CN117813097A - 1- (4- { [4- (dimethylamino) piperidin-1-yl ] carbonyl } phenyl) -3- [4- (4, 6-dimorpholin-4-yl-1, 3, 5-triazin-2-yl) phenyl ] urea (Ji Dali plug) and combinations thereof for use in the treatment of cancer - Google Patents

Abstract

The present invention provides methods of treating cancer in a human subject. The method comprises the following steps: selecting a subject in need of cancer treatment; administering to the subject a therapeutically effective amount of jidalisal, at least once a week, for a period of three weeks; interrupting administration of the Ji Dali plug for a period of one week; and resuming administration of Ji Dali plugs after the disruption period, at least once a week. The administration for the at least three weeks and the discontinuing administration for the at least one week constitute a cycle, wherein the cycle is repeated for at least two cycles.

Description

1- (4- { [4- (dimethylamino) piperidin-1-yl ] carbonyl } phenyl) -3- [4- (4, 6-dimorpholin-4-yl-1, 3, 5-triazin-2-yl) phenyl ] urea (Ji Dali plug) and combinations thereof for use in the treatment of cancer

RELATED APPLICATIONS

The present application claims priority from U.S. provisional application No. 63/285,327 filed on 12 months 2 of 2021 and U.S. provisional application No. 63/225,707 filed on 7 months 26 of 2021, the entire contents of which are hereby incorporated by reference.

Technical Field

The present invention relates to methods of treating cancer in a patient by administering 1- (4- { [4- (dimethylamino) piperidin-1-yl ] carbonyl } phenyl) -3- [4- (4, 6-dimorpholin-4-yl-1, 3, 5-triazin-2-yl) phenyl ] urea.

Background

1- (4- { [4- (dimethylamino) piperidin-1-yl ] carbonyl } phenyl) -3- [4- (4, 6-dimorpholin-4-yl-1, 3, 5-triazin-2-yl) phenyl ] urea, also known as gedatolib (gedatolib), has the following chemical structure:

1- (4- { [4- (dimethylamino) piperidin-1-yl ] carbonyl } phenyl) -3- [4- (4, 6-dimorpholin-4-yl-1, 3, 5-triazin-2-yl) phenyl ] urea

1- (4- { [4- (dimethylamino) piperidin-1-yl ] carbonyl } phenyl) -3- [4- (4, 6-dimorpholin-4-yl-1, 3, 5-triazin-2-yl) phenyl ] urea is an inhibitor of PI3 kinase and mTOR, which is useful in the treatment of cancer. Mammalian target of rapamycin (mTOR) is a cell signaling protein that regulates tumor cell response to nutrients and growth factors, and controls tumor blood supply by acting on Vascular Endothelial Growth Factor (VEGF). Inhibitors of mTOR starve cancer cells and shrink tumors by inhibiting the effects of mTOR. All mTOR inhibitors bind to mTOR kinase. This combination has at least two important roles. First, mTOR is the downstream mediator of the PI3K/Akt pathway. The PI3K/Akt pathway is thought to be overactive in many cancers and may be responsible for the broad response of various cancers to mTOR inhibitors. Overactivation of the upstream pathway also typically results in overactivation of the mTOR kinase. However, in the presence of mTOR inhibitors, this overactivation process is blocked. This blocking prevents mTOR from signaling downstream pathways that control cell growth. Overactivation of the PI3K/Akt kinase pathway is often associated with mutations in the PTEN gene, a correlation that is common in many cancers and can help predict what tumors will respond to mTOR inhibitors. The second major role of mTOR inhibitors is to combat angiogenesis by reducing VEGF levels.

Breast cancer is the most common form of cancer and is the leading cause of cancer death in women worldwide. Today, systemic treatment of breast cancer provides three main different treatment modalities, and the applicability of these different treatment options depends essentially on the patient's receptor status (Bernard-Marty et al, 2004). Endocrine and biological therapies require the presence of corresponding receptors on cancer cells, whereas cytotoxic chemotherapy does not rely on those specific receptors.

Endocrine therapy alone, or in combination with cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors, PI 3K-alpha inhibitors or mTOR inhibitors, is generally the treatment of choice in patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER 2-) breast cancer (NCCN breast cancer treatment guidelines, 2021).

Selective Estrogen Receptor (ER) modulators (tamoxifen), selective ER degradation agents (fulvestrant) and Aromatase Inhibitors (AI) are established standard of care for women with hr+/HER 2-metastatic breast cancer (mBC). When treating mBC, the choice among these regimens depends on the type and duration of the previous endocrine therapy treatment and the time since the end of the previous endocrine therapy. In addition to the well-known efficacy of these treatments as first-line therapies for non-visceral crisis females, most patients develop endocrine resistance, leading to treatment failure. Primary endocrine resistance is defined as recurrence within the first two years of prior endocrine therapy or disease progression within the first six months of first line endocrine therapy for mBC. Secondary resistance refers to the resistance to mBC: (1) relapse after the first two years of assisted endocrine therapy; (2) relapse within 12 months of completion of the endocrine assist therapy; or (3) disease progression after more than six months from initiation of endocrine therapy.

Several mechanisms are responsible for endocrine resistance, including deregulation of various components of the ER pathway (aberrant ER expression, ER cofactor overexpression and cofactor down-regulation), modulation of alterations in signaling molecules involved in the cell cycle or cell survival, and activation of escape pathways that can provide for cell replication.

One common mechanism of endocrine therapy resistance is activation of cyclin dependent kinase 4 and 6 (CDK 4/6) pathways. These kinases drive cell cycle progression and division. Inhibition of CDK4/6 activation prevents estrogen from activating the cyclin D1-CDK4/6-Rb complex, thus blocking an important mechanism of resistance to endocrine therapy. The resulting cell cycle arrest results in a significant delay in tumor progression.

CDK4/6 inhibitors were first introduced in 2015. Administration of endocrine therapy in combination with an oral CDK4/6 inhibitor results in an improved clinical efficacy when compared to endocrine therapy as monotherapy. Treatment of HR+/HER 2-advanced breast cancer patients with a combination of piperaquib Bai Xili (palbociclib) and letrozole (letrozole) or fulvestrant (fulvestrant) in two randomized, double-blind clinical trials showed a significant prolongation of the median progression-free survival (PFS) period in patients receiving a combination of piperaquine Bai Xili and letrozole or fulvestrant (Turner et al, N.Engl. J. Med. Volume 373:209-219 (2015); finn et al, N.Engl. J. Med. Volume 375:1925-1936 (2016) patients who had developed disease progression during or after prior endocrine therapy, as compared to patients receiving letrozole or fulvestrant as a single agent.

Another common mechanism of endocrine inhibitor resistance is the activation of the PI3K pathway, an important intracellular pathway that regulates cell growth and metabolism. About one third of endocrine therapy resistant hr+ breast cancer tumors have an activating mutation of the PI3K catalytic subunit, termed PIK3CA. Fulvestrant used in combination with the oral PI 3K-a inhibitor apilimib (alpelinib) approved by the FDA at month 5 of 2019 has demonstrated improved clinical efficacy in patients suffering from tumorigenic PIK3CA mutations and not yet received CDK4/6 inhibitor treatment. These patients had developed disease progression during or after prior endocrine therapy.

Similar to CDK4/6 and PI3K, the mTOR pathway is also identified as a mechanism of endocrine therapy resistance. Everolimus (everolimus) is an mTOR inhibitor, currently approved by the FDA, for use in combination with exemestane (AI) in the treatment of hr+/HER2 advanced breast cancer. The combination of everolimus and fulvestrant also shows clinical benefit. These patients had developed disease progression during or after prior AI therapy.

Despite new treatment options, women with hr+/HER 2-breast cancer, particularly those with cancer that has metastasized to other organs and is resistant to endocrine therapy, still face poor long-term prognosis. Thus, breast cancer treatment is needed for patients who have not been successfully treated with endocrine therapy.

Disclosure of Invention

The present invention provides methods of treating cancer in a patient. The method comprises intravenously administering a Ji Dali plug to the patient once a week for three weeks, followed by a week without administration of a Ji Dali plug. This regimen of administration was then repeated as needed, which consisted of a 28 day period (three weekly doses of jidalisal followed by one week without Ji Dali plugs). It has been demonstrated that administration of Ji Dali plugs over a period of three weeks of administration, one week of disruption, is more successful than administration of Ji Dali plugs over a weekly or aperiodic manner in cancer treatment.

Accordingly, in one aspect, the present invention relates to a method of treating cancer in a human subject. The method comprises the following steps: selecting a human subject in need of cancer treatment; administering to the human subject a therapeutically effective amount of a jideli plug, or a pharmaceutically acceptable salt, solvate or ester thereof, at least once a week for a period of three weeks; interrupting administration of the Ji Dali plug or pharmaceutically acceptable salt, solvate or ester thereof for a period of one week; and resuming administration of the gedaltei or pharmaceutically acceptable salt, solvate or ester thereof at least once per week after the discontinuation period. The administration for at least three weeks and the discontinuation of administration for at least one week constitute a cycle, and the cycle is repeated for at least two cycles.

In some embodiments, administration of the gedaltei, or a pharmaceutically acceptable salt, solvate or ester thereof, is resumed, at least once per week for a period of three weeks. The administration period may be performed for at least 3 periods, at least 4 periods, at least 5 periods, at least 6 periods, at least 7 periods, at least 8 periods, at least 9 periods, or at least 10 or more periods. In a further embodiment, the Ji Dali plug or pharmaceutically acceptable salt, solvate or ester thereof is administered weekly at a dose of 180 mg.

In some embodiments, the method comprises: co-administering a CDK4/6 inhibitor to the human subject at least once a week for a period of three weeks; interrupting administration of the CDK4/6 inhibitor for a period of one week; and resuming administration of the CDK4/6 inhibitor for at least one week after the interruption period. The cycle of administration and discontinuation of the CDK4/6 inhibitor is repeated for at least two cycles. In a further embodiment, CDK4/6 is selected from the group consisting of piperaquine Bai Xili, rebaudimide (ribociclib), abbe ciclib (abaciclib), trehaliciril (trilaciclib), daricilli (dalpiciclib), liviciclib (riviciclib), and combinations thereof. Preferably, the CDK4/6 inhibitor is piperaquine Bai Xili. Furthermore, the piperazine Bai Xili can be administered at a dose of 125mg per day.

In some embodiments, the method comprises co-administering an estrogen receptor antagonist to a human subject. Preferably, the estrogen receptor antagonist is fulvestrant. Fulvestrant may be administered at a dose of 500mg every two weeks. Furthermore, fulvestrant may be administered at a dose of 500mg every four weeks. In some cases, fulvestrant is first administered at a dose of 500mg every two weeks and then reduced to a dose of 500mg every four weeks.

Another aspect of the invention relates to a method of treating cancer in a human subject, the method comprising: selecting a human subject in need of treatment for cancer; administering to the human subject a therapeutically effective amount of a jideli plug or a pharmaceutically acceptable salt, solvate or ester thereof and a CDK4/6 inhibitor, at least once a week for a period of three weeks; interrupting administration of the Ji Dali plug or pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor for a period of one week; and resuming administration of the gedaltei or pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor after the disruption period, at least once a week. The administration for at least three weeks and the discontinuation of administration for at least one week constitute a cycle, and the cycle is repeated for at least two cycles.

In some embodiments, administration of the gedaltei or pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor is resumed, at least once per week, for a period of three weeks.

Another aspect of the invention relates to a method of treating cancer in a human subject, the method comprising: selecting a human subject in need of treatment for cancer; administering to the human subject a therapeutically effective amount of a jideli plug or a pharmaceutically acceptable salt, solvate or ester thereof and a CDK4/6 inhibitor, at least once a week for a period of three weeks; interrupting administration of the Ji Dali plug or pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor for a period of one week; resuming administration of the gedaltei or a pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor after an interruption period, at least once per week, wherein administration for at least three weeks and interruption for at least one week constitutes a cycle, wherein the cycle is repeated for at least two cycles; administering an estrogen receptor antagonist to a human subject.

In some embodiments, the cancer of the subject is a solid cancer. Exemplary solid cancers include, but are not limited to, breast cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, prostate cancer, testicular cancer, penile cancer, lung cancer, colorectal cancer, melanoma, bladder cancer, brain/Central Nervous System (CNS) cancer, esophageal cancer, gastric cancer, head/neck cancer, kidney cancer, liver cancer, pancreatic cancer, and sarcomas.

