Compositions and methods for treating mucositis

Abstract

In one aspect, a method is provided for treating a human subject having or susceptible to mucositis, comprising administering to the human subject an effective amount of EC-18, thereby treating or preventing mucositis.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 257,099, filed October 18, 2021, which is incorporated herein by reference in its entirety.

[0002] In one aspect, methods, compositions, and kits are provided for treating, preventing, or reducing the incidence or severity of mucositis in a human subject. In a further aspect, methods, compositions, and kits are provided for treating, preventing, or reducing the incidence or severity of oral mucositis in a human subject. In a still further aspect, methods, compositions, and kits are provided for treating, preventing, or reducing the incidence or severity of chemoradiation-induced oral mucositis (CRIOM) in a human subject. In a still further aspect, methods, compositions, and kits are provided for treating, preventing, or reducing the incidence or severity of radiation-induced oral mucositis (RIOM). [Background technology]

[0003] Oral mucositis is a frequent and severe adverse event in patients undergoing chemoradiation therapy, including for head and neck cancer, and can lead to treatment dropout and thereby reduce patient survival.

[0004] Oral mucositis is characterized by painful ulcerative lesions of the oral mucosa observed in cancer patients treated with chemotherapy and / or radiation therapy. Lalla et al., MASCC / ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014;120:1453-1461. doi:10.1002 / cncr.28592; Kashiwazaki et al., Professional oral health care reduces oral mucositis and febrile neutropenia in patients treated with allogeneic bone marrow transplantation. Support. Care Cancer. 2012;20:367-373. doi:10.1007 / s00520-011-1116-x.

[0005] The National Cancer Institute (NCI) has published the Common Terminology Criteria for Adverse Events (CTCAE), which includes separate subjective and objective scales for mucositis: Grade 1 - erythema of the mucosa; Grade 2 - patchy ulcer or pseudomembrane; Grade 3 - confluent ulcer or pseudomembrane; bleeding with minor trauma; Grade 4 - tissue necrosis; significant spontaneous bleeding; life-threatening consequences; and Grade 5 - death.

[0006] Efforts have been made to address chemoradiation-induced oral mucositis (CRIOM) and radiation-induced oral mucositis (RIOM). See, e.g., Liu et al. Status of Treatment and Prophylaxis for Radiation-Induced Oral Mucositis in Patients With Head and Neck Cancer. Front. Oncol. 11:642575. doi:10.3389 / fonc.2021.642575. Current clinical approaches are often unsatisfactory.

[0007] New therapies for treating, preventing, or reducing the incidence or severity of mucositis are desirable. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Lalla et al.,MASCC / ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy.Cancer.2014;120:1453-1461.doi:10.1002 / cncr.28592 [Non-patent document 2] Kashiwazaki et al.Professional oral health care reduces oral mucositis and febrile neutropenia in patients treated with allogeneic bone marrow transplantation.Support.Care Cancer.2012;20:367-373.doi:10.1007 / s00520-011-1116-x [Non-patent document 3] Liu et al.Status of Treatment and Prophylaxis for Radiation-Induced Oral Mucositis in Patients With Head and Neck Cancer.Front.Oncol.11:642575.doi:10.3389 / fonc.2021.642575 Summary of the Invention [Means for solving the problem]

[0009] The present inventors have now found that the compound EC-18 is effective in treating human subjects suffering from or susceptible to oral mucositis.

[0010] In particular, the inventors have found that EC-18 is effective in treating human subjects suffering from or susceptible to oral mucositis that develops during the course of chemoradiotherapy for the treatment of head and neck cancer.

[0011] EC-18 treatment for this indication has been shown to be effective in a dose-dependent manner.

[0012] In one embodiment, the mucositis can be oral mucositis, gastrointestinal mucositis, or alimentary mucositis, hi another embodiment, the mucositis can be associated with cancer, chemotherapy, radiation therapy, or a combination of chemotherapy and radiation therapy.

[0013] In one aspect, methods are provided for treating severe mucositis, including severe oral mucositis (SOM), which may include symptoms of widespread oral ulcers.

[0014] EC-18 can be represented by the structure of Formula 1 below: [ka]

[0015] The compound of Formula 1 is sometimes referred to in this disclosure as "PLAG" or "EC-18."

[0016] As described above, EC-18 can be used to treat human subjects suffering from or susceptible to mucositis, such as oral mucositis, which may be associated with cancer, chemotherapy, radiation therapy, or a combination of chemotherapy and radiation therapy. EC-18 can also be used to treat human subjects suffering from or susceptible to mucositis (e.g., oral mucositis) in human subjects suffering from or susceptible to mucositis due to head and neck cancer. EC-18 can also be used to treat human subjects suffering from or susceptible to mucositis (e.g., oral mucositis) in human subjects suffering from or susceptible to mucositis due to head and neck cancer associated with human papillomavirus (HPV) or infection therewith.

