TREATMENT OF CANCER WITH 2-DEOXYGLUCOSE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Patent Application Nos. 60/680,708, filed 12 May 2005, and 60/787,304, filed 29 March 2006, the contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] The compound 2-deoxyglucose (2-DG) has been identified as a selective poison for the slowly- or non-dividing cancer cells residing in the hypoxic zones of tumors (see PCT Publication No. 2001/82926, incorporated by reference). A variety of therapies for treating cancer with 2-DG in combination with other agents that target rapidly-dividing cancer cells have been described (see U.S. Patent No. 6,670,330, incorporated by reference), as have dosing schedules and routes of administration for such therapies (see U.S. Patent No. 6,979,675, incorporated by reference).

[0003] Cancer is, however, a disease that can arise in many different cell and tissue types and so take many different forms. Not surprisingly, an anti-cancer agent is rarely, if ever, equally efficacious against many different types of cancers, and different cancers can require different doses or routes of administration for the most efficacious treatment with a given agent. Accordingly, there remains a need for methods for treating particular types of cancer with 2-DG. The present invention meets this need.

SUMMARY OF THE INVENTION

[0004] In a first aspect, the present invention provides a method of treating cancer, said method comprising administering multiple daily doses of 2-deoxy-D- glucose (2-DG) so as to achieve a maximal plasma concentration (C _max ) of about at least 125 μg/mL after each dose. In one embodiment the C _max does not exceed about 250 μg/mL. In another embodiment, the C _ma χ does not exceed about 175

μg/mL. In one embodiment, the 2-DG is administered orally at a daily dose of greater than 60 mg/kg of patient weight so as to achieve a C _max of about at least 125 μg/mL. In another embodiment, the 2-DG is administered orally at a daily dose of about 90 mg/kg to achieve a C _max of about at least 150 μg/mL. [0005] In a second aspect, the present invention provides a method of treating a cancer selected from the group consisting of non-small-cell lung cancer, non- Hodgkins lymphoma, thyroid cancer, adenoid cystic carcinoma of the trachea, breast cancer, and head and neck cancer, said method comprising administering multiple doses of 2-deoxy-D-glucose (2-DG) so as to achieve a C _max of about at least 125 μg/mL after each dose, hi one embodiment, 2-DG is administered on a daily basis for at least five consecutive days per week for at least 3 weeks. In one embodiment, 2-DG is administered daily for at least a month. In one embodiment docetaxel is co-administered with 2-DG.

BRIEF DESCRIPTION OF THE FIGURES

[0006] Figure 1 shows a plot of individual maximum plasma concentrations of

2-DG (C _πax ). Week 1, Day 1 (solid line) ; Week 1, Day 5 (dashed line). Week 3,

Day 1 (dash-dot line). In this plot the dash-dot and solid lines overlap.

[0007] Figure 2 shows a plot of dose-normalized plasma 2-DG concentrations when 2-DG is administered alone or in combination with docetaxel.

[0008] Figure 3 illustrates serum glucose concentrations after dosing (mean of all dose levels).

[0009] Figure 4 shows the maximal sustained area under the plasma concentration curve (AUC) over the 2-DG dose range studied (2 - 88 mg/kg).

Legend is as in Figure 1.

DETAILED DESCRIPTION OF THE INVENTION [0010] The present invention provides methods of treating cancer by administering a therapeutically effective dose of 2-DG, alone or in combination with other anti-cancer therapies, including surgical resection, radiation therapy, and drug therapy. To aid in the appreciation of the invention, this description is

divided into the following topics: (i) therapeutically effective administration of 2- DG; (ii) co-administration with other anti-cancer agents; (iii) treatment of particular cancers; and (iii) formulation and packaging of 2-DG.