In some embodiments, the solid cancer of the subject is hormone dependent cancer. Exemplary hormone-dependent cancers include, but are not limited to, breast cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, prostate cancer, testicular cancer, and penile cancer. In some embodiments, the hormone-dependent cancer is breast cancer. In further embodiments, the breast cancer of the subject is metastatic breast cancer, hormone-resistant breast cancer, estrogen receptor positive breast cancer, estrogen receptor negative breast cancer, progesterone receptor positive breast cancer, triple negative breast cancer, HER2 positive breast cancer, or HER2 negative breast cancer. Breast cancer may also be a Basal (Basal) subtype or a Luminal (Luminal) subtype. In further embodiments, the human subject is a pre-menopausal female patient or a post-menopausal female patient.

In some embodiments, the human subject fails the previous treatment of the cancer in less than twelve months (e.g., in less than six months). In some embodiments, the human subject fails to treat the cancer in two or more previous treatments. The previous treatment of failure may be endocrine or non-endocrine treatment of cancer. In one embodiment, the human subject fails at least one endocrine treatment of the cancer. In one embodiment, the human subject fails at least one non-endocrine treatment of the cancer.

Detailed Description

A method of treating cancer (e.g., breast cancer) in a human patient is disclosed. The method comprises administering to the patient a therapeutically effective amount of a jideli plug or a pharmaceutically acceptable salt, solvate or ester thereof, at least once a week for a period of three weeks, followed by a period of one week without administration of a Ji Dali plug or a pharmaceutically acceptable salt, solvate or ester thereof. The method consisted of a 28 day cycle (three weekly doses of Ji Dali plugs, one week without Ji Dali plugs) which was repeated for at least two cycles. It has surprisingly been found that the use of this periodic method of administration to treat cancer patients is more successful than the use of gemfibrozil in a non-periodic regimen of administration.

In order to make the description easier to understand, certain terms are first defined. Other definitions are set forth in the detailed description. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The use of "or" and "means" and/or "unless stated otherwise.

The term "about" as used herein, when referring to a measurable value (such as an amount, duration, etc.), encompasses variations up to + -10% from the specified value. Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used herein are to be understood as being modified by the term "about".

Ji Dali plug is a small molecule that has shown promise in cancer treatment, inhibiting phosphatidylinositol-3 kinase and mammalian target of rapamycin. Phosphatidylinositol-3 kinase (PI 3K) is an enzyme that phosphorylates the 3-position of the inositol ring of phosphatidylinositol (D.Whitman et al, (1988)). There are a number of PI3K subtypes, three major subtypes of PI3K have now been identified based on their in vitro substrate specificity. These three subtypes are referred to as class I (a and b), class II and class III (b.vanhaesebroeck, (1997)).

The phosphoinositide 3-kinase signaling pathway is one of the most highly mutated systems in human cancers. PI3 ks are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3' -OH group on phosphatidylinositol or phosphoinositides. The PI3K family includes 15 kinases with different substrate specificities, expression patterns and regulation patterns. Class I PI3 ks (p110α, p110β, p110δ and p110γ) are typically activated by tyrosine kinase or G protein coupled receptors, producing phosphatidylinositol (3, 4, 5) -triphosphate (PIP 3), which PIP3 binds to downstream effectors such as effectors in the AKT/PDK1 pathway, mTOR, tec family kinases and Rho family gtpases. Class II and III PI3 ks play a key role in intracellular transport through the synthesis of phosphatidylinositol 3-diphosphate (PI (3) P) and phosphatidylinositol (3, 4) -diphosphate (PI (3, 4) P2). PI3K is a protein kinase that controls cell growth (mORC 1) or monitors genome integrity (ATM, ATR, DNA-PK and hSmg-1).

There are four mammalian isoforms of class I PI 3K: PI3K- α, PI3K- β, PI3K- δ (class Ia PI 3K) and PI3K- γ (class Ib PI 3K). These enzymes catalyze the production of PIP3, leading to activation of downstream effector pathways important for cell survival, differentiation and function. PI3K- α and PI3K- β are widely expressed and are important mediators of cell surface receptor signaling. PI3K- α is the isoform most commonly mutated in cancer and plays a role in insulin signaling and glucose homeostasis (Knight et al, (2006); vanhaesebroeck et al, (2010)). PI3K- β is activated in cancers where phosphatases and tensin homolog (PTEN) are deleted. Both isoforms are targets for developing small molecule therapies for cancer.

PI 3K-delta and PI 3K-gamma are preferentially expressed in leukocytes and play an important role in leukocyte function. These isoforms also contribute to the development and maintenance of hematological malignancies (Vanhaesbroeck et al, (2010); clayton et al, (2002); fung-Leung, (2011); OKkenhaug et al, (2002)). PI 3K-delta is activated by cellular receptors (e.g., receptor tyrosine kinases) either through interaction with the src homology 2 (SH 2) domain of the PI3K regulatory subunit (p 85) or through direct interaction with the RAS.

Selectivity over other related kinases is also an important consideration in the development of PI3K inhibitors. While selective inhibitors may be preferred in order to avoid undesirable side effects, inhibition of multiple targets in the PI3K/Akt pathway (e.g., pi3kα and mTOR [ mammalian target of rapamycin ]) has been reported to potentially bring about greater efficacy.

Mammalian target of rapamycin (mTOR) is a cell signaling protein that regulates tumor cell response to nutrients and growth factors, and controls tumor blood supply by acting on Vascular Endothelial Growth Factor (VEGF). Inhibitors of mTOR starve cancer cells and shrink tumors by inhibiting the effects of mTOR. All mTOR inhibitors bind to mTOR kinase. This combination has at least two important roles. First, mTOR is the downstream mediator of the PI3K/Akt pathway. The PI3K/Akt pathway is thought to be overactive in many cancers and may be responsible for the broad response of various cancers to mTOR inhibitors. Overactivation of the upstream pathway also typically results in overactivation of the mTOR kinase. However, in the presence of mTOR inhibitors, this overactivation process is blocked. This blocking prevents mTOR from signaling downstream pathways that control cell growth. Overactivation of the PI3K/Akt kinase pathway is often associated with mutations in the PTEN gene, a correlation that is common in many cancers and can help predict what tumors will respond to mTOR inhibitors. The second major role of mTOR inhibitors is to combat angiogenesis by reducing VEGF levels.

The terms "Ji Dali plug" and "1- (4- { [4- (dimethylamino) piperidin-1-yl ] carbonyl } phenyl) -3- [4- (4, 6-dimorpholin-4-yl-1, 3, 5-triazin-2-yl) phenyl ] urea" as used herein refer to the same compound and are used interchangeably. In some embodiments of the invention, pharmaceutically acceptable salts, solvates, or esters of gedaltei may be used in methods of treating cancer, as known to those of skill in the art.

Representative "pharmaceutically acceptable salts" include, but are not limited to, for example, water-soluble and water-insoluble salts such as acetate, aluminum salts, azulene sulfonic acid (4, 4-diaminostilbene-2, 2-disulfonate), benzathine (N, N '-dibenzylethylenediamine), benzenesulfonate, benzoate, bicarbonate, bismuth salts, bisulfate, bitartrate, borate, bromide, butyrate, calcium salt, calcium ethylenediamine tetraacetate, dextroamphenesulfonate (camphorsulfonate), carbonate, chloride, choline, citrate, clavulanate, diethanolamine, dihydrochloride, diphosphate, edetate, ethanedisulfonate (camphorsulfonate), ethanesulfonate, ethylenediamine, fumarate, gluconate (glucoheptonate), gluconate, glucuronate, glutamate, hexafluorophosphate, hexylresorcinol (hexymetrix), hydramine (N, N' -bis (dehydroabietyl) ethylenediamine), hydrobromide, hydrochloride, hydroxynaphthoate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, iodide, isothionate (2-hydroxyethanesulfonate), lactate, lactobionate, laurate, laurylsulfate, lithium salt, magnesium salt, malate, maleate, mandelate, meglumine (1-deoxy-1- (methylamino) -D-glucitol), methylsulfonate, bromomethane, methylnitrate, methyl sulfate, mucinate, naphthalene sulfonate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate (4, 4' -methylenebis-3-hydroxy-2-naphthoate or enhydrochloride), pantothenate, phosphate, picrate, polygalacturonate, potassium salt, propionate, p-toluenesulfonate, salicylate, sodium salt, stearate, basic acetate, succinate, sulfate, sulfosalicylate, threonate, tannate, tartrate, theachlorate (8-chloro-3, 7-dihydro-1, 3-dimethyl-1H-purine-2, 6-dione), triethyliodide, tromethamine (2-amino-2- (hydroxymethyl) -1, 3-propanediol), valerate, and zinc salts.

Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl esters of acidic groups including, but not limited to, carboxylic acid, phosphoric acid, phosphinic acid, sulfonic acid, sulfinic acid, and boric acid.

Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvents or water molecules, or 1 to about 100, or 1 to about 10, or 1 to about 2, 3, or 4 solvents or water molecules.

The term "inhibit" or "decrease" as used herein refers to any statistically significant decrease in biological activity, including partial and complete blockade of activity. For example, "inhibit" or "decrease" can refer to a statistically significant decrease in biological activity of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100%. The terms "inhibit" or "block" (e.g., referring to inhibition/blocking of binding or activity) are used interchangeably and encompass both partial and complete inhibition/blocking.

As used herein, the term "subject" includes any human or non-human animal. For example, the methods and compositions described herein can be used to treat a subject (e.g., a human patient) having cancer. Preferably, the subject is a human suffering from breast cancer and experiencing its cancer progression during a previous treatment (e.g., endocrine treatment) in less than 12 months (e.g., in less than 6 months).

By "therapeutically effective amount" is meant an amount of Ji Dali plug or other active agent presented herein that is effective to produce a therapeutic effect when administered to a subject.

As used herein, "administering" refers to physically introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those of skill in the art. Preferred routes of administration of the therapeutic agents described herein include intravenous, intraperitoneal, intramuscular, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. Alternatively, the antibodies described herein may be administered by a non-parenteral route, such as a topical, epidermal, or mucosal route of administration, e.g., intranasal, oral, vaginal, rectal, sublingual, or topical administration. Administration may also be performed, for example, once, multiple times, and/or over one or more extended periods of time.

As used herein, the term "treatment" or the like refers to reducing or lessening the severity of at least one symptom or indication to temporarily or permanently eliminate the cause of the symptom or to obtain a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; the extent of the condition, disorder or disease is reduced; stabilization (i.e., not worsening) of the condition, disorder, or disease state; a delay or slowing of progression of a condition, disorder or disease onset; improvement of a condition, disorder or disease state; and alleviation (whether partial or complete), whether detectable or undetectable, or enhancement or improvement of a condition, disorder, or disease. Treatment includes causing clinically significant remissions without undue side effects. Treatment also includes an extended survival period compared to the expected survival period when untreated. Treatment may result in Partial Remission (PR) or Complete Remission (CR).

The term "endocrine therapy" or "hormonal therapy" (also sometimes referred to as "anti-hormonal therapy") refers to therapies that target hormone signaling, such as hormonal inhibition, hormonal receptor inhibition, use of hormone receptor agonists or antagonists, use of scavenger receptors or orphan receptors, use of hormone derivatives, and interference with hormone production. Specific examples are tamoxifen therapy, which modulates estrogen receptor signaling, or aromatase therapy, which interferes with steroid hormone production.

The term "previous treatment failure" means that a subject who has undergone cancer treatment has undergone progression of the cancer during the treatment, for example, within a particular period of time of the treatment (such as within twelve months or six months of initiation of the treatment). The term "progression" of cancer refers to increased growth and/or spread (e.g., metastasis), typically measured by methods established in the art for assessing cancer growth and/or spread, including, but not limited to, body scans (e.g., MRI scans, PET scans, CAT scans, etc.), biopsies, and/or measurement of biomarkers. In some embodiments, progression is defined as an increase in the sum of diameters of a target measurable lesion (e.g., tumor) by at least 20% from the minimum sum or baseline sum of diameters observed, wherein the absolute value of the sum of diameters increases by at least 5mm.

The terms "treatment modality", "treatment mode", "schedule", "regimen" and "treatment regimen" refer to the timely sequential or simultaneous administration of an antineoplastic agent, and/or an anti-vascular agent, and/or an immunostimulant, and/or a blood cell proliferation agent, and/or radiation therapy, and/or hyperthermia, and/or cryotherapy for the treatment of cancer. These applications may be performed in an assisted and/or neoassisted mode. The composition of such a "regimen" may vary in terms of the dosage of the single agent, the time frame of application, and the frequency of administration within a prescribed therapeutic window.

