Injectable formulations comprising tirbanibulin

Abstract

The disclosure provides an injectable pharmaceutical formulation comprising tirbanibulin, in free or pharmaceutically acceptable salt form, for local injection to treat cancerous, precancerous and proliferative conditions of the skin, together with injection devices and methods of treatment.

Description

INJECTABLE FORMULATIONS COMPRISING TIRBANIBULINTECHNICAL FIELD

[0001] The present disclosure relates to tirbanibulin formulations for local (e.g. intralesional or perilesional) injection, and an injection syringe system preloaded with a tirbanibulin formulation, for use in treatment of cancerous, precancerous and proliferative skin conditions.BACKGROUND OF THE INVENTION

[0002] Skin cancer is one of the most common cancers worldwide, and particularly in Australia, New Zealand, Europe and in the United States. Skin cancer can be broken down to melanoma skin cancer, where the cancer develops in the skin’s melanocytes and non-melanoma skin cancer where the cancer forms in the basal, squamous or Merkel cells of the skin. Basal cell carcinoma (BCC) is the most common form of skin cancer and cutaneous squamous cell carcinoma (SCC) is the second most common form of skin cancer. While melanomas are more deadly, non-melanoma skin cancers are much more common.

[0003] Standard treatment for skin cancer is surgical removal of the cancer. The primary goal is complete resection of the cancer, and acceptable cosmetic outcome is a secondary goal. Factors associated with poor prognosis in SCC, for example, include tumor size > 2 cm, tumor depth > 2mm, perineural invasion, host immunosuppression, and recurrent lesions. However, some patients who develop advanced SCC, which encompasses both locally advanced and metastatic SCC, are not candidates for surgery. Some such patients may be administered postoperative radiation therapy or chemotherapy, but these may not be attractive options due to safety and tolerability concerns.

[0004] Most patients are cured by surgery for BCC, but a small percentage of patients experience recurrent lesions or develop unresectable locally advanced or metastatic disease. Recognition of the oncogenic role of the G-protein receptor smoothened (SMO) in BCC led to the development of vismodegib and sonidegib, orally available inhibitors of SMO, generally referred to as Hedgehog Inhibitors (HHIs). However, in addition to adverse side-effects of the fflHs, it was found that for patients that progress on one HHI (vismodegib), subsequent treatment with another HHI (sonedegib) did not result in tumor inhibition.

[0005] Surgical resection is also the centerpiece of clinical management of SCC. However, some patients who develop advanced SCC, which encompasses both locally advanced and metastatic SCC, are not candidates for surgery. Some such patients may be administered post-operative radiation therapy or chemotherapy, but these may not be attractive options due to safety and tolerability concerns. Multiple surgeries over time can be disfiguring and lead to surgical fatigue - i.e., physical and emotional debilitation resulting from serial surgical procedures. Updated 2020 European guidelines now recommend the use of anti-PD-1 agents (such as cemiplimab, nivolumab or pembrolizumab) as a first-line treatment in advanced stages of cutaneous SCC patients who are not candidates for curative surgery or curative radiation. However, there remains a need to provide safe and effective therapies for skin cancer, such as SCC and BCC, especially skin cancer that has recurred despite prior surgeries.

[0006] Tirbanibulin is a synthetic, antiproliferative agent that binds tubulin, inhibits tubulin polymerization, and disrupts Src signaling in actively dividing cells. It is sold under the trade name KLISYRI® as an ointment, approved for topical use to treat actinic keratosis of the face or scalp. Tirbanibulin is described and claimed, e.g., in US 7300931 and WO 2006 / 071960, tirbanibulin salt forms (e.g., hydrochloride or mesylate salt) and salt polymorphs are described, e.g. in WO 2008 / 144045 and WO 2010 / 135429, and polymorphs of the free base are described, e. g. , in US 10669236 and WO 2019 / 051147.

[0007] There is a need for further safe and effective therapies for the treatment of skin cancer, especially when the skin cancer has recurred despite prior surgeries.BRIEF SUMMARY OF THE INVENTION

[0008] In the first aspect, the present disclosure provides an injectable pharmaceutical formulation comprising tirbanibulin, in free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable diluent or carrier, wherein the formulation is suitable for local injection, e.g., perilesional or intralesional injection.

