Leuprolide acetate compositions and methods of use for treating breast cancer

Abstract

Compositions and methods for suppressing ovarian function in subjects with hormone receptor-positive breast cancer. The present invention relates to methods for suppressing ovarian function in breast cancer patients and methods for treating hormone receptor-positive (HR-positive) breast cancer by administering an extended-release biodegradable polymer composition comprising leuprolide or a pharmaceutically acceptable salt or analog thereof. Thus, in one aspect, the present disclosure provides a method for suppressing ovarian function in subjects with HR-positive breast cancer by administering to an HR-positive breast cancer patient in need of such treatment a therapeutically effective amount of a flowable extended-release composition comprising an organic solvent, leuprolide or a pharmaceutically acceptable salt or analog thereof, and a biodegradable polymer.

Description

[Technical field]

[0001] The present invention relates generally to the field of oncology. Described herein are leuprolide compositions particularly useful for suppressing ovarian function and for treating hormone receptor positive breast cancer. [Background technology]

[0002] Breast cancer is the most common form of cancer and the leading cause of cancer deaths in women worldwide. Approximately 80% of all breast cancers express and are dependent on the estrogen receptor (ER) for tumor growth and progression. Modulation of hormone activity and / or synthesis, particularly estrogen, is the mainstay of therapeutic approaches in women with hormone receptor-positive (HR-positive) breast cancer. In pre- / peri-menopausal patients with intermediate- or high-risk HR-positive human epidermal growth factor receptor 2 (HER2)-negative disease receiving endocrine therapy (including aromatase inhibitors [AIs]), ovarian suppression is an important component of therapy to further reduce estrogen levels.

[0003] In clinical practice consistent with the American Society of Clinical Oncology and National Comprehensive Cancer Network® guidelines, gonadotropin-releasing hormone (GnRH) agonists are used in the United States to suppress ovarian function in premenopausal / perimenopausal patients with breast cancer at intermediate to high risk for recurrence. GnRH agonists are not administered as monotherapy in the treatment of patients with HR-positive breast cancer. Current treatment strategies include the use of adjuvant endocrine therapy, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and other drugs that reduce the release of endogenous non-ovarian estrogens (such as aromatase inhibitors [AIs]).

[0004] There is a need for drug formulations that provide effective and consistent suppression of ovarian function for long-term use in conjunction with these adjuvant endocrine therapies and other breast cancer treatments in patients with HR-positive breast cancer. Summary of the Invention [Means for solving the problem]

[0005] The present invention relates to methods for suppressing ovarian function in breast cancer patients and methods for treating hormone receptor positive (HR-positive) breast cancer by administration of extended release biodegradable polymer compositions comprising leuprolide or a pharma-ceutically acceptable salt or analogue thereof.

[0006] Thus, in one aspect, the present disclosure provides a method of suppressing ovarian function in a subject with HR-positive breast cancer by administering to a HR-positive breast cancer patient in need of such treatment a therapeutically effective amount of a flowable extended release composition comprising an organic solvent, leuprolide or a pharma- ceutically acceptable salt or analog thereof, and a biodegradable polymer. Upon injection of the flowable extended release composition into the subject and contact with bodily fluids, the organic solvent in the flowable extended release composition dissipates and an in situ solid or semi-solid depot is formed.

[0007] In these methods, the biodegradable polymer can be a poly(lactide-co-glycolide) (PLG) copolymer comprising a molar ratio of lactide to glycolide monomers ranging from about 70:30 to about 80:20, inclusive, or in one embodiment up to about 85:15, inclusive, where the polymer is substantially free of titratable carboxylic acid groups and at least one distal end group of the polymer is hydroxyl terminated. In these methods, the biodegradable polymer can be a poly(lactide-co-glycolide) copolymer preferably comprising a molar ratio of lactide to glycolide monomers of 75:25, where the polymer is substantially free of titratable carboxylic acid groups and at least one distal end group of the polymer is hydroxyl terminated. In these methods, the biodegradable polymer can have a weight average molecular weight of about 15 kDa to about 45 kDa, or about 15 kDa to about 26 kDa, or about 17 kDa to about 21 kDa. In these methods, the biodegradable polymer can be present in an amount of about 35% to about 60% by weight of the flowable extended release composition.

[0008] In these methods, the organic solvent is N-methyl-2-pyrrolidone (NMP), acetone, cyrene, butyrolactone, ε-caprolactone, caprolactam, N-cyclohexyl-2-pyrrolidone, diethylene glycol monomethyl ether, dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide (DMSO), ethyl acetate, ethyl lactate, N-ethyl-2-pyrrolidone, glycerol formal, glycofurol, N-hydroxyethyl-2-pyrrolidone, isopropylideneglycerol, lactic acid, methoxypolyethylene glycol, methoxypropylene glycol, methyl acetate, methyl ethyl ketone, methyl lactate, ammonium nitr ... The organic solvent may be selected from benzyl benzyl benzoate (BnBzO), polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, polyoxyl 35, polyethylene glycol (PEG), hydrogenated castor oil, polyoxyl 40 hydrogenated castor oil, sorbitan monolaurate, sorbitan monostearate, sorbitan monooleate, benzyl alcohol, n-propanol, isopropanol, tert-butanol, propylene carbonate, propylene glycol, 2-pyrrolidone, α-tocopherol, triacetin, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, triethyl citrate, esters thereof, and combinations thereof. In these methods, the organic solvent is preferably N-methyl-2-pyrrolidone.

[0009] In these methods, the pharma- ceutically acceptable salt or analog of leuprolide may be selected from the group consisting of leuprolide acetate, leuprolide monoacetate, leuprolide oleate, leuprolide palmitate, leuprolide mesylate, leuprolide trifluoroacetic acid (TFA), leuprolide trifluoroacetate, leuprolide (5-9), (D-His2)-leuprolide trifluoroacetate (TFA), leuprolide hydrochloride (HCL), leuprolide-D5 acetate, leuprolide (L-Leu), and combinations thereof. In these methods, the pharma- ceutically acceptable salt of leuprolide is preferably leuprolide acetate. In these methods, the composition may contain about 26 mg to about 30 mg of leuprolide free base equivalent, for example, the flowable extended release composition may contain about 28 mg to about 32 mg of leuprolide acetate. In these methods, the composition may preferably contain about 28 mg of leuprolide free base equivalent, for example, a flowable extended release composition may contain about 30 mg of leuprolide acetate.

[0010] In these methods, the HR-positive breast cancer can be estrogen receptor (ER) and / or progesterone receptor (PgR) positive breast cancer. In these methods, the breast cancer can be HR-positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer.

[0011] In these methods, the subject can be a pre-menopausal or peri-menopausal woman. In these methods, the subject can be at least 18 years old. In these methods, the subject can be at least 18 years old and less than 40 years old, or at least 18 years old and less than 45 years old, or at least 18 years old and less than 55 years old.

[0012] In these methods, the flowable extended release composition may be administered simultaneously with one or more therapeutic treatments for HR-positive breast cancer, including but not limited to endocrine therapy. In these methods, the flowable extended release composition may be administered simultaneously with an antihormonal agent and / or an aromatase inhibitor. In these methods, the flowable extended release composition may be administered simultaneously with one or more of tamoxifen, letrozole, anastrozole and exemestane. Alternatively or in addition, the flowable extended release composition may be administered simultaneously with chemotherapy and / or radiation therapy.

[0013] In these methods, the fluid extended release composition may be administered subcutaneously to the subject. In these methods, the fluid extended release composition may be administered to the subject about once every 90 days (i.e., about once every 3 months). In these methods, the fluid extended release composition may be administered to the subject at least 2 times, at least 3 times, at least 4 times, at least 8 times, at least 12 times, at least 16 times, at least 20 times, or more than 20 times.

[0014] In these methods, administration of the flowable extended release composition can result in an in vivo release of about 10 mg of leuprolide acetate per month from the in situ solid or semi-solid depot formulation to the subject. In these methods, administration of the flowable extended release composition can result in an approximately linear release of leuprolide, or a pharma- ceutically acceptable salt or analog thereof (e.g., leuprolide acetate) from the composition to the subject over a period of about 90 days (i.e., about 3 months) following a plasma concentration burst after administration.

[0015] In these methods, administration of the flowable extended release composition can provide in the subject an area under the curve (AUC) of leuprolide acetate of between about 10 days·ng / mL and about 225 days·ng / mL. In these methods, administration of the flowable extended release composition can provide in the subject a mean area under the curve (AUC) of leuprolide acetate of between about 75 days·ng / mL and about 100 days·ng / mL over about 80 days. In these methods, administration of the flowable extended release composition provides an initial burst release of leuprolide acetate from the composition to the subject, and administration of the flowable extended release composition can provide in the subject an area under the curve (AUC) of leuprolide acetate of between about 90 days·ng / mL and about 370 days·ng / mL, or a mean area under the curve (AUC) of leuprolide acetate of between about 205 days·ng / mL and about 210 days·ng / mL over about 80 days.

[0016] In these methods, the subject's estradiol (E2) production can be reduced to postmenopausal levels (<20 pg / mL) by administering the flowable extended release composition alone or by co-administering the flowable extended release composition with one or more endocrine therapies for HR-positive breast cancer, including but not limited to antihormonal agents and aromatase inhibitors. In these methods, the subject's estradiol can be reduced to about 20 pg / mL or less, or about 10 pg / mL or less by administering the flowable extended release composition alone or by co-administering the flowable extended release composition with one or more of antihormonal agents and / or aromatase inhibitors. In these methods, the subject's estradiol can be reduced to about 2.7 pg / mL or less by co-administering the flowable extended release composition with aromatase inhibitors. In these methods, administration of the flowable extended release composition alone or in combination with one or more of an antihormonal agent and / or an aromatase inhibitor can reduce a subject's follicle stimulating hormone (FSH) levels to about 40 IU / L or less.

[0017] In another aspect, the disclosure provides articles of manufacture comprising a first container containing leuprolide or a pharma- ceutically acceptable salt or analog thereof, and a second container containing a biodegradable polymer and an organic solvent. These articles may include instructions for their use, and may also include instructions for combining the contents of the first and second containers to form a flowable extended release composition for administration to a subject. In these articles, the first container may contain about 26 mg to about 30 mg of leuprolide free base equivalent, e.g., the first container may contain about 28 mg to about 32 mg of leuprolide acetate. In these articles, the first container may preferably contain about 28 mg of leuprolide free base equivalent, e.g., about 30 mg of leuprolide acetate. In these articles, the second container can contain less than 1.0 mL of the biodegradable polymer / organic solvent composition, more preferably, the second container can contain about 0.30 mL to about 0.50 mL of the biodegradable polymer / organic solvent composition, or preferably about 0.375 mL of the biodegradable polymer / organic solvent composition.

[0018] In these articles, the biodegradable polymer can be a poly(lactide-co-glycolide) copolymer comprising a molar ratio of lactide to glycolide monomers ranging from about 70:30 to about 80:20, inclusive, or in one embodiment up to about 85:15, inclusive, where the polymer is substantially free of titratable carboxylic acid groups and at least one distal end group of the polymer is hydroxyl terminated. In these articles, the biodegradable polymer can be a poly(lactide-co-glycolide) copolymer preferably comprising a molar ratio of lactide to glycolide monomers of 75:25, where the polymer is substantially free of titratable carboxylic acid groups and at least one distal end group of the polymer is hydroxyl terminated. In these articles, the biodegradable polymer can have a weight average molecular weight of about 15 kDa to about 45 kDa, or about 15 kDa to about 26 kDa, or about 17 kDa to about 21 kDa. In these articles, the biodegradable polymer can comprise about 35% to about 60% by weight of the flowable extended release composition.

[0019] In these articles, the organic solvent is N-methyl-2-pyrrolidone (NMP), acetone, silane, butyrolactone, ε-caprolactone, caprolactam, N-cyclohexyl-2-pyrrolidone, diethylene glycol monomethyl ether, dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide (DMSO), ethyl acetate, ethyl lactate, N-ethyl-2-pyrrolidone, glycerol formal, glycofurol, N-hydroxyethyl-2-pyrrolidone, isopropylideneglycerol, lactic acid, methoxypolyethylene glycol, methoxypropylene glycol, methyl acetate, methyl ethyl ketone, methyl lactate, benzyl benzoate (Bn BzO), polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, polyoxyl 35, polyethylene glycol (PEG), hydrogenated castor oil, polyoxyl 40 hydrogenated castor oil, sorbitan monolaurate, sorbitan monostearate, sorbitan monooleate, benzyl alcohol, n-propanol, isopropanol, tert-butanol, propylene carbonate, propylene glycol, 2-pyrrolidone, α-tocopherol, triacetin, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, triethyl citrate, esters thereof, and combinations thereof. In these articles, the organic solvent is preferably N-methyl-2-pyrrolidone.

[0020] In these articles, the first and second containers can be the first and second chambers of a dual chamber syringe, and the contents of the first and second chambers can be mixed by adding the contents of the second chamber to the first chamber or the contents of the first chamber to the second chamber and mixing the contents to form a flowable extended release composition. In these articles, the first and second containers can be the first and second syringes, and the contents of the first and second syringes can be mixed by connecting the syringes together and transferring the contents back and forth between the two syringes until the contents are effectively mixed together to form a flowable extended release composition. In these articles, the injection volume of the flowable extended release composition can be less than about 1.0 mL, preferably less than about 0.5 mL, or more preferably about 0.375 mL.

[0021] These articles may also contain a needle adapted for insertion into a syringe containing the composition for subcutaneous administration of the flowable extended release composition to a subject.These articles may also contain a package insert providing efficacy and / or safety data for the use of the flowable extended release composition in suppressing ovarian function in subjects with HR-positive breast cancer.