The term "cytotoxic chemotherapy" refers to various therapeutic modalities that affect cell proliferation and/or survival. Treatment may include administration of alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, and other antineoplastic agents, including monoclonal antibodies and kinase inhibitors. In particular, the cytotoxic treatment may involve taxane treatment. Taxanes are plant alkaloids that block cell division by preventing microtubule function. The prototype of the taxane is the natural product paclitaxel, originally called tacazole, originally derived from the bark of the Pacific yew tree. Docetaxel is a semisynthetic analog of paclitaxel. The taxane enhances the stability of microtubules and prevents chromosome segregation at a later stage.

Various aspects described herein are described in further detail in the subsections that follow.

I. Ji Dali plug

Provided herein are methods of treating cancer by administering a therapeutically effective amount of jideli plug, or a pharmaceutically acceptable salt, solvate, or ester thereof, to a subject (e.g., a human subject who failed prior treatment of cancer (e.g., endocrine treatment of cancer) over a period of less than twelve months (e.g., a period of six months) in a periodic manner. For example, periodic administration may include administration of Ji Dali plugs to the subject for three weeks followed by discontinuation of administration for a period of one week. This cycle may be repeated as many times as necessary to achieve the desired result.

Ji Dali plug is a class I isoform of PI3K/mTOR inhibitor with high potency (NCT 02626507, 24, 4, 2020). Chemical synthesis of Ji Dali plugs is disclosed in U.S. Pat. nos. 8,039,469, 8,217,036, 8,445,486, 8,575,159, 8,748,421, 8,859,542, 9,174,963, 10,022,381, all of which are incorporated herein by reference in their entirety. Ji Dali plugs can be prepared in crystalline form and are chemically and physically stable in this form for up to 3 years at 25 ℃ and 60% Relative Humidity (RH). However, this free base is not sufficiently water soluble to prepare an aqueous solution formulation suitable for intravenous or parenteral administration at the desired therapeutic dosage level. Thus, formulations have been developed that allow therapeutic dosage levels.

Pharmaceutical formulations comprising therapeutic dosage levels of jideli are known in the art and include aqueous intravenous formulations as well as nanoparticulate formulations.

PCT application publication WO2016097949 discloses an aqueous intravenous formulation of Ji Dali plugs with lactic acid and/or orthophosphoric acid, which forms a clear, particle-free solution. These formulations contained Ji Dali plug, lactic acid and water. Ji Dali plug is present in the solution at a concentration of less than 6mg/mL (preferably about 5 mg/mL) and sufficient lactic acid is present to provide a clear solution (preferably at least 2.5 molar equivalents). Ji Dali plug forms 1:1 (molar equivalent) lactate with lactic acid. Thus, formulations can be prepared using the free base of the gedaltei or using the lactate salt of the gedaltei.

The formulation with orthophosphoric acid contained Ji Dali plug, orthophosphoric acid and water. Ji Dali plug is present at a solution concentration of less than 4mg/mL (preferably 3.0mg/mL to 3.5 mg/mL) and sufficient orthophosphoric acid is present to provide a clear solution (preferably at least 5 molar equivalents).

Formulations comprising Ji Dali plugs and cyclodextrin are disclosed in PCT application publication WO 2019234632. The pharmaceutical aqueous formulation comprises a Ji Dali plug or a pharmaceutically acceptable organic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic acid (which is not a sulfonic acid), a pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin, and water. The Ji Dali plug is present at a solution concentration of at least 6mg/mL and the solution is clear.

The pharmaceutically acceptable organic acid (including salts thereof) used is lactic acid, tartaric acid, malic acid, citric acid, succinic acid, acetic acid or maleic acid. Where applicable, the acids may be used in their racemic forms or as single stereoisomers (or mixtures thereof). Examples of pharmaceutically acceptable beta-cyclodextrin are 2-hydroxypropyl-beta-cyclodextrin and sulfobutyl ether-beta-cyclodextrin (SBECD). Examples of such pharmaceutically acceptable gamma-cyclodextrins are gamma-cyclodextrin and 2-hydroxypropyl-gamma-cyclodextrin. Preferred amounts of the pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin for the formulation are 2% to 30% w/v, 5% to 20% w/v or 15% to 30% w/v, and preferably about 20% w/v or about 25% w/v. Preferably, the pharmaceutically acceptable amount of beta-cyclodextrin or gamma-cyclodextrin used in the formulation of the invention is about 20% w/v.

Formulations comprising Ji Dali plugs and methanesulfonic acid and/or ethanesulfonic acid are disclosed in PCT application publication WO 2019038657.

These formulations comprise Ji Dali plug or mesylate salt thereof, methanesulfonic acid and water. Ji Dali plug is present at a solution concentration of less than 35mg/mL or up to 30mg/mL (preferably 6mg/mL to 30 mg/mL) and sufficient methanesulfonic acid is present to provide a clear solution. Another formulation disclosed is jidalisal or its ethanesulfonate, ethanesulfonic acid, and water. Ji Dali plug is present at a solution concentration of less than 35mg/mL or up to 30mg/mL (preferably 6mg/mL to 30 mg/mL) and sufficient ethanesulfonic acid is present to provide a clear solution.

The use of methanesulfonic acid and ethanesulfonic acid enables up to 30mg/mL of a Ji Dali plug solution concentration to be achieved for an aqueous pharmaceutical solution formulation suitable for intravenous or parenteral administration to a patient, i.e., a clear, substantially particle-free solution.

In the above aqueous formulation, a solution concentration of at least 6mg/mL of Ji Dali plug is required to allow dosing of the subject using a single vial form of a commercially available pharmaceutical product. A lyophilized pharmaceutical product (for reconstitution) containing less than 6mg/mL of the pharmaceutical product solution would require multiple vials to provide the desired therapeutic dose. In view of the current regulatory expectations for these product types, multi-vial dose delivery methods are not desirable.

Any of the above formulations can be freeze-dried to provide a freeze-dried solid composition, and the compatibilizer can be added to the formulation prior to the start of the freeze-drying process. If the formulation of the invention contains a pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin, a compatibilizer may not be present. The primary function of the compatibilizer is to provide non-collapsible structural integrity to the freeze-dried solid, which will allow for rapid reconstitution of the aqueous formulation constitution prior to administration, and which should also promote efficient lyophilization. Compatibilizers are typically used when the total mass of solutes in the formulation is less than 2g/100 mL. A compatibilizer may also be added to achieve isotonicity with blood. The compatibilizer may be selected from a sugar, sugar alcohol, amino acid, or polymer, or a mixture of any two or more thereof. Preferably, the compatibilizer is a sugar or sugar alcohol, or a mixture thereof. Preferably, the sugar is sucrose. Preferably, the sugar alcohol is mannitol. The constitution of the freeze-dried solid composition may be achieved using an appropriate amount of water and/or an aqueous solution of a suitable tonicity adjusting agent to ensure a clear solution is obtained.

Therapeutic agents containing at least one basic nitrogen atom (i.e., protonatable nitrogen-containing therapeutic agents) such as gedalisal represent an important group of therapeutic agents. However, nanoparticle formulations of such drugs are often hampered by undesirable properties, such as unfavorable burst profiles and poor drug loading. PCT application publication WO2015138835 discloses therapeutic nanoparticles with Ji Dali plugs of controlled release rate of therapeutic agent.

These therapeutic nanoparticles include Ji Dali plugs (preferably in an amount of about 1 to 20 weight percent), a substantially hydrophobic acid, and a polymer selected from the group consisting of diblock polylactic acid-polyethylene glycol copolymers or diblock poly (lactic acid-co-glycolic acid) -polyethylene glycol copolymers, and combinations thereof. The molar ratio of the substantially hydrophobic acid to the Ji Dali plug is in the range of about 0.25:1 to about 2:1, and the pK of the protonated jidali plug _a pK of specific hydrophobic acid _a About 1.0pK _a Units of (3). The hydrophobic acid and the gemfibrozil form hydrophobic ion pairs in the therapeutic nanoparticle. In addition, the nanoparticle may include a targeting ligand that may increase target binding (cell binding/target uptake) such that the nanoparticle has target specificity.

In general, "nanoparticle" refers to any particle having a diameter of less than 1000 nm. Preferably, the therapeutic nanoparticle may have a diameter in the range of 60nm to 120 nm. For example, the nanoparticle may have a diameter of about 60nm, about 70nm, about 80nm, about 90nm, about 100nm, or about 110nm, up to about 70nm, about 80nm, about 90nm, about 100nm, about 110nm, or about 120 nm.

As used herein, a "substantially hydrophobic acid" is an acid having a pKa in water of about-1.0 to about 5.0. Preferably, the substantially hydrophobic acid has a pKa in water of from about 2.0 to about 5.0. Exemplary substantially hydrophobic acids include, but are not limited to, fatty acids. For example, the fatty acid may be a saturated fatty acid including, but not limited to, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachic acid, heneicosanoic acid, behenic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, cerotic acid, heptacosanoic acid, montanic acid, icosanoic acid, triacontanoic acid, tricontanoic acid, or combinations thereof. In addition, the fatty acid may be omega-3 fatty acids including, but not limited to, hexadecatrienoic acid, alpha-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, or combinations thereof. The fatty acid may also be omega-6 fatty acids including, but not limited to, linoleic acid, gamma-linolenic acid, eicosadienoic acid, dihomo-gamma-linolenic acid, arachidonic acid, docosadienoic acid, epinephrine acid, docosapentaenoic acid, tetracosatetraenoic acid, tetracosapentaenoic acid, or combinations thereof. The fatty acid may also be an omega-9 fatty acid including, but not limited to, oleic acid, eicosenoic acid, midate, erucic acid, nervonic acid, or combinations thereof. The fatty acid may also be a polyunsaturated fatty acid including, but not limited to, rumenic acid, alpha-calendic acid, beta-calendic acid, jacaranganic acid, alpha-eleostearic acid, beta-eleostearic acid, catalpic acid, punicic acid, rumelonic acid, alpha-pantoic acid, beta-pantoic acid, primaries pentaenoic acid (bosseopentaenoic acid), pinolenic acid, arhat pine acid, or combinations thereof.

Alternatively, the hydrophobic acid may be a bile acid. For example, in some embodiments, bile acids include, but are not limited to, chenodeoxycholic acid, ursodeoxycholic acid, deoxycholic acid, hyocholic acid, β -murine cholic acid, lithocholic acid, amino acid conjugated bile acids, or combinations thereof.

Alternatively, the hydrophobic acid may include, but is not limited to, dioctyl sulfosuccinic acid, 1-hydroxy-2-naphthoic acid, dodecyl sulfuric acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, pamoic acid, undecanoic acid, or combinations thereof.

The nanoparticles may be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition. As will be appreciated by those skilled in the art, the carrier may be selected based on the route of administration, the location of the target tissue, the time course of drug delivery, and the like.

The pharmaceutical nanoparticle composition can be administered to a patient or subject by any means known in the art, including oral and parenteral routes. Nanoparticle compositions can be administered by injection (e.g., intravenous, subcutaneous or intramuscular, intraperitoneal injection), rectal, vaginal, topical (e.g., by powder, cream, ointment, or drops), or by inhalation (e.g., by spray).

Injectable formulations (e.g., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be used are water, ringer's solution, u.s.p. And isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. In one embodiment, the conjugate of the invention is suspended in a suspension comprising 1% (w/v) sodium carboxymethyl cellulose and 0.1% (v/v) Tween ^TM 80 in a carrier liquid. The injectable formulation may be sterile, for example, filtered through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition which may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the encapsulated or unencapsulated conjugate is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) wetting agents such as glycerin, (d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glyceryl monostearate, (h) absorbents such as kaolin and bentonite clays, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

It will be appreciated that the exact dosage of the nanoparticle comprising the Ji Dali plug is selected by the individual physician according to the patient to be treated, and that in general, the dosage and mode of administration are adjusted to provide an effective amount of the jidalisade nanoparticle to the patient to be treated. As used herein, an "effective amount" of a nano-particle containing gedaltei refers to the amount necessary to initiate a desired biological response. As will be appreciated by one of ordinary skill in the art, the effective amount of the gedaltei-containing nanoparticle may vary depending on factors such as the desired biological endpoint, the target tissue, the route of administration, and the like. For example, an effective amount of nanoparticle may be an amount that results in a reduction in tumor size over a desired period of time. Other factors that may be considered include the severity of the disease state; age, weight, and sex of the patient receiving the treatment; diet, time of administration and frequency; a pharmaceutical combination; reaction sensitivity; and tolerance/response to treatment.