[0017] In certain preferred embodiments, a human patient may receive multiple doses of EC-18 per day.

[0018] In a preferred embodiment, a human patient may receive EC-18 in an oral form, such as a capsule or tablet.

[0019] In certain preferred embodiments, a human patient may receive a daily dosage of EC-18 of up to 500 mg per day, or up to 600, 700, 800, 900, or 1000 mg of EC-18, or up to 1100, 1200, 1300, 1400, 1500 mg of EC-18 per day, or up to 1600, 1700, 180, 199, or 2000 mg of EC-18 per day, or up to 2100, 2200, 2300, 2400, 2500 mg of EC-18 per day, or up to 2500, 300, 3500, or 4,000 mg or more of EC-18 per day.

[0020] A human subject can be determined to be undergoing or susceptible to treatment by undergoing chemotherapy or radiation cancer therapy. Such a subject can, for example, present with oral ulcers.

[0021] In certain embodiments, a human subject is identified and selected for treatment as disclosed herein, and then EC-18 is administered to the identified and selected subject. In particular, a human patient can be identified as suffering from or susceptible to oral mucositis, the identified patient is selected for treatment, and an effective amount of EC-18 is administered to the identified and selected patient. A human patient can also be identified as suffering from or susceptible to oral mucositis and as being HPV-positive, the identified patient is selected for treatment, and an effective amount of EC-18 is administered to the identified and selected patient.

[0022] In certain embodiments, EC-18 can be administered to a subject in combination with or in coordination with one or more therapeutic agents different from EC-18. For example, EC-18 can be administered in combination with palifermin; pentoxifylline with vitamin E; chlorhexidine gluconate (including oral rinses); hyaluronic acid, including sodium hyaluronate; a superoxide dismutase mimetic, such as superoxide dismutase mimetic M40403; and / or dusketide or other innate defense regulators.

[0023] In a further aspect, a pharmaceutical composition comprising EC-18 is provided. The composition may suitably comprise one or more pharmaceutically acceptable carriers. In a preferred embodiment, the composition may be formulated or otherwise adapted for the treatment of mucositis as disclosed herein. In a preferred embodiment, the composition may be adapted for oral administration, such as in the form of a tablet or capsule.

[0024] In yet a further aspect, a kit for use in treating or preventing mucositis as disclosed herein is provided. The kit of the present invention may suitably include 1) a therapeutically effective amount of EC-18; and 2) instructions for using EC-18 to treat or prevent mucositis. The instructions may suitably be in written form, including product labeling.

[0025] Human subjects for treatment can be male or female. In some embodiments, the human is an adult (at least 16, 18, or 21 years of age). In some embodiments, the human is a pediatric patient (under 18, 16, 14, 12, 10, 8, or 6 years of age).

[0026] In one embodiment, a method for treating or preventing oral mucositis associated with chemotherapy and / or radiation therapy can comprise administering to a human subject a composition comprising an effective amount of EC-18. In another embodiment, a method for treating or preventing gastrointestinal mucositis, such as may be associated with chemotherapy and / or radiation therapy, can comprise administering to a human subject an effective amount of a composition comprising EC-18. In another embodiment, a method for treating or preventing gastrointestinal mucositis, such as may be associated with chemotherapy and / or radiation therapy, can comprise administering to a human subject an effective amount of a composition comprising EC-18.

[0027] In one embodiment, a method for treating or preventing cancer-associated mucositis may comprise administering to a human subject a composition comprising an effective amount of EC-18. In another embodiment, a method for treating or preventing cancer-associated oral mucositis may comprise administering to a human subject a composition comprising an effective amount of EC-18. In another embodiment, a method for treating or preventing cancer-associated gastrointestinal mucositis may comprise administering to a human subject a composition comprising an effective amount of EC-18. In another embodiment, a method for treating or preventing cancer-associated gastrointestinal mucositis may comprise administering to a human subject a composition comprising an effective amount of EC-18.

[0028] In one embodiment, a method for treating or preventing mucositis associated with hematopoietic stem cell transplantation (HSCT) may comprise administering to a human subject a composition comprising an effective amount of EC-18. In another embodiment, a method for treating or preventing oral mucositis associated with hematopoietic stem cell transplantation (HSCT) may comprise administering to a human subject a composition comprising an effective amount of EC-18. In another embodiment, a method for treating or preventing gastrointestinal mucositis associated with hematopoietic stem cell transplantation (HSCT) may comprise administering to a human subject a composition comprising an effective amount of EC-18. In another embodiment, a method for treating or preventing gastrointestinal mucositis associated with hematopoietic stem cell transplantation (HSCT) may comprise administering to a human subject a composition comprising an effective amount of EC-18.