Therapeutically effective administration of 2-DG

[0011] The present invention arose in part from the discoveries that the desired therapeutic effect of 2-DG in the treatment of cancer can be achieved by repeated administration of the compound in an effective dose range to achieve a certain maximal plasma concentration (C _max ) after each dose and that certain cancers are highly susceptible to such treatment. In one aspect, the invention provides a method of treating cancer in a patient by administering a therapeutically effective dose of 2-DG to a patient, where the C _max achieved is at least 125 μg/mL after each therapeutically effective dose. While "patient" typically refers to a human, those of skill in the art will appreciate that the methods and compositions of the invention can be used to treat cancer in any mammal, including non-human primates and experimental models of human cancers. In one embodiment of the invention, the patient is a human patient. As used herein, "treating" cancer (or treating a patient with cancer) refers to taking steps to obtain beneficial or desired results, including but not limited to, alleviation or amelioration of one or more symptoms of the cancer, diminishment of extent of disease, delay or slowing of disease progression, amelioration, palliation or stabilization of the disease state, partial or complete remission, prolonged survival and other beneficial results known in the art.

[0012] In accordance with the methods of the present invention, 2-DG can be orally administered in a daily dose in the range of about 50 mg of 2-DG/kg of patient weight to about 150 mg/kg of 2-DG per patient weight, hi one embodiment, 2-DG is administered in a daily dose of about 65 mg/kg of 2-DG per body weight of the patient to be treated. In another embodiment, the therapeutically effective dose is a daily dose of about 90 mg/kg of 2-DG per body weight of the patient to be treated. In another embodiment, the therapeutically

effective dose is about 125 mg/kg of 2-DG per body weight of the patient to be treated.

[0013] To achieve therapeutic effectiveness, the therapeutically effective daily dose of 2-DG is usually administered multiple times to the patient. In one embodiment, 2-DG is administered daily for a period of time. Typically, daily administration for at least 5 consecutive days is employed. In other embodiments, administration is for at least 7 consecutive days, or at least 10 consecutive days, or at least a month, or at least 3 months. Depending on the dose, formulation, and route of administration selected by the practitioner and the convenience of the patient, the entire daily dose may be administered once daily or the daily dose may be administered in multiple smaller doses through the course of a day (including by infusion with a pump or intravenous administration). For example, the dose may be divided into two smaller doses and administered twice daily, or divided into three smaller doses and administered thrice daily. It will be apparent to the reader that, as used herein, "daily" administration is not limited to one administration per day but can include multiple administrations and thus that "daily dose" refers to the entire amount of drug administered to a patient per each 24 hour period.

[0014] For optimum treatment benefit, the administration of the therapeutically effective dose is continued for multiple days, typically for at least three weeks, and often for at least a month, and sometimes for several months or longer. Thus, a patient may be administered 2-DG in accordance with the present methods for several consecutive days, a week, a month, two months, three months, six months, or a year or longer.

[0015] Consistent with administration regimens of other anticancer agents, 2- DG may be administered in multiple "rounds" of administration. For example, in some embodiments, 2-DG may be administered once daily for at least five to ten consecutive days, and such five to ten day treatments may be repeated once, twice, or three or more times, sometimes with a no-treatment (with 2-DG) period ranging from one to several weeks between each multiple-day treatment. Other

multiple-round schedules for administration will be apparent to the skilled practicioner guided by this disclosure.

[0016] In one aspect, "administering a therapeutically effective dose or regimen of 2-DG" refers to (i) administering 2-DG in the ranges stated (e.g., 50 mg to 150 mg of 2-DG per kg of patient weight, typically 50 to 100 mg of 2-DG per kg of patient weight) for a specified minimum number of days within a specified time period, wherein the administration of 2-DG has a therapeutic effect on the cancer in the patient. Illustrative therapeutically effective dose regimens for 2-DG include those described herein, such as administration of 2-DG for 5 consecutive days, 7 consecutive days, 10 consecutive days, at least 5 days per week, at least 5 days per week for one month, at least 10 consecutive days per month, and at least 20 consecutive days per month.

[0017] As is understood in the art for other cancer drugs, treatment with 2-DG may be suspended temporarily if toxicity is observed, or for the convenience of the patient and then resumed, without departing from the scope of the invention. 2-DG toxicity may result in symptoms consistent with hypoglycemia (including sweating, irritability, or nausea). In re-treatment regimens, the dose can be adjusted to reflect patient tolerance of the prior treatment. In any event, if toxicity is observed during repeat administration, dosing can be temporarily stopped as severe symptoms are observed. The period of temporary halting of administration (drug holiday) can be ended at the time when the first organ of toxicity (for example, brain) no longer contains significant concentrations of 2-DG (which can be measured or determined indirectly by cessation of symptoms). Therefore, an intermittent dosing period can be defined not only by specific days but individualized by drug holidays that are based on symptoms and normal organ clearance of 2-DG.