[0022] A preferred embodiment of the present disclosure includes an extended release composition for suppression of ovarian function in a subject with HR-positive breast cancer, comprising about 0.375 mL of a composition comprising N-methyl-2-pyrrolidone, 30 mg of leuprolide acetate, and a biodegradable polymer comprising a 75:25 poly(lactide-co-glycolide) (PLG) copolymer segment, wherein the polymer is substantially free of titratable carboxylic acid groups and at least one distal end group of the polymer is hydroxyl terminated. In these extended release compositions, the biodegradable thermoplastic polymer can have the chemical formula: HO-(P)-C(=O)O-Ra-O(O=)C-(P)-OH, where Ra is an alkane diradical containing about 4 to about 8 carbons and is the residue of an alkane diol, and P is a polymer segment of lactide, glycolide, or (lactide-co-glycolide) repeat units.

[0023] This summary is not intended, nor should it be interpreted, as being representative of the full scope and scope of the present invention. Moreover, in this specification, references to "the disclosure" or aspects thereof should be understood to mean a certain embodiment of the present invention, and should not necessarily be interpreted as limiting all embodiments to the particular description. The disclosure is described in various levels of detail in this summary, as well as in the accompanying drawings and detailed description, and no limitation on the scope of the disclosure is intended by either including or not including elements, components, etc. in this summary. Additional aspects of the present invention will be more readily apparent from the detailed description, particularly when taken in conjunction with the drawings. [Brief description of the drawings]

[0024] [Figure 1] FIG. 1 shows the simulated linear serum leuprolide concentration-time profile for administration of 30 mg leuprolide acetate injection every three months over two doses.

[0025] [Diagram 2] FIG. 2 shows simulated log-linear serum leuprolide concentration-time profiles for administration of 30 mg leuprolide acetate injection every three months over two doses.

[0026] [Diagram 3] FIG. 3 shows the simulated maximum plasma concentrations (Cmax) for administration of two amounts of leuprolide acetate in a biodegradable polymer that releases leuprolide over a period of 3 or 4 months.

[0027] [Figure 4] FIG. 4 shows a schematic diagram of a human clinical study of the efficacy of an injectable extended release depot formulation of 30 mg leuprolide acetate suspension designed to release leuprolide acetate at a rate of 10 mg / month over a period of three months ("TOL2506"). Arrows indicate administration of doses of TOL2506. (Abbreviations: mo=months; QD=daily; SC=subcutaneous; PO=oral administration) DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Glossary of some abbreviations used herein: area under the concentration-time curve (AUC), confidence interval (CI), maximum concentration (C max ), complete response (CR), dose-limiting toxicity (DLT), gel permeation chromatography (GPC), mitomycin, cisplatin and 5-fluorouracil (MCF), estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), cyclophosphamide, methotrexate, estradiol (E2), estrone (E1), estrone sulfate (E1S), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), luteinizing hormone releasing hormone (LHRH), metastatic breast cancer (MBC), not significant (NS), overall survival (OS), progressive disease (PD), progression-free survival (PFS), pharmacokinetics (PK), partial response (PR), progesterone receptor (PgR), serious adverse events (SAE) and time to maximum plasma concentration (t max)。

[0029] Definition The term "alkyl" refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. A "lower alkyl" group is a branched or unbranched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred alkyl groups have 1 to 4 carbon atoms. An alkyl group can be a "substituted alkyl" in which one or more hydrogen atoms are replaced by a substituent such as halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl. For example, lower alkyl or (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl or hexyl; (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (C3-C6)cycloalkyl(C1-C6)alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl or 2-cyclohexylethyl; (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isopropyl, butyl, butyl, sec-butyl, pentyl, 3-pentyl or hexyl; -butoxy, sec-butoxy, pentoxy, 3-pentoxy or hexyloxy; (C2-C6)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl; (C2-C6)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl;(C1-C6)alkanoyl can be acetyl, propanoyl or butanoyl; halo(C1-C6)alkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or pentafluoroethyl; hydroxy(C1-C6)alkyl can be hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl or 1-hydroxyhexyl. or 6-hydroxyhexyl; (C1-C6) alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl or hexyloxycarbonyl; (C1-C6) alkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio or hexylthio; (C2-C6) alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy or hexanoyloxy;

[0030] The terms "molecular weight" and "average molecular weight", unless otherwise specified, refer to weight average molecular weight as measured by conventional gel permeation chromatography (GPC) equipment (such as an Agilent 1260 Infinity Quaternary LC equipped with an Agilent G1362A refractive index detector) utilizing polystyrene standards and tetrahydrofuran (THF) as the solvent.

[0031] The term "chemotherapy", as used herein, refers to treatment that involves the administration of chemotherapy, as defined herein below.

[0032] As used herein, the term "endocrine therapy" or "hormonal therapy" for breast cancer refers to a treatment that blocks the attachment of estrogen and / or progesterone to the receptor in breast cancer cells. Exemplary endocrine therapy agents include selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), aromatase inhibitors (AIs), and can include agents or treatments that result in ovarian suppression.

[0033] "Survival" refers to a patient remaining alive, and includes overall survival and progression-free survival.

[0034] "Overall survival" or "OS" refers to a patient remaining alive for a defined period of time from the time of diagnosis or treatment, such as 1 year, 5 years, etc. For the purposes of clinical breast cancer treatment trials, overall survival (OS) is defined as the time from the date of randomization of a patient population to the date of death from any cause.

[0035] "Progression-free survival" or "PFS" refers to a patient remaining alive without the progression or worsening of breast cancer. For the purposes of clinical breast cancer treatment trials, progression-free survival (PFS) is defined as the time from randomization of the study population to the first occurrence of either the first documented progressive disease, or unmanageable toxicity or death from any cause. Disease progression may be documented by any clinically accepted method, such as radiographic progressive disease.

[0036] By "prolonged survival" is meant an increase in overall survival or progression-free survival in breast cancer patients, e.g., patients treated according to the present invention, compared to untreated patients and / or compared to patients who have been treated with one or more approved anti-tumor agents but have not been treated according to the present invention.

[0037] "Objective response" refers to a measurable response, including complete response (CR) or partial response (PR).

[0038] By "complete response" or "CR" is intended the disappearance of all signs of cancer in response to treatment. It does not necessarily mean that the cancer has been cured.

[0039] "Partial response" or "PR" refers to a decrease in the size of one or more tumors or lesions, or the extent of cancer in the body, in response to treatment.

[0040] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0041] "Advanced" breast cancer is one that has spread outside the breast, either by local invasion or metastasis. Thus, the term "advanced" cancer includes both locally advanced and metastatic disease.

[0042] A "refractory" cancer is one in which an antitumor agent, such as chemotherapy, has been administered to a breast cancer patient, or has progressed despite being administered. An example of a refractory cancer is one that is platinum-refractory.

[0043] A "recurrent" cancer is one that has regrown, either at the original site or at a distant site, after responding to an initial treatment such as surgery.

[0044] A "locally recurrent" cancer is one that returns after treatment in the same place as the previously treated cancer.

[0045] "Unresectable" or "unresectable" cancer cannot be removed (cut out) by surgery.

[0046] "Early stage breast cancer," as used herein, refers to breast cancer that has not spread beyond the breast or axillary lymph nodes. Such cancers are generally treated with neoadjuvant or adjuvant therapy.

[0047] "Neoadjuvant therapy" refers to systemic therapy given before surgery.

[0048] "Adjuvant therapy" refers to systemic therapy given after surgery.

[0049] "Metastatic" cancer refers to cancer that has spread from one part of the body (eg, the breast) to another part of the body.

[0050] As used herein, a "patient" or a "subject" is a human patient. The patient may be a female or male patient. The patient may be a "cancer patient", i.e., a patient suffering from or at risk of suffering from one or more symptoms of cancer, particularly breast cancer.

[0051] "Patient population" refers to a group of cancer patients. Such populations can be used to demonstrate statistically significant efficacy and / or safety of a drug, such as leuprolide.

[0052] A "relapsed" patient is one who has signs or symptoms following remission of cancer. Optionally, the patient relapses following adjuvant or neoadjuvant therapy.

[0053] The term "peri-menopause" or "menopausal transition" is understood to mean the period approaching menopause during which a woman's body makes a natural transition toward permanent infertility (menopause). Women may begin perimenopause at different ages and may notice signs of progression toward menopause, such as irregular menstrual periods, during their 40s or even as early as their mid-30s. During perimenopause, estrogen levels may rise and fall irregularly, menstrual cycles may become longer or shorter, and menstrual cycles may begin in which the ovaries do not release eggs (ovulation).

[0054] The term "postmenopausal female" is understood to include not only women of advanced age who have passed menopause, but also women who have had a hysterectomy or who have suppressed estrogen production for some other reason, such as those taking long-term corticosteroids, those suffering from Cushing's syndrome, or those with gonadal dysgenesis.

[0055] "Antineoplastic agent" refers to a drug used to treat cancer.

[0056] "Treatment" refers to both therapeutic treatment and preventive or preventive measures, as well as adjunctive (add-on) regimens administered simultaneously with therapeutic treatment measures to provide additional clinical benefits to patients and / or maximize the effectiveness of therapeutic treatment measures.Such subjects in need of treatment include subjects who already have cancer, and subjects who want to prevent cancer.Thus, the patient to be treated may have been diagnosed with cancer, or may have a predisposition to or be susceptible to cancer.

[0057] The term "effective amount" refers to the amount of drug or drug composition that is effective for suppressing ovarian function, treating cancer, and / or providing another clinical benefit to the patient, such as increasing or maximizing the effectiveness of therapeutic treatment against cancer in the patient.An effective amount of drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down to some extent, and preferably stop) the invasion of cancer cells into peripheral organs; inhibit (i.e., slow down to some extent, and preferably stop) tumor metastasis; inhibit tumor growth to some extent; suppress ovarian function; suppress estradiol levels; suppress follicle-stimulating hormone (FSH) levels; and / or alleviate to some extent one or more symptoms associated with cancer.To the extent that the drug can prevent the growth of existing cancer cells and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic.

[0058] The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents the function of cells and / or causes destruction of cells. The term includes radioactive isotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 and radioactive isotopes of Lu), chemotherapeutic agents, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin (including fragments and / or variants thereof).

[0059] "Chemotherapy" is the use of chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents used in chemotherapy include alkylating agents such as cyclosphosphamide, thiotepa and CYTOXAN; alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; TLK286 (TELCYTA); acetogenins (especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL); beta-lapachone; lapachol; colchicine; betulinic acid; camptothecin (synthetic analogue topotecan (HYCAMTIN), CPT-11 (Irinotecan), camptothecin, CAMPTOSAR, acetylcamptothecin, scopolecin and 9-aminocamptothecin; bryostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); podophyllotoxin; podophyllic acid; teniposide; cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including the synthetic analogues KW-2189 and CB1-TM1); eleutherobin; pancratistatin sarcodictin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicine, phenesterine, prednimustine, trofosfamide and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimnustine; bisphosphonates such as clodronate;Enediyne antibiotics and anthracyclines, such as annamycin, AD32, alcarubicin, daunorubicin, dexrazoxane, DX-52-1, epirubicin, GPX-100, idarubicin, KRN5500, menogaril, dynemicin (including dynemicin A), esperamicin, neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, ausramycin, Azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, liposomal doxorubicin and deoxydoxorubicin), esorubicin, marcellomycin, mitomycin Antibiotics such as (e.g., mitomycin C), mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; folic acid analogues such as denopterin, pteropterin, and trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; an Pyrimidine analogues such as cytabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane and testolactone; anti-adrenal such as aminoglutethimide, mitotane and trilostane; folic acid supplements such as folinic acid (leucovorin); aceglatone;Antifolate antineoplastic agents (such as pemetrexed, ALIMTA, LY231514), dihydrofolate reductase inhibitors (such as methotrexate), antimetabolites (such as 5-fluorouracil (5-FU) and its prodrugs (such as UFT), S-1 and capecitabine), and thymidylate synthase inhibitors and glycinamide ribonucleotide formyltransferase inhibitors (such as raltitrexed (TOMUDEX, TDX)); inhibitors of dihydropyrimidine dehydrogenase such as eniluracil; aldophosphamide glycosides; cido;aminolevulinic acid;amsacrine;bestrabucil;bisantrene;edatraxate;defofamine;demecolcine;diaziquone;elfornitine;elliptinium acetate;epothilone;etoglucide;gallium nitrate;hydroxyurea;lentinan;lonidynin;maytansinoids such as maytansine and ansamitocins;mitoguazone;mitoxantrone;mopidamol;nitraelin;pentostatin;fenameth;pirarubicin;rosoxantrone;2-ethylhydrazide;procarbazine;lazo Xanthanes;Rhizoxin;Schizophyllan;Spirogermanium;Tenuazonic acid;Triaziquone;2,2',2"-Trichlorotriethylamine;Trichothecenes (especially T-2 toxin, Veracrine A, Roridin A and Anguidine);Urethane;Vindesine (ELDISINE, FILDESIN);Dacarbazine;Mannomustine;Mitobronitrol;Mitolactol;Pipobroman;Gacytosine;Arabinoside ("Ara-C");Taxanes;Chlorambucil;Gemcitabine (Gemzar);6-Thioguanine;Mercaptopurine;Platinum;Cysprosyltransferases; Platinum or platinum-based analogues such as platin, oxaliplatin and carboplatin; vinblastine (VELBAN); etoposide (VP-16); ifosfamide; mitoxantrone; vincristine (ONCOVIN); vinca alkaloids; vinorelbine (NAVELBINE); novantrone; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; topoisomerase inhibitors RFS2000; difluoromethylornithine (DMFO);Retinoids, such as retinoic acid; pharma- ceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above, such as CHOP (short for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone), and FOLFOX (short for a treatment regimen with oxaliplatin (ELOXATIN) in combination with 5-FU and leucovorin);

[0060] Antihormonal agents that act to regulate or inhibit hormone action on tumors and / or suppress ovarian function include antiestrogens and selective estrogen receptor modulators (SERMs) (including, for example, toremifene, which is tamoxifen (NOLVADEX), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxyfene, keoxifene, LY117018, onapristone, and FARESTON); aromatase inhibitors; and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation (such as PKC-alpha, Raf, H-Ras, and epidermal growth factor receptor (EGF-R)); vaccines (such as gene therapy vaccines, for example, ALLOVECTIN vaccine, LEUVECTIN vaccine, and VAXID vaccine); PROLEUKIN vaccine, These include rIL-2, a topoisomerase 1 inhibitor that is LURTOTECAN, ABARLIX rmRH, and pharma- ceutically acceptable salts, acids, or derivatives of any of the above. In these methods, the antihormonal agent can be tamoxifen.