[0029] The subject may have mucositis (e.g., oral mucositis or orostomatitis) or may be at risk for developing mucositis (e.g., a patient undergoing or about to undergo chemotherapy and / or radiation therapy). As a further example, a subject in need may have AV (atrophic vaginitis) or vaginal mucositis or may be at risk for developing vaginal mucositis or AV (e.g., a woman exhibiting symptoms that may precede a woman at risk for developing clinical symptoms of AV, e.g., vaginal dryness).

[0030] In one embodiment, a method of treating or preventing mucositis associated with hematopoietic stem cell transplantation (HSCT) may comprise administering to a human subject a composition comprising an effective amount of EC-18.

[0031] In one embodiment, the subject may have human papillomavirus (HPV) infection. In one embodiment, the subject may test positive for human papillomavirus (HPV), for example, test positive for HPV by cervical examination. The present inventors have surprisingly found that human subjects who are treated for mucositis as disclosed herein and who are also HPV-positive show particularly favorable therapeutic benefit from EC-18 treatment.

[0032] In a further aspect, there is provided a use of EC-18, including treating a human subject suffering from or susceptible to a condition as disclosed herein, particularly oral mucositis that occurs during the course of chemoradiotherapy for the treatment of head and neck cancer. In a further aspect, there is provided a use of EC-18 for the preparation of a medicament, including treating a human subject suffering from or susceptible to a condition as disclosed herein, particularly oral mucositis that occurs during the course of chemoradiotherapy for the treatment of head and neck cancer.

[0033] Other aspects of the invention are disclosed below.

[0034] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0035] [Figure 1] Figure 1 shows the patient flow chart for both Stages 1 and 2, along with the definition of each patient population. To faithfully observe and analyze the efficacy of EC-18 compared to placebo, the per protocol (PP) analysis was performed up to the short-term follow-up (STFU) period (approximately 4-6 weeks after the 7-week active treatment period). The efficacy results reported here are based on the placebo (Stage 1 n = 2, Stage 2 n = 18: Total: 20) and EC-18 groups (Stage 1 n = 5, Stage 2 n = 17: Total: 22). [Figure 2] Figures 2A-2B show the duration of severe oral mucositis (SOM) at the primary endpoint. In the PP population (the population used for supportive efficacy analyses), the median duration of SOM from baseline to the STFU period was shorter in the EC-18 2000 mg group compared to placebo (0.0 days vs. 13.5 days). [Figure 3] Figures 3A-3B show the incidence of SOM in the secondary efficacy endpoints. In the PP population, the incidence of SOM from baseline to the active treatment period and STFU was reported less frequently in the EC-18 2000 mg group compared with the placebo group (10 [45.5%] vs. 14 [70.0%]). [Figure 4] Figure 4 shows the cumulative incidence of SOM at each weekly interval over the 7 weeks of treatment. In the PP population, the incidence of SOM from baseline to the active treatment period was reported less frequently in the EC-18 2,000 mg group compared with the placebo group [(36.4%) vs (65.0%) subjects]. [Figure 5] 5A-5B show the secondary endpoint of time to signs of SOM. [Figure 6]FIG. 6 (including FIG. 6A and FIG. 6B) shows the time to opioid use as a secondary endpoint. [Figure 7] FIG. 7 shows covariate analysis based on cisplatin regimen and HPV status. [Figure 8] FIG. 8 shows a comparison of total TGFβ levels between the EC-18 and placebo groups. [Figure 9] 9A-9B show a comparison of TGFβ in the EC-18 and placebo groups with (FIG. 9A) and without (FIG. 9B) SOM. [Figure 10] 10A-10B show a comparison of TGFβ levels in the EC-18 and placebo groups with HPV+ (FIG. 10A) and without HPV (FIG. 10B). [Figure 11] 11A-11B show a comparison of TGFβ levels in EC-18 and placebo groups treated with cisplatin once a week (FIG. 11A) and cisplatin once every three weeks (FIG. 11B). [Figure 12] FIG. 12 shows a comparison of IL-1β levels in total between the EC-18 and placebo groups. [Figure 13] 13A-13B show a comparison of IL-1β in the EC-18 and placebo groups with (FIG. 13A) and without (FIG. 13B) SOM. [Figure 14] 14A-14B show a comparison of IL-1β levels between the EC-18 group with HPV+ (FIG. 14A) and HPV- (FIG. 14B) and the placebo group. [Figure 15] 15A-15B show a comparison of IL-1β levels between the EC-18 and placebo groups receiving weekly cisplatin (FIG. 15A) and tri-weekly cisplatin (FIG. 15B). DETAILED DESCRIPTION OF THE INVENTION

[0036] The inventors have now demonstrated in human clinical trials that EC-18 is highly effective in treating, reducing the severity of, and otherwise ameliorating mucositis in patients who have received chemotherapy and / or radiation therapy for the treatment of cancer.