[0018] To decrease potential side effects and/or increase efficacy, the present invention provides a number of embodiments of the methods described herein. In one embodiment, the 2-DG is administered in a formulation that doesn't contain glucose. In one embodiment, the patient fasts from 8 to 16 hours prior to the administration of the 2-DG. In one embodiment, the patient is maintained on a

low glucose diet during the time period when 2-DG is administered. In one embodiment, 2-DG is administered to a patient on a low carbohydrate diet, such as the Atkins diet.

[0019] 2-DG can be administered in any number of ways known to those of skill in the art (e.g., including oral, parenteral, intramuscular, topical, or subcutaneous routes), but is generally administered orally or by parenteral injection (e.g., intravenous administration). Although intravenous administration is generally preferred for anticancer agents, surprisingly, oral administration of 2- DG can be equally efficacious and is better tolerated (less toxic) than i.v. administration. Thus, in one embodiment of the invention, 2-DG is administered orally, and multiple doses are administered over a period of time as described above.

[0020] Using this therapeutically effective dosing and administration regimen, practitioners of skill in the art can significantly improve treatment outcomes achieved with currently used cancer therapies (including surgical resection, radiation therapy, and drug therapies), as well as with new drug therapies in development. In one important aspect, the present invention provides new methods for treating cancer by using other anti-cancer drugs in combination with 2-DG, as discussed in the following section.

Co-administration with other anti-cancer agents

[0021] In accordance with the methods of the invention, 2-DG can be coadministered in combination with other anti-cancer agents. Without intending to be bound by any particular mechanism or effect, such co-administration can in some cases provide one or more of several unexpected benefits including:

(i) co-administration of 2-DG and the anticancer agent has a synergistic effect on induction of cancer cell death;

(ii) co-administration provides a better therapeutic result than administration of the anticancer agent alone, e.g., greater alleviation or amelioration of one or more symptoms of the cancer, diminishment of extent of disease, delay or slowing of disease progression, amelioration, palliation or

stabilization of the disease state, partial or complete remission, prolonged survival or other beneficial therapeutic results;

(iii) co-administration of 2-DG increases the sensitivity of cancer cells to the anticancer agent, allowing lower doses of the agent to be administered to the patient or allowing an agent to be used for treatment of cells otherwise resistant to the agent or otherwise refractory to treatment;

(iv) co-administration of 2-DG and the anticancer agent increases killing of cells in hypoxic regions of tumors that are not efficiently killed by the agent alone.

[0022] As used herein, 2-DG is "co-administered" with another anticancer agent (also referred to herein as "Agent") when the 2-DG and Agent are administered as part of the same course of therapy. In one embodiment, 2-DG is first administered prior to administration of the Agent, (i.e., the initiation of the other cancer therapy), and treatment with 2-DG is continued throughout the course of administration of the Agent (i.e., the course of the other therapy). In another embodiment, 2-DG is administered after the initiation or completion of the other cancer therapy. In other embodiments, 2-DG is first administered contemporaneously with the initiation of the other cancer therapy. In one embodiment, 2-DG is first administered prior to administration of the Agent, and treatment with 2-DG is continued after the cessation of administration of the Agent. In one embodiment, 2-DG is first administered prior to administration of the Agent, and treatment with 2-DG is continued during part of the period of administration of the Agent.

[0023] Anticancer drug therapy today typically involves multiple rounds, or "cycles," of administration of the anti-cancer agent(s). In the context of administering 2-DG, each cycle of administration (as well as a complete set of cycles) can be viewed as administration of a second drug. Thus, 2-DG can be administered in any or all of the multiple cycles of treatment with the other Agent; in general, 2-DG will be given on a daily basis for at least two or more days during each cycle. In one aspect of the invention, 2-DG is co-administered with the Agent according to a schedule repeated at each round. For example, in one