[0061] "Taxanes" are chemotherapy drugs that inhibit mitosis and interfere with microtubules. Examples of taxanes include paclitaxel (TAXOL); albumin-engineered nanoparticle formulations of paclitaxel or nab-paclitaxel (ABRAXANE) that do not contain cremophor; and docetaxel (TAXOTERE).

[0062] "Anthracycline" is a type of antibiotic derived from the fungus Streptococcus peucetius, examples of which include daunorubicin, doxorubicin, and epirubicin. "Anthracycline-based chemotherapy" refers to a chemotherapy regimen that consists of or includes one or more anthracyclines. Examples include 5-FU, epirubicin, and cyclophosphamide (FEC); 5-FU, doxorubicin, and cyclophosphamide (FAC); doxorubicin and cyclophosphamide (AC); epirubicin and cyclophosphamide (EC); and the like.

[0063] For purposes herein, "carboplatin-based chemotherapy" refers to a chemotherapy regimen consisting of or including one or more carboplatins. Examples are TCH (docetaxel / TAXOL, carboplatin and trastuzumab / HERCEPTIN).

[0064] "Aromatase inhibitors" inhibit the enzyme aromatase, which regulates estrogen production in the adrenal gland. Examples of aromatase inhibitors include 4(5)-imidazole, aminoglutethimide, megestrol acetate, which is MEGASE, exemestane, which is AROMASIN, formestanie, fadrozole, vorozole, which is RIVISOR, letrozole, which is FEMARA, and anastrozole, which is ARIMIDEX. In these methods, the aromatase inhibitor can be one or more of letrozole, anastrozole, and exemestane.

[0065] "Cyclin-dependent kinase 4 and 6 inhibitors," also referred to as "CDK4 / 6 inhibitors," inhibit the CDK4 and CDK6 enzymes. Examples of CDK4 / 6 inhibitors include abemaciclib, palbociclib, and ribociclib.

[0066] "Phosphoinositide 3-kinase inhibitors," also referred to as "PI3K inhibitors," inhibit one or more phosphoinositide 3-kinase enzymes that are part of the PI3K / AKT / mTOR pathway. Examples of PI3K inhibitors include alpelisib, idelalisib, and buparlisib.

[0067] "Inhibitors of the mammalian target of rapamycin", also referred to as "mTOR inhibitors", inhibit the mammalian target of rapamycin (mTOR), a serine / threonine-specific protein kinase belonging to the family of phosphatidylinositol-3 kinase (PI3K)-related kinases (PIKKs). Examples of mTOR inhibitors include temsirolimus, sirolimus, everolimus and ridaforolimus.

[0068] "Antimetabolic chemotherapy" is the use of drugs that are structurally similar to metabolites, but cannot be productively used by the body. Many antimetabolic chemotherapy drugs interfere with the production of nucleic acids, RNA and DNA. Examples of antimetabolic chemotherapy drugs include gemcitabine (GEMZAR), 5-fluorouracil (5-FU), capecitabine (XELODA™), 6-mercaptopurine, methotrexate, 6-thioguanine, pemetrexed, raltitrexed, arabinosylcytosine ARA-C, cytarabine (CYTOSAR-U), dacarbazine (DTIC-DOME), azocytosine, deoxycytosine, pyridmidene, fludarabine, cladrabine, 2-deoxy-D-glucose, and the like.

[0069] "Chemoresistant" cancer means that a patient's cancer has progressed while undergoing a chemotherapy regimen (i.e., the patient is "chemotherapy refractory") or that the patient has progressed within 12 months (e.g., within 6 months) after completing a chemotherapy regimen.

[0070] The term "platin" is used herein to refer to platinum-based chemotherapy, including, without limitation, cisplatin, carboplatin, and oxaliplatin.

[0071] The term "fluoropyrimidine" is used herein to refer to antimetabolite chemotherapeutics, including, without limitation, capecitabine, floxuridine and fluorouracil (5-FU).

[0072] A "fixed" or "constant" dose of a therapeutic agent, as used herein, refers to the dose administered to a human patient, without regard to the patient's body weight (WT) or body surface area (BSA). Thus, a fixed or constant dose can be expressed as a mg / kg dose or a mg / m 2 It is provided as an absolute amount of therapeutic agent, not as a dose.

[0073] A "loading" dose, as used herein, generally comprises an initial dose of a therapeutic agent administered to a patient, followed by one or more maintenance doses thereof. Generally, a single loading dose is administered, but multiple loading doses are contemplated herein. Usually, the amount of the loading dose administered exceeds the amount of the maintenance dose administered, and / or the loading dose is administered more frequently than the maintenance dose, so as to achieve the desired steady-state concentration of the therapeutic agent more quickly than can be achieved with the maintenance dose.

[0074] A "maintenance" dose, as used herein, refers to one or more doses of a therapeutic agent administered to a patient over a treatment period.Usually, a maintenance dose is administered at treatment intervals, such as about every month, about every two months, about every three months, or about every four months, preferably every three months.

[0075] "Infusion" or "infusing" refers to the introduction of a drug-containing solution into the body through a vein for therapeutic purposes. Generally, this is accomplished by an intravenous (IV) bag.

[0076] A "package insert" is a pamphlet that must be placed inside the package of all prescription drugs by mandate of the Food and Drug Administration (FDA) or other regulatory agency. The pamphlet generally contains the trademark for the drug, its generic name and its mechanism of action; lists its indications, contraindications, warnings, precautions, adverse effects, and dosage forms; and contains instructions regarding the recommended dose, time, and route of administration.

[0077] The phrase "safety data" relates to data generated in controlled clinical trials that indicate the incidence and severity of adverse events to guide users regarding the safety of a drug, including guidance on how to monitor and prevent adverse reactions to the drug.

[0078] "Efficacy data" refers to data obtained in controlled clinical trials that demonstrate that a drug effectively meets a primary clinical endpoint, such as by achieving a particular pharmacokinetic endpoint in a sufficient percentage of subjects (e.g., suppression of estradiol levels), or in some instances, treats a disease, such as cancer.

[0079] "Stable mixture," when referring to a mixture of two or more drugs, means that each of the drugs in the mixture essentially retains its physical and chemical stability in the mixture as assessed by one or more analytical assays. Exemplary analytical assays for this purpose include color, appearance and clarity (CAC), concentration and turbidity analysis, particulate analysis, size exclusion chromatography (SEC), ion exchange chromatography (IEC), capillary zone electrophoresis (CZE), image capillary isoelectric focusing (iCIEF), and potency assays.

[0080] "Monotherapy" is therapy that uses one type of treatment, such as radiation therapy or surgery alone, to treat a particular disease or condition, or in drug therapy, monotherapy refers to the use of a single drug or modality to treat a disease or condition.

[0081] "Combination therapy" is therapy that uses more than one type of treatment, such as radiation therapy or surgery, to treat a particular disease or condition, or in drug therapy, combination therapy refers to the use of more than one medication or modality to treat a particular disease or condition.

[0082] A drug that is administered "concurrently" with another type of treatment or one or more other drugs is administered during the same treatment cycle as the other treatment or drug, such that the patient receives the benefits of both drugs and / or therapies during the treatment cycle. In the methods of the present disclosure, the treatment cycle for a breast cancer patient can be three months in length, and the drugs and / or therapies administered concurrently with the leuprolide formulations of the present disclosure include, without limitation, selective estrogen receptor modulators (SERMs; such as tamoxifen, toremifene, raloxifene, ospemifene, and bazedoxifene), selective estrogen receptor degraders (SERDs; such as fulvestrant), aromatase inhibitors (AIs; such as anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole. These may include one or more endocrine therapies, such as temsirolimus, sirolimus, everolimus, and ridaforolimus; inhibitors of the mammalian target of rapamycin (mTOR) (such as temsirolimus, sirolimus, everolimus, and ridaforolimus); phosphatidylinositol 3-kinase inhibitors (PI-3 kinase or PI3K; such as alpelisib, idelalisib, and buparlisib); cyclin-dependent kinase 4 and 6 inhibitors (CDK4 / 6 inhibitors; such as abemaciclib, palbociclib, and ribociclib); chemotherapy; immunotherapy, gene therapy, radiation therapy; and surgery.

[0083] Leuprolide Composition Leuprolide is a synthetic nonapeptide that is a potent gonadotropin-releasing hormone receptor (GnRHR) agonist (LHRH agonist analogue) approved in the United States and other countries for the symptomatic treatment of prostate cancer, endometriosis, uterine fibroids, central precocious puberty, and in vitro fertilization. As its underlying mechanism, leuprolide inhibits the secretion of luteinizing hormone and follicle-stimulating hormone by gonadotropic cells, which in turn inhibits the production of gonadal steroids. With continued use, leuprolide causes desensitization and downregulation of the pituitary, affecting the pituitary-gonadal axis, resulting in the inhibition of luteinization and circulating levels of sex hormones. The use of leuprolide products in one condition does not indicate that the same active ingredient, delivery system, or dose is effective in another condition, nor does it provide similar benefits. Clinicians consider a treatment effective if it provides a positive benefit across defined outcomes applicable to a particular patient population in a particular condition.

[0084] Biodegradable polymers have been used in many medical applications, including drug delivery devices. Drugs are generally incorporated into polymer compositions and formed into desired shapes outside the body. This solid implant is then inserted into the subject's body, usually through an incision. Alternatively, small dispersed particles (microspheres) composed of these polymers can be injected into the body by a syringe. Certain of these polymers can be injected by a syringe as a flowable polymer composition that forms a solid or semi-solid implant in situ. An exemplary polymer composition of leuprolide for reducing serum testosterone levels to treat prostate cancer in male patients is described in detail in U.S. Patent No. 9,254,307, issued February 9, 2016, the entirety of which is incorporated herein by reference.

[0085] Leuprolide microsphere products are difficult to manufacture and they all require deep intramuscular (im) injections using large volumes of fluid to ensure that all of the microspheres are properly administered to the patient. These injections are often very painful and result in tissue damage.

[0086] Currently, there are no leuprolide-based extended release formulations approved for use in human subjects with hormone receptor-positive breast cancer that require administration only once every 3 months and / or achieve leuprolide dosing at a level of up to about 10 mg / mL of leuprolide per month. For the product of the present invention, a 3-month dosing period can be beneficial to both patients and physicians, as it provides a significantly reduced frequency of injections (considering that adjuvant endocrine therapy is recommended for 5 years) and increased confidence that estradiol (E2) is effectively suppressed. Furthermore, the present combination of a higher active drug dose of a polymeric delivery system every 3 months or less is expected to provide higher drug exposure than previously available to breast cancer patients, thus reducing the possibility of deviation in E2 above postmenopausal levels throughout the dosing period. Finally, the subcutaneous delivery route of the leuprolide-based extended release formulations of the present disclosure improves patient tolerance / compliance and increased injection site flexibility compared to the current use of GnRH agonists in microsphere formulations delivered by deep intramuscular injection of large volumes.

[0087] A flowable extended release composition suitable for use in the disclosed method, which may also be referred to as a controlled release composition, can be used to provide a biodegradable or bioerodible microporous implant or depot formulation formed in situ in a subject. The flowable composition is composed of a biodegradable thermoplastic polymer or copolymer in combination with a suitable organic solvent. The biodegradable thermoplastic polyester or copolymer is substantially insoluble in water and body fluids, and is biocompatible and biodegradable and / or bioerodible in the subject's body. The flowable composition is administered to tissue as a liquid or gel, where a solid or semi-solid implant is formed in situ upon dissipation of the solvent. The composition is biocompatible, and the polymer matrix does not cause substantial tissue irritation or necrosis at the implant site. The implants so formed are optimally used to deliver leuprolide or a pharma- ceutically acceptable salt or analog thereof (e.g., leuprolide acetate) to a subject in a controlled or extended release manner for a period of about 30 to about 120 days, preferably about 90 days.

[0088] The flowable extended release composition can be a liquid or gel suitable for injection in a patient (e.g., a human). As used herein, "flowable" refers to the ability of the composition to be injected into a patient's body via a vehicle (e.g., a syringe). For example, the composition can be injected under the patient's skin (i.e., subcutaneously) with the use of a syringe. The ability of the composition to be injected into a patient typically depends on the viscosity of the composition. Thus, the composition has a suitable viscosity prior to injection, such that the composition can be forced into the patient's body with a vehicle (e.g., a syringe). The composition may be administered by injection with a syringe equipped with a 6-32 or larger gauge needle, preferably an 18-30 gauge needle, or otherwise by injection using an auto-injector. As used herein, a "liquid" is a substance that undergoes continuous deformation under shear stress.

[0089] The flowable extended release composition useful in the method of the present disclosure is a thermoplastic composition, which can be dissolved in a biocompatible polar aprotic solvent with a solid biodegradable polyester and leuprolide acetate to form a flowable composition, and then administered by syringe and needle.Any suitable biodegradable thermoplastic polyester can be used, provided that the biodegradable thermoplastic polyester is at least substantially insoluble in aqueous media or body fluids.Suitable biodegradable thermoplastic polyesters are disclosed, for example, in U.S. Patent Nos. 5,324,519; 4,938,763; 5,702,716; 5,744,153; and 5,990,194, where suitable biodegradable thermoplastic polyesters are disclosed as thermoplastic polymers.Examples of suitable biodegradable thermoplastic polyesters include polylactide, polyglycolide, polycaprolactone, their copolymers, their terpolymers, and any combination thereof. Preferably, the suitable biodegradable thermoplastic polyester is polylactide, polyglycolide, copolymers thereof, terpolymers thereof or combinations thereof.