[0009] The injectable formulation as further disclosed herein may be filled in an appropriate injection ampoule, vial, or preloaded into a syringe, e.g., for injection with a standard needle and syringe or micro-injection needle syringe. Therefore, in a second aspect, the present disclosure provides an injection syringe, e.g., for the treatment of skin cancer, comprising the injectable formulation as further disclosed herein. In one embodiment, the injection syringe systemcomprises a vial or ampoule pre-loaded with the injectable formulation as further disclosed herein. In another embodiment, the injectable syringe system comprises a micro-needle syringe preloaded with the injectable formulation as further disclosed herein.

[0010] The injectable formulation as further described herein, e.g., in an injectable syringe system described herein, is useful for the treatment of various types of skin cancer by intralesional injection. Therefore, in the third aspect, the present disclosure provides a method for treating skin cancer in a subject in need thereof, comprising injecting the injectable formulation as described herein, into a skin cancer lesion or proximal to a skin cancer lesion.DETAILED DESCRIPTION

[0011] The present invention provides an injectable pharmaceutical formulation comprising tirbanibulin, in free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable diluent or carrier, wherein the formulation is suitable for local injection, e.g., perilesional or intralesional injection (Injectable Formulation 1). For example, Injectable Formulation I may be as follows:1.1 Injectable Formulation 1, wherein the tirbanibulin is in free base form.1.2 Any foregoing Injectable Formulation, wherein the concentration of tirbanibulin is 0.1% to 10% by weight.1.3 Any foregoing Injectable Formulation wherein the pharmaceutically acceptable diluent or carrier comprises one or more of a solubilizing agent, buffer, isotonicity agent, antioxidants, preservatives and solubility and / or viscosity-enhancing agents.1.4 Any foregoing Injectable Formulation which is non-aqueous.1.5 Any foregoing Injectable Formulation wherein the tirbanibulin is in solution, or in an emulsion, liposome, microparticle, microcapsule, or nanoparticle or in a solid dispersion.1.6 Injectable Formulation 1.5 wherein the tirbanibulin is in solution.1.7 Injectable formulation 1.6 wherein the tirbanibulin is dissolved in a solution comprising propylene glycol.1.8 Injectable Formulation 1.5 wherein the tirbanibulin is an emulsion or microemulsion.1.9 Injectable Formulation 1.5, wherein the tirbanibulin is in nanoparticle form, e.g., in nanodispersion, nanoemulsion, or lipid nanoparticle form.1.10 Any foregoing Inj ectable Formulation for use in the treatment of a cancerous, precancerous or proliferative condition of the skin in a patient, e.g. in accordance with any of Methods 1, et seq.

[0012] The Injectable Formulation 1, et seq., may be provided in a unit dose form, e.g., in an injection ampoule or vial, or preloaded into a syringe with a needle, e.g., for injection with a standard needle and syringe or micro-injection needle syringe. Therefore, in another aspect, the present disclosure provides an injection device (Injection Device 1), e.g., for the treatment of skin cancer, comprising any of Injectable Formulation I, et seq.; for example,1.1 Injection Device 1, comprising a syringe, vial, or ampoule, comprising 0.1 - 10 mg, e.g. 1-5 mg, of tirbanibulin in free base or pharmaceutically acceptable salt form, wherein if the tirbanibulin is in pharmaceutically acceptable salt form, the amount is the free base equivalent amount.1.2 Injection Device 1 or 1.1, comprising about 1 mg to about 2.5 mg of tirbanibulin in free base or pharmaceutically acceptable salt form, wherein if the tirbanibulin is in pharmaceutically acceptable salt form, the amount is the free base equivalent amount.1.3 Any foregoing Injection Device, comprising about 1.3 mg to about 2.5 mg of tirbanibulin in free base or pharmaceutically acceptable salt form, wherein if the tirbanibulin is in pharmaceutically acceptable salt form, the amount is the free base equivalent amount.1.4 Any foregoing Injection Device, comprising about 2.5 mg of tirbanibulin in free base or pharmaceutically acceptable salt form, wherein if the tirbanibulin is in pharmaceutically acceptable salt form, the amount is the free base equivalent amount.1.5 Any foregoing Injection Device, comprising a syringe preloaded with any of Injectable Formulation I, et seq. and a needle suitable for intralesional or perilesional injection, e.g. a needle which is 29 gauge or smaller diameter [NB: smaller diameter equates to higher gauge] and 2.5 cm or smaller in length.1.6 Injection Device 1.5, wherein the needle is a microneedle, e.g., 0.5 - 3 mm in length, e.g. having a tip diameter of 1-25 pm and a needle shaft width of 10-300 pm.1.7 Injection Device 1.5, wherein the needle is a 30- or 31 -gauge needle.1.8 Any foregoing Injection Device for use in the treatment of a cancerous, precancerous or proliferative condition of the skin in a patient, e.g. in accordance with any of Methods 1, et seq.