conventional therapy, paclitaxel is administered at 135 mg/m ² by IV as a 24-hour infusion once every 21 days, e.g., Days 21, 42, 63, and 84 of a course of treatment. In this example, each round of paclitaxel administration can be accompanied by 2-DG co-administration which is concurrent with the paclitaxel administration (e.g., 2-DG is administered on Days 21, 42, 63, and 84), precedes the paclitaxel administration (e.g., 2-DG is administered on Days 20, 41, 62, and 83), and immediately after the paclitaxel administration (e.g., 2-DG is administered on Days 22, 43, 64, and 85). For convenience, however, and particularly if the Agent is administered by IV infusion, the physician may omit the preceding day dose of 2-DG for the first cycle. Alternatively, 2-DG may be administered continuously throughout multiple cycles of administration of the anticancer Agent (e.g., in the paclitaxal example, daily beginning on or before day 21 and extending until the end of therapy; every other day beginning on or before day 21 and extending until the end of therapy, etc.). It will be understood that the above example is for illustration only, and not intended to limit the invention in any fashion. Those of skill in the art will also appreciate that in many cases the schedule of co-administration may differ in the first therapeutic cycle for the convenience of the patient (e.g., no 2-DG administration prior to the first administration of paclitaxel).

[0024] 2-DG can be administered in accordance with the methods of the invention in combination with any anti-cancer agent. Specific dose regimens for known and approved anti-cancer agents (i.e., the recommended effective dose) are known to physicians and are given, for example, in the product descriptions found in the Physician's Desk Reference 2003, (Physicians' Desk Reference, 57th Ed) Medical Economics Company, Inc., Oradell, NJ and/or are available from the Federal Drug Administration. Illustrative dosage regimens for certain anti-cancer drugs are also provided below.

[0025] Cancer drugs can be classified generally as alkylators, anthracyclines, antibiotics, aromatase inhibitors, bisphosphonates, cyclo-oxygenase inhibitors, estrogen receptor modulators, folate antagonists, inorganic aresenates, microtubule inhibitors, modifiers, nitrosoureas, nucleoside analogs, osteoclast

inhibitors, platinum containing compounds, retinoids, topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, and tyrosine kinase inhibitors. In accordance with the methods of the present invention, 2-DG can be co-administered with any anticancer drug from any of these classes or can be administered prior to or after treatment with any such drug or combination of such drugs. In addition, 2-DG can be administered in combination with a biologic therapy (e.g., treatment with interferons, interleukins, colony stimulating factors and monoclonal antibodies). [0026] Thus, the present invention provides methods of treating cancer in which 2-DG or a pharmaceutically acceptable salt thereof and one or more additional anti-cancer agents are administered to a patient. Specific embodiments of such other anti-cancer agents include without limitation the taxanes, including but not limited to, docetaxel and paclitaxel. Another embodiment is the co-administration of 2-DG and another anti-cancer drug to which a cancer can develop resistance via an energy-requiring pump that transports the cancer drug out of the cancer cell to a patient that has developed resistance to the drug; in this embodiment, 2-DG's ability to decrease energy production in the cancer cell in effect renders the otherwise resistant cell sensitive again to the drug. The methods of the present invention are generally applicable to all cancers but have particularly significant therapeutic benefit in the treatment of solid tumors, which are characterized by extensive regions of hypoxic tissue, and particular types of such solid tumors. Particular cancers that can be treated with the methods of the present invention are discussed in the following section.

Treating particular cancers

[0027] The methods and compositions of the invention may be used to treat any cancer, whether malignant or benign. In one important embodiment, the invention provides methods of treating particular types of malignant cancer, including but not limited to non-small-cell lung cancer, non-Hodgkins lymphoma, thyroid cancer, adenoid cystic carcinoma of the trachea, breast cancer, head and neck cancer, prostate cancer, colon cancer, small cell lung cancer, parotid adenocystic carcinoma, adenocarcinoma, and squamous cell cancer including squamous cell