[0037] In one embodiment, a human subject undergoing treatment with the present method may be suffering from one or more types of cancer, including solid tumors such as may be associated with head and neck cancer. The human subject may be undergoing cancer chemotherapy, such as with cyclophosphamide, doxorubicin, etoposide, ifosfamide, mesna, cisplatin, gemcitabine, and / or tamoxifen, or one or more other chemotherapeutic agents.

[0038] Combination therapy As described above, EC-18 can be administered in combination with other therapeutic agents, including humans, to treat subjects suffering from or susceptible to mucositis, or suffering from the symptoms of mucositis. One or more different therapeutic agents that can be administered in combination include, for example, palifermin; pentoxifylline with vitamin E; chlorhexidine gluconate (including oral rinses); hyaluronic acid, including sodium hyaluronate; superoxide dismutase mimics, such as superoxide dismutase mimic M40403; dusketide or other innate defense regulators.

[0039] As used herein, the term "in combination" in the context of administering a therapy to a subject refers to the use of two or more therapies for a therapeutic benefit. The term "in combination" in the context of administration can also refer to the prophylactic use of a therapy to a subject when used with at least one additional therapy. The use of the term "in combination" does not restrict the order in which therapies (e.g., a first and second therapy) are administered to a subject. The treatment can be administered prior to (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), simultaneously with, or subsequently (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second treatment to a subject in need of treatment as disclosed herein. The treatments are administered to a subject within a series of time intervals so that the treatments can act together. In certain embodiments, the treatments are administered to a subject within a series of time intervals that provides a greater benefit than if administered otherwise. Any additional treatments can be administered in any order with other additional treatments.

[0040] Administration of EC-18 and one or more different therapeutic agents may be by any suitable means that, in combination with other ingredients, results in a concentration of the therapeutic agent effective to ameliorate, reduce, or stabilize the symptoms of mucositis, including the onset of symptoms of mucositis.

[0041] EC-18 and one or more different therapeutic agents can be administered simultaneously or sequentially, hi some embodiments, the one or more different therapeutic agents have been reported for use in treating mucositis.

[0042] As described above, 1) EC-18 and 2) one or more different therapeutic agents can be "co-administered," i.e., coordinately administered together to a subject, either as separate pharmaceutical compositions or mixed into a single pharmaceutical composition. By "co-administered," one or more additional different therapeutic agents can also be administered simultaneously with EC-18, or sequentially or separately from EC-18, including at different times and frequencies (e.g., each agent is administered at least 5, 10, 30, 60, 120, 180, 240, 300, 360, 420, or 500 minutes apart). The one or more different therapeutic agents can be administered by any suitable route of administration, such as orally, intravenously, subcutaneously, intramuscularly, intranasally, etc. The therapeutic agents can also be administered by any conventional route. In at least certain embodiments, one or more different therapeutic agents can be administered orally.

[0043] In some embodiments, EC-18 and / or one or more different therapeutic agents may be administered daily, e.g., every 24 hours, or continuously or several times per day, e.g., every 1 hour, every 2 hours, every 3 hours, every 4 hours, every 5 hours, every 6 hours, every 7 hours, every 8 hours, every 9 hours, every 10 hours, every 11 hours, or every 12 hours.

[0044] Exemplary effective daily doses of the different therapeutic agents include 0.1 μg / kg to 100 μg / kg body weight, for example 0.1, 0.3, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99 μg / kg body weight.

[0045] Alternatively, the different therapeutic agents are administered about once per week, e.g., about once every seven days. Alternatively, the different therapeutic agents are administered twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week. Exemplary effective weekly doses of the different therapeutic agents include 0.0001 mg / kg to 4 mg / kg body weight, e.g., 0.001, 0.003, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, or 4 mg / kg body weight. For example, effective weekly doses of the different therapeutic agents are 0.1 μg / kg body weight to 400 μg / kg body weight.

[0046] Compositions and Treatments Pharmaceutical compositions containing EC-18 may contain conventional pharmaceutically acceptable carriers, excipients, or diluents. The amount of EC-18 is not particularly limited and can vary widely. Specifically, the amount is 0.0001 to 100% by weight, preferably 0.001 to 90% by weight, based on the total amount of the composition. For example, the composition may contain 70 to 80% by weight of EC-18.

[0047] The appropriate dosage of EC-18 can vary appropriately. Preferably, a dosage that alleviates mucositis or reduces the likelihood of mucositis in a human subject is provided. Exemplary daily dosages for a human patient in need of treatment with EC-18 include 0.0001 mg / kg to 4 mg / kg body weight, or 0.01 mg / kg to 4 mg / kg body weight, for example, up to or about 0.001, 0.003, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg body weight of a human subject. For example, in some embodiments, an effective weekly dose of EC-18 can be 0.1 μg / kg to 400 μg / kg body weight of a human patient in need thereof. In preferred embodiments, an oral formulation, such as a tablet or capsule (e.g., a soft gelatin capsule), containing 250 to 1000 mg, e.g., 500 mg, of EC-18 is utilized. Optimal dosages can also be empirically determined for a particular patient or identified patient group (e.g., patients with a history of one or more other pre-existing conditions, e.g., hypertension; cancer patients; patients with HPV or an infection thereof).