[0013] The injectable formulation 1 et seq., e.g., in an injectable syringe system described herein may be useful for the prophylaxis or therapeutic or abscopal treatment of various types of skin cancer. Therefore, in another aspect, the present disclosure provides a method (Method 1) of treatment (including treatment, prophylaxis, or inhibition) of a cancerous, precancerous or proliferative condition of the skin in a patient, characterized by one or more lesions (e.g., including skin tumors and other abnormal proliferative conditions of the skin, and post-operative lesions where a tumor or other abnormal growth was removed), comprising administering one or more doses of Injectable Formulation I et seq. by local injection in or near the lesion to be treated; for example,1.1. Method 1, wherein Injectable Formulation 1 et seq. is administered by Injection Device 1, et seq.1.2. Any foregoing Method wherein the cancerous, precancerous or proliferative condition is selected from basal cell carcinoma, squamous cell carcinoma, melanoma, Merkel cell carcinoma, dermatofibrosarcoma protuberans, melanoma tumor syndromes, cutaneous lymphoma, Kaposi’s sarcoma, sebaceous carcinoma, actinic keratosis, Malignant Adnexal tumors of the skin and warts.1.3. Method 1.2 wherein the cancerous or precancerous condition is basal cell carcinoma (BCC).1.4. Method 1.2 wherein the cancerous or precancerous condition is squamous cell carcinoma (SCC).1.5. Method 1.2 wherein the cancerous or precancerous condition is melanoma.1.6. Method 1.2 wherein the cancerous or precancerous condition is cutaneous lymphoma.1.7. Method 1.2 wherein the cancerous or precancerous condition is actinic keratosis.1.8. Method 1.2 wherein the proliferative condition is warts, preferably recalcitrant warts.1.9. Any of the foregoing Methods, wherein the cancerous or precancerous condition is a low- risk skin cancer as defined by the National Comprehensive Cancer Network (NCCN).1.10. Any of the foregoing Methods, wherein the cancerous or precancerous condition is a high-risk skin cancer as defined by the National Comprehensive Cancer Network (NCCN).. Any of the foregoing Methods, wherein the cancerous or precancerous condition is a very high-risk skin cancer as defined by the National Comprehensive Cancer Network (NCCN).. Any of the foregoing Methods, wherein the cancerous or precancerous condition is a recurrent skin cancer (e.g., recurrent after treatment). . Any of the foregoing Methods, wherein the cancerous or precancerous condition is a regional or distant metastatic cancer. . Any of the foregoing Methods, wherein the cancerous, precancerous or proliferative condition is at least 0.1 cm in surface diameter, e.g., at least 1 cm, e.g., equal to or greater than 2 cm (e.g., between 2 cm and 4 cm). . Any of the foregoing Methods, wherein the lesion is greater than or equal to 1 cm in surface diameter. . Any of the foregoing Methods, wherein the lesion is greater than or equal to a 2 cm (e.g., between 2 cm and 4 cm) in surface diameter. . Any of the foregoing Methods, wherein the lesion is greater than or equal to 4 cm in surface diameter. . Any of the foregoing Methods, wherein the lesion is greater than or equal to 2mm deep.. Any of the foregoing Methods, wherein the lesion is located on the face (e.g., eyelids, nose, ears and lips). . Any of the foregoing Methods, wherein the lesion is located on head or neck. . Any of the foregoing Methods, wherein the lesion is located on trunk, arms or legs.. Any of the foregoing Methods, wherein the lesion is located on the scalp. . Any of the foregoing Methods, wherein the lesion is located on hands, feet, shin or sex organs. . Any of the foregoing Methods, wherein the patient has had prior cancer treatment (e.g., surgery, radiation, chemotherapy and / or other anti-tumor therapy). . Any of the foregoing Methods wherein the method is a method of prophylaxis, to prevent or reduce the likelihood of recurrence of the cancerous, precancerous or proliferative condition, in a patient who has already been treated for a cancerous, precancerous or proliferative condition. . Any of the foregoing Methods wherein the method reduces the size of the lesion. . Any of the foregoing Methods wherein the method eliminates the lesion.. Any of the foregoing Methods wherein the method inhibits the growth or spread of the cancerous, precancerous or proliferative condition. . Any of the foregoing Methods wherein the lesion comprises a skin tumor. . Any of the foregoing Methods wherein the lesion comprises a post-operative lesion at the site where a tumor or other abnormal growth was surgically removed. . Any of the foregoing Methods, wherein the patient is at elevated risk of recurrence of cancer. . Any of the foregoing Methods, wherein the patient has weakened immune system (e.g., long-term use of corticosteroid, having human immunodeficiency virus or AIDS, or having received an organ transplant). . Any of the foregoing Methods, wherein the patient has previously received an organ or tissue transplant. . Any of the foregoing Methods, wherein the lesion is about 1 cm2to about 100 cm2, e.g., about 1 cm2to about 50 cm2, about 5 cm2to about 25 cm2. . Any of the foregoing Methods, wherein the lesion is about 10 cm2to about 25 cm2.. Any of the foregoing Methods, wherein the lesion is about 1 cm2to about 25 cm2. . Any of the foregoing Methods, wherein the Injectable Formulation I et seq. is administered up to 10 times, e.g., once, twice, or three times, or once monthly for up to 6 months. . Any of the foregoing Methods, wherein the Injectable Formulation I et seq. is administered intralesionally. . Any of the foregoing Methods, wherein the Injectable Formulation I et seq. is administered perilesionally (e.g., near the edge of the lesion , e.g. within 2 cm from the edge of the lesion). . Any of the foregoing Methods, wherein the Injectable Formulation I et seq. is administered at a volume proportional to the volume of the lesion. . Any of the foregoing Methods, wherein the dosage of tirbanibulin in free base or pharmaceutically acceptable salt form is from about 0.1 mg to about 2.5 mg per cm3of lesion volume, wherein if the tirbanibulin is in pharmaceutically acceptable salt form, the amount is the free base equivalent amount.1.42. Any of the foregoing Methods, wherein one or more doses of the Injectable Formulation I et seq. is injected into one or more locations of the tumor or skin cancer lesion.1.43. Any of the foregoing Methods, wherein the dosage of tirbanibulin in free base or pharmaceutically acceptable salt form is 0.1 - 10 mg, e.g. about 1 to about 5 mg, per treatment, wherein if the tirbanibulin is in pharmaceutically acceptable salt form, the amount is the free base equivalent amount.1.44. The foregoing Method, wherein the tirbanibulin is free base form and the dosage per treatment from about 1 mg to about 5 mg.1.45. Any of the foregoing Methods, further comprising administering one or more cancer therapeutic treatment (e.g., cancer agent such as anti-PDl or chemotherapy, radiation therapy).1.46. Any of the foregoing Methods wherein the systemic exposure to tirbanibulin is significantly lower than the intralesional exposure, e.g., wherein the plasma concentration of tirbanibulin as a result of the method is Cmax of less than 3 ng / mL and AUC of less than 50 ng*h / mL.1.47. Any of the foregoing Methods wherein the volume of the injection is about 0.05 mL to about 0.5 mL.e.g., about 0.1 mL to about 0.2 mL, per square centimeter of the lesion surface.1.48. The foregoing Method wherein the plasma concentration of tirbanibulin as a result of the method is Cmax of less than 1.5 ng / mL and AUC of less than 25 ng*h / mL.1.49. Any of the foregoing Methods wherein the Injectable Formulation forms a depot at the site of injection and the tirbanibulin is released gradually over time.