cancer of the soft palate in humans and other mammals. These methods comprise administering a therapeutically effective amount of 2-DG or a pharmaceutically acceptable salt thereof either alone or in combination with an anti-neoplastically effective amount of one or more additional anti-cancer agents. [0028] In one preferred embodiment of the invention, 2-DG is administered to treat non-small-cell lung cancer (NSCLC). NSCLC is currently treated by radiation therapy, surgery, and/or chemotherapy. Simultaneous administration of 2-DG as described herein can improve treatment outcomes for all current therapies. Current treatment regimens for non-small-cell lung cancer include without limitation administration of Gemcitabine (Eli Lilly, difluorodeoxy- cytidine), vinorelbine, paclitaxel, docetaxel, cisplatin, carboplatin, or Lrinotecan (camptothecin-11) as single agents; and administration of etoposide and cisplatin, Vindesine (deacetyl vinblastine carboxamide) and cisplatin, paclitaxel and carboplatin, Gemcitabine and carboplatin, docetaxel and cisplatin, vinorelbine and cisplatin, or Irinotecan and cisplatin in combination therapies. See Bunn, 15 Sep. 2002, J. Clin. One. 20(18s): 23-33, incorporated herein by reference, hi accordance with the methods of the present invention, 2-DG can be coadministered in such therapeutic regimens to improve patient outcomes. For example and without limitation, co-administration of 2-DG in combination with docetaxel as described herein can improve treatment outcomes for patients with NSCLC.

[0029] In another embodiment of the invention, 2-DG is administered in combination with docetaxel as described herein to treat breast cancer. Breast cancer is currently commonly treated by various combinations of surgery, radiation therapy, chemotherapy, and hormone therapy. As shown in the Example below, co-administration of 2-DG and docetaxel in accordance with the methods of the invention is efficacious in the treatment of breast cancer. [0030] The Example below also illustrates that the methods of the invention are efficacious in the treatment of non-Hodgkins lymphoma, thyroid cancer, adenoid cystic carcinoma of the trachea, and head and neck cancer, hi that illustrative Example, 2-DG was formulated as a liquid for oral administration. This and other

formulations useful in the methods of the invention are described in the following section.

Formulation and packaging of 2-DG

[0031] The methods of the invention can be practiced employing any route of administration suitable for the physician, patient, and the type of cancer to be treated. 2-DG can be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it can be enclosed in hard or soft shell gelatin capsules, or compressed into tablets, or suspended in a liquid or gel, or incorporated directly with the food of the diet. For oral therapeutic administration, 2-DG can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations contain enough of the active agent to deliver the therapeutically active doses described above. The tablets, troches, pills, capsules, and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; a sweetening agent such as saccharin; and/or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it can contain, in addition to materials of the above types, a liquid carrier. Various other materials can be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules can be coated with shellac. A syrup or elixir can contain the active compound, a sweetening agent, methyl and propylparabens as preservatives, and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed, m addition, the active compound can be incorporated into sustained-release preparations and formulations.

[0032] In one embodiment, the formulation is crystalline in nature, and the 2- DG is packaged in a sachet for later decantation into a potable liquid for oral

administration to the patient. In this embodiment, the liquid can be syrup or, more conveniently, a commonly consumed liquid, such as water, fruit juice, Crystal Light™ (Kraft), or cola. Usually, the liquid used to dissolve, dilute, or suspend 2- DG in a formulation of the invention will be glucose-free. In another embodiment, the 2-DG is formulated as a tablet or pill containing 2-DG in an amount in the range of about 10 mg to about 10 g. hi some embodiments, each tablet or pill contains about 100 mg to about 5 g of 2-DG. hi one embodiment, each tablet or pill contains 1 g of 2-DG.

[0033] 2-DG formulations useful in the methods of the invention include, but are not limited to, those suitable for oral administration and for parenteral injection. For parenteral injection (e.g., intravenous, intramuscular, subcutaneous, intraperitoneal, intratumoral), 2-DG is dissolved or suspended in a sterile solution suitable for injection. For parenteral administration, the 2-DG formulations of the invention can contain 2-DG admixed with one or more pharmaceutically acceptable ingredients, such as a tonicity agent (including but not limited to NaCl, mannitol, and the like), an antioxidant (including but not limited to sodium bisulfite, sodium metabisulfite, ascorbic acid, and the like), and a preservative (including but not limited to benzyl alcohol, methyl paraben, propyl paraben, a combination of methyl and propyl parabens, and the like), hi one embodiment, a suitable liquid formulation useful in a method of the invention comprises 2-DG at a concentration in the range of 50 to 250 mg/mL. In one embodiment, the concentration of 2-DG is 100 mg/mL.