[0048] The pharmaceutical compositions of the present invention may further contain other active ingredients having therapeutic effects. The pharmaceutical compositions may be formulated into solid, liquid, gel, or suspension forms for oral or parenteral administration, such as tablets, boluses, powders, granules, capsules (e.g., hard or soft gelatin capsules), emulsions, suspensions, syrups, emulsions, sterile aqueous solutions, non-aqueous solutions, lyophilized preparations, etc. Conventional excipients or diluents, such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants, may be used in formulating the compositions. Solid formulations for oral administration include tablets, boluses, powders, granules, capsules, etc., and can be prepared by mixing one or more active ingredients with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to the excipient, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include emulsions, suspensions, syrups, etc., and may contain conventional diluents such as water and liquid paraffin, or various excipients such as wetting agents, diaphoretics, flavorings, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, lyophilized preparations, suppositories, etc., and solvents for such solutions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and esters for syringe injection such as ethyl oleate. Suppository bases may include Witepsol®, Macrogol, Tween 61, cocoa butter, laurin, and glycerogelatin.

[0049] EC-18 can be administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" refers to an amount sufficient to achieve the desired results in medical treatment. The "pharmaceutically effective amount" can be determined based on the subject's category, age, sex, severity and type of disease, drug activity, drug sensitivity, administration time, administration route, excretion rate, etc. The composition of the present invention can be administered alone or together with other therapeutic agents, sequentially or simultaneously. The composition of the present invention can be administered once or multiple times. The preferred amount of the composition of the present invention can vary depending on the patient's condition and weight, the severity of the disease, the drug formulation, administration route, and the duration of treatment. The appropriate total daily dose can be determined by a physician and is generally about 0.001 to about 5,000 mg / kg, preferably about 0.05 to 1,000 mg / kg, and can be administered twice a day or multiple times a day in divided doses.

[0050] The term "administration" means introducing the pharmaceutical composition of the present invention into a patient in need thereof by any suitable method. The route of administration may be oral or parenteral, as long as it can reach the target tissue, and examples of administration that can be used include, but are not limited to, oral administration, intraperitoneal administration, transdermal administration (topical application, etc.), intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, intranasal administration, rectal administration, intranasal administration, and intraperitoneal administration. Oral administration is preferred.

[0051] As described above, in this treatment method, EC-18 is administered to a human subject suffering from or susceptible to mucositis, such as oral mucositis that may be associated with cancer, chemotherapy, radiation therapy, or a combination of chemotherapy and radiation therapy. In a particular treatment, EC-18 is administered to a human subject suffering from or susceptible to oral mucositis who has head and neck cancer.

[0052] EC-18 may also be used to treat human subjects suffering from or susceptible to mucositis (e.g., oral mucositis) in human subjects having or susceptible to mucositis in head and neck cancers associated with human papillomavirus (HPV) infection or infection therewith.

[0053] As mentioned above, the human subject undergoing treatment may have human papillomavirus (HPV) infection. In one embodiment, the subject may test positive for human papillomavirus (HPV), for example, test positive for HPV by cervical screening. See the results described in the following examples, which demonstrate the effective EC-18 treatment of HPV-positive human subjects.

[0054] A human subject can be determined to be undergoing or susceptible to treatment by undergoing chemotherapy or radiation cancer therapy. Such a subject can, for example, present with oral ulcers.

[0055] As described above, a human subject may be identified and selected for treatment as disclosed herein, and then EC-18 is administered to the identified and selected subject. For example, a human patient may be identified as suffering from or susceptible to oral mucositis, the identified patient selected for treatment, and an effective amount of EC-18 is administered to the identified and selected patient. A human patient may also be identified as suffering from or susceptible to oral mucositis and HPV-positive, the identified patient selected for treatment, and an effective amount of EC-18 is administered to the identified and selected patient.

[0056] The subject may have mucositis (e.g., oral mucositis or orostomatitis) or may be at risk of developing mucositis (e.g., a patient undergoing or about to undergo chemotherapy and / or radiation therapy).

[0057] In one embodiment, a method of treating or preventing mucositis associated with hematopoietic stem cell transplantation (HSCT) may comprise administering to a human subject a composition comprising an effective amount of EC-18.

[0058] In yet a further aspect, there is provided a kit for use in treating or preventing mucositis as disclosed herein. The kit of the present invention may suitably include 1) a therapeutically effective amount of EC-18; and 2) instructions for using EC-18 to treat or prevent mucositis. The instructions may suitably be in written form, including product labeling. [Example]

[0059] The following examples are illustrative.