[0014] The disclosure further provides tirbanibulin for use in the treatment of a cancerous, precancerous or proliferative condition of the skin in a patient by local injection, e.g. in accordance with any of Methods 1, et seq.

[0015] The disclosure further provides the use of tirbanibulin in the manufacture of a medicament, e.g., in the manufacture of any of Injectable Formulation 1, et seq. or any of Injection Device 1, et seq., for the treatment of a cancerous, precancerous or proliferative condition of the skin in a patient by local injection, e.g. in accordance with any of Methods 1, et seq.

[0016] The injectable formulation as described herein, e.g. Injectable Formulation 1, et seq. which may be formulated with suitable carriers, excipients, buffers, and other agents that provide suitable transfer, delivery, tolerance, and the like. A source for general information about suitable formulations can be found in Remington: The Science and Practice of Pharmacy (Academic Press) 23rded. (2020). The injectable formulation as described herein, e.g. Injectable Formulation 1, et se suitable for intralesional or perilesional administration, which includes administration directly into or near a skin cancer lesion and administration in or near the skin overlying the skin cancer lesion. The pharmaceutical composition may be delivered by subcutaneous injection with a standard fine gauge needle (e.g., 30 or 31 gauge) and syringe, or in certain embodiments, the pharmaceutical composition may be delivered by subcutaneous injection with micro-injection needle syringe that are loaded with tirbanibulin.