[0034] For oral administration, 2-DG may be administered in a form suitable for oral administration, including dosage forms of tablet, capsule, caplet, and solution (e.g., dissolved or suspended in a sterile solution for administration). For oral administration, one can employ either preservative-free or preservative- containing formulations. Illustrative preservatives that can be employed in the preservative-containing oral liquid formulations useful in the methods of the invention include, but are not limited to, benzyl alcohol (0.1-1%), methylparaben (0.05-0.5%), propylparaben (0.01-0.1%) and mixtures of methyl and propyl parabens. hi one embodiment, the liquid 2-DG formulation contains 100 mg/mL

of 2-DG, 0.18% methylparaben, and 0.2% propylparaben. In another formulation of the invention, the 2-DG is either a solid or amorphous or crystalline in nature, and the 2-DG is packaged in a sachet or other container for dissolution in a liquid for oral administration to the patient. In one embodiment, crystalline 2-DG is admixed with one or more preservatives to prepare a stable formulation of the invention. In another embodiment, the 2-DG is formulated as a tablet or pill containing 2-DG in the range of about 50 mg to about 5 g. [0035] The preparation of representative pharmaceutical formulations for oral administration of 2-DG is can be accomplished as follows. In one embodiment, 2-DG is dispensed into hard-shell gelatin capsules containing between 100 mg and 1 g of 2-DG; optionally, about 0.5% (weight/weight) magnesium stearate can be added, hi addition, a mixture of 2-DG and lactose can be used in the capsule. In another embodiment, 2-DG (20.0% - 89.9% wt/wt, depending on whether lactose is present, and how much); magnesium stearate (0.9%); starch (8.6%); optionally lactose (0 - 69.6%) and PVP (polyvinylpyrrolidine; 0.9%) are, with the exception of the magnesium stearate, combined and granulated using water as a granulating liquid. The formulation is then dried, mixed with the magnesium stearate and formed into tablets with a tableting machine. In another embodiment, 2-DG is dissolved in a mixture of propylene glycol, polyethylene glycol 400, and polysorbate 80; water is added; and the resulting mixture is dispensed into bottles. In another embodiment, a mixture of 2-DG (20% to 60% wt./wt), peanut oil (38% - 78%), and 2.0% (wt./wt.) Span 60 is prepared, melted, mixed, and filled into soft elastic capsules.

[0036] In another embodiment, a liquid formulation of 2-DG (100 mg/mL); Methylparaben, NF (1.8 mg/mL); and Propylparaben, NF (0.2 mg/mL) in purified water is prepared in 40 mL clear Type I glass vials (with screw cap), as follows. The nominal fill volume is 20 mL, and the target fill volume is 23 mL (in-process range: 22 - 24 mL). About 40% batch volume of purified water is placed in a suitable size container. The water is heated to and maintained at a temperature of 70 ± 5 ⁰ C. Accurately weighed methylparaben and propylparaben are transferred to the hot water and mixed to dissolve. After completion of dissolution, 2-DG is

added and mixed to dissolve. The solution is diluted to final volume or weight (density = 1.025 g/niL) with purified water and mixed thoroughly; then, the solution is filtered through a 0.2-micron filter into a clean receiving vessel. The solution is filled into vials and the vials capped. An in-process check of appearance, pH (range 5.0 - 7.0), and 2-DG content by HPLC (range: 95.0 - 105.0 mg/mL) is performed.

[0037] The 2-DG can also be administered parenterally or intraperitoneally. For parenteral administration, the 2-DG solution can be administered by intravenous infusion, typically by diluting the drug product in Sterile Water for Injection, Bacteriostatic Water for Injection, Sodium Chloride Injection (0.45%, 0.9%), Dextrose Injection (2.5%, 5%, 10%), Lactated Ringer's Injection, and the like, provided, however, that in a preferred embodiment, the formulations used is essentially free of glucose or complex sugars that contain glucose. A solution of the active compound as a free acid or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms .

[0038] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and, in final form, must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0039] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and

the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying technique, which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile filtered solution thereof.