Aqueous pharmaceutical formulations of Ji Dali plugs suitable for intravenous administration, such as those described above, typically have a pH of 3 to 9. However, lower pH values are tolerated in certain circumstances. The pH may range from about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 up to about 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9. Preferably, the pH is 3 to 8 or 4 to 8.

The weekly dose of Ji Dali plugs administered by intravenous route for the treatment of cancer using the above formulation is preferably in the range of 100mg/mL to 400mg/mL per week. For example, the dosage may be about 100mg/mL weekly, about 110mg/mL weekly, about 120mg/mL weekly, about 130mg/mL weekly, about 140mg/mL weekly, about 150mg/mL weekly, about 160mg/mL weekly, about 170mg/mL weekly, about 180mg/mL weekly, about 190mg/mL weekly, about 200mg/mL weekly, about 210mg/mL weekly, about 220mg/mL weekly, about 230mg/mL weekly, about 240mg/mL weekly, about 250mg/mL weekly, about 260mg/mL weekly, about 270mg/mL weekly, about 280mg/mL weekly, about 290mg/mL weekly, about 300mg/mL weekly, about 310mg/mL weekly, about 320mg/mL weekly, about 330mg/mL weekly, about 340mg/mL weekly, about 350mg/mL weekly, about 360mg/mL weekly, about 370mg/mL weekly, about 380mg/mL weekly, about 390mg/mL weekly, or about 400mg/mL weekly.

CDK4/6 inhibitors

In some embodiments of the present application, a method of treating cancer comprises co-administering a CDK4/6 inhibitor with a Ji Dali plug to a subject. As used herein, the term "CDK4/6 inhibitor" includes compounds that inhibit CDK4 activity, CDK6 activity, or CDK4 and CDK6 activity.

The regulation of the cell cycle is governed and controlled by specific proteins that are activated and deactivated in a precisely timed manner primarily by the phosphorylation/dephosphorylation process. A key protein that coordinates the initiation, progression and completion of the cell cycle program is the Cyclin Dependent Kinase (CDK). Cyclin-dependent kinases belong to the serine-threonine protein kinase family. They are heterodimeric complexes consisting of a catalytic kinase subunit and a regulatory cyclin subunit. CDK activity is controlled by binding of its corresponding regulatory subunit (cyclin) to CDK inhibitor proteins (Cip and Kip proteins, INK 4), by its phosphorylation state and by ubiquitin-mediated proteolytic degradation.

There are four CDKs that are closely related to cell proliferation: CDK1, predominantly modulates the transition from G2 phase to M phase; and CDK2, CDK4 and CDK6, regulate the transition from G1 phase to S phase. Activation of CDK 4-cyclin D and CDK 6-cyclin D induces phosphorylation of retinoblastoma protein (pRb) in early to mid G1 phases when the cells respond to mitotic stimuli. phosphorylation of pRb releases the transcription factor E2F, which enters the nucleus to activate transcription of other cyclin proteins, thereby promoting further progression of the cell cycle. CDK4 and CDK6 are closely related proteins with substantially indistinguishable biochemical properties.

A variety of CDK4/6 inhibitors have been identified, including specific pyrido [2,3-d ] pyrimidines, 2-anilinopyrimidines, diarylureas, benzoyl-2, 4-diaminothiazoles, indolo [6,7-a ] pyrrolo [3,4-c ] carbazoles, and oxindoles. For example, WO 03/062236 identified a series of 2- (pyridin-2-ylamino-pyrido [2,3] pyrimidin-7-one for the treatment of Rb positive cancers showing a selective.Tate et al describe the antitumor activity of the CDK4/6 inhibitor Abeli (LY 2835219) ("Semi-Mechanistic Pharmacokinetic/Pharmacodynamic Modeling of the Antitumor Activity of LY2835219, a New Cyclin-Dependent Kinase 4/6Inhibitor,in Mice Bearing Human Tumor Xenografts", clin Cancer Res (2014, 7, 15) volume 20:3763), raet al describe the use of the der 4/6inhibitor Racemide (LEE 011) to reduce proliferation of neuroblastoma cell lines ("Du 4/6", clin 4/6 (19:3, 11, and 2:6173) as an iodine-containing pyrimidine inhibitor of Va 4/6) and the like, J.Med. Chem. Volume 48 (2005) pages 2371-2387). WO 99/15500 filed by Glaxo Group Ltd discloses protein kinase and serine/threonine kinase inhibitors. WO 2010/020675 filed by Novartis AG describes pyrrolopyrimidine compounds as CDK inhibitors. WO 2011/101409, also filed by Novartis, describes pyrrolopyrimidines with CDK4/6 inhibitory activity. WO 2005/052147 filed by Novartis and WO 2006/074985 filed by Janssen Pharma disclose additional CDK4 inhibitors. WO 2012/061156 filed by Tavares and assigned to G1 Therapeutics describes CDK inhibitors. WO 2013/148748, filed by Francis Tavares and assigned to G1 Therapeutics, describes lactam kinase inhibitors.

Selective CDK4/6 inhibitors are generally designed to target CDK4/6 replication-dependent cancers. For example, michaud et al reported that the CDK4/6 inhibitor PD-0332991 was inactive against Rb negative tumors. (Michaud et al, "Pharmacologic Inhibition of Cyclin-Dependent Kinase 4and 6Arrests the Growth of Glioblastoma Multiform Intracranial Xenografts." Cancer Res. Volume 70: pages 3228-3238 (2010)).

In some embodiments, the CDK4/6 inhibitor is selected from the group consisting of piperine Bai Xili, rebaudimide, abbe-sirolimus, trasturil, darcy-sirolimus, and combinations thereof.

CDK4/6 inhibitors may be administered using methods known in the art. In some embodiments, the CDK4/6 inhibitor is piperaquine Bai Xili. Pepper Bai Xili (Ibrance) ^TM The psilon company, new York, NY) was obtained in the form of 125mg, 100mg, and 75mg tablets and capsules. See Ibrance ^TM Prescription information. The recommended dose of Bai Xi is 125mg, orally once a day for 21 consecutive days, and then stopping the treatment for 7 days, constituting a complete cycle of 28 days. As above. The treatment cycle may be modified based on the outcome of the treatment and the patient's tolerance. As above. For example, if the patient develops neutropenia, the administration of the pimple Bai Xili can be reduced to 100mg or 75mg once a day for 21 consecutive days, followed by stopping the treatment for 7 days. As above.

Rabociclib (Kisqali) ^TM The North Switzerland pharmaceutical company (Novartis, switzerland)) was obtained as 200mg tablets. See Kisqali ^TM Prescription information. The recommended dose of reboxetine was 600mg (three 200mg tablets) taken orally once a day for 21 consecutive days, and then stopped for 7 days, constituting a complete cycle of 28 days. As above. The treatment cycle may be modified based on the outcome of the treatment and the patient's tolerance. As above. For example, if a patient develops negative side effects, the administration of rebaudimide may be reduced to 400mg or 200mg once a day for 21 consecutive days, followed by cessation of treatment for 7 days. As above.

Abeli (Verzenio) ^TM Gift pharmaceutical (Eli Lilly, indianapolis, ind.) of Ind.) is obtained as 200mg, 150mg, 100mg and 50mg tablets. See Verzenio ^TM Prescription information. The recommended dose of abbe-cili when administered in combination with fulvestrant is 150mg twice daily. As above. The recommended dose of abbe-cili when not administered with fulvestrant is 200mg twice daily. As above. If the dose has to be reduced, it is recommended to reduce the dose of abbe-cili by 50mg each time. As above.

Traracilli (Cosela) ^TM G1 Therapeutics, inc.) in North Carolina (NC) were obtained as 300mg of lyophilized powder in single dose vials. See Cosela ^TM Prescription information. The recommended dose of treoxeli is 240mg/m per dose ² Administered as Intravenous (IV) infusion. As above. Troxili was reconstituted with 19.5mL of 0.9% sodium chloride injection or 5% dextrose injection (USP) to achieve a concentration of 15 mg/mL. As above. The administration of trehaline is typically by 30 minutes intravenous infusion and must be completed within 4 hours before chemotherapy begins when chemotherapy is administered daily. As above.

Clinical trials are underway with darcy (SHR 6390, jiangsu Hengrui pharmaceutical Co., ltd.) at a dose of 150mg, orally once daily on days 1 to 21 of each 28-day cycle, and then discontinuing the treatment for 7 days. See NCT04236310, month 1, 17 of 2020. The use of darcilii in combination with letrozole or anastrozole or fulvestrant in patients with advanced breast cancer both HR positive and HER2 negative is currently being investigated.

Clinical trials are underway with lividirie (P276-00, the group of pilamard (Piramal Enterprises ltd., mumbai, IN)) at 185mg/m IN 200mL5% glucose over 30 minutes per day on days 1 to 5 of a 21 day cycle ² Is administered as intravenous infusion. See NCT00898287, 2012, 1 month and 20 days. The use of livincicli in combination with gemcitabine and carboplatin in patients with metastatic triple negative breast cancer has been studied.

Estrogen receptor antagonists

The Estrogen Receptor (ER) is a ligand-activated transcriptional regulator protein that mediates induction of a variety of biological effects through interactions with endogenous estrogens. Endogenous estrogens include 17β (beta) -estradiol and estrone. ER has been found to have two isoforms, ER- α (alpha) and ER- β (beta).

In some embodiments of the present application, a method of treating cancer comprises co-administering to a subject an estrogen receptor antagonist together with gemfibrozil and optionally a CDK4/6 inhibitor. As used herein, the term "estrogen receptor antagonist" includes compounds that act competitively by substituting estrogen from the receptor.

ARN-810 (GDC-0810,Seragon Pharmaceuticals,Genentech Inc.) is a small molecule, non-steroidal, selective ER modulator that antagonizes the effects of estrogens and induces ER degradation by the proteasome. ARN-810 is undergoing clinical trials as an oral delivery therapy for the treatment of advanced metastatic ER-alpha positive (er+) breast cancer.

PCT application publication WO2013/090836 discloses fluorinated estrogen receptor modulators and uses thereof.

PCT application publication WO2014/205136 discloses azetidine estrogen receptor modulators and uses thereof.

U.S. patent application publication No. 2003/01330274 discloses 2-phenyl-1- [4- (2-aminoethoxy) benzyl ] -indole as an estrogenic agent.

One exemplary estrogen receptor antagonist for use in the methods of the present application is fulvestrant.

Fulvestrant (Faslodex) ^TM The aslican pharmaceutical company of Cambridge, england (AstraZeneca, cambridge, UK)) can be obtained as an injection for intramuscular administration, provided in 250mg/5mL vials. See Faslodex ^TM Prescription information. The recommended dose of fulvestrant was 500mg, which was slowly injected intramuscularly to the buttocks (gluteus area) on days 1, 15, 29 with two 5mL injections, once a month thereafter. See above. For patients with moderate liver injury, the recommended dose is 250mg, injected intramuscularly once at 5mL on days 1, 15, 29, and monthly thereafter. See above.

IV. preparation

In some embodiments, the gemfibrozil, CDK4/6 inhibitor, and estrogen receptor antagonist used in the methods of the present application may be formulated with one or more pharmaceutically acceptable excipients to form a pharmaceutical composition.

The pharmaceutical compositions used in the methods disclosed herein may be particularly formulated in solid or liquid form, including forms suitable for parenteral administration, for example by intravenous, subcutaneous, intratumoral or intramuscular injection or infusion, for example as a sterile solution or suspension.

Injectable formulations of the pharmaceutical compositions used in the methods disclosed herein or formulations for infusion may be prepared by known methods. For example, injectable or infusible formulations may be prepared, for example, by dissolving, suspending or emulsifying the FcRn inhibitor or salt thereof in a sterile aqueous or oily medium conventionally used for injection. As the aqueous medium for injection or infusion, for example, physiological saline, isotonic solution containing glucose and other auxiliary agents, and the like can be cited, and they may be used in combination with suitable solubilizing agents such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adducts of hydrogenated castor oil)), and the like. As the oily medium, for example, sesame oil, soybean oil, etc. may be employed, which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injectable or infusible formulation so prepared is preferably filled in a suitable injection ampoule or vial or bag suitable for infusion.

