fraction thereof; and(d) a herbal extract comprising a combination of S, G, P and Z, a fraction thereof or any active chemical present in the herbal extract or fraction thereof; and wherein the anticancer agent is regorafenib.

Images