[0040] As used herein, a "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents, absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can be incorporated into the compositions of the invention.

[0041] The present invention having been described in detail in the preceding sections, the following examples are provided to illustrate certain aspects of, but not to limit, the invention.

EXAMPLE l Combining Glycolytic Inhibitors with Chemotherapy: Phase I Trial of 2-

Deoxyglucose and Docetaxel in Patients with Solid Tumors [0042] The slow growing cell population of solid tumors that is associated with hypoxia presents a formidable mode of resistance to chemotherapeutic agents; however, anaerobic metabolism of these tumor cells also provides a window of selectivity for glycolytic inhibitors, such as 2-DG. Thus, the combination of a chemotherapeutic agent (to target the rapidly dividing cells) and 2-DG (to selectively kill slowly dividing cells) can be more effective than either agent alone, as has been previously demonstrated in mouse xenografts of human osteosarcoma and lung cancer cell lines with 2-DG in combination with adriamycin or paclitaxel (Cancer Res; 2004 64:31-4).

[0043] A phase I human clinical trial was conducted with the following aims: (1) to determine the maximum tolerated dose (MTD) of daily oral doses of 2-DG

given alone and in combination with weekly docetaxel in patients with advanced solid malignancies who failed chemotherapy previously or for whom there was no standard curative treatment available; (2) to evaluate the pharmacokinetics (PK) of 2-DG after single and multiple doses when given alone and in combination with weekly docetaxel in subjects with advanced solid malignancies; and (3) to evaluate the biologic effect of 2-DG alone and in combination with weekly docetaxel on tumor uptake of ¹⁸ F-fluorodeoxyglucose using positron-emission tomography (FDG-PET).

[0044] In this trial, there were two studies. In the first study, 2-DG was administered orally once daily for 7 days every other week (Weeks 1, 3, 5 and 7 of every 8-week cycle) starting at a dose of 2 mg/kg, and docetaxel was administered at 30 mg/ni ² IV over 1 hour on Day I/Week 2 for 3 of every 4 weeks (Weeks 2, 3, 4, 6, 7 and 8 of every 8-week cycle). A modified accelerated titration design was used in which single subjects were enrolled at each dose level, and dose increases are 100% until dose-limiting toxicity (DLT) occurred. Cohorts of 3-6 patients were then enrolled at dose increases of 40%. MTD is the dose level one below that which resulted in 2 DLTs in 3-6 patients. In another study, 2-DG was administered orally once daily for 21 days, followed by a week of no dosing, followed by 21 days administration (Weeks 1, 2, 3, 5, 6, 7 of every 8- week cycle) starting at a dose of 2 mg/kg, and docetaxel was administered at 30 mg/m ² IV over 1 hour on Day I/Week 2 for 3 of every 4 weeks (Weeks 2, 3, 4, 6, 7 and 8 of every 8-week cycle).

[0045] Pharmacokinetics . Blood samples were collected for PK analysis of 2- DG on Days 1 and 5 of Week 1 and Day 1 of Week 3 (sampling times: 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose). Blood samples were collected for PK analysis of docetaxel on Day 1 of Weeks 2 and 3 (sampling times: 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose). Urine samples were collected for PK analysis of 2-DG on Days 1 and 5 of Week 1 and Day 1 of Week 3 (pre-dose and 0-4, 4-8, 8- 12, and 12-24 hours post-dose). Plasma and urine concentrations of 2-DG and plasma concentrations of docetaxel were analyzed using validated LC/MS/MS assays.