[0017] Injectable formulations of the pharmaceutical composition may be prepared by known methods. For example, the injectable formulation may be prepared, e.g., by dissolving, suspending, or emulsifying the tirbanibulin in free or pharmaceutically acceptable salt form in a sterile medium conventionally used for injection. Tirbanibulin is insoluble in water but somewhat soluble in organic solvents, e.g., about 1.2% w / w in propylene glycol, but if concentrations of greater than 1% w / w are desired, it is preferred to use a suspension or emulsion formulation. Agents such as buffer, stabilizers, isotonicity agents, antioxidants, preservatives, and solubility and / or viscosity-enhancing agents may be included. A buffer may include acetate, phosphate, citrate, histidine and TRIS. Tonicity of the formulation may be adjusted by including dextrose, mannitol, glycerol or sodium chloride. For actives with poor solubility, solubilizers such as surfactant, solvent, co-solvent complexing agents or their combinations may be used.Water soluble organic solvents and surfactants may include propylene glycol, polyethylene glycol 300 / 400, glycerin, ethanol, polysorbate 80, Cremophor EL, N-methyl-2-pyrrolidone (NMP). As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO- 50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. The oily medium, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.

[0018] In some embodiments, the injectable formulation is provided in a pre-loaded syringe, an appropriate injection vial, or an appropriate injection ampoule.

[0019] In some embodiments, the injectable formulation is provided in an array of microneedles. Microneedles as used herein comprise solid, hollow, coated, dissolving, and hydrogel -forming microneedles.

[0020] In certain embodiments, the present disclosure provides a pharmaceutical composition or formulation comprising a therapeutic amount of tirbanibulin and a pharmaceutically acceptable carrier. In certain embodiments, the present disclosure provides for tirbanibulin formulated in a pharmaceutical composition for administration by intralesional injection.

[0021] In certain embodiments, the methods disclosed herein includes intralesionally or perilesionally administering to the tumor of a subject in need thereof a therapeutically effective amount of tirbanibulin or the injectable formulation as disclosed herein in multiple doses, e.g., as part of a specific therapeutic dosing regimen. For example, the above-mentioned therapeutic dosing regimen may comprise administering one or more doses of tirbanibulin or the injectable formulation disclosed herein to the subject at a frequency of about once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, once a month, once every two months, once every three months, once every four months, twice a day, twice every two days, twice every three days, twice every four days, twice every five days, twice every six days, twice a week, twice every two weeks, twice every three weeks, twice every four weeks, twice every five weeks, twice every six weeks, twice every eight weeks, twice every twelve weeks, twice a month, twice every two months, twice every three months, twice every four months, three times a day, three times every two days, three times every three days, three times every four days, three times every five days, three times every six days, three times a week, three times every two weeks, three times every three weeks, three times every four weeks, three times every five weeks, three times every six weeks, three times every eight weeks, three times every twelve weeks, three times a month, three times every two months, three times every three months, three times every four months or less frequently or as needed so long as a therapeutic response is achieved.

[0022] In certain embodiments, the tirbanibulin is administered in multiple treatments, e.g. one, two or three treatments, or monthly for up to six months, depending on the severity of the condition and response to the treatment. For example, in some embodiments, up to three three treatments with the injectable tirbanibulin formulation disclosed herein are administered, e.g., wherein the condition is a low-risk or medium-risk skin cancer as defined by the National Comprehensive Cancer Network (NCCN), while additional treatments, e.g. up to six treatments, are administered wherein the skin cancer is a high-risk skin cancer as defined by the National Comprehensive Cancer Network (NCCN), or wherein the condition is not responsive to the initial treatments. In certain embodiment, a treatment cycle comprises 1 monthly treatments during a six-month period wherein the skin cancer is at an advanced stage.

[0023] In certain embodiments, one or more doses of tirbanibulin or the injectable formulation disclosed herein are intralesionally or perilesionally administered into or near a tumor lesion having a surface diameter of at least 1 cm. In certain embodiments, the lesion has a surface diameter of no more than 2 cm. In one embodiment, the tumor lesion has a surface diameter of 1.0 cm to 2.0 cm. In other embodiments, the tumor lesion is at least 1 cm in each of the longest perpendicular surface diameters of the lesion. In other embodiments, the tumor lesion is no more than 2 cm in each of the longest perpendicular surface diameters of the lesion. In another embodiment, the tumor lesion is 1.0 cm to 2.0 cm in each of the longest perpendicular surface diameters of the lesion. In another embodiment, the tumor lesion is equal to or greater than 2 cm (e.g., between 2 cm and 4 cm) in surface diameter, in still another embodiment, greater than 4 cm in surface diameter, in yet another embodiment, 3-6 cm in surface diameter or 4-6 cm in diameter. In one embodiment, the tumor or skin cancer lesion is equal to or greater than 2mm deep.