[0090] The type, molecular weight and amount of biodegradable thermoplastic polyester present in the composition will generally depend on the desired properties of the extended release implant. For example, the type, molecular weight and amount of biodegradable thermoplastic polyester can affect the length of time that leuprolide is released from the extended release implant. Specifically, one embodiment of the present invention is a three-month delivery system of leuprolide acetate (i.e., a formulation that requires administration only about once every three months). In such an embodiment, the biodegradable thermoplastic polyester can be poly(DL-lactide-co-glycolide) (PLG) that does not have carboxylic acid end groups and preferably contains lactide to glycolide monomers in a molar ratio of about 70:30 to about 80:20 or 85:15, preferably about 75:25. The biodegradable polymer can be present at about 35% to about 60% by weight of the composition and can have a weight average molecular weight of about 15 kDa to about 45 kDa (inclusive), or about 15 kDa to about 26 kDa (inclusive), or about 17 kDa to about 21 kDa (inclusive).

[0091] In these PLG polymers, the end groups of poly(DL-lactide-co-glycolide) can be either hydroxyl or ester, depending on the polymerization method. Ring-opening polymerization of cyclic lactide or glycolide monomers with water, lactic acid, or glycolic acid results in polymers with the same end groups. However, ring-opening of cyclic monomers with monofunctional alcohols such as methanol, ethanol, or 1-dodecanol results in polymers with one hydroxyl group and one ester end group. Ring-opening polymerization of cyclic monomers with diols such as 1,6-hexanediol or polyethylene glycol results in polymers with only hydroxyl end groups. Preferably, the PLG polymers used in the methods of the present disclosure are formed using ring-opening polymerization of cyclic monomers with 1,6-hexanediol, and therefore have only hydroxyl end groups.

[0092] Any suitable solvent may be used, provided that the solvent is miscible to dispersible in aqueous media or body fluids. Suitable solvents are disclosed, for example, in Aldrich Handbook of Fine Chemicals and Laboratory Equipment, Milwaukee, Wis. (2000); U.S. Patent Nos. 5,324,519; 4,938,763; 5,702,716; 5,744,153; and 5,990,194. The solvent should be capable of diffusing into body fluids, so that the flowable composition coagulates or solidifies. The solvent may or may not dissolve the polymer. Preferred solvents for biodegradable polymers are non-toxic and otherwise biocompatible. Suitable solvents may include one or more solvents selected from the group consisting of amides, acids, alcohols, esters of monobasic acids, ether alcohols, sulfoxides, lactones, polyhydroxy alcohols, esters of polyhydroxy alcohols, ketones, and ethers.Preferably, the solvent is N-methyl-2-pyrrolidone (NMP), acetone, silane, butyrolactone, ε-caprolactone, caprolactam, N-cyclohexyl-2-pyrrolidone, diethylene glycol monomethyl ether, dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide (DMSO), ethyl acetate, ethyl lactate, N-ethyl-2-pyrrolidone, glycerol formal, glycofurol, N-hydroxyethyl-2-pyrrolidone, isopropylideneglycerol, lactic acid, methoxypolyethylene glycol, methoxypropylene glycol, methyl acetate, methyl ethyl ketone, methyl lactate, benzyl benzoate (BnBzO), polysorbate 80 (PBA), or the like. Preferably, the solvent is an organic solvent selected from at least one of polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, polyoxyl 35, polyethylene glycol (PEG), hydrogenated castor oil, polyoxyl 40 hydrogenated castor oil, sorbitan monolaurate, sorbitan monostearate, sorbitan monooleate, benzyl alcohol, n-propanol, isopropanol, tert-butanol, propylene carbonate, propylene glycol, 2-pyrrolidone, α-tocopherol, triacetin, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, triethyl citrate, esters thereof, and combinations thereof. Preferably, the solvent is N-methyl-2-pyrrolidone (NMP).

[0093] The solvent can be present in any suitable amount, provided that the solvent is miscible to dispersible in aqueous media or body fluids. The type and amount of solvent present in the composition usually depends on the desired properties of the extended release implant. For example, the type and amount of solvent can affect the length of time that leuprolide is released from the extended release implant. For example, the composition can be used to formulate a three-month polymeric delivery system of leuprolide acetate. In such a system, the biocompatible polar aprotic solvent, N-methyl-2-pyrrolidone, is preferably present at about 50% to about 60% by weight of the composition.

[0094] Thus, the flowable extended release composition useful in the method of the present disclosure can include an organic solvent, leuprolide, or its pharmaceutically acceptable salt or analogue, and a biodegradable polymer. Pharmaceutically acceptable salts or analogues of leuprolide include leuprolide acetate, leuprolide monoacetate, leuprolide oleate, leuprolide palmitate, leuprolide mesylate, leuprolide trifluoroacetate (TFA), leuprolide trifluoroacetate, leuprolide (5-9), (D-His2)-leuprolide trifluoroacetate (TFA), leuprolide hydrochloride (HCL), leuprolide-D5 acetate, and combinations thereof. The sequence and chemical structure of any of these leuprolide salts are readily known and available. A particularly preferred pharmaceutically acceptable salt of leuprolide is leuprolide acetate.

[0095] In some embodiments, the biodegradable polymer can be a poly(lactide-co-glycolide) (PLG) copolymer comprising a molar ratio of lactide to glycolide monomers of about 70:30 to about 80:20, where the polymer is substantially free of titratable carboxylic acid groups and at least one distal end group of the polymer is hydroxyl terminated. Preferably, the biodegradable polymer comprises a 75:25 poly(lactide-co-glycolide) copolymer segment, where the polymer is substantially free of titratable carboxylic acid groups and at least one distal end group of the polymer is hydroxyl terminated. The biodegradable polymer can include a 85:15 poly(lactide-co-glycolide) copolymer segment, where the polymer is substantially free of titratable carboxylic acid groups and at least one distal end group of the polymer is hydroxyl terminated.

[0096] The biodegradable polymer can have a weight average molecular weight of about 12 kDa to about 45 kDa, or a weight average molecular weight of about 15 kDa to about 45 kDa, about 15 kDa to about 26 kDa, about 15 kDa to about 21 kDa, about 19 kDa to about 26 kDa, or about 17 kDa to about 21 kDa (inclusive). Preferably, the biodegradable polymer has a weight average molecular weight of about 12 kDa to about 45 kDa (inclusive) from any whole number to any other whole number.

[0097] Polymers have the chemical formula: HO-(P)-C(=O)O-Ra-O(O=)C-(P)-OH where Ra is an alkane diradical containing from about 4 to about 8 carbons and is the residue of an alkane diol, and P is a polymer segment of lactide, glycolide, or co(lactide-glycolide) repeat units. may have the following structure:

[0098] The polymers of the present invention are structurally comprised of a compound of formula (I): [ka] (wherein "L / G" represents a PLG copolymer segment, the H atoms at both distal ends represent hydrogen atoms carried by terminal hydroxyl groups, and R a R is an alkane diradical. a R shown on one side of the core b and R c The groups can be either hydrogen or methyl, provided that both R b The groups are either hydrogen or methyl at the same time, and both R c The groups are simultaneously either hydrogen or methyl, but R b and R c does not have to be the same.

[0099] Thus, the group designated as "L / G" in formula (I) has the structure: [ka] (In the formula, R d The groups are independently hydrogen or methyl, again with the proviso that, as noted above, hydrogen or methyl substituents are generally found in pairs as they are incorporated as repeat units derived from dimeric lactide or glycolide reagents, and therefore represent lactide / glycolide copolymer segments. d Besides this requirement for the R groups, the methyl and hydrogen groups are randomly distributed throughout the copolymer segment L / G, and due to the faster reaction rate of the GG groups, the methyl and hydrogen groups are more frequently located in the R a It is understood that the repeat units tend to be found adjacent to the alkanediols. The wavy lines indicate the points of attachment to other radicals, e.g., hydrogen atoms at the distal end and core alkanediol hydroxyl groups at the proximal end. The number of repeat units, n, ranges from about 20 up to about 750 for each copolymer segment, providing a polymer with a weight average molecular weight of about 6 kDa with weights ranging up to about 200 kDa. It is understood that no two L / G copolymer segments need be identical, and that either the sequence or molecular weight of each copolymer segment in a given polymer molecule may not be identical. Additionally, the specific composition of each molecule within a sample of polymer will vary in the same manner.

[0100] Yet another polymer of the present invention is structurally a compound of formula (II): [ka] (wherein L represents a polylactide or polylactate polymer segment, the H atoms at both distal ends represent hydrogen atoms carried by hydroxyl groups, and R a R is an alkane diradical. a R on both sides of the core b The groups are all methyl.

[0101] As noted above, in the polymers of formula (I) and (II), the distal end of the copolymer segment contains a hydroxyl group. Thus, the proximal end of the copolymer segment contains a carboxyl moiety at the opposite end of the lactide or glycolide repeat unit that is linked by an ester bond to the hydroxyl group of the core alkanediol. This structural element results in no titratable carboxylic acid groups in the polymers of the invention, and the product is a neutral polymer.

[0102] The core alkanediol can be an α,ω-diol in which the copolymer segments are linked via two primary hydroxyl groups. Specific examples of α,ω-diols include 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, and 1,8-octanediol. A particularly preferred alkanediol is 1,6-hexanediol.

[0103] The polymer of formula (I) can be formed by a polymerization reaction, R a The core alkanediol, including serves as an initiator for the ring-opening polymerization of lactide and glycosidic reagents. The mole percentage, and therefore the weight percentage, of alkanediol present in the polymerization reaction has an effect on the molecular weight of the biodegradable polymer formed. The use of a higher percentage of alkanediol in the polymerization reaction results in a lower molecular weight polymer, on average, with relatively shorter PL or PLG copolymer segments linked to the alkanediol core.

[0104] A preferred embodiment according to the present invention is a process for the preparation of a polymer of formula (I), comprising the steps of contacting an alkanediol, a glycolide, a lactide and a catalyst, the catalyst being adapted to catalyze the ring-opening polymerization of lactide and glycolide initiated on the alkanediol.

[0105] The polymers of the invention comprising PLG copolymer segments are preferably prepared using a catalyst suitable for the ring-opening polymerization of lactide and glycolide. The catalyzed ring-opening reaction first occurs between the lactide or glycolide reagent and the hydroxyl group of the alkanediol core unit, thus forming an ester bond with the lactide or glycolide unit. Thus, after the first step of polymerization, only the hydroxyl groups on the growing polymer chain are continuously available for further lactide or glycolide addition. As the polymerization continues, each step continues to result in the formation of only hydroxyl-terminated copolymer segments attached to the alkanediol. In this way, polymerization occurs until the supply of lactide and glycolide reagents is exhausted, producing a polymer terminated with a hydroxyl group. It is understood that the polymers of the invention comprising PL copolymer segments can be made in the same way, except for the glycolide reagent alone.

[0106] The alkanediol can be an α,ω-diol, such as 1,6-hexanediol. The alkanediol can be present in the polymerization reaction mixture in an amount ranging from about 0.05% to about 5.0% by weight, preferably from about 0.5% to about 2.0% by weight.

[0107] The catalyst can be any catalyst suitable for ring-opening polymerization, but a preferred catalyst is a tin salt of an organic acid. The tin salt can be either in the stannous (divalent) or stannous (tetravalent) form. A particularly preferred catalyst is stannous octoate. The catalyst can be present in the polymerization reaction mixture in any suitable amount, typically ranging from about 0.01% to 1.0% by weight.

[0108] The polymerization reaction can be carried out under various conditions of temperature, time and solvent. Alternatively, no solvent may be present and the polymerization may be carried out in a neat melt. Polymerization reactions in which the reactants include an alkanediol (such as hexane-1,6-diol), lactide and glycolide in a specified proportion by weight, and a catalyst such as stannous octoate, are preferably carried out as a neat melt in the absence of oxygen at elevated temperatures for a period of at least several hours. Preferably, the reaction is carried out at about 140° C., either under vacuum or under an atmosphere of an inert gas such as nitrogen.

[0109] The weight percent, and therefore the mole percent, of lactide or glycolide repeat units in the polymer can be varied by changing the weight percentages of the two reactants present in the polymerization reaction mixture. The properties of the polymer can be altered by varying the ratio of lactide to glycolide monomer components and by the percentage of alkanediol initiator present.

[0110] Specifically, the molecular weight range of the polymer can be controlled by the amount of core alkanediol present in the polymerization reaction relative to the amount of lactide and glycolide. The greater the weight percentage, and therefore the mole fraction, of alkanediol in the polymerization reaction mixture, the shorter the chain length of the polymer attached to the alkanediol core will be due to the reduced availability of lactide or glycolide reagent molecules per initiating hydroxyl group.

[0111] Another polymer of the present disclosure has the chemical structure: [ka] where R1 is H or CH3; R2 is an alkyl group, and the polymer is substantially free of titratable carboxylic acid groups. Includes.

[0112] "Titratable carboxylic acid groups," as used herein, refer to carboxylic acid groups that are in the free form, i.e., not bound as an ester or other derivative, where the carboxylic acid group can have a free proton that can dissociate (ionize) in aqueous solution to form a carboxylate anion and a proton (acid). Thus, an organic polymer that does not have titratable carboxylic acid groups is not an acidic polymer; all of the carboxylate moieties within the polymer are bound to esters, amides, or other non-acidic derivatives.

[0113] The solubility of biodegradable thermoplastic polyester in various solvents varies depending on its composition, its crystallinity, its hydrophilicity, hydrogen bonding and molecular weight. It has also been found that solutions containing very high concentrations of high molecular weight polymers sometimes solidify or solidify slower than more dilute solutions. It is suspected that high concentrations of polymers hinder the diffusion of solvent from inside the polymer matrix, thus preventing the penetration of water into the matrix, which can cause the polymer chains to precipitate. Thus, there is an optimum concentration at which the solvent can diffuse out of the polymer solution and water can penetrate into the polymer and solidify it.