[0060] Example 1: Patient population and clinical trial Human patients with the following characteristics were enrolled: 18 years or older Diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or nasopharynx Plan to receive IMRT in daily fractions of 2.0 Gy to 2.2 Gy up to a cumulative dose of 60 Gy to 72 Gy. A radiation field that includes at least two mucositis sites at risk (buccal mucosa, floor of mouth, ventral and lateral tongue, soft palate), both of which receive a minimum cumulative dose of 55 Gy. -Planning to receive cisplatin-based single-agent chemotherapy

[0061] EC-18 was administered up to 2000 mg / day to various patients in the treatment groups. The recommended treatment was 500 mg EC-18 capsules administered four times throughout the day (e.g., two 500 mg EC-18 capsules administered within 30 minutes after breakfast and dinner) for a total daily dose of 2000 mg EC-18. The treatment protocol lasted for 7 weeks, with radiation therapy and cisplatin therapy continuing concurrently.

[0062] The EC-18 treatment group demonstrated clear therapeutic benefits over the control group, including reduced mucosal inflammatory symptoms.

[0063] Twenty-five large centers and hospitals experienced in head and neck cancer treatment were selected for the study. Stage 1: Evaluate safety and MTD available for Stage 2 iDSMB: Data Safety Monitoring Board reviews safety data every 2 weeks and approves Stage 2 using MTD 2000mg Stage 2: Evaluate safety and efficacy Active treatment for 7 weeks and STFU for 4-6 weeks until OM resolves 2.0–2.2 Gy in daily fractions (5 days a week for 7 weeks) and cisplatin weekly (40 mg / m²) or every 3 weeks (100 mg / m²). Minimum cumulative radiation dose 55Gy

[0064] Efficacy was measured by the duration of severe oral mucositis (SOM) and the incidence of SOM during active treatment.

[0065] Figure 1 (flow diagram) shows the patient pool at study initiation and factors that led to the efficacy analysis population.

[0066] In Stage 1, we included placebo and 2000 mg patients from Stage 1 into Stage 2 for efficacy analysis: Placebo group: Stage 1 n=2, Stage 2 n=18: Total: 20 EC-18 2000mg group: Stage 1 n=5, Stage 2 n=17: Total: 22

[0067] Figures 2A-2B summarize the efficacy results. When measuring the median duration and incidence of SOM, highly effective results are observed. The placebo group experienced a median SOM duration of nearly 14 days compared to the EC-18 group, which did not experience SOM.

[0068] The 14-day duration of SOM for this placebo group is somewhat similar to what we have reported for other drugs where we are analyzing the correct population.

[0069] Similarly, many journals and papers have reported that the incidence of SOM in placebo groups ranges from 65% to 70%. Compared to the placebo incidence of SOM, the incidence of SOM in the EC-18 group was 45%, a reduction of over 35% compared to the placebo group.

[0070] The graphs in Figures 3A-3B show the incidence of SOM at each weekly interval. SOM does not begin until week 3 and peaks at week 7 (after which the cumulative radiation dose is 70 Gy) and week 8, one week after the last radiation treatment. As can be seen from Figures 3A-3B, the incidence of SOM in the EC-18 group is lower than that of the placebo group (PP group or PP). As shown in Figure 4, oral mucositis (OM) rarely occurs after a single radiation dose, and SOM is seen with increasing cumulative doses (from week 3 or 4 onwards), with some extending beyond week 7. In Figure 4, the EC-18 treatment group is shown on the right side of each period (weeks 4, 5, 6, and 7, respectively), and placebo is shown on the left side for each period or alone at week 3.

[0071] 5A-5B also show the time to signs of SOM, a secondary endpoint: In the PP population, signs of SOM were delayed by 8 days in the EC-18 2,000 mg group compared to the placebo group (51 days vs. 43 days).

[0072] Figure 6 (including Figures 6A and 6B) shows the time to opioid use in the secondary endpoints. In the PP population, the time to first use of an opioid analgesic was delayed for evaluable subjects (subjects who were not taking opioid analgesics immediately before study start or at baseline and subjects for whom data was available) between the EC-18 2000 mg group (n = 8) and the placebo group (n = 6). The EC-18 2,000 mg group had a median delay of 6.3 days compared with the placebo group (32.3 days vs. 26 days). The EC-18 2,000 mg group had a median delay of 11.5 days compared with the placebo group (37 days vs. 25.5 days). In Figure 6B, for each period (6.3 days or 11.5 days), placebo is shown on the left (26 for 6.3 days and 25.5 for 11.5 days) and EC-18 2000 mg is shown on the right (32.3 for 6.3 days and 37 for 11.5 days).