The pharmaceutically acceptable excipient may be a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, manufacturing aid (e.g., lubricant, talc, magnesium, calcium or zinc stearate, or stearic acid), solvent or encapsulating material, which involves carrying or transporting the therapeutic compound, compatibilizer, salt, surfactant, and/or preservative for administration to a subject. Some examples of materials that may be used as pharmaceutically acceptable excipients include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; gelatin; talc; a wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as ethylene glycol and propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; a buffering agent; water; isotonic saline; a pH buffer; and other non-toxic compatible substances for pharmaceutical formulations.

Compatibilizers are compounds that increase the quality of a pharmaceutical formulation and contribute to the physical structure of the lyophilized form of the formulation. Suitable compatibilizers according to the invention include mannitol, glycine, polyethylene glycol and sorbitol.

The use of surfactants may reduce aggregation of the reconstituted protein and/or reduce particle formation in the reconstituted formulation. The amount of surfactant added is such that it reduces aggregation of the reconstituted protein and minimizes particle formation after reconstitution. Suitable surfactants according to the invention include polysorbates (e.g. polysorbate 20 or 80); poloxamers (e.g., poloxamer 188); triton; sodium Dodecyl Sulfate (SDS); sodium lauryl sulfate; sodium octyl glucoside; lauryl-sulfobetaine, myristyl-sulfobetaine, linoleoyl-sulfobetaine or stearyl-sulfobetaine; lauryl-sarcosine, myristyl-sarcosine, linoleoyl-sarcosine or stearyl-sarcosine; linoleoyl-betaine, myristyl-betaine or cetyl-betaine; lauramidopropyl-betaine, cocamidopropyl-betaine, oleamidopropyl-betaine, myristamidopropyl-betaine, palmitoamidopropyl-betaine, or isostearamidopropyl-betaine (e.g., lauramidopropyl); myristamidopropyl-dimethylamine, palmitoamidopropyl-dimethylamine or isostearamidopropyl-dimethylamine; methyl cocoyl-sodium taurate or methyl cocoyl-disodium taurate; and polyethylene glycol, polypropylene glycol, and copolymers of ethylene glycol and propylene glycol (e.g., pluronics, PF68, etc.).

Preservatives may be used in the formulations provided herein. Suitable preservatives for use in the formulations of the present invention include octadecyl dimethyl benzyl ammonium chloride, hexamethyl ammonium chloride, benzalkonium chloride (a mixture of alkyl benzyl-dimethyl ammonium chlorides wherein the alkyl group is a long chain compound) and benzethonium chloride. Other types of preservatives include aromatic alcohols such as phenol, butanol and benzyl alcohol, alkyl parahydroxybenzoates (such as methyl parahydroxybenzoate or propyl parahydroxybenzoate), catechol, resorcinol, cyclohexanol, 3-pentanol and m-cresol. Other suitable excipients can be found in standard pharmaceutical textbooks, for example in "Remington's Pharmaceutical Sciences", the Science and Practice of Pharmacy, 19 th edition, mack Publishing Company, easton, pa. (1995).

In some embodiments, the gemfibrozil and optional CDK4/6 inhibitor and/or estrogen receptor antagonist used in the methods disclosed herein may be lyophilized and provided in a composition for reconstitution prior to administration.

V. kit and unit dosage form

Also provided herein are kits comprising a pharmaceutical composition comprising a therapeutically effective amount of jidalisade and optionally a CDK4/6 inhibitor and/or an estrogen receptor antagonist, suitable for use in the methods described herein, and a pharmaceutically acceptable carrier. The kit optionally may also include instructions, for example, including a dosing schedule, to allow a practitioner (e.g., doctor, nurse, or patient) to administer the composition contained therein to a patient suffering from cancer. The kit may further comprise a syringe.

Optionally, the kit comprises a plurality of packages of single dose pharmaceutical compositions, each package containing an effective amount of a Ji Dali plug (e.g., 180 mg) for single administration according to the methods provided above. The apparatus or device required to administer the pharmaceutical composition may also be included in the kit. For example, the kit may provide one or more prefilled syringes containing therein an amount of liquid required to reconstitute the gedali plug.

VI subject population

A subject treated with the methods described herein can have one or more of the following features.

In one embodiment, the subject is in need of treatment for cancer. In some embodiments, the cancer is a solid cancer (solid tumor). The solid cancer may be selected from breast cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, prostate cancer, testicular cancer, penile cancer, lung cancer, colorectal cancer, melanoma, bladder cancer, brain/CNS cancer, esophageal cancer, gastric cancer, head/neck cancer, renal cancer, liver cancer, pancreatic cancer, and sarcoma.

Cancers that may be treated with the methods and compositions described herein include, but are not limited to, solid cancers that are hormone dependent, hormone responsive and/or hormone sensitive (collectively, "hormone responsive cancers"). Exemplary cancers that may be treated include, but are not limited to, androgen-responsive cancers, such as estrogen-responsive cancers and testosterone-responsive cancers. In some embodiments, the cancer may be a non-hormone reactive cancer that was previously responsive to hormone therapy but later became non-hormone non-responsive. Exemplary hormone-dependent cancers include, but are not limited to, breast cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, prostate cancer, testicular cancer, and penile cancer. In some embodiments, the hormone-dependent cancer is breast cancer.

In some embodiments, the subject of the methods herein is in need of treatment for breast cancer. Breast cancer may be diagnosed using any method known in the art. For example, cancer can be diagnosed by testing a subject for a tumor (e.g., tumor biopsy), blood, body fluids, or other tissue. The subject may also receive a biomarker test to determine the classification of breast cancer.

The term "biomarker" refers in the most general sense to a cellular condition or a biological measure of the health or disease state of a patient. A non-limiting list of general biomarkers includes biological derived molecules found in mammals, biological activity of mammalian cells or tissues, gene copy number, gene mutation, single nucleotide polymorphism, gene expression level, mRNA level, splice variant, transcriptional modification, post-transcriptional modification, epigenetic modification, differential expression of cell surface markers, proteins or nucleic acids (including all forms of functional RNA), amplification of nucleic acids, cell morphology, post-translational modification, protein truncation, phosphorylation, dephosphorylation, ubiquitination, deubiquitination, metabolites, hormones at any stage of biosynthesis, cytokines, chemokines, and combinations thereof. The subset of biomarkers is used for diagnostic and treatment selection purposes to assist a pathologist in diagnosing disease and assisting a physician in prescribing treatment. Biomarkers generally measure gene copy number, gene mutation, or protein levels in fixedly mounted tissues without specifying the status or activity of the protein.

The term "biomarker status" refers to an assessment of a biomarker in cells of one or more patients, and is typically reported as "biomarker positive" when the biomarker is present, or as "biomarker negative" when the biomarker is not present. When a protein receptor is used as a biomarker (e.g., HER2/ErbB2 or ER), a biomarker positive result is also referred to as receptor over-expression or amplification, while a biomarker negative result is referred to as receptor normal expression or non-amplification. For diseases in which the biomarker or biomarker signature is a prognostic indicator of disease progression or predictive of efficacy, current clinical practice relies on measurement of the amount of the biomarker or its associated mutation to refine the diagnosis of the patient by classifying the patient as either negative or positive for the biomarker.

The term "HER2/ErbB2 status" refers to an assessment of the expression of HER2/ErbB2 as a biomarker in a patient or patient cells (e.g., cancer cells), and the status is typically reported as "HER2/ErbB2 positive" when there is an excess compared to a normal healthy non-breast cancer tissue sample, or as "HER2/ErbB2 negative" when the biomarker is present at a level no greater than a normal healthy non-breast cancer tissue sample, as determined by the IHC staining test of a fixed tissue sample. Various methods are known in the art for assessing the status of HER2/ErbB2, typically focusing on the amount of receptor expressed by a patient's cells (IHC), or mRNA levels (qPCR), or gene copy number (FISH), thereby diagnosing the patient as HER2/ErbB positive (when the receptor is overexpressed or amplified in the patient's cells) or HER2/ErbB negative (when the receptor is not overexpressed or amplified in the patient's cells). Overexpression and amplification are terms of art that describe levels higher than those found in similar tissues from normal disease-free individuals.

The term "estrogen receptor status" or "ER status" refers to an assessment of expression of ER as a biomarker in a patient or patient cells (e.g., cancer cells), and the status is typically reported as "ER positive" when the biomarker is overexpressed in the nuclei of a stained fixed sample, or as "ER negative" when the biomarker is normally expressed or absent in the nuclei of a stained fixed sample. Various methods are known in the art for assessing the status of ER, typically focusing on the amount of receptor expressed by a patient's cells (IHC), or mRNA levels (qPCR), to diagnose a patient as ER-positive (when the receptor is expressed in a patient's cells) or ER-negative (when the receptor is not expressed in a patient's cells).

The term "targeted pathway drug", "pathway drug" or "targeted drug" refers to any molecule or antibody having therapeutic capabilities that is designed to bind to a particular biological molecule (e.g., protein) involved in a disease process, thereby modulating its activity.

The term "HER2 therapy" or "HER2 targeted therapy" refers to treatment with one or more therapeutic agents designed to specifically target HER2 molecules and/or signaling pathways (including, but not limited to, e.g., antibodies and small molecules that target HER2 molecules and/or signaling pathways). Such HER2 therapies may also target other members of the HER family, such as therapies targeting both HER1 and HER2, HER1, HER2 and HER4, or HER3 alone.

The term "ER therapy", "ER-targeted therapy" or "hormonal therapy" refers to treatment with one or more therapeutic agents designed to specifically target ER molecules and/or signaling pathways, including but not limited to aromatase inhibitors, selective estrogen receptor modulators, and selective estrogen receptor degradants, as well as combinations of such therapies with therapies that inhibit cyclin dependent kinases CDK4 and CDK 6.

In some embodiments, the breast cancer is metastatic breast cancer, hormone-resistant breast cancer, estrogen receptor positive breast cancer, estrogen receptor negative breast cancer, progesterone receptor positive breast cancer, triple negative breast cancer, HER2 positive breast cancer, or HER2 negative breast cancer. In further embodiments, the subject is a pre-menopausal female patient or a post-menopausal female patient.

In some embodiments, the breast cancer is a basal subtype or a luminal subtype. Breast cancer is known to be a heterogeneous disease. There are different subtypes that can be defined based on (i) molecular profiling of breast cancer tumors, (ii) gene array testing, or (iii) immunohistochemical analysis methods. Specifically, the breast catheter is a bilayer structure consisting of a luminal layer and a myoepithelial layer adhered to a basement membrane. The term "basal carcinoma" refers to certain cancers that originate from the basal lamina of the stratified epithelium. The basal subtype of breast cancer exists in the basal layer of the ductal epithelium of the breast, rather than in the apical or luminal layers. Such cancers have unique cytological features and gene expression profiles, such as the intermediate filament profile (cytokeratin) that is first observed in basal cells of the skin.

About 14% -20% of breast cancers are basal-like. Basal-like breast cancers differ from luminal cancers in that they are triple negative for the immunophenotype marker ER-/PR-/HER2-, but express CK5/6. Basal-like breast cancers exhibit increased hypoxia and high tumor grade, and have invasive phenotypes characterized by high cell proliferation and poor clinical outcome. Most BRCA1 breast cancers and many BRCA2 breast cancers are triple negative/basal-like. Triple negative/basal-like tumors are often invasive and have a poorer prognosis than estrogen receptor positive subtypes (luminal a and luminal B tumors). Triple negative/basal-like tumors are commonly treated with some combination of surgery, radiation therapy and chemotherapy. These tumors cannot be treated with hormone therapy or trastuzumab because they are hormone receptor negative and HER2/neu negative.

Most breast cancers are luminal tumors. Luminal tumor cells look like breast cancer cells, starting with the internal (luminal) cells of the inner layer of the breast duct. Luminal a breast cancers are er+ and/or pr+, HER2- (low Ki 67). About 42% -59% of breast cancers are luminal a. Luminal a tumors tend to have low or moderate tumor grade. Of the four subtypes, luminal a tumors tend to have the best prognosis, have fairly high survival rates, and fairly low recurrence rates. Only about 15% of luminal a tumors have p53 mutations, a factor associated with a poor prognosis.