[0114] In the flowable extended release compositions useful in the methods of the present disclosure, leuprolide is preferably present as an acetate salt (i.e., leuprolide acetate), although other pharma- ceutically acceptable salts or analogs of leuprolide are disclosed herein and are expressly contemplated for use in the present invention. The leuprolide salt, in some embodiments, is lyophilized prior to use. Typically, the leuprolide salt can be dissolved in an aqueous solution, sterile filtered, and lyophilized in a syringe. The polymer / solvent solution can be loaded into another syringe. The two syringes can then be connected together, and the contents can be transferred back and forth between the two syringes until the polymer / solvent solution and the leuprolide acetate are effectively mixed together to form a flowable composition. The flowable composition can be drawn into one syringe. The two syringes can then be disconnected. Alternatively, the lyophilized leuprolide salt or leuprolide / solvent solution and the polymer / solvent solution can be contained in a dual chamber syringe, and the contents of the two chambers can be mixed to form a flowable composition. The needle can be inserted into a syringe containing the flowable composition. Alternatively, the polymer, solvent and leuprolide salt can be formulated in a single syringe. The flowable composition can then be injected into the body through the needle. For example, the flowable composition can be formulated and administered to a patient as described in U.S. Pat. Nos. 5,324,519; 4,938,763; 5,702,716; 5,744,153; and 5,990,194, or as described herein. Once in place, the solvent dissipates and the remaining polymer solidifies to form a solid or semi-solid structure or depot. The solvent dissipates and the polymer solidifies to capture or encase leuprolide salt in a solid or semi-solid matrix.

[0115] To form an exemplary flowable extended release composition useful in the methods of the present disclosure, poly(DL-lactide-co-glycolide) having a 75:25 molar ratio of lactide to glycolide can be dissolved in NMP to obtain a solution having 45% by weight of polymer. The solution can be filled into a 3.0 cc polypropylene syringe with a male luer lock fitting and finally sterilized by exposure to 23.2-24.6 kilograys of gamma radiation or by exposure to e-beam irradiation. The weight average molecular weight of the polymer after irradiation can be 15,094 Daltons. Leuprolide acetate can be dissolved in water, sterile filtered through a 0.2 cm filter, and filled into a polypropylene or cyclic olefin based syringe with a male luer lock fitting. The aqueous solution can be frozen and the water removed by vacuum to obtain a lyophilized cake of leuprolide. Just prior to administration to a subject, the two syringes can be connected together using a coupler and the contents of the two syringes mixed by transferring material back and forth between the two syringes to obtain a reconstituted product having, for example, about 4-8% leuprolide acetate by weight. The product can then be drawn into a syringe fitted with a male luer lock fitting and a 0.5 inch 20 gauge needle for injection into a subject, preferably subcutaneous injection.

[0116] The release of leuprolide acetate from these solid or semi-solid implants follows the same general rules for drug release from monolithic polymeric devices. Release of leuprolide acetate can be affected by the size and shape of the implant, the loading of leuprolide acetate within the implant, permeability factors including leuprolide acetate and the particular polymer, and degradation of the polymer.

[0117] The amount of leuprolide acetate incorporated into the flowable in situ solid forming implant depends on the desired release profile, the concentration of leuprolide acetate required for the desired biological effect, and the length of time that leuprolide acetate is released into the subject for treatment. There is no critical upper limit for the amount of leuprolide acetate incorporated into the polymer solution, except for a critical upper limit for the viscosity of the solution or dispersion that is acceptable for injection through a syringe needle. The lower limit of leuprolide acetate incorporated into the delivery system simply depends on the activity of leuprolide acetate, as well as the length of time required for treatment and the disease being treated. Specifically, in an exemplary embodiment of the present disclosure, the composition can be used to formulate leuprolide acetate in a three-month delivery system, in which case leuprolide acetate can be preferably present at about 4% to about 8% by weight of the composition, or in a total amount of between about 22 mg to about 40 mg of leuprolide acetate or leuprolide base equivalent. Preferably, the amount of leuprolide acetate ranges from about 28 mg to about 32 mg, more preferably about 30 mg. A solid or semi-solid implant formed from the flowable composition releases the leuprolide acetate contained within its matrix at a controlled rate until the leuprolide acetate is effectively depleted.

[0118] These compositions can be used to formulate leuprolide acetate in a three-month delivery system, where less than about 1.0 mL, preferably less than about 0.50 mL inclusive, preferably about 0.30 mL to about 0.50 mL, or more preferably about 0.375 mL of the flowable composition can be administered to a subject as a single dose, preferably subcutaneously.

[0119] manufactured goods The present disclosure also provides an article of manufacture or kit according to the above polymer composition and the method of mixing and administration. An exemplary article of manufacture of the present disclosure can include a container of the extended release leuprolide composition of the present disclosure, as described above. The container can be a single syringe. In these articles of manufacture, the syringe can contain about 26 mg to about 30 mg of leuprolide free base equivalent, preferably about 28 mg of leuprolide free base equivalent (e.g., about 28 mg to about 32 mg of leuprolide acetate, preferably about 30 mg of leuprolide acetate). In these articles, the syringe can contain less than about 1.0 mL of the extended release composition, preferably less than about 0.5 mL of the extended release composition, preferably about 0.30 mL to about 0.50 mL of the extended release composition, or more preferably about 0.375 mL of the extended release composition. In these articles, the biodegradable polymer can be a poly(lactide-co-glycolide) copolymer comprising a molar ratio of lactide to glycolide monomers of about 70:30 to about 80:20, where the polymer is substantially free of titratable carboxylic acid groups and where at least one distal end group of the polymer is hydroxyl terminated. In these articles, the biodegradable polymer can be a poly(lactide-co-glycolide) preferably comprising a molar ratio of lactide to glycolide monomers of 75:25, where the polymer is substantially free of titratable carboxylic acid groups and where at least one distal end group of the polymer is hydroxyl terminated. In these articles, the biodegradable polymer can be preferably poly(lactide-co-glycolide) comprising an 85:15 molar ratio of lactide to glycolide monomers, where the polymer is substantially free of titratable carboxylic acid groups and where at least one distal end group of the polymer is hydroxyl terminated. The biodegradable polymer can be present at about 35% to about 60% by weight of the composition and have a weight average molecular weight of about 12 kDa to about 45 kDa.The biodegradable polymer can have a weight average molecular weight of about 15 kDa to about 45 kDa, about 15 kDa to about 26 kDa, about 15 kDa to about 21 kDa, about 19 kDa to about 26 kDa, or about 17 kDa to about 21 kDa (inclusive). In some embodiments, the biodegradable polymer has a weight average molecular weight of about 12 kDa to about 45 kDa (inclusive) to any other integer. The organic solvent can be N-methyl-2-pyrrolidone (NMP).

[0120] Another exemplary article of manufacture according to the present disclosure can include a first container containing a lyophilized salt (e.g., leuprolide acetate) or leuprolide / solvent solution, and a second container containing a solution containing a biodegradable polymer and an organic solvent, and instructions for combining and / or mixing the contents of the first and second containers to form a flowable extended release composition for administration to a subject. In these articles, the first and second containers can be the first and second chambers of a dual-chamber single syringe. The contents of the first and second chambers can be combined in the syringe to form a flowable composition by adding the contents of the second chamber to the first chamber and then mixing the polymer solution and leuprolide. Alternatively, the contents of the first chamber can be added to the second chamber and then mixed to form a flowable composition. In these articles of manufacture, the first chamber can contain about 26 mg to about 30 mg of leuprolide free base equivalent, preferably about 28 mg of leuprolide free base equivalent (e.g., about 28 mg to about 32 mg of leuprolide acetate, preferably about 30 mg of leuprolide acetate), and the second chamber can contain less than about 1.0 mL of the biodegradable polymer / organic solvent composition, preferably less than about 0.5 mL of the biodegradable polymer / organic solvent composition, preferably about 0.30 mL to about 0.50 mL of the biodegradable polymer / organic solvent composition, or more preferably about 0.375 mL of the biodegradable polymer / organic solvent composition.

[0121] In these articles, the first and second containers can be the first and second syringes, respectively, of a two-syringe system. The contents of the first and second syringes can be combined by connecting the syringes together and transferring the contents back and forth between the two syringes until the polymer / solvent solution and the leuprolide are effectively mixed together to form a flowable composition. In these articles, the first syringe can contain about 26 mg to about 30 mg of leuprolide free base equivalent, preferably about 28 mg of leuprolide free base equivalent (e.g., about 28 mg to about 32 mg of leuprolide acetate, preferably about 30 mg of leuprolide acetate). In these articles of manufacture, the second syringe can contain less than about 1.0 mL of the biodegradable polymer / organic solvent composition, preferably less than about 0.5 mL, preferably about 0.30 mL to about 0.50 mL of the biodegradable polymer / organic solvent composition, or more preferably about 0.375 mL of the biodegradable polymer / organic solvent composition.

[0122] These articles of manufacture may further comprise a needle adapted for insertion into a syringe containing the flowable leuprolide composition for subcutaneous administration of the flowable leuprolide composition to a subject. Optionally, the flowable leuprolide composition is stable for at least or up to 30 minutes at 25 degrees Celsius. The stability of the flowable leuprolide composition may be assessed by one or more assays selected from the group consisting of color, appearance and clarity (CAC), concentration and turbidity analysis, particulate analysis, size exclusion chromatography (SEC), ion exchange chromatography (IEC), capillary zone electrophoresis (CZE), image capillary isoelectric focusing (iCIEF) and potency assay.

[0123] These articles of manufacture can further include instructions for its use for suppressing ovarian function in subjects with HR-positive breast cancer. These articles of manufacture can also include a package insert providing efficacy and / or safety data for the use of leuprolide in suppressing ovarian function in subjects with HR-positive breast cancer who are concomitantly treated with a therapeutic treatment for the cancer.

[0124] Treatment The stage of breast cancer is based on several factors, such as the size of the tumor, if the cancer is found in lymph nodes, and how far the cancer has spread. The stages are numbered 0, I, II, III, or IV, with stage I being the least advanced stage and stage IV being the most advanced. Stage 0 is considered non-invasive breast cancer. Stages I-II are considered early stage breast cancer. Stage III is considered locally advanced breast cancer. Stage IV is considered metastatic breast cancer. These descriptions are broad descriptions of the stages of breast cancer and may not include all possibilities. The methods of the present disclosure can be used to suppress ovarian function in subjects with hormone receptor positive breast cancer at any stage, including stages 0, I, II, III, or IV, and partial stages thereof.

[0125] Stages I, IIA, and IIB (and some stage IIIA cancers) are considered early-stage breast cancer. At these stages, the cancer has not spread beyond the breast or axillary lymph nodes (the ones under the arm).

[0126] Locally advanced breast cancer includes stages IIIA, IIIB, and IIIC. Stage IIIA breast cancer includes cases where the tumor size is not large, but the cancer has spread to many axillary (under the arm) lymph nodes or lymph nodes near the breastbone. Stage IIIA breast cancer includes cases where the tumor is large, but has not spread to many lymph nodes. Stage IIIB describes breast cancer where the tumor has spread to the chest wall or skin of the breast and may or may not have spread to lymph nodes. Stage IIIC describes cancer that has spread to lymph nodes under or above the collarbone, to many axillary (under the arm) lymph nodes, or to lymph nodes near the breastbone. The tumor can be of any size.

[0127] Stage IV describes metastatic breast cancer, which is cancer that has spread from the breast to the bones or other parts of the body, such as the liver, lungs or brain (visceral metastases).

[0128] In premenopausal women, approximately 60% of breast tumors are HR-positive and can benefit from estrogen suppression by surgical, radiological or pharmacological means. Conventional medical treatments involving ovarian ablation or suppression by radiation or oophorectomy permanently preclude future childbearing potential. Alternatively, the use of adjuvant endocrine therapies (also referred to as "hormonal therapy") such as selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and drugs that reduce the release of endogenous non-ovarian estrogens (such as aromatase inhibitors) temporarily suppress estrogen production and preserve the possibility of future pregnancy. These drugs can be combined with gonadotropin-releasing hormone (GnRH) agonists or antagonists, such as leuprolide, to induce and maintain ovarian suppression. Gonadotropin-releasing hormone (also commonly referred to as luteinizing hormone-releasing hormone (LHRH)) agonists mimic the effects of GnRH by promoting the release of the gonadotropic hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. These hormones stimulate the production of sex steroids in the ovaries, and continuous exposure of the pituitary gland to GnRH agonists leads to downregulation of the GnRH receptor and subsequent inhibition of the hypothalamic pituitary gonadotropic (HPG) axis, suppressing the release of estrogen by the ovaries. Suppression of estrogen by sustained release of GnRH agonists administered concomitantly with therapeutic treatments for breast cancer, including but not limited to endocrine therapy, may be beneficial in the treatment of premenopausal and perimenopausal patients with HR-positive breast cancer.

[0129] The disclosed three-month injectable extended release compositions of leuprolide acetate for suppression of estrogen to postmenopausal levels in pre- and peri-menopausal women with HR-positive breast cancer provide an important alternative option for inclusion in the treatment regimen of HR-positive breast cancer patients.

[0130] The present disclosure provides a method of suppressing ovarian function in a subject with HR-positive breast cancer by administering a therapeutically effective amount of a flowable extended release composition of the present invention comprising leuprolide. The present disclosure also provides a method of treating HR-positive breast cancer in a subject by administering a flowable extended release composition of the present invention and a therapeutic treatment for HR-positive breast cancer at the same time. In these methods, the breast cancer can be an advanced breast cancer. In these methods, the breast cancer can be metastatic or locally advanced. The breast cancer can be an estrogen receptor (ER) positive and / or progesterone receptor (PgR) positive breast cancer. In these methods, the breast cancer can be an HR-positive human epidermal growth factor receptor 2 (HER2) negative breast cancer.

[0131] In these methods, the subject can have a confirmed diagnosis of stage I, II, III or IV HR-positive breast cancer, such as HR-positive HER2-negative breast cancer. The subject or patient can be a pre- or peri-menopausal woman with HR-positive breast cancer. In these methods, the subject is a candidate for endocrine therapy with ovarian suppression. In these methods, the subject's last menstrual period can have been within 12 months prior to treatment with the leuprolide composition of the present disclosure. In these methods, the subject can have had a baseline estradiol (E2) concentration greater than 30 pg / mL and / or a follicle stimulating hormone (FSH) concentration greater than 40 IU / L prior to treatment with the leuprolide composition of the present disclosure. In some embodiments, the subject can be a man with HR-positive breast cancer. In these methods, the subject can be at least 18 years old. In these methods, the subject can be at least 18 years old and less than 40 years old, or at least 18 years old and less than 45 years old, or at least 18 years old and less than 55 years old.