[0046] Pharmacodynamic assessments. Plasma glucose on Days 1 and 5 of Week 1 and Day 1 of Weeks 2 and 3 (pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose) was determined using the hexokinase-glucose-6-ρhosphate dehydrogenase glucose analysis method, which does not cross-react with 2-DG. Hemoglobin AIc (Hgb AIc) was measured at baseline and at the end of each cycle. Plasma insulin and lactic acid were measured pre-dose and 1, 4 and 24 hours post-dose on Days 1 and 5 of Week 1 and day 1 of Week 3. FDG-PET was measured at baseline, and Day 7 of Weeks 1, 2 and 3. [0047] Antitumor activity. Response was evaluated according to RECIST criteria after every 8 weeks of treatment. Twenty one (21) patients with various types of malignancies (i.e. non-small lung cancer (NSCLC); small cell tongue primary cancer with liver metastasis; small cell lung cancer; basaloid type non- small cell lung cancer; adenoid cystic cancer of trachea; parotid adenocystic carcinoma with lung metastasis; metastatic breast carcinoma; medullary breast cancer; head and neck cancer; adenoid cystic carcinoma with metastasis to right temporal bone; adenocarcinoma of unknown origin; T-cell non-Hodgkin's lymphoma producing measurable solid tumors of the skin; large cell lymphoma originating in the breast (tumor removed but solid tumors in chest and neck); adenocarcinoma of the scalp; squamous cell cancer of the soft palate with metastasis; thyroid cancer; and prostate cancer) entered the trial at 2-DG doses up to 88 mg/kg. One patient discontinued for an adverse event (docetaxel-related sensory neuropathy). Single cases of DLT occurred: transient asymptomatic (64 mg/kg) and symptomatic (88 mg/kg) Grade 3 hyperglycemia. The MTD was not reached.

[0048] Eight of twenty patients with post-treatment tumor assessments have achieved disease stabilization (NSCLC, non-Hodgkins lymphoma, thyroid cancer, adenoid cystic carcinoma of trachea, unknown primary, 3 head and neck cancers). One patient with breast cancer had a partial response, and PET showed decreased standard uptake values in all lesions after 2-DG alone. Eleven patients had a best response of progressive disease. The most common non-hematologic adverse events were fatigue, dizziness and sweating. No hematologic toxicity occurred

during the first week of 2-DG alone. Three patients developed Grade 2 neutropenia, and none had Grade 1 neutropenia. Three subjects developed Serious Adverse Events (SAEs), exacerbation of gastritis, postoperative respiratory depression and dysesthesia and numbness due to previously unrecognized brain metastases.

[0049] As illustrated in Figures 1 and 4, 2-DG exhibits linear pharmacokinetics (the maximal plasma concentration (C _max ) and maximal sustained area under the plasma concentration curve (AUC)) over the dose range studied (2 - 88 mg/kg) following single and multiple doses. 2-DG is rapidly absorbed (T _max 0.5 - 1 h) with a terminal half-life of 5-10 h. 2-DG minimally accumulates upon multiple dosing as a result of increased half-life at 63 and 88 mg/kg. As illustrated in Figure 2, PK analysis did not reveal any interaction between 2-DG and docetaxel. 2-DG kinetics is not altered by docetaxel; and docetaxel kinetics is not altered by 2-DG.

[0050] Pharmacodynamic assessments (FDG-PET). 10 patients had post- treatment FDG-PET at baseline and at Week 2, Day 1 (after 1 week of 2-DG and before docetaxel). The one patient with a confirmed PR by RECIST had a decrease in SUV of both lesions after 1 week of 2-DG.

[0051] Figure 3 illustrates mean serum glucose levels. Because of competition with 2-DG, serum glucose increases rapidly but returns to baseline in most patients by 24 hours post-dose. The effect is dampened by the fifth day of dosing (Week 1, Day 5). The effect of the premedication with dexamethasone (for docetaxel) is similar to the effect of 2-DG (Week 2, Day 1; no 2-DG administered). By Week 3 (Week 3, Day 1), when both dexamethasone and 2-DG are administered, the glucose response is similar to that when the two agents are administered separately. There is a trend towards higher serum glucose with higher doses of 2-DG, but inter-subject variability was large. In 5 patients with pre- and post-treatment Hgb AIc measurements, the largest increase was 0.5% after 8 weeks on study.

[0052] These results demonstrate that the combination of 2-DG and docetaxel is safe and exhibits anti-tumor activity. To enhance the efficacy, continuous daily

dosing of 2-DG in combination with weekly dosing of docetaxel may be administered in accordance with the methods of the invention.

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[0053] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention. In addition, many modifications maybe made to adapt a particular situation, material, composition of matter, process, process step or steps, to achieve the benefits provided by the present invention without departing from the scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an indication that any such document is pertinent prior art, nor does it constitute any admission as to the contents or date of the same.