Luminal B breast cancers are er+ and/or pr+, her2+ (or HER2 with high Ki 67). About 6% -17% of breast cancers are luminal B. Women with luminal B tumors are usually diagnosed at a younger age than those with luminal a tumors. Luminal B tumors also tend to have factors that lead to a poorer prognosis compared to luminal a tumors, including: poor tumor grading; larger tumor size; and p53 gene mutation. In general, the survival rate of women with a luminal B tumor is quite high, although not as high as women with a luminal a tumor.

In some embodiments, the breast cancer is ductal carcinoma in situ (intraductal carcinoma), lobular carcinoma in situ, invasive (or invasive) ductal carcinoma, invasive (or invasive) lobular carcinoma, inflammatory breast cancer, triple negative breast cancer, paget's disease of the nipple, phyllode tumor, angiosarcoma, or invasive breast cancer. In some embodiments, invasive breast cancers are further classified as subtypes. In some embodiments, the subtype includes adenoid cystic (or adenocystic) carcinoma, lower adenosquamous carcinoma, medullary carcinoma, mucinous (or glioblastoma), papillary carcinoma, tubular carcinoma, metaplasia carcinoma, micropapillary carcinoma, or mixed carcinoma.

In some embodiments, breast cancers are classified according to the stage of tumor cells or the extent of spread within breast tissue and other parts of the body. Breast cancer has five stages, stages 0-IV. The methods of treating cancer described herein can be used to treat breast cancer patients classified as stage 0-IV.

Stage 0 breast cancer refers to non-invasive breast cancer, or evidence that no cancerous or abnormal non-cancerous cells have broken through the primary site. Stage I breast cancer refers to invasive breast cancer in which cancer cells have invaded surrounding tissues. Stage I is subdivided into stage IA and stage IB, where stage IA describes tumor sizes up to 2cm, and there is no spread of cancer cells. Stage IB describes no tumor in the breast, but 0.2mm to 2mm small tumor cell mass in the lymph nodes. Stage II breast cancer is further subdivided into stage IIA and stage IIB. Stage IIA describes the presence of a tumor of 2cm to 5cm in the breast alone, or no tumor in the breast but 2mm to 2cm in the axillary lymph nodes. Stage IIB describes the presence of a tumor of greater than 5cm in the breast alone, or 2cm to 5cm in the breast and 0.2mm to 2mm small tumors in the axillary lymph nodes. Stage III breast cancer is further subdivided into stage IIIA, stage IIIB and stage IIIC. Stage IIIA describes the absence of a tumor in the breast or the presence of a tumor greater than 5cm, and the presence of a small tumor in 4-9 axillary lymph nodes or a small tumor of 0.2mm-2mm size in axillary lymph nodes. Stage IIIB describes the spread of the tumor into the chest wall or breast skin leading to swelling or ulceration, and the presence of the tumor in up to 9 axillary lymph nodes. Inflammatory breast cancer is also known as stage IIIB. Stage IIIC describes no tumor or spread of tumor to the chest wall or breast skin, tumor being present in 10 or more axillary lymph nodes. Stage IV breast cancer refers to invasive breast cancer that has metastasized to lymph nodes and other parts of the body.

In other embodiments, the cancer may be adrenal cancer, lymphatic system cancer such as lymph node cancer, leukemia, lymphoma, myeloma, fahrenheit macroglobulinemia, monoclonal gammaglobulinopathy, benign monoclonal gammaglobulopathy, heavy chain disease, bone and connective tissue sarcoma, brain tumor, thyroid cancer, pancreatic cancer, pituitary cancer, eye cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gall bladder cancer, bile duct cancer, lung cancer, oral cancer, skin cancer, kidney cancer, wilms' tumor, and bladder cancer.

In some embodiments, the human subject fails prior treatment (e.g., endocrine treatment) of the cancer (e.g., breast cancer) in less than twelve months (e.g., less than six months). In some embodiments, the human subject fails to treat the cancer in two or more previous treatments. The previous treatment of failure may be endocrine and/or non-endocrine treatment of cancer.

VII application of

It was found that administration of Ji Dali plugs was more effective in 28 day cycles (three weeks weekly administration and one week without Ji Dali plugs) when compared to the non-periodic (weekly) administration schedule. A 28 day cycle includes intravenous administration of Ji Dali plugs once a week for three weeks (e.g., on days 1, 8, and 15 of the cycle), followed by one week without administration of Ji Dali plugs (e.g., without administration of Ji Dali plugs on day 21).

One aspect of the invention relates to a method of treating cancer in a human subject. The method comprises selecting a human subject in need of treatment for cancer. A therapeutically effective amount of jidalisade or a pharmaceutically acceptable salt, solvate or ester thereof is administered to a human subject at least once a week for a period of three weeks. The administration of the Ji Dali plug or pharmaceutically acceptable salt, solvate or ester thereof is discontinued for a subsequent week. Administration of the gedaltei or pharmaceutically acceptable salt, solvate or ester thereof is then resumed at least once per week after the discontinuation period. The administration for at least three weeks and the discontinuation of administration for at least one week constitute a cycle, and the cycle is repeated for at least two cycles.

In some embodiments, administration of the gedaltei, or a pharmaceutically acceptable salt, solvate or ester thereof, is resumed, at least once per week for a period of three weeks.

In further embodiments, the administration period is performed for at least 3 periods, at least 4 periods, at least 5 periods, at least 6 periods, at least 7 periods, at least 8 periods, at least 9 periods, or at least 10 or more periods. Administration may be performed as many cycles as possible to achieve the desired result (e.g., alleviation of cancer), or until treatment is no longer needed. For example, administration may be performed for at least 20 cycles, at least 30 cycles, at least 40 cycles, or at least 50 cycles.

In some embodiments, the Ji Dali plug or pharmaceutically acceptable salt, solvate or ester thereof is administered once per week at a dose of 180 mg. As will be apparent to those of skill in the art, the dosage of Ji Dali plugs administered to a subject can be increased or decreased depending on the subject, the severity of the disease, and the mode of administration. For example, the dosage of gemfibrozil administered may be in the range of about 25 mg/week, 50 mg/week, 100 mg/week, 150 mg/week, or 200 mg/week, up to about 50 mg/week, 100 mg/week, 150 mg/week, 225 mg/week, or 250 mg/week.

The methods described herein may further comprise administering an additional therapeutic compound. Additional therapeutic compounds may be administered simultaneously with the Ji Dali plug. Alternatively, administration of the additional therapeutic compound may be performed asynchronously to administration of the Ji Dali plug.

In some embodiments, the method further comprises administering a CDK4/6 inhibitor to the human subject at least once a week for a period of three weeks. The administration of the CDK4/6 inhibitor is then discontinued for a period of one week, followed by resumption of administration of the CDK4/6 inhibitor for at least one week. The cycle of administration and discontinuation of the CDK4/6 inhibitor is repeated for at least two cycles.

In some embodiments of the method of treating cancer, administration of the CDK4/6 inhibitor is concurrent with administration of the Ji Dali plug, or pharmaceutically acceptable salt, solvate or ester thereof, within a few weeks. CDK4/6 inhibitors useful in the methods herein include, but are not limited to, pimento Bai Xili, rabociclib, abeli, triamcinolone acetonide, darzepine, livalvuline, and combinations thereof. Preferably, the CDK4/6 inhibitor is piperaquine Bai Xili. The pimples Bai Xili can be administered in dosages determined by the physician to produce the desired result. For example, the dose of pimple Bai Xi advantageously may be 125mg per day, 100mg per day or 75mg per day. Preferably, the dose of pimple Bai Xi is 125mg per day.

Some embodiments of a method of treating cancer comprise administering an estrogen receptor antagonist to a human subject. Examples of estrogen receptor antagonists useful in the methods of the invention are described above. Preferably, the estrogen receptor antagonist is fulvestrant. Fulvestrant may be administered at doses determined by the physician to produce the desired result. For example, the dose of fulvestrant may be 500mg or 200mg as an intramuscular injection for 6 weeks every other week (e.g. on day 1, day 15, day 29) and once a month thereafter. In some embodiments, fulvestrant is administered at a dose of 500mg every two weeks. In a further embodiment, fulvestrant is administered at a dose of 500mg every four weeks.

Another aspect of the present application relates to a method of treating cancer in a human subject comprising selecting a human subject in need of treatment for cancer. The method comprises administering to the human subject a therapeutically effective amount of a jideli plug or a pharmaceutically acceptable salt, solvate or ester thereof and a CDK4/6 inhibitor, at least once a week for a period of three weeks. The administration of the Ji Dali plug or pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor is discontinued for a subsequent week. Administration of the gedaltei or pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor is then resumed after the disruption period, at least once per week. The administration for at least three weeks and the discontinuation of administration for at least one week constitute a cycle, and the cycle is repeated for at least two cycles.

In some embodiments, administration of the gedaltei or pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor is resumed, at least once per week, for a period of three weeks.

Another aspect of the present application relates to a method of treating cancer in a human subject. The method comprises the following steps: selecting a human subject in need of treatment for cancer; administering to the human subject a therapeutically effective amount of a jideli plug or a pharmaceutically acceptable salt, solvate or ester thereof and a CDK4/6 inhibitor, at least once a week for a period of three weeks; interrupting administration of the Ji Dali plug or pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor for a period of one week; resuming administration of the gedaltei or a pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor after an interruption period, at least once per week, wherein administration for at least three weeks and interruption for at least one week constitutes a cycle, wherein the cycle is repeated for at least two cycles; administering an estrogen receptor antagonist to a human subject.

In some embodiments, the Ji Dali plug is administered intravenously to a human subject once a week for three weeks, followed by a week without the Ji Dali plug for treatment of hormone-dependent cancer (e.g., breast cancer). In some embodiments, the subject fails a prior treatment (e.g., endocrine treatment) of breast cancer in less than twelve months (e.g., less than six months). In some embodiments, the subject fails to treat the cancer in two or more previous treatments. The previous treatment of failure may be endocrine treatment of cancer and/or non-endocrine treatment of cancer.

The method of the invention may be used as an adjunct therapy. As used herein, "adjuvant therapy" refers to therapy performed on a cancer patient immediately after an initial non-chemotherapeutic therapy (e.g., surgery or radiation therapy). In general, the goal of adjuvant therapy is to provide a significantly smaller risk of relapse than would be the case without adjuvant therapy. For example, the subject may undergo surgery or radiation therapy after which they receive treatment using the methods described herein.

The results and efficacy of the methods described herein can be assessed using any suitable method. Cancer symptoms that can be reduced or eliminated by the methods disclosed herein include, but are not limited to, any subjective, objective, or quantitative evidence of a disease or other physical abnormality in a subject or patient. For example, symptoms may include tumor size, pain, headache, nausea, blood markers (e.g., CA 15.3, TRU-QUANT, CA 27.29, CA125, CEA (carcinoembryonic antigen), circulating tumor cells) and the like, which indicate cancer or cancer progression.

In some embodiments, the method of treatment results in an improved Progression Free Survival (PFS), overall Survival (OS), and quality of life.

In some embodiments, the subject achieves Partial Remission (PR). Partial remission may be defined as a reduction in tumor size but not complete remission. The reduction in tumor size may allow the subject to undergo surgery to ablate the tumor.

In some embodiments, the subject achieves Complete Remission (CR). Complete remission may be defined as complete remission of cancer.

Additional combination therapies

In some embodiments, the invention provides methods of treating cancer comprising administering to a subject a Ji Dali plug (e.g., according to the dosing regimen described herein) in combination with one or more additional anti-cancer agents or a combination treatment regimen. In embodiments, the anti-cancer agent is a checkpoint inhibitor. In embodiments, the checkpoint inhibitor is a biotherapeutic agent or a small molecule. The checkpoint inhibitor may be a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. Checkpoint inhibitors may inhibit checkpoint proteins selected from the group consisting of CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, and combinations thereof. The checkpoint inhibitor may interact with a ligand of a checkpoint protein, which may be a CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligand, or a combination thereof. In some embodiments, the therapeutic agent is an immunostimulant, a T cell growth factor, an interleukin (e.g., IL-7 or IL-15), an antibody, a vaccine (e.g., a Dendritic Cell (DC) vaccine), or a combination thereof.

In some embodiments, the effectiveness of the treatment is determined by clinical outcome, such as an increase, enhancement, or prolongation of T cell anti-tumor activity; the number of anti-tumor T cells or activated T cells is increased compared to the pre-treatment number, or a combination thereof. In another aspect, the clinical outcome is tumor stabilization, tumor regression, or stabilization; tumor shrinkage; tumor necrosis; an anti-tumor response of the immune system; inhibit expansion, recurrence or spread of the tumor, or a combination thereof.