[0132] The method of the present disclosure may be used in combination regimens for the treatment of HR-positive breast cancer by subcutaneously administering a flowable extended release leuprolide composition simultaneously with the therapeutic treatment of HR-positive breast cancer.In these methods, the flowable extended release composition can be administered to a subject about once every 90 days (i.e., about once every 3 months) for at least 2 doses, at least 3 doses, at least 4 doses, at least 5 doses, at least 6 doses, at least 7 doses, at least 8 doses, at least 9 doses, at least 10 doses, at least 11 doses, at least 12 doses, at least 13 doses, at least 14 doses, at least 15 doses, at least 16 doses, at least 17 doses, at least 18 doses, at least 19 doses, at least 20 doses, or more doses until clinically progressive disease or unmanageable toxicity is observed.Longer treatment periods, including more treatment cycles, are contemplated.

[0133] The disclosed methods can be used to treat HR-positive breast cancer by administering a flowable extended release leuprolide composition in conjunction with one or more adjuvant endocrine therapies, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and other drugs that reduce the release of endogenous non-ovarian estrogens (e.g., aromatase inhibitors; AIs). The disclosed methods can be used to treat HR-positive breast cancer by administering a flowable extended release leuprolide composition in conjunction with one or more CDK4 / 6 inhibitors, PI3K inhibitors, and / or mTOR inhibitors.

[0134] In these methods, the flowable extended release leuprolide composition may be administered simultaneously with tamoxifen. Tamoxifen is a triphenylethylene-based anti-oestrogen non-steroidal SERM that exhibits anti-estrogenic effects in breast tissue by competitively binding to estrogen receptors in breast cells. Tamoxifen may be administered orally, for example, 20 mg once a day, or 10 mg twice a day, or as otherwise prescribed, by tablet or liquid. In these methods, the flowable extended release leuprolide composition may be administered simultaneously with one or more of letrozole, anastrozole and exemestane. Letrozole and anastrozole are non-steroidal aromatase inhibitors, which reduce estrogen levels by blocking the aromatase enzyme (also called estrogen synthase), which is responsible for the production of estrogen by aromatization of androgens in adipose tissue. Letrozole may be administered orally in tablet form, for example, a 2.5 mg tablet taken orally once a day, or as otherwise prescribed.Anastrozole may also be administered orally in tablet form, for example, a 1 mg tablet taken orally once a day, or as otherwise prescribed.Exemestane is a steroidal aromatase inhibitor that may be administered orally in tablet form, for example, a 25 mg tablet taken orally once a day, or as otherwise prescribed.

[0135] The method of the present disclosure can be used for the treatment of HR-positive breast cancer by administering a flowable extended release composition comprising leuprolide simultaneously with chemotherapy, such as anthracycline-based chemotherapy or carboplatin-based chemotherapy.Anthracycline-based chemotherapy for breast cancer can include 5-FU, epirubicin and cyclophosphamide (FEC).Carboplatin-based chemotherapy can include trastuzumab (e.g., TCH regimen), as well as taxanes (e.g., docetaxel), carboplatin.The HR-positive breast cancer treatment methods contemplated herein can include neoadjuvant and adjuvant therapy.

[0136] The disclosed treatment methods can result in suppression of the subject's estradiol (E2) production to postmenopausal levels (<20pg / mL). The disclosed treatment methods can result in suppression of the subject's estradiol (E2) levels to less than about 20pg / mL for about 6 weeks or longer after administration of the leuprolide composition. In some examples, the methods result in suppression of the subject's estradiol levels to less than about 20pg / mL for about 12 weeks or longer after administration of the leuprolide composition, about 24 weeks or longer after administration of the leuprolide composition, about 36 weeks or longer after administration of the leuprolide composition, or about 48 weeks or longer after administration of the leuprolide composition. In some examples, the methods result in suppression of subject estradiol to less than about 20 pg / mL in greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or about 100%, or any integer percentage between 80% and 100%, to any other integer percentage, of patients treated with the leuprolide composition. These results can be obtained by administration of the extended release leuprolide composition alone, or by co-administration of the extended release leuprolide composition with tamoxifen or other antihormonal agents, aromatase inhibitors, CDK4 / 6 inhibitors, PI3K inhibitors, and / or mTOR inhibitors.

[0137] The disclosed treatment method can result in suppression of the subject's estradiol (E2) level to less than about 10 pg / mL. The disclosed treatment method can result in suppression of the subject's estradiol (E2) level to less than about 10 pg / mL for about 6 weeks or longer after administration of the leuprolide composition. In some examples, the method results in suppression of the subject's estradiol level to less than about 10 pg / mL for about 12 weeks or longer after administration of the leuprolide composition, about 24 weeks or longer after administration of the leuprolide composition, about 36 weeks or longer after administration of the leuprolide composition, or about 48 weeks or longer after administration of the leuprolide composition. In some examples, the methods result in suppression of a subject's estradiol to less than about 10 pg / mL in greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or about 100%, or any integer percentage between 80% and 100%, to any other integer percentage, of patients treated with the leuprolide composition. These results can be obtained by administration of the extended release leuprolide composition alone, or by co-administration of the extended release leuprolide composition with tamoxifen or other antihormonal agents, aromatase inhibitors, CDK4 / 6 inhibitors, PI3K inhibitors, and / or mTOR inhibitors.

[0138] When the method includes administration of an aromatase inhibitor or similar therapeutic agent, the disclosed therapeutic method can result in suppression of the subject's estradiol (E2) levels to less than about 2.7 pg / mL. In some examples, the method results in suppression of the subject's estradiol levels to less than about 2.7 pg / mL for about 6 weeks or longer after administration of a leuprolide composition administered simultaneously with another therapeutic agent, such as an aromatase inhibitor. In some examples, the method results in suppression of the subject's estradiol levels to less than about 2.7 pg / mL for about 12 weeks or longer after administration of the leuprolide composition administered concurrently with another therapy, such as an aromatase inhibitor, for about 24 weeks or longer after administration of the leuprolide composition administered concurrently with another therapy, such as an aromatase inhibitor, for about 36 weeks or longer after administration of the leuprolide composition administered concurrently with another therapy, such as an aromatase inhibitor, or for about 48 weeks or longer after administration of the leuprolide composition administered concurrently with another therapy, such as an aromatase inhibitor. In some examples, the method results in suppression of the subject's estradiol to less than about 2.7 pg / mL in greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or about 100% of patients treated with the leuprolide composition administered concurrently with another therapy, such as an aromatase inhibitor, or any integer percent to any other integer percent between 80% and 100%. These results can be obtained by co-administration of an extended release leuprolide composition with letrozole, anastrozole, exemestane and / or other aromatase inhibitors, antihormones, CDK4 / 6 inhibitors, PI3K inhibitors, and / or mTOR inhibitors. These results can be obtained by co-administration of an extended release leuprolide composition with one or more of letrozole, anastrozole, and exemestane.

[0139] The therapeutic methods of the present disclosure can result in suppression of a subject's follicle stimulating hormone (FSH) levels to less than about 40 IU / L. In some examples, the methods result in suppression of a subject's FSH levels to less than about 40 IU / L for about 6 weeks or longer after administration of the leuprolide composition. In some examples, the methods result in suppression of a subject's FSH levels to less than about 40 IU / L for about 12 weeks or longer after administration of the leuprolide composition, about 24 weeks or longer after administration of the leuprolide composition, about 36 weeks or longer after administration of the leuprolide composition, or about 48 weeks or longer after administration of the leuprolide composition. In some examples, the methods result in suppression of a subject's FSH levels to less than about 40 IU / L in greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or about 100%, or any integer percent between 80% and 100%, to any other integer percent, of patients treated with the leuprolide composition. These results can be obtained by administration of the extended release leuprolide composition alone, or by co-administration of the extended release leuprolide composition with tamoxifen or other antihormonal agents, aromatase inhibitors, CDK4 / 6 inhibitors, PI3K inhibitors, and / or mTOR inhibitors.

[0140] The therapeutic methods of the present disclosure can result in the suppression of the menstrual cycle of the subject. In some examples, the methods result in the absence of menstruation for about 6 weeks or longer after administration of the leuprolide composition. In some examples, the methods result in the absence of menstruation for about 12 weeks or longer after administration of the leuprolide composition, for about 24 weeks or longer after administration of the leuprolide composition, for about 36 weeks or longer after administration of the leuprolide composition, or for about 48 weeks or longer after administration of the leuprolide composition. In some examples, the methods result in the absence of menstruation in more than about 80%, more than about 85%, more than about 90%, more than about 95%, or about 100% of the patients treated with the leuprolide composition, or any other integer percentage between 80% and 100%. These results can be obtained by administration of the extended release leuprolide composition alone, or by co-administration of the extended release leuprolide composition with tamoxifen or other antihormonal agents, aromatase inhibitors, CDK4 / 6 inhibitors, PI3K inhibitors and / or mTOR inhibitors.

[0141] In an exemplary embodiment of the treatment method of the present disclosure, about 28mg of leuprolide free base equivalent (e.g., about 30mg of leuprolide acetate) is subcutaneously administered to HR-positive breast cancer patients in a volume of about 0.375mL of the flowable extended release composition of the present disclosure.A maintenance dose of the same composition and amount of leuprolide acetate is preferably administered for at least 1 dose, at least 2 doses, at least 3 doses, at least 4 doses, at least 5 doses, at least 6 doses, at least 7 doses, at least 8 doses, at least 9 doses, at least 10 doses, at least 11 doses, at least 12 doses, at least 13 doses, at least 14 doses, at least 15 doses, at least 16 doses, at least 17 doses, at least 18 doses, at least 19 doses, at least 20 doses, or further doses until clinically progressive disease or unmanageable toxicity is observed.Longer treatment periods, including more treatment cycles, are contemplated.

[0142] Dosages, schedules and methods for administration of the disclosed leuprolide acetate compositions used to treat HR-positive breast cancer are disclosed in the Examples below, although other dosages, schedules and methods are contemplated.

[0143] All publications, patents, and patent documents are incorporated herein by reference, as if individually incorporated by reference.The invention is now illustrated by the following non-limiting examples. EXAMPLES

[0144] Example 1 Pharmacokinetic Simulation Pharmacokinetic simulations were generated to determine estimates of serum leuprolide concentrations and pharmacokinetic (PK) parameters following administration of 30 mg leuprolide acetate for injection every 3 months over two doses.

[0145] Simulations were performed using serum leuprolide concentration data collected from male subjects with advanced prostate cancer who were administered ELIGARD® (leuprolide acetate for injectable suspension) 22.5 mg every 3 months (7.5 mg / month). The pharmacokinetic behavior of leuprolide was predicted after two 3-month doses (achieving 10 mg / month) (30 mg leuprolide acetate injections). Simulations were performed using Phoenix WinNonlin software (v6.4; Certara Corporation, Princeton, NJ).

[0146] The simulated plasma leuprolide concentration-time curves are presented in Figure 1 (linear) and Figure 2 (log-linear). PK parameters were estimated assuming dosing over two dosing intervals (once every 3 months), including burst kinetics after each dose (Table 1). PK parameters were also estimated in the absence of two bursts (once after each dose; Table 2). maxcalculated different timed controlled release profiles of drug release from various doses of leuprolide acetate and 75:25 PLG biodegradable polymer composition (Table 3). [Table 1] [Table 2]

[0147] Example 2 Human clinical studies A clinical study is conducted in human patients to evaluate ovarian suppression following subcutaneous administration of leuprolide acetate in breast cancer patients.

[0148] The primary objective of this clinical study is to evaluate the suppression of estradiol to postmenopausal levels following administration of a leuprolide acetate polymer formulation of the present disclosure in greater than 85% of premenopausal human female subjects with hormone receptor-positive (HR-positive) human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

[0149] Secondary objectives of the study are to evaluate the safety and tolerability of leuprolide acetate polymer formulation in premenopausal subjects with HR-positive, HER2-negative breast cancer and to determine the pharmacokinetic and pharmacodynamic (PD) profiles of leuprolide acetate polymer formulation following administration of leuprolide acetate polymer formulation in premenopausal subjects with HR-positive, HER2-negative breast cancer.

[0150] The Study is conducted as a Phase 3, single-arm, open-label study to evaluate the efficacy of an injectable extended-release depot formulation of 30 mg leuprolide acetate suspension (the "Leuprolide Investigational Formulation"), designed to release leuprolide acetate at a rate of 10 mg / month over a three-month dosing period, to suppress ovarian function in premenopausal women with HR-positive, HER2-negative early-stage breast cancer.

[0151] The leuprolide investigational formulation is a 30 mg suspension of leuprolide acetate for subcutaneous (SC) injection provided in a single-use kit. The kit consists of a two-syringe mixing system, a sterile needle (18 gauge, 5 / 8 inch), and a pouch of silica gel desiccant to control water uptake. Each syringe is individually packaged. One syringe contains the polymeric delivery system and the other contains lyophilized leuprolide acetate powder. Upon constitution, the leuprolide acetate is administered as a single dose with an injection volume of 0.5 mL or less. The polymeric delivery system consists of poly-(DL-lactide-co-glycolide [PLG]) or poly(DL-lactide-co-glycolide)-COO (PLGH) dissolved in N-methyl-2-pyrrolidone (NMP). The PLG copolymer has a molar ratio of DL-lactide to glycolide of 75:25. The ratio of PLG to NMP is 45:55 (% w / w). The polymer solution is finally sterilized by gamma irradiation. The final composition of the reconstituted product is presented in the table below. [Table 3]

[0152] The two-syringe mixing system kit is allowed to come to room temperature at least 30 minutes prior to reconstitution and administration. Once the contents of the two syringes are mixed, the final product is administered in less than 30 minutes.