[0024] In certain embodiments, the present disclosure provides methods for treating skin cancer, comprising selecting a subject with a skin cancer lesion (e.g. a tumor or other abnormal hyperproliferative growth) and administering one or more doses of tirbanibulin or the injectable formulation disclosed herein intralesionally or perilesionally near or into one or more locations of the lesion. In certain embodiments, tirbanibulin or the injectable formulation disclosed herein is intralesionally or perilesionally administered into or near 1, 2, 3, 4, 5, 6, or 7 locations in a single skin cancer lesion. In certain embodiments, tirbanibulin may be intralesionally administered into 2 to 5 locations of the lesion.

[0025] Cancerous and precancerous skin lesions to be treated can be selected from melanoma skin cancer, non-melanoma skin cancer (basal cell carcinoma, squamous cell carcinoma, melanoma, Merkel cell carcinoma), dermatofibrosarcoma protuberans, melanoma tumor syndromes, cutaneous lymphoma, Kaposi’s sarcoma, sebaceous carcinoma, actinic keratosis, or malignant adnexal tumors of the skin. Basal cell carcinoma (BCC) is the most common type of skin cancer, and they develop from basal cells of which are found in the deepest part of the outer layer of the skin (the epidermis). Squamous cell skin cancer (SCC) is the second most common type of skin cancer, and they begin in cells called keratinocytes, which are found in the epidermis. Melanoma comes from skin cells called melanocytes. These cells produce melanin, the dark pigment that gives skin its color. Dermatofibrosarcoma protuberans (DFSP) is a rare skin cancer that begins in the person’s dermis (skin’s middle layer). Merkel cell carcinoma (MCC) is a rare type of skin cancer, and it starts in the Merkel cells, which are usually in the top layer of the skin (the epidermis). These cells are near the nerve endings, and they help us respond to touch. Cutaneous lymphoma (CTCL) is a rare type of cancer that begins in white blood cells (T-cells). These cells normally help the body’s germ-fighting immune system. But in CTCL, the T-cells develop abnormalities that make them attack the skin. Kaposi’s sarcoma (KS) is a rare type of soft tissue sarcoma, and it develops from cells called endothelial cells, which line the blood and lymph vessels. It is commonly found on the skin, but it can also affect the inside of the body, such as the lymph nodes, lungs, bowel, liver, and spleen. Sebaceous carcinoma is a rare skin cancer that develops in a person’s skin oil-producing glands and this cancer most commonly affects the eyelids. Actinic keratosis (AK) is a common precancerous skin condition caused by excessive exposure to ultraviolet light. AKs are rough, dry, tan-, pink-, or red- colored blemishes (lesions) that often appear on the part of the head, including the face, throat, neck, nose, forehead, ears, or lips. AK may also appear or other body parts that receive prolonged sunlight, e.g., the hands, the back, and other areas on the trunk and legs. Malignant adnexal tumors of the skin are an infrequent, heterogeneous group of tumors that originate from eccrine, apocrine, and sebaceous sweat glands. Warts are proliferative diseases caused by human papillomavirus (HPV) infection of keratinocytes. Cutaneous HPV infection commonly manifests as warts including flat warts (verruca plana, on hands and face), common warts (verruca vulgaris), planta warts (verruca plantaris, on soles of feet), and condyloma acuminatum (anogenital warts, on genitalia, anus orperianal area). Most cutaneous HPV infection leads to benign proliferative lesions, while rarely develops into cutaneous cancers such as squamous cell carcinoma.

[0026] Intralesional administration, as disclosed herein, refers to the direct delivery of a compound, such as tirbanibulin or the injectable formulation disclosed herein, percutaneously or directly into a skin lesion or intradermally into the skin overlying a skin cancer or tumor lesion.

[0027] Intralesional administration provides for several advantages in the treatment of skin cancers, precancerous and proliferative conditions. For instance, intralesional administration provides an improved localized treatment that introduces the tirbanibulin directly to the tumor lesion of the subject, thus allowing for efficient administration of the compound at a high concentration specifically at the site of administration without a high level of systemic exposure to the drug. Additionally, intralesional administration of a compound would eliminate the need for surgery, which is often a painful and disfiguring procedure, particularly in instances where repeated surgeries (which cause further disfigurement) would otherwise be needed. Perilesional administration refers to administration near the edge of the skin cancer lesion such as 2 cm from the edge of the skin cancer lesion.