[0073] Figure 7 shows the analysis of covariance based on cisplatin regimen and HPV status. The observed incidence of SOM in subjects was lower in the EC-18 2000 mg group compared to the placebo group for weekly cisplatin (37.5% vs. 70.0%) and once every three weeks cisplatin (66.7% and 70.0%), respectively. The observed incidence of SOM in subjects with HPV+ was lower in the EC-18 2000 mg group compared to the placebo group (35.3% vs. 66.7%). Meanwhile, no difference was observed in HPV-negative subjects in the EC-18 2000 mg group compared to the placebo group (75% vs. 71.4%).

[0074] Safety results (e.g., serious adverse events (SAEs)) indicate that no significant differences in SAEs were observed across study arms. Furthermore, all reported SAEs were attributable to chemoradiation therapy and not to EC-18. Stage 1 had a total of 17 SAEs from a total of 24 patients, and Stage 2 had a total of 31 SAEs from a total of 81 patients. Patients in 020-018 were deemed by the investigators to be unrelated to the study drug. Many SAEs occurred due to nausea and vomiting, which are common symptoms of chemotherapy.

[0075] Example 2: Cytokine profiles from patient plasma samples in CRIOM Phase 2 Assay Information: Luminex Assay Plasma samples collected from the patients listed in Table 1 below were thawed and centrifuged at 10,000 rpm at 4°C for 2 minutes, and the supernatants were used for analysis. The supernatants were serially diluted, and 50 μL of each sample was dispensed into each well of a 96-well plate. 50 μL of the diluted microparticle cocktail (R&D Systems) shown in Table 2 was added to each well containing the sample and incubated at room temperature for 2 hours on an 800 rpm shaker. The sample mixture was removed and washed three times with 100 μL of wash buffer. Next, 50 μL of diluted Biotin-Antibody Cocktail (R&D Systems) was added to each well and incubated at room temperature for 1 hour on an 800 rpm shaker, followed by three washes with wash buffer. 50 μL of diluted Biotin-Antibody Cocktail (R&D Systems) was added to each well and incubated at room temperature for 30 minutes on an 800 rpm shaker. After washing three times with washing buffer, 100 ul of washing buffer was added to each well, and the fluorescence intensity of the samples was obtained within 90 minutes using a Luminex analyzer (Luminex).

[0076] Standards, controls and samples were quantitatively analyzed using the mean of results obtained in duplicate.

[0077] The absolute mean fluorescence intensity (MFI) value of each sample was obtained by comparing it with the standard curve. Values ​​derived as less than the standard were marked as 0 because they were trace values ​​outside the detection range of the assay kit.

[0078] A standard curve was obtained using the best-fit method in MasterPlex QT 2010 (MiraiBio, Hitachi, California, USA), and the measured response (MFI) for each standard concentration with the largest R-squared value among all calculation methods (maximum value = 1.0) was calculated. Sample concentrations were calculated based on this standard curve. [Table 1] [Table 2]

[0079] Comparison of total TGFβ levels between the EC-18 group and the placebo group. The TGF-β concentration in the EC-18 treatment group was significantly higher than that in the placebo group at week 7 of chemoradiotherapy treatment. As shown in Figure 8, the TGF-β concentration in the EC-18 treatment group was significantly higher than that in the placebo group at week 7 of chemoradiotherapy treatment. In Figure 8, in the graph on the left, the EC-18 treatment group (active drug) is shown on the right for each period, and the placebo is shown on the left for each period.

[0080] Comparison of TGFβ between the EC-18 group with or without SOM and the placebo group The TGF-β concentration in the EC-18 treatment group was higher than that in the placebo group, regardless of the incidence of SOM. As shown in Figures 9A-9B, the TGF-β concentration in the EC-18 treatment group was higher than that in the placebo group, regardless of the incidence of SOM. In Figures 9A and 9B, the EC-18 treatment group (active drug) is shown on the right side of each period, and the placebo is shown on the left side of each period in the graphs on the left.

[0081] Comparison of TGFβ levels between the EC-18 group and the placebo group with HPV+ / HPV- In the HPV-positive population, TGF-β concentrations were significantly higher in the EC-18 group compared with placebo. Although the number of HPV-negative patients was too small to conclude the statistical significance of the difference in TGFβ, TGFβ levels in the EC-18 group were similar to placebo. As shown in Figures 10A-10B, in the HPV-positive population, TGF-β concentrations in the EC-18 group were significantly higher compared with placebo. In Figures 10A and 10B, the EC-18 treatment group (active drug) is shown on the right for each period, and placebo is shown on the left for each period.

[0082] Comparison of TGF-β levels between EC-18 groups treated with weekly cisplatin or cisplatin once every three weeks and placebo groups In the subpopulation treated with cisplatin once weekly, TGF-β concentrations in the EC-18 group were significantly higher than those in the placebo group. However, TGF-β concentrations were not significantly different between the EC-18 group treated with cisplatin once every three weeks and the placebo group. As shown in Figures 11A-11B, in the subpopulation treated with cisplatin once weekly, TGF-β concentrations in the EC-18 group were significantly higher than those in the placebo group, but not in the EC-18 group treated with cisplatin once every three weeks. In Figures 11A and 11B, the EC-18 treatment group (active drug) is shown on the right for each period, and the placebo is shown on the left for each period.