[0153] Human subjects will participate in the study for up to 56 weeks, including a 4-week screening period, a 48-week treatment period, and a final study visit within 4 weeks of the final treatment period visit. Eligible subjects will enroll in the treatment period in one of two arms: those receiving tamoxifen concurrently with the leuprolide study formulation, or those beginning treatment with an aromatase inhibitor (AI) (letrozole, anastrozole, or exemestane) starting 6 weeks after the first dose of the leuprolide study formulation. A schematic diagram of the study design is shown in Figure 4.

[0154] At the time points indicated in Figure 4, leuprolide study formulation will be administered as subcutaneous injections given 84 ± 2 days apart (i.e., every 12 weeks) for 48 weeks. Tamoxifen or AI therapy will be administered as daily oral doses according to product labeling for these marketed drugs. At the end of the treatment period, subjects will be eligible for continued treatment based on rescue use (expanded access) criteria.

[0155] Approximately 260 subjects will be enrolled in the study, and all eligible subjects will receive the leuprolide study formulation. The principal investigator conducting the study, in consultation with the subject, will determine whether the subject will receive tamoxifen beginning simultaneously with the leuprolide study formulation, or treatment with letrozole, anastrozole, or exemestane beginning 6 weeks after the first dose of leuprolide study formulation / mL. No dose adjustments are permitted for the leuprolide study formulation. Dose adjustments of tamoxifen, letrozole, anastrozole, and exemestane, and / or switches between tamoxifen and an AI will be made at the discretion of the investigator.

[0156] If appropriate, subjects will be discontinued early from the study, efforts will be made to collect all scheduled clinical and laboratory data for end of treatment visits, and the subject will be followed for safety, and the Investigator will complete and report as thoroughly as possible the reasons for the subject's withdrawal.

[0157] Enrolled subjects will meet all of the following inclusion criteria: 1. Understand the nature of the tests used in this study and are able to provide written informed consent prior to participating in the study. 2. Premenopausal women between the ages of 18 and 55 (inclusive). 3. Have a confirmed diagnosis of stage I, II, III, or IV HR-positive, HER2-negative breast cancer. 4. Candidate for endocrine therapy + ovarian suppression. 5. Premenopausal status is defined as any of the following: a. Baseline E2 >30 pg / mL; b. Your last menstrual period was within the last 12 months; and / or c. If treatment-induced amenorrhea is present, plasma estradiol must be >30 pg / mL and / or FSH must be >40 IU / mL.

[0158] Enrolled subjects will not meet any of the following exclusion criteria: 1. Body mass index (BMI) < 15.00 kg / m 2 has. 2. Women who are breastfeeding. 3. Life expectancy <12 months. 4. Active or ongoing non-breast malignancy. 5. Patients have an Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 3. 6. Prior tamoxifen, other selective estrogen receptor modulators (e.g., raloxifene) or antagonists (e.g., fulvestrant), aromatase inhibitors / inactivators, mTOR inhibitors or hormone replacement therapy within 1 year prior to breast cancer diagnosis. 7. Prior neoadjuvant or adjuvant endocrine therapy since breast cancer diagnosis. 8. The presence of any other medical condition, or serious intercurrent illness, or clinically significant findings on physical examination, laboratory tests, or medical history that, in the opinion of the Investigator, may interfere with the conduct of the trial, the subject's safety, or the interpretation of the study results. 9. Subjects who are currently receiving and / or have previously received GnRH analogues within one year prior to breast cancer diagnosis. 10. Psychiatric, addictive or other disorders that would prevent compliance with the study. 11. Use of any recreational drugs (cocaine, amphetamines, barbiturates, benzodiazepines, and morphine) or a history of drug or alcohol abuse within the past 6 months, or a positive result on a urine drug / alcohol screen (a single repeat test may be performed within 2 weeks of the initial result). 12. The following: a. Oral or transdermal hormone treatment within 30 days prior to screening; b. estrogen, progesterone, or androgen within 30 days prior to screening; and / or c. Hormonal contraceptives within 30 days prior to screening Medications that are likely to affect subject safety and / or affect the PK and hormonal assessment of the drug, including but not limited to: 13. Known hypersensitivity, idiosyncratic or allergic reaction to GnRH, GnRH agonist analogues or any of the components of the IP. 14. Female subjects who are sexually active with a male partner throughout the study and are unwilling to use non-hormonal contraception. 15. Females of childbearing potential with a positive serum pregnancy test at Screening and / or Day 0. 16. Unacceptable Hematological Conditions: Hemoglobin ≤ 9 g / dL; b. Absolute neutrophil count ≤ 1500 cells / μL; and / or c. Platelet count ≤75,000 cells / μL. 17. Unacceptable liver function: Alanine aminotransferase (ALT) ≥ 2 × upper limit of normal (ULN); b. Aspartate aminotransferase (AST) ≥ 2 × ULN; c. Bilirubin ≥ 2 × ULN; and / or d. Alkaline phosphatase ≥ 2 × ULN. 18. Unacceptable renal function: Creatinine ≥ 3X ULN; and / or b. Creatinine clearance ≤ 30 mL / min. 19. At the discretion of the investigator and sponsor / DSMB, exposure to any investigational drug within 60 days prior to the first dose of the investigational formulation of leuprolide. 20. Blood donation and / or blood loss (1 unit or 350 ml) within 90 days prior to receiving the first dose of an investigational leuprolide formulation.

[0159] A subject will be discontinued from the study for any of the following reasons: 1. Subject withdrawal of consent. 2. Investigator discretion. 3. The subject becomes pregnant. 4. A change in the subject's condition that, in the investigator's judgment, makes the subject unacceptable for further treatment with the study drug. 5. Serious adverse events (AEs) or AEs that, in the investigator's judgment, would prevent the subject from being tolerated on further study drug treatment. 6. Subject non-compliance with the study protocol. 7. Termination of the study by the sponsor, Institutional Review Board (IRB) or Independent Ethics Committee (IEC), or other regulatory authority. 8. Subject fails to suppress estradiol to postmenopausal levels (<20 pg / mL) on two consecutive visits after Week 6.

[0160] This is an open-label study, and all enrolled subjects will receive the investigational formulation of leuprolide. The investigator, in consultation with the subject, will decide whether the subject will receive combination treatment with tamoxifen, letrozole, anastrozole, or exemestane. The study will not stratify with respect to tamoxifen or letrozole / anastrozole / exemestane treatment. Patients receiving tamoxifen will receive tamoxifen orally administered via tablet or liquid at 20 mg once daily or 10 mg twice daily. Patients receiving aromatase inhibitors will receive either letrozole, a 2.5 mg tablet taken orally once daily; or anastrozole, a 1 mg tablet taken orally once daily; or exemestane, a 25 mg tablet taken orally once daily.

[0161] The leuprolide study formulation will be administered as a subcutaneous injection. The specific location selected for injection of the leuprolide study formulation will be an area with adequately soft or loose subcutaneous tissue (e.g., upper or mid-abdominal area). Areas with thickened or fibrous subcutaneous tissue or areas that may be chafed or compressed (i.e., by belts or waistbands of clothing) will be avoided. Local or topical anesthetics to "numb" the study drug injection site are permitted but will be recorded as concomitant medication, including the time of administration.

[0162] At the screening period, subjects will sign informed consent and will be screened based on demographics and physical examination, including vital signs, ECOG status, past medical / surgical history, medication history, electrocardiogram (ECG) and laboratory tests (including baseline estrone [E1], estradiol, FSH and LH). Menstrual status will be collected at screening and each visit. BMI will be recorded at screening and each dosing visit.

[0163] Eligible subjects will be enrolled in one of two treatment periods as determined by the investigator: those receiving tamoxifen concurrently with the leuprolide study formulation, or those beginning treatment with letrozole, anastrozole, or exemestane starting 6 weeks after the first dose of the leuprolide study formulation. Both groups will receive their first dose of the leuprolide study formulation on day 0. The next three doses of the leuprolide study formulation will be administered on days 84 (week 12), 168 (week 24), and 252 (week 36). A window of ±3 days will be allowed for administration of the leuprolide study formulation. Study subjects will report to the clinical site for IP administration on these days, and for assessments over 8 hours after the dose.

[0164] Subject follow-up visits will occur at weeks 2, 4, and 6. All subjects will have blood samples collected for PK and PD assessments at baseline (day 0), weeks 6, 12, 24, 36, and 48. Samples collected at dosing visits will be collected 30 minutes prior to administration of the study leuprolide formulation. At dosing visits occurring at weeks 0 and 12, pre-dose blood samples will be followed by 4- and 8-hour post-dose sample collections.

[0165] A subset of 20 subjects will require an additional visit within the first 24 weeks to collect PK samples. Estradiol from samples collected at weeks 2, 4, 6, 12, 24, 36 and 48 will be measured by a sensitive, validated liquid chromatography-tandem mass spectrometry method. Fifteen blood samples of 3 mL each will be collected into tubes containing K2EDTA anticoagulant at pre-specified time points for measurement of E1, estradiol, FSH, LH and progesterone. The hormone analysis methods are outlined in the table below. [Table 4]

[0166] After completion of the treatment period, subjects will be eligible to continue treatment with the investigational formulation of leuprolide by rescue use (expanded access) for up to an additional four years.

[0167] Steady-state and / or pre-dose concentrations of leuprolide levels are statistical descriptions of leuprolide concentrations collected at each evaluation point at least 1 month after the first dose and before any subsequent doses of leuprolide study formulation. Steady-state (area under the curve, AUC tau ss ) over the dosing interval and for the entire treatment period. max ] or the maximum concentration at steady state [C max ss ]), as well as C max Time to and C max ss Time to max and Tmax ss ) are determined during each dosing interval. Mean steady-state concentrations and time to steady-state are estimated from pre-dose (concentration immediately prior to dose administration) concentrations.

[0168] Subjects will be monitored for the occurrence of AEs, as well as changes in vital signs and laboratory data throughout their participation in the study. Gynecologic examinations may be performed at the discretion of the investigator, if medically indicated.

[0169] Blood glucose levels, glycosylated hemoglobin and electrolytes and bone mineral density can be measured at screening, periodically during the course of the trial, and at the end of the study visit.

[0170] Data regarding disease classification (histologic type and stage of carcinoma) and diagnostic imaging / extent of disease will be collected for all study subjects, and the TNM classification system will be used to grade the extent of disease. Complete demographic and medical history information will be obtained during the initial screening visit, and all concurrent medical conditions and any significant medical conditions (e.g., hospitalizations, surgeries, previous cancer history, etc.) in the last 60 days will be collected. From this point on, any information and report of an untoward event will be collected as an adverse event (AE). An AE is the onset of an undesirable medical condition or a worsening of a pre-existing medical condition following enrollment in a clinical study, including, but not limited to, after or during exposure to the product, whether or not it is deemed to be incidentally related to the pharmaceutical product. In clinical studies, an AE can include an undesirable medical condition that occurs at any time, including baseline or washout phase, even when no study treatment is administered. A serious adverse event (SAE) is an AE that meets one or more of the following criteria: results in death, is immediately life-threatening, requires hospitalization of the subject or an extension of an existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital anomaly or birth defect, may endanger the subject, or is a significant medical event that may require medical intervention to prevent any one of these outcomes. An unexpected adverse reaction is any untoward and unintended response associated with the administration of any dose of the investigational formulation of leuprolide that is not consistent with the applicable product information.

[0171] All concomitant medications administered during each study subject's participation will be recorded until the end of the study. Vital sign measurements taken and recorded from each study participant include systolic and diastolic blood pressure, heart rate, respiratory or pulse rate, and temperature (blood pressure and heart rate will be recorded after the subject has rested in a seated position for at least 5 minutes). A physical examination (PE) will be performed on all study subjects, including examination of the skin, head, eyes, ears, nose, and throat, lymph nodes, heart, chest, lungs, abdomen, extremities, and nerves, including height and weight. BMI will be recorded at the start and end of each dosing interval. A full PE will be performed at screening. This will be followed by an abbreviated PE, or a full PE may be performed at the discretion of the investigator.

[0172] A 12-lead ECG will be obtained in triplicate and will include heart rate, PR interval, QRS duration, QT interval and corrected QT (QTc) interval (ECG measurements will be taken after the subject has rested in the supine position for at least 10 minutes prior to evaluation). Any ECG results outside the normal range will be repeated at the discretion of the investigator. Any results outside the normal range that are deemed clinically significant will be recorded as an adverse event. Bone mineral density will be measured using dual energy x-ray absorptiometry (DEXA) scanning.

[0173] Hematology and clinical chemistry laboratory analyses will be performed on each study participant at a local laboratory and will include complete blood count, white blood cell count, and urinalysis.

[0174] Evaluation of blood samples taken from study participants at the 6-week visit indicates that over 85% of study subjects had estradiol levels below 20 pg / mL, indicating ovarian suppression.

[0175] Additional evaluation of blood samples taken from study participants treated with the study formulation of leuprolide and tamoxifen indicates that more than 85% of study subjects had estradiol levels below 20 pg / mL at one or more of weeks 12, 24, 36, and 48 of the study.

[0176] Additional evaluation of blood samples taken from study participants treated with the study formulation leuprolide and letrozole, anastrozole, or exemestane indicates that more than 85% of study subjects had estradiol levels below 2.7 pg / mL at one or more of weeks 12, 24, 36, and 48 of the study.

[0177] Additional evaluation of blood samples taken from all study participants indicates that over 85% of study subjects had FSH levels below 40 IU / L at one or more of weeks 6, 12, 24, 36 and 48 of the study.

[0178] Additional evaluation of study participant data indicates that the majority of participants reported missing menses at one or more of weeks 6, 12, 24, 36, and 48.

[0179] Percent changes in baseline estradiol and FSH levels (from "baseline levels" collected from each study participant prior to the first dose of leuprolide study formulation) are determined by analysis of study participant blood samples taken at 6, 12, 24, 36, and 48 weeks. Similarly, the number (percent) of study subjects with clinically significant suppressed mean serum LH levels (compared to baseline levels) at 6, 12, 24, 36, and 48 weeks is determined. Similarly, the number (percent) of study subjects with clinically significant suppressed mean serum FSH levels (compared to baseline levels) at 6, 12, 24, 36, and 48 weeks is determined. Similarly, statistical changes in serum E1 and progesterone levels (compared to baseline levels) of study subjects are determined at 6, 12, 24, 36, and 48 weeks.