[0028] The term “recurrent” refers to a frequent or repeated diagnosis of skin cancer in a patient or a frequent or repeated occurrence of individual tumor lesion(s), such as primary tumor lesions and / or new tumor lesions that may represent recurrence of a prior tumor lesions. In certain embodiments, intralesional administration of tirbanibulin inhibits the recurrence of tumor lesions in patients.

[0029] The term “patient” may include a human or a non-human patient.

[0030] The term “recalcitrant” refers to a wart that was not successfully treated by prior treatment.

[0031] The National Comprehensive Cancer Network (NCCN) provides guidelines which comprise recommendations for the prevention, diagnosis, and management of malignancies across the continuum of care. The guidelines provide classifications on the risk of the cancer coming back after treatment (recurrence). The risks for basal cell skin cancer are generally broken down into Stage 0-4 for skin cancer, and for basal cell skin cancer and squamous cell carcinoma, into 3 categories: low risk, high risk, and / or very high risk or regional or distant metastatic for each type of cancer. For general skin cancer, stage 0 is also known as carcinoma in situ, which means there are cancer cells, but they have not yet spread or grown into surroundingareas of the skin. Squamous cell carcinoma in situ is also called Bowen’s disease. Bowen’s disease might develop into squamous cell carcinoma if left untreated. Stage 1 is defined by the cancer being 2 cm across or smaller. Stage 2 is defined by the cancer being larger than 2 cm across but no larger than 4 cm. Stage 3 is when the cancer is either larger than 4 cm across, has grown into nearby bones, space around a nerve or below the layer of fat under the skin (subcutaneous tissue) or if the cancer is smaller than 4 cm but it has spread to bone marrow or bone, including the bottom of the skull, or the cancer has spread to another part of the body (distant spread). For skin cancer that affects the eyelid, different characteristics apply to the various stages. Stage 1 of such cancer means the cancer has not spread into lymph nodes or another part of the body but it may have spread into the edge of the eyelid or tissue supporting the eyelid or through the full thickness of the eyelid and the cancer is 10 mm across or smaller (Stage 1 A) or it has spread into the edge of the eyelid or the tissue supporting the eyelid and is larger than 10 mm across but no larger than 20mm (Stage IB). Stage 2 means the cancer has not spread into lymph nodes or to another part of the body. It is split into 2 groups - stage 2A and 2B. Stage 2A means: (i) the cancer is larger than 10mm across but no larger than 20mm. It has spread into the edge of the eyelid, or the tissue supporting the eyelid, or through the full thickness of the eyelid; or (ii) the cancer is larger than 20mm across but no larger than 30mm. It might have spread into the edge of the eyelid where the eyelashes are, or the tissue supporting the eyelid, or through the full thickness of the eyelid. Stage 2B means the cancer is any size and has grown into nearby structures such as the eye, sinuses, tear ducts or brain. Stage 3 means the cancer is (i) any size and it might have spread into the edge of the eyelid, the tissue supporting the eyelid, through the full thickness of the eyelid, or into nearby structures; or (ii) it has spread to nearby lymph nodes, but it has not spread to another part of the body. It is split into 2 groups - stage 3A and stage 3B. Stage 3A means the cancer has spread to a single lymph node on the same side of the body as the cancer, and the lymph node is 3 cm or smaller. Stage 3B can mean different things, e.g. the cancer has spread to: (i) a single lymph node on the same side of the body as the cancer, and the lymph node is larger than 3 cm (ii) lymph nodes on the other side of the body to the eyelid cancer, or to lymph nodes on both sides of the body. Stage 4 means the cancer has spread to another part of the body such as the lungs.

[0032] Specifically for basal cell skin cancer and squamous cell carcinoma, the cancer is classified based on risk of recurrence. Low risk means lower chance of the cancer coming back after treatment. High risk means higher chance of the cancer coming back after treatment.

[0033] Low risk basal cell skin cancer is defined by the following factors: small and superficial (found only on top layer of skin), clear, defined edge, and has not been treated before. High risk is defined by the following factors: located on areas of the face, such as the eyelids, nose, ears, and lips, has previously come back after treatment, and equal to or wider than 2 centimeters. Finally regional or distant metastatic basal cell skin cancer is defined by whether the lesion has spread to a distant site.