In further embodiments, the checkpoint inhibitor and the Ji Dali plug are administered simultaneously or sequentially in either order. In further embodiments, the Ji Dali plug is administered prior to the checkpoint inhibitor.

In embodiments, the additional anti-cancer agent that can be co-administered to the subject is a chemotherapeutic agent, such as a cytotoxic chemotherapeutic drug compound.

The term "chemotherapy" or "chemotherapeutic agent" as used herein refers to treatment with a cytostatic or cytotoxic agent (i.e., a compound) to reduce or eliminate the growth or proliferation of unwanted cells (e.g., cancer cells). Thus, as used herein, "chemotherapy" or "chemotherapeutic agent" refers to a cytotoxic or cytostatic agent for the treatment of a proliferative disease (e.g., cancer).

Exemplary cytotoxic chemotherapeutic drug compounds include, but are not limited to, cyclophosphamide, ifosfamide, methotrexate, substituted nucleotides, substituted nucleosides, fluorouracil, mitomycin, doxorubicin, vincristine, vindesine, paclitaxel, cisplatin, carboplatin, etoposide, or combinations thereof.

In some embodiments, in addition to the Ji Dali plug, supportive care is also administered to the subject, e.g., pain medications for headache, treatment for infusion-related reactions (IRR), and prevention for infusion-related reactions. Symptoms of IRR include, for example, flushing, heart rate and blood pressure changes, dyspnea, bronchospasm, back pain, fever, urticaria, edema, nausea and rash.

In some embodiments, the treatment of IRR is selected from: acetaminophen, IV hydrating agent, diphenhydramine, histamine ₂ Blockers (e.g., famotidine) and corticosteroids.

In some embodiments, the prevention of IRR (e.g., if the subject experiences IRR in need of treatment with a corticosteroid) comprises administering hydrocortisone (e.g., hydrocortisone IV) prior to administering the Ji Dali plug.

The contents of all figures and all references, genbank sequences, journal publications, patents and published patent applications cited in this application are expressly incorporated herein by reference in their entirety. Furthermore, when the definition or use of a term in a reference, which is incorporated by reference, is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

The following examples are illustrative only and should not be construed as limiting the scope of the disclosure in any way, as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure.

Examples

Example 1: three arm phase 1b trial of gedalisal + pimela Bai Xili + fulvestrant in women with metastatic breast cancer or locally advanced/recurrent breast cancer

Upregulation of the PI3K/AKT/mTOR pathway promotes hormone-dependent and independent ER transcriptional activity that contributes to endocrine resistance, leading to tumor cell growth, survival, motility, and metabolism. In vivo experiments have also demonstrated that PI3K and mTOR inhibition can restore sensitivity to endocrine therapies, providing a powerful theoretical basis for the combination of both therapies. In addition, the PI3K/AKT/mTOR pathway, like other mitogenic pathways, also promotes cyclin D and CDK4/6 activity to drive the proliferative cell cycle. Internal preclinical studies by the company xenobiotics provide evidence in cell line xenograft models that suggest that the combination of PI3K and CDK4/6 inhibitors can overcome the inherent and adaptive resistance to endocrine therapies, leading to tumor regression. In the MCF7 xenograft model (er+/HER 2-/PIK3CA mutant), ji Dali plug in combination with pimento Bai Xili and fulvestrant resulted in persistent tumor regression. Importantly, within 20 days of triple therapy, the tumor regressed to a minimum volume and continued to remain dormant for up to 90 days without further therapy.

To evaluate this hypothesis, the psilosis company initiated a phase 1 trial dose discovery trial in patients with er+/HER 2-metastatic breast cancer, employing four sets of extensions to evaluate the safety and efficacy of Ji Dali plugs when added to standard doses of pimentole Bai Xili plus or pimentole Bai Xili plus fulvestrant. The PI3K mutant status is not used as a qualification criterion. The trial patient entry was completed. A preliminary analysis of 103 patients who entered the expanded portion of the group 1b phase clinical trial by the database expiration date of day 1, 2021, 11 showed that:

60% Objective Remission Rate (ORR): of the 88 evaluable patients, 53 patients exhibited partial remission, either confirmed or not confirmed, PR (48 confirmed, 5 not confirmed).

75% Clinical Benefit Rate (CBR): of the 88 evaluable patients, 66 patients exhibited confirmed PR or disease stabilization for 24 weeks.

Patients entering arm D represent the study population to be entered into the group trial-patients whose immediate prior therapy was endocrine therapy combined CDK4/6 inhibitor.

The median survival in no progression was 13.2 months.

In contrast, the weighted average median PFS for standard care therapy was about 5.7 months.

1. Purpose(s)

The main objective of this study was to evaluate the safety, tolerability and Maximum Tolerated Dose (MTD) of the triplet combinations of Ji Dali plugs added to standard doses of either pimentazole Bai Xili/letrozole or pimentazole Bai Xili/fulvestrant. Another object was to determine if the triplet combination of Ji Dali secapine Bai Xili/letrozole OR jialisecapine Bai Xili/fulvestrant produced a better Objective Relief (OR) in patients with metastatic breast cancer (mBC) than the historical control data of the doublet combination of piperaquine Bai Xili plus letrozole OR fulvestrant.

Secondary objectives included further evaluation of the safety and tolerability of the combinations tested in the study to evaluate the antitumor activity of the dose escalation portion, evaluation of other efficacy parameters in the expansion portion, including Duration of Remission (DR) and Progression Free Survival (PFS), characterization of the potential for prolonged QTc interval, evaluation of single and multi-dose Pharmacokinetics (PK) of Ji Dali plug and pip Bai Xili, and multi-dose pharmacokinetics (only for the dose escalation portion) of fulvestrant and letrozole, and evaluation of single and multi-dose Pharmacokinetics (PK) of gedaltesection (only for the dose expansion portion).

2. Study design

This is a phase 1, multicenter, open-label study for mBC patients. The study has two parts, dose escalation and dose expansion. The dose escalation portion will identify the MTD of the combination of Ji Dali secapine Bai Xili/letrozole and jidalisiapine Bai Xili/fulvestrant. The dose extension section will estimate the objective remission rate of the combination of gedalisil plus Bai Xili/letrozole and the combination of Ji Dali plus Bai Xili/fulvestrant.

The dose escalation and dose expansion study population consisted of patients with ER positive, HER2 negative, metastatic or locally recurrent/advanced breast cancer (mBC) in any menopausal state.

The dose escalation portion of the study initially assessed the safety and tolerability of either a 180 mg/week dose of jida plus standard dose of pimento Bai Xili/letrozole or a 180 mg/week dose of jida plus standard dose of pimento Bai Xili/fulvestrant. The dose escalation section then explores the escalation dose of the gedalisal for each regimen. During the dose escalation, 10 DLTs can evaluate patients receiving treatment at the expected MTD.

Once the MTD for each combination is determined, an extension portion is activated, which includes 4 arms, as follows: (1) arm A: first-line endocrine therapy; (2) arm B: two-wire or three-wire endocrine therapy and previously not receiving piper Bai Xili (or other CDK inhibitor) therapy; (3) arm C: two-wire or three-wire endocrine therapy and pre-receiving a therapy of piperi Bai Xili (or other CDK inhibitor), wherein Ji Dali plugs are administered once a week for four weeks; and (4) arm D: two-or three-wire endocrine therapy and progress during the course of treatment with piper Bai Xili (or other CDK inhibitor) therapy (as the most recent regimen), ji Dali plugs were administered on a three week dosing/one week break (3:1) schedule.

All cycles were 28 days in length. IV administration of Ji Dali plugs weekly on days 1, 8, 15 and 22 of each cycle (except arm D, where Ji Dali plugs were administered on days 1, 8 and 15 of each cycle), oral administration of piper Bai Xili at 125 mg/day for 3 weeks, followed by 1 week of discontinuation; repeated in each subsequent cycle. Letrozole is administered orally at 2.5mg per day continuously (daily), fulvestrant is administered intramuscularly at a dose of 500mg on day 1 of cycle 1, day 15 of cycle 1, day 1 of cycle 2, and then day 28 of each subsequent cycle (+ -3 days).

Treatment continues until disease progression, uncontrolled toxicity, patient or researcher decides to discontinue treatment or research is terminated. Patients experiencing toxicity, including DLT, manage or interrupt treatment by dose adjustment.

3. Study procedure

Safety laboratory tests (hematology, blood chemistry, urine analysis, coagulation) and tumor assessment were completed within 72 hours prior to the scheduled visit on day 1 of any cycle to facilitate the results obtained by the investigator at the time of the clinical visit.

From research findings, other tests may be required and/or the frequency of examination or clinical follow-up increased for patient management. The results of these additional tests or checks are recorded in a Case Report Form (CRF).

Patients will be assigned individual trial identification numbers when approved and enrolled in the group.

Screening evaluations must be performed within 28 days prior to the start of the study product (unless otherwise indicated). The baseline tumor biopsy sample may be archived and must be taken within 28 days prior to the start of the study product if the patient agrees to a new tumor biopsy.

As part of the screening/baseline assessment, all patients received complete medical history queries, including ongoing concomitant medication, clinical assessments (including physical examination, vital signs, height, weight, ECOG physical status, baseline signs and symptoms, triple 12 leads, resting electrocardiogram [ ECG ] and tumor assessment). The required baseline laboratory tests included: hematology, coagulation and chemistry, hbA1c, pregnancy tests and urine analysis.

The record of tumor phenotype and genotype includes histological or cytological classification, staging information, tumor grading, histological subtype, ER/progesterone receptor status, HER2 status, and any known tumor-specific molecular markers. Information about the method used for the initial diagnostic biopsy (biopsy site, biopsy date, biopsy type) is provided. Genomic methods for determining mutation status are provided. Information is provided to all patients regarding previous anti-tumor treatments, optimal response and duration of treatment.

All patients participating in this study were required to agree to obtain an archived tumor biopsy and to examine genetic variations of proteins and genes associated with various cell signaling pathways. These include, but are not limited to, components of PI3K and other signaling pathways such as PTEN, PIK3CA, PIK3R1, and AKT.

If an archived biopsy is not available at baseline, a new tumor biopsy needs to be taken before entering the study. After the screening evaluation is completed and qualifications are confirmed, the patient can be placed into the group.

Participants received treatment according to the study arm assigned to them. Treatment continues until the disease progresses or unacceptable toxicity occurs.

4. Study drug administration

Administration of the study product is performed by members of appropriate qualification, trained in the pharmaceutical clinical trial quality administration Specification (GCP), and having vaccine experience in researchers (e.g., doctors, nurses, doctor assistants, medical practitioners, pharmacists or medical assistants) as permitted by local, state and institutional guidelines.

Application of Ji Dali plug

IV infusion was administered Ji Dali plugs weekly over about 30 minutes. (dose escalation; dose extension: arm a, arm B and arm C).

In arm D of the dose extension section, ji Dali plugs were administered as IV infusions over a three week dosing/one week break schedule for approximately 30 minutes. No pre-operative medication is required.

Application of piperaquine Bai Xili

The patient was instructed to whole grain swallow the Bai Xili capsule and not to manipulate or chew the capsule prior to swallowing. If the capsule breaks, cracks or other imperfections, it should not be ingested. Patients are encouraged to take medications at about the same time each day. The patient was instructed to record daily administration in the patient diary and take the pipet Bai Xili with food. In each 28 day cycle, the pipet Bai Xili was orally administered once a day for 21 days, followed by discontinuation of the treatment for 7 days.

Administration of letrozole

The recommended dose of letrozole is to administer a tablet of 2.5mg once a day, with or without meals.

Administration of fulvestrant

Fulvestrant requires a loading dose during the first month of treatment. Fulvestrant (500 mg) was administered at doses of fulvestrant (500 mg) on days 1, 15 and 1 of cycle 2 to accommodate PK schedules. Thereafter, a monthly dose is administered on day 28 (±3 days) of the subsequent cycle.

The injection of fulvestrant is administered by Intramuscular (IM) injection. The 500mg dose was given as two injections of 250mg each, as one 5mL injection slowly injected into each buttock (1-2 minutes per injection).

5. Endpoint (endpoint)

The common primary efficacy endpoint for this study was (1) first cycle Dose Limiting Toxicity (DLT); and (2) Objective Relief (OR) assessed by the investigator.