[0083] Comparison of total IL-1β levels between the EC-18 group and the placebo group The IL-1β concentration in the EC-18 treatment group was significantly lower than that in the placebo group throughout the 7-week treatment period. The IL-1β concentration decreased, even though it was below the detection limit, at weeks 4 and 7 of treatment. As shown in Figure 12, the IL-1β concentration in the EC-18 treatment group was significantly lower than that in the placebo group throughout the 7-week treatment period. In Figure 12, the EC-18 treatment group (active drug) is shown on the right side of each period in the graph on the left, and the placebo is shown on the left side of each period.

[0084] Comparison of IL-1β between the EC-18 group with or without SOM and the placebo group IL-1β concentrations in the EC-18 treatment group were significantly lower than those in the placebo group, regardless of the incidence of SOM. As shown in Figures 13A-13B, IL-1β concentrations in the EC-18 treatment group were significantly lower than those in the placebo group, regardless of the incidence of SOM. In Figures 13A and 13B, in the graphs on the left, the EC-18 treatment group (active drug) is shown on the right for each period, and the placebo is shown on the left for each period.

[0085] Comparison of IL-1β levels between the EC-18 group with HPV+ / HPV- and the placebo group IL-1β concentrations in the EC-18 treatment group were significantly lower than those in the placebo group, regardless of HPV infection status. As shown in Figures 14A-14B, IL-1β concentrations in the EC-18 treatment group were significantly lower than those in the placebo group, regardless of HPV infection status. In Figures 14A and 14B, the EC-18 treatment group (active drug) is shown on the right side of each period, and the placebo is shown on the left side of each period in the graphs on the left.

[0086] 4. Comparison of IL-1β levels between the EC-18 group treated with cisplatin once a week or cisplatin once every three weeks and the placebo group IL-1β concentrations in the EC-18 treatment group were significantly lower than those in the placebo group, regardless of whether cisplatin treatment was administered weekly or once every three weeks. As shown in Figures 15A-15B, IL-1β concentrations in the EC-18 treatment group were significantly lower than those in the placebo group, regardless of whether cisplatin treatment was administered weekly or once every three weeks. In Figures 15A and 15B, the EC-18 treatment group (active drug) is shown on the right side of each period in the left graph, and the placebo is shown on the left side of each period.

[0087] All documents mentioned herein are incorporated herein by reference.

Claims

1. A pharmaceutical composition comprising an effective amount of EC-18 for treating a human subject having or susceptible to mucositis.

2. A pharmaceutical composition comprising an effective amount of EC-18 for treating a human subject having or susceptible to oral mucositis.

3. A pharmaceutical composition comprising an effective amount of EC-18 for treating a human subject having or susceptible to chemotherapy-associated mucositis.

4. A pharmaceutical composition comprising an effective amount of EC-18 for treating a human subject having or susceptible to chemotherapy-associated oral mucositis.

5. A pharmaceutical composition comprising an effective amount of EC-18 for treating a human subject having or susceptible to mucositis associated with radiation therapy.

6. A pharmaceutical composition comprising an effective amount of EC-18 for treating a human subject having or susceptible to oral mucositis associated with radiation therapy.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the human subject has been diagnosed with head and neck cancer.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the human subject is undergoing treatment for cancer.

9. The pharmaceutical composition of claim 8, wherein the human subject is undergoing cisplatin therapy.

10. 10. The pharmaceutical composition of claim 8 or 9, wherein the human subject is undergoing radiation therapy for cancer.

11. A pharmaceutical composition described in any one of claims 1 to 10, containing an effective amount of EC-18 for co-administration with one or more different drugs for the treatment of mucositis.

12. A pharmaceutical composition described in any one of claims 1 to 11, containing an effective amount of EC-18 for co-administration with one or more of the following: palifermin; pentoxifylline with vitamin E; chlorhexidine gluconate (including oral rinses); hyaluronic acid including sodium hyaluronate; a superoxide dismutase mimetic, for example, superoxide dismutase mimetic M40403; dusketide or other innate defense regulators.

13. (a) EC-18 and (b) instructions for using EC-18 to treat mucositis in a human subject; and Includes a kit.

14. A pharmaceutical composition comprising an effective amount of EC-18 for treating a human subject having or susceptible to mucositis in HPV-associated head and neck cancer.

15. A pharmaceutical composition comprising an effective amount of EC-18 for treating a human subject: 1) having or susceptible to mucositis, and / or 2) being HPV positive.

16. 16. The pharmaceutical composition of claim 14 or 15, wherein the subject is identified as 1) suffering from mucositis and / or 2) testing positive for HPV infection.

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