[0034] For squamous cell skin cancer, the risks are broken down as low-, high-, or very high- risk skin cancer. A high-risk squamous cell skin cancer has an increased risk of local recurrence. A very high-risk squamous cell skin cancer has an increased risk of local recurrence and of metastasis (spread). The factors to determine the risk level of squamous cells are as follows: location and size, tumor shape, tumor return after treatment, tumor formed in damaged skins, nerve damage, tumor grade, tumor type, connective tissue in the tumor, how deep the tumor is, cancer cells in lymph or blood vessels, and whether there is a weaken immune system in the subject. Squamous cell skin cancer on the head or neck is more likely to return after treatment than tumors on the trunk, arms, or legs. Therefore, high risk includes tumors on the trunk, arms, or legs that are between 2 cm and 4cm or tumor of any size on the head, face, neck, hands, feet, shins or sex organs. Any tumor over 4 cm in any location is considered very high-risk squamous cell carcinoma.

[0035] The methods disclosed herein are applicable to all stages and risk levels of the cancer, particularly the high or very high risk of recurrent skin cancer.Example 1 - Mouse models

[0036] The efficacy of tirbanibulin intralesional administration is assessed in a mouse model, e.g. a syngeneic mouse model, i.e. a murine tumor model using immunocompetent mice engrafted with SCC or melanoma cells (KLN205 cells, PDVC57 cells or B16F10 cells) or other types of cells, such as colon (MC38 or CT26) or breast cancer (4T1 cells), or a xenograft model using immunocompromised mice engrafted with human tumor cells, e.g. SCC-9, SCC-15 andSCC-25 cells. Mice with established tumors are treated with control vehicle or tirbanibulin intralesionally at different doses. Tumor volumes are measured twice weekly using a digital caliper. Tumor growth, body weight changes and clinical signs are monitored along the duration of the experiment.

[0037] The foregoing experiment is repeated in mice receiving with anti-PD-1 treatment (i.p. 10 mg / kg, every 3 days) with and without tirbanibulin intralesional treatment to assess efficacy of tirbanibulin intralesional treatment on tumor growth inhibition compared to anti-PDl treatment alone.

Claims

CLAIMSWe claim:

1. An injectable pharmaceutical formulation comprising tirbanibulin in free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable diluent or carrier, in a form suitable for local injection, e.g., any of Injectable Formulations 1, et seq. supra.

2. The injectable formulation of claim 1 wherein the tirbanibulin in free or pharmaceutically acceptable salt form is present in an amount from about 0.1% to about 10% by weight, wherein when the tirbanibulin is in pharmaceutically acceptable salt form, the amount is the free base equivalent.

3. The injectable formulation according to claim 1, wherein the tirbanibulin in free or pharmaceutically acceptable salt form is formulated in a solution or emulsion form, or encapsulated in liposomes, microparticles, microcapsules or nanoparticles.

4. An injection device comprising an injectable formulation according to any one of the foregoing claims, in a unit dose form, e.g., any of Injection Device 1, et seq., supra.

5. The injection device according to the foregoing claim, wherein the tirbanibulin in free or pharmaceutically acceptable salt form is in a dose of about 0.01 mg to about 10 mg, e.g., 1 mg to about 2.5 mg, wherein when the tirbanibulin is in pharmaceutically acceptable salt form, the amount is the free base equivalent.

6. The injection device according to claim 3 or 4 wherein the injection device comprises a syringe and a needle suitable for intralesional or perilesional injection.

7. A method for treatment (including treatment, prophylaxis, or inhibition) of a cancerous or precancerous condition or a proliferative condition of the skin in a patient, wherein the condition is characterized by one or more lesions (e.g., including skin tumors and other abnormal proliferative conditions of the skin, and post-operative lesions where a tumor or other abnormal growth was removed), comprising administering one or more doses of the injectable formulation of any of claims 1, 2, or 3, by local injection in or near the lesion to be treated; e.g., any of Methods 1, et seq. supra.

8. The method of claim 7, wherein the cancerous, precancerous or proliferative condition is selected from basal cell carcinoma, squamous cell carcinoma, melanoma, Merkel cell carcinoma, dermatofibrosarcoma protuberans, melanoma tumor syndromes, cutaneouslymphoma, Kaposi’s sarcoma, sebaceous carcinoma, actinic keratosis, Malignant Adnexal tumors of the skin and warts.

9. The method of claim 7 or 8 wherein the dosage of tirbanibulin in free base or pharmaceutically acceptable salt form is 0.1 - 10 mg, e.g. about 1 to about 5 mg, per treatment, wherein if the tirbanibulin is in pharmaceutically acceptable salt form, the amount is the free base equivalent amount.