The secondary efficacy endpoints studied were:

1) Safety, including adverse events characterized by type, frequency, severity, time, severity, and relationship to study treatment, as well as laboratory abnormalities characterized by type, frequency, severity, and time.

2) Tumor response to dose escalation portion of study.

3) For the extension of the study DR and PFS (as assessed using RECIST v 1.1) were used.

4) QTc interval.

5) Single and multi dose PK parameters for Ji Dali plug and piptants Bai Xili. Multi-dose PK parameters of fulvestrant and letrozole (dose escalation fraction only).

6) Single dose and multi-dose PK parameters for Ji Dali plug (dose extension only).

7. Results

Arm D patient received Ji Dali plug (180 mg IV, three weeks dosing/one week discontinuation). After analysis of the data, it was found that synchronizing the Ji Dali plug treatment schedule with the three week dosing/one week break schedule of the pipy Bai Xi was more effective in patients who had not obtained significant benefit from previous treatment with endocrine therapy. This was determined by analyzing the objective remission rate and duration of treatment in those patients who received gedaltei treatment on a weekly schedule in < 12 months in comparison to those patients who received gedaltei treatment on a three week dosing/one week discontinuation schedule (arm D). A subset of this patient population (subjects who failed prior treatment within < 6 months) was also analyzed. Twenty patients on arm C and eleven patients on arm D develop progress in their immediate prior therapy within ∈12 months. The median treatment duration for the immediate prior therapies for these patients was essentially the same (146 days versus 155 days). In these patients, 15% in arm C and 73% in arm D reported partial objective relief. Arm C patient received a median treatment duration of 131 days for Ji Dali plug, pimento Bai Xili, and fulvestrant, whereas arm D patient received a median treatment duration of 276 days, more than twice that of arm C. The median treatment duration was 0.9 times in arm C and 1.8 times in arm D, receiving Ji Dali plugs, compared to the immediate prior therapy. Twelve patients on arm C and seven patients on arm D progressed within less than or equal to 6 months after the immediately previous therapy. The median treatment duration for the immediate prior therapies for these patients was essentially the same (97 days versus 106 days). In these patients, 0% in arm C and 71% in arm D reported a partial objective relief. Arm C patient received a median treatment duration of Ji Dali plug, pimple Bai Xili and fulvestrant of only 81 days, while arm D patient received a median treatment duration of 270 days, that is 3 times more than arm C. The median treatment duration to receive Ji Dali plugs was only 0.8-fold in arm C and 2.6-fold in arm D compared to the immediate prior therapy. The results are summarized in table 1.

TABLE 1 comparison of weekly administration of Ji Dali plug to periodic administration of Gidalteh for patients who failed prior treatment in less than 12 months

As can be seen from the data presented in table 1, for subjects whose previous treatment failed in less than 12 months (e.g., less than 6 months), it is advantageous to receive a three week dosing, one week discontinuation of the periodic dosing schedule of gedali (arm D). Arm D reported a higher partial objective relief when compared to weekly administration of Ji Dali plug (arm C) and had twice the median treatment duration of arm C.

The benefits of the three week dosing, periodic dosing schedule of one week interruptions of Ji Dali plugs were also observed in patients failing two or more previous treatment lines for cancer. The likelihood of achieving objective remission for patients in arm D is up to 2.4 times higher (30% or more reduction in tumor mass) and the time elapsed when their tumor does not progress (progression free survival) is up to 2.28 times longer than for patients in arm C. The results of this patient population analysis are summarized in table 2.

TABLE 2 comparison of weekly administration of Ji Dali plug to periodic administration of Gidaltep for patients failing two or more previous treatment lines

The conventional method of determining the dosing schedule for a cancer patient treatment regimen is to determine the maximum tolerated dose in a phase 1 clinical trial. This method is based on the principle that the efficacy of a cancer therapeutic agent is directly related to the amount of drug administered. Thus, reducing the dosage of therapeutic agents is generally desirable to increase the patient's resistance to drugs. However, in this example, jidalism unexpectedly showed excellent efficacy when the dose administered was less than the maximum tolerated dose (180 mg per week).

Those skilled in the art will appreciate that many and various modifications may be made without departing from the scope and spirit of the disclosure. Accordingly, it should be understood that the various embodiments of the invention described herein are illustrative only and are not intended to limit the scope of the invention. All references cited herein are incorporated by reference in their entirety.

Claims (50)

1. A method of treating cancer in a human subject, the method comprising:

selecting a human subject in need of treatment for cancer;

administering to the human subject a therapeutically effective amount of a jideli plug, or a pharmaceutically acceptable salt, solvate or ester thereof, at least once a week for a period of three weeks;

Interrupting administration of the Ji Dali plug or pharmaceutically acceptable salt, solvate or ester thereof for a period of one week; and

administration of the gedaltei or a pharmaceutically acceptable salt, solvate or ester thereof is resumed after an discontinuation period, at least once per week,

wherein administration for at least three weeks and discontinuation of administration for at least one week constitutes a cycle, wherein the cycle is repeated for at least two cycles.

2. The method of claim 1, wherein administration of gedaltei, or a pharmaceutically acceptable salt, solvate or ester thereof, is resumed for a period of three weeks at least once per week.

3. The method of claim 1 or 2, wherein the administration cycle is performed for at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles, or at least 9 cycles.

4. A method according to any one of claims 1 to 3, wherein the Ji Dali plug or pharmaceutically acceptable salt, solvate or ester thereof is administered weekly at a dose of 180 mg.

5. The method of any one of claims 1 to 4, further comprising:

administering a CDK4/6 inhibitor to the human subject at least once a week for a period of three weeks;

Interrupting administration of the CDK4/6 inhibitor for a period of one week; and

resuming administration of the CDK4/6 inhibitor after the disruption period for at least one week, wherein the cycle of administration and disruption of administration of the CDK4/6 inhibitor is repeated for at least two cycles.

6. A method according to claim 5, wherein administration of the CDK4/6 inhibitor is concurrent with administration of the Ji Dali plug, or pharmaceutically acceptable salt, solvate or ester thereof, within weeks.

7. The method of claim 5 or 6, wherein the CDK4/6 inhibitor is selected from the group consisting of piperine Bai Xili, rebaudimide, abbe-sirolimus, fraxiril, darcy-sirolimus, lividipine, and combinations thereof.

8. The method according to any one of claims 5 to 7, wherein the CDK4/6 inhibitor is piper Bai Xili.

9. The method according to claim 8, wherein the piperazine Bai Xili is administered at a dose of 125mg per day.

10. The method of any one of claims 5-9, further comprising administering an estrogen receptor antagonist to the human subject.

11. The method of claim 10, wherein the estrogen receptor antagonist is fulvestrant.

12. The method of claim 11, wherein the fulvestrant is administered at a dose of 500mg every two weeks.

13. The method of claim 11, wherein the fulvestrant is administered at a dose of 500mg every four weeks.

14. The method of any one of claims 1-4, further comprising administering an estrogen receptor antagonist to the human subject.

15. The method of claim 14, wherein the estrogen receptor antagonist is fulvestrant.

16. The method of claim 15, wherein the fulvestrant is administered at a dose of 500mg every two weeks.

17. The method of claim 15, wherein the fulvestrant is administered at a dose of 500mg every four weeks.

18. A method of treating cancer in a human subject, the method comprising:

selecting a human subject in need of treatment for cancer;

administering to the human subject a therapeutically effective amount of a jideli plug or a pharmaceutically acceptable salt, solvate or ester thereof and a CDK4/6 inhibitor at least once a week for a period of three weeks;

interrupting administration of the Ji Dali plug or pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor for a period of one week; and

restoring administration of the gedaltei or pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor after an interruption period, at least once per week,

Wherein administration for at least three weeks and discontinuation of administration for at least one week constitutes a cycle, wherein the cycle is repeated for at least two cycles.

19. A method according to claim 18, wherein administration of gedaltei or a pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor is resumed, at least once per week for a period of three weeks.

20. The method of claim 18 or 19, wherein the administration cycle is performed for at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles, or at least 9 cycles.

21. The method of any one of claims 18 to 20, wherein the Ji Dali plug or pharmaceutically acceptable salt, solvate or ester thereof is administered weekly at a dose of 180 mg.

22. The method according to any one of claims 18 to 21, wherein the CDK4/6 inhibitor is selected from the group consisting of piperaquine Bai Xili, rebaudil, abbe-sirolimus, trazoxili, darcy-sirolimus, livalaciril, and combinations thereof.

23. The method according to any one of claims 18 to 22, wherein the CDK4/6 inhibitor is piper Bai Xili.

24. The method according to claim 23, wherein the piperazine Bai Xili is administered at a dose of 125mg per day.

25. The method of any one of claims 18-24, further comprising administering an estrogen receptor antagonist to the human subject.

26. The method of claim 25, wherein the estrogen receptor antagonist is fulvestrant.

27. The method of claim 26, wherein the fulvestrant is administered at a dose of 500mg every two weeks.

28. The method of claim 26, wherein the fulvestrant is administered at a dose of 500mg every four weeks.

29. A method of treating cancer in a human subject, the method comprising:

selecting a human subject in need of treatment for cancer;

administering to the human subject a therapeutically effective amount of a jideli plug or a pharmaceutically acceptable salt, solvate or ester thereof and a CDK4/6 inhibitor at least once a week for a period of three weeks;

interrupting administration of the Ji Dali plug or pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor for a period of one week;

restoring administration of the gedaltei or pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor after an interruption period, at least once per week,

wherein administration for at least three weeks and discontinuation of administration for at least one week constitutes a cycle, wherein the cycle is repeated for at least two cycles; and

Administering an estrogen receptor antagonist to the human subject.

30. A method according to claim 29, wherein administration of gedaltei or a pharmaceutically acceptable salt, solvate or ester thereof and the CDK4/6 inhibitor is resumed, at least once per week for a period of three weeks.

31. The method of claim 29 or 30, wherein the administration cycle is performed for at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles, or at least 9 cycles.

32. The method of any one of claims 29 to 31, wherein the Ji Dali plug is administered weekly at a dose of 180 mg.

33. The method according to any one of claims 29 to 32, wherein the CDK4/6 inhibitor is selected from the group consisting of piperaquine Bai Xili, rebaudil, abbe-sirolimus, trazoxili, darcy-sirolimus, livalaciril, and combinations thereof.

34. A method according to any one of claims 29 to 33 wherein the CDK4/6 inhibitor is piper Bai Xili.

35. The method according to claim 34, wherein the piperazine Bai Xili is administered at a dose of 125mg per day.

36. The method according to any one of claims 29 to 35, wherein the estrogen receptor antagonist is fulvestrant.

37. The method of claim 36, wherein the fulvestrant is administered at a dose of 500mg every two weeks.

38. The method of claim 36, wherein the fulvestrant is administered at a dose of 500mg every four weeks.

39. The method of any one of the above claims, wherein the cancer is a solid cancer.

40. The method of claim 39, wherein the solid cancer is selected from the group consisting of breast cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, prostate cancer, testicular cancer, penile cancer, lung cancer, colorectal cancer, melanoma, bladder cancer, brain/CNS cancer, esophageal cancer, gastric cancer, head/neck cancer, renal cancer, liver cancer, pancreatic cancer, and sarcoma.

41. The method of claim 39 or 40, wherein the solid cancer is hormone dependent cancer.

42. The method of claim 41, wherein the hormone dependent cancer is selected from the group consisting of breast cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, prostate cancer, testicular cancer, and penile cancer.

43. The method of claim 41 or 42, wherein the hormone dependent cancer is breast cancer.

44. The method of claim 43, wherein the breast cancer is metastatic breast cancer, hormone-resistant breast cancer, estrogen receptor positive breast cancer, estrogen receptor negative breast cancer, progesterone receptor positive breast cancer, triple negative breast cancer, HER2 positive breast cancer, or HER2 negative breast cancer.

45. The method of claim 43 or 44, wherein the breast cancer is a basal subtype or a luminal subtype.

46. The method of any one of claims 1 to 43, wherein the human subject is a pre-menopausal female patient or a post-menopausal female patient.

47. The method of any one of claims 1-46, wherein the human subject failed prior treatment for cancer in less than twelve months.

48. The method of any one of claims 1-47, wherein the human subject failed prior treatment for cancer in less than six months.

49. The method of any one of claims 1-48, wherein the human subject failed two or more previous treatments for cancer.

50. The method of any one of claims 47-49, wherein the previous treatment that failed is endocrine treatment of cancer.