[0180] The various features and processes described above may be used independently of each other or may be combined in various ways. All possible combinations and subcombinations are intended to fall within the scope of the present disclosure. Furthermore, certain method or process blocks may be omitted in some implementations. The methods and processes described herein are also not limited to any particular order, and the blocks or states associated therewith may be performed in other orders as appropriate. For example, the described blocks or states may be performed in orders other than those specifically disclosed, or multiple blocks or states may be combined into a single block or state. The example blocks or states may be performed in series, in parallel, or in some other manner. Blocks or states may be added or removed from the disclosed example embodiments. The example systems and components described herein may be configured differently than those described. For example, elements may be added, removed, or rearranged compared to the disclosed example embodiments.

[0181] Conditional terms used herein, such as "can," "could," "might," "may," "for example," among others, are generally intended to state that certain embodiments include certain features, elements, and / or steps, but other embodiments do not, unless otherwise specified or understood within the context in which they are used. Thus, such conditional terms are not generally intended to imply that features, elements, and / or steps are more or less required for one or more embodiments, or that one or more embodiments necessarily include logic for determining whether those features, elements, and / or steps are to be included in or performed in any particular embodiment, with or without authorial input or prompting. Terms such as "comprising," "including," "having," and the like, are synonymous and used inclusively in an open-ended manner and do not exclude additional elements, features, acts, operations, and the like. Similarly, the term "or" is used in its inclusive sense (and not its exclusive sense), so for example, when used to connect a list of elements, the term "or" means one, some, or all of the elements in the list.

[0182] While certain example embodiments have been described, these embodiments are presented by way of example only and are not intended to limit the scope of the invention disclosed herein. The accompanying claims and their equivalents are intended to cover such forms or modifications that come within the scope and spirit of the invention disclosed herein. In certain embodiments, for example, the following items are provided: (Item 1) 1. A method of suppressing ovarian function in a subject having hormone receptor positive breast cancer, comprising administering to the subject a therapeutically effective amount of a flowable extended release composition, the flowable extended release composition comprising: a. an organic solvent; b. leuprolide or a pharma- ceutically acceptable salt or analog thereof, and c. A biodegradable polymer comprising a copolymer segment of poly(lactide-co-glycolide) (PLG), wherein the molar ratio of lactide to glycolide monomers is between 70:30 and 80:20, said biodegradable polymer having substantially no titratable carboxylic acid groups, and at least one distal end group of said biodegradable polymer is hydroxyl terminated. Including, the flowable extended release composition is formulated for subcutaneous injection about once every three months, and when the flowable extended release composition contacts body fluids, the organic solvent dissipates and an in situ solid or semi-solid depot formulation is formed. method. (Item 2) The method of item 1, wherein the hormone receptor positive breast cancer is estrogen receptor (ER) and / or progesterone receptor (PgR) positive breast cancer. (Item 3) 3. The method of claim 1 or 2, wherein the hormone receptor positive breast cancer is human epidermal growth factor receptor 2 (HER2) negative breast cancer. (Item 4) 4. The method of any one of items 1 to 3, wherein the subject is a premenopausal female. (Item 5) 4. The method of any one of items 1 to 3, wherein the subject is a peri-menopausal woman. (Item 6) 6. The method of any one of items 1 to 5, wherein the subject is at least 18 years of age. (Item 7) 7. The method of any one of items 1 to 6, wherein the subject is under 55 years of age. (Item 8) 8. The method of any one of items 1 to 7, wherein the flowable extended release composition is administered simultaneously with a therapeutic treatment of breast cancer. (Item 9) 9. The method of claim 8, wherein the therapeutic treatment is an endocrine therapy. (Item 10) 10. The method of claim 9, wherein the endocrine therapy comprises administering one or more of a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), and an aromatase inhibitor (AI). (Item 11) 11. The method of claim 10, wherein the selective estrogen receptor modulator is tamoxifen. (Item 12) 11. The method of claim 10, wherein the aromatase inhibitor is one or more of letrozole, anastrozole and exemestane. (Item 13) 9. The method of claim 8, wherein the therapeutic treatment is chemotherapy. (Item 14) 14. The method of item 13, wherein the chemotherapy is selected from the group consisting of vinorelbine, carboplatin, bevacizumab, liposomal doxorubicin, cisplatin, cyclophosphamide, methotrexate, 5-fluorouracil, cyclin-dependent kinase (CDK) inhibitors, taxanes, and combinations thereof. (Item 15) 9. The method of claim 8, wherein the therapeutic treatment is radiation therapy. (Item 16) 16. The method of any one of items 1 to 15, wherein the flowable extended release composition is administered to the subject at least twice approximately every three months. (Item 17) Item 17. The method of item 16, wherein the flowable extended release composition is administered to the subject at least four times approximately every three months. (Item 18) 17. The method of claim 16, wherein the flowable extended release composition is administered to the subject at least eight times approximately every three months. (Item 19) Item 17. The method of item 16, wherein the flowable extended release composition is administered to the subject at least 12 times approximately every 3 months. (Item 20) 20. The method of any one of items 1 to 19, wherein the flowable extended release composition suppresses estradiol levels in the subject. (Item 21) 21. The method of claim 20, wherein the flowable extended release composition suppresses the subject's estradiol levels to less than about 20 pg / mL. (Item 22) 21. The method of claim 20, wherein the flowable extended release composition suppresses the subject's estradiol levels to less than about 10 pg / mL. (Item 23) 21. The method of claim 20, wherein the flowable extended release composition is administered simultaneously with an aromatase inhibitor to suppress the subject's estradiol levels to less than about 2.7 pg / mL. (Item 24) 24. The method of any one of items 1 to 23, wherein the flowable extended release composition suppresses the subject's follicle stimulating hormone (FSH) levels to less than about 40 IU / L. (Item 25) 25. The process according to any one of the preceding claims, wherein the molar ratio of lactide to glycolide monomers is 75:25. (Item 26) 26. The method according to any one of items 1 to 25, wherein the biodegradable polymer has a weight average molecular weight of about 15 kDa to about 45 kDa. (Item 27) 27. The method according to item 26, wherein the weight average molecular weight is about 17 kDa to about 21 kDa. (Item 28) 28. The method of any one of the preceding claims, wherein the biodegradable polymer is present in an amount of about 35% to about 60% by weight of the flowable extended release composition. (Item 29) The biodegradable polymer has the formula: HO-(P)-C(=O)O-Ra-O(O=)C-(P)-OH where Ra is an alkane diradical containing from about 4 to about 8 carbons and P is a polymer segment containing lactide, glycolide or (lactide-co-glycolide) repeat units. 29. The method according to any one of items 1 to 28. (Item 30) The biodegradable polymer has the formula (I):

change

change

change

Claims

1. a. N-methyl-2-pyrrolidone, b. leuprolide or a pharma- ceutically acceptable salt thereof, wherein the amount of leuprolide free base equivalent is 28 mg, or said pharma-ceutically acceptable salt of leuprolide is leuprolide acetate, and the amount of leuprolide acetate is 30 mg; and c. A biodegradable polymer comprising a copolymer segment of poly(lactide-co-glycolide) (PLG), wherein the molar ratio of lactide to glycolide monomers is 75:25, said biodegradable polymer having substantially no titratable carboxylic acid groups, and at least one distal end group of said biodegradable polymer is hydroxyl terminated.

1. An extended release composition for suppressing ovarian function in a subject with hormone receptor positive breast cancer, comprising: The extended release composition is for administration by subcutaneous injection once every three months, and when the extended release composition contacts body fluids, the N-methyl-2-pyrrolidone dissipates to form an in situ solid or semi-solid depot formulation; wherein said extended release composition suppresses estradiol levels in said subject to less than 20 pg / mL; wherein the extended release composition suppresses mean serum luteinizing hormone (LH) levels in the subject. Extended release composition.

2. 1. An article of manufacture for suppressing ovarian function in a subject with hormone receptor positive breast cancer, comprising: a. a first container containing leuprolide or a pharma- ceutically acceptable salt thereof, wherein the amount of leuprolide free base equivalent is 28 mg, or the pharma-ceutically acceptable salt of leuprolide is leuprolide acetate, and the amount of leuprolide acetate is 30 mg; b. a second container comprising a biodegradable polymer and N-methyl-2-pyrrolidone, the biodegradable polymer comprising a copolymer segment of poly(lactide-co-glycolide) (PLG) having a molar ratio of lactide to glycolide monomers of 75:25, the biodegradable polymer being substantially free of titratable carboxylic acid groups; and c. instructions Including, said article of manufacture is for combining the contents of said first container and the contents of said second container to obtain an extended release composition for administration to said subject once every three months for suppression of ovarian function in said subject; wherein said extended release composition suppresses estradiol levels in said subject to less than 20 pg / mL; wherein the extended release composition suppresses mean serum luteinizing hormone (LH) levels in the subject. Manufactured articles.

3. The article of manufacture of claim 2 , wherein the pharma- ceutically acceptable salt of leuprolide is lyophilized.

4. 3. The article of manufacture of claim 2, further comprising a package insert providing efficacy and / or safety data for the use of leuprolide in said suppressing ovarian function in said subject with hormone receptor positive breast cancer.

5. 1. Use of an extended release composition in the manufacture of a medicament for suppressing ovarian function in a subject with hormone receptor positive breast cancer, the extended release composition comprising: a. N-methyl-2-pyrrolidone, b. leuprolide or a pharma- ceutically acceptable salt thereof, wherein the amount of leuprolide free base equivalent is 28 mg, or said pharma-ceutically acceptable salt of leuprolide is leuprolide acetate, and the amount of leuprolide acetate is 30 mg; and c. A biodegradable polymer comprising a copolymer segment of poly(lactide-co-glycolide) (PLG), wherein the molar ratio of lactide to glycolide monomers is 75:25, said polymer having substantially no titratable carboxylic acid groups, and at least one distal end group of said polymer is hydroxyl terminated. Including, the extended release composition is formulated for subcutaneous injection once every three months, and when the extended release composition contacts body fluids, the N-methyl-2-pyrrolidone dissipates to form an in situ solid or semi-solid depot; wherein said extended release composition suppresses estradiol levels in said subject to less than 20 pg / mL; wherein the extended release composition suppresses mean serum luteinizing hormone (LH) levels in the subject. use.

6. The use according to claim 5, wherein the hormone receptor positive breast cancer is estrogen receptor (ER) and / or progesterone receptor (PgR) positive breast cancer.

7. The use according to claim 5, wherein the hormone receptor positive breast cancer is human epidermal growth factor receptor 2 (HER2) negative breast cancer.

8. 6. The use of claim 5, wherein the subject is a premenopausal woman, a perimenopausal woman, at least 18 years old, and / or the subject is under 55 years old.

9. 9. The use according to any one of claims 5 to 8, wherein the extended release composition is administered simultaneously with a therapeutic treatment of breast cancer, the therapeutic treatment being endocrine therapy, chemotherapy or radiation therapy.

10. 10. The use of claim 9, wherein the endocrine therapy comprises administering one or more of a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD) and an aromatase inhibitor (AI).

11. The use according to claim 10, wherein the selective estrogen receptor modulator is tamoxifen.

12. 11. The use according to claim 10, wherein the aromatase inhibitor is one or more of letrozole, anastrozole and exemestane.

13. 13. The use according to any one of claims 5 to 12, wherein the extended release composition is for administration to the subject at least twice, at least four times, at least eight times or at least twenty times every three months.

14. 6. The use of claim 5, wherein the extended release composition suppresses the subject's estradiol levels to less than 10 pg / mL.

15. 6. The use of claim 5, wherein the extended release composition is administered simultaneously with an aromatase inhibitor and suppresses the subject's estradiol levels to less than 2.7 pg / mL.

16. 16. The use of any one of claims 5 to 15, wherein the extended release composition suppresses the subject's follicle stimulating hormone (FSH) levels to less than 40 IU / L.

17. The biodegradable polymer has the formula: HO-(P)-C(=O)O-Ra-O(O=)C-(P)-OH where Ra is an alkane diradical containing 4 to 8 carbons and P is a polymer segment containing lactide, glycolide or (lactide-co-glycolide) repeat units; 17. Use according to any one of claims 5 to 16.

18. The biodegradable polymer has the formula (I): 【Chemistry 5】 wherein: R ａ is an alkane diradical, Both R ｂ The group is either hydrogen or a methyl group, Both R ｃ The group is either hydrogen or a methyl group, Each L / G independently has the structure: 【Chemistry 6】 and a lactide / glycolide copolymer segment comprising dimeric lactide units and dimeric glycolide units having the formula: Each R ｄ The R groups are independently hydrogen or methyl groups, provided that the R ｄ Provided that the groups are the same, The wavy lines are attachment points between the lactide units of the dimer or the glycolide units of the dimer; n is an integer from 20 to 750 for each of said lactide / glycolide copolymer segments; 18. Use according to any one of claims 5 to 17.

19. The biodegradable polymer has the structure: 【Chemistry 7】 wherein R1 is H or CH ３ and R2 is an alkyl group.

17. Use according to any one of claims 5 to 16.

20. 20. The use of claim 19, wherein the in situ solid or semi-solid depot releases 10 mg of leuprolide acetate per month to the subject.

21. The use according to any one of claims 5 to 20, wherein the biodegradable polymer has a weight average molecular weight of from 15 kDa to 45 kDa.

22. 22. The use according to claim 21, wherein the weight average molecular weight is between 17 kDa and 21 kDa.

23. The use according to any one of claims 5 to 22, wherein the biodegradable polymer is present in an amount of from 35% to 60% by weight of the extended release composition.

24. 3. The article of manufacture of claim 2 for use in suppressing ovarian function in said subject with hormone receptor positive breast cancer.

Images