JP6860949B2 - How to treat cancer - Google Patents

Description

This application claims the benefit of US Provisional Patent Application No. 61 / 819,505 filed March 3, 2013, which provisional patent application is incorporated herein by reference in its entirety.

<Technical field>
The present invention relates to a method of treating cancer based on co-administration of HDAC inhibitors.

Cancers, tumors, tumor-related disorders, and neoplastic disease states are serious and often life-threatening illnesses. These diseases and disorders, characterized by rapidly proliferating cell proliferation, continue to be the subject of research efforts towards identifying effective therapeutic agents for their treatment. Such agents prolong patient survival, inhibit neoplasm-related rapidly proliferating cell proliferation, or affect neoplasm remission.

In general, surgery and radiation therapy are the first modality considered for the treatment of cancer that is considered to be locally restricted and provide the best prognosis. Chemotherapy treatments for certain cancers typically result in disappointing survival, but still provide life-prolonging effects. Chemotherapy regimens of epidermal growth factor receptor (EGFR) inhibitors, such as the use of erlotinib and gefitinib, are utilized, for example, in lung cancer patients. If the patient does not respond to treatment with an EGFR inhibitor, further conventional treatment will result in limited benefits, as is currently available. Chemotherapy regimens of aromatase inhibitors, such as the use of letrozole, anastrozole, or exemestane, are utilized in breast cancer patients. If the patient does not respond to treatment with an aromatase inhibitor, further conventional treatment results in limited benefits.

Although various EGFR inhibitors have been approved for the treatment of lung cancer, EGFR inhibitor treatment encounters limitations such as side effects resulting from its use. The greater concern is that the use of EGFR inhibitors for the treatment of tumors can initially reduce the size of the tumor, while the size of the tumor eventually expands, showing, among other things, the development of resistance. The view is getting stronger. Erlotinib, a widely used EGFR inhibitor, may be typical of the type of therapeutic agent used in the treatment of cancer in that its use has an effect on cancer, but (not known at all) others. Due to these factors, the tumor develops resistance and progression.

Despite the approval of various aromatase inhibitors for the treatment of early and late breast cancer, like most therapeutic agents, their use results in side effects. For example, common side effects include burning, vasodilation, and nausea. The greater concern is that the use of aromatase inhibitors for the treatment of tumors can initially reduce the size of the tumor, while the size of the tumor eventually expands, showing, among other things, the development of resistance. The view is getting stronger. Letrozole, a widely used aromatase inhibitor, can be typical of the type of therapeutic agent used in the treatment of cancer in that its use has an effect on cancer, but (not known at all). ) Due to other factors, the tumor develops resistance and progression.

Histone deacetylase (HDAC) inhibitors are a new class of therapeutic agents that promote the differentiation and apoptosis of blood and solid malignancies through chromatin remodeling and gene expression regulation. Various HDAC inhibitors have been identified: benzamide (entinostat), short chain fatty acids (ie, sodium phenylbutyric acid); hydroxamic acid (ie, hydroxamic acid suberoylanilide and tricostatin A); 2-amino-8- Cyclic tetra comprising an oxo-9,10-epoxy-decanoyl moiety (ie, trapoxin A) and a cyclic peptide without a 2-amino-8-oxo-9,10-epoxy-decanoyl moiety (ie, FK228). Contains peptides. Entinostat is a benzamide HDAC inhibitor that undergoes clinical trials in many types of solid tumors and blood cancers. Entinostat is rapidly absorbed, has a half-life of about 100 hours, and, importantly, changes in histone acetylation persist for several weeks after administration of entinostat.

Therefore, what is needed is to take advantage of the synergistic effects found in therapeutic combinations that can increase the efficacy of the drug and typically reduce and / or eliminate side effects associated with conventional treatments. A composition and / or method for the treatment of cancer.

One embodiment provides a method of treating cancer in a patient in need, the method comprising oral administration of entinostat, wherein the entinostat is administered under fed conditions. The Cmax of entinostat is increased when entinostat is administered under fasting conditions.

One embodiment provides a method of treating cancer in a patient in need, the method comprising oral administration of entinostat, wherein the entinostat is administered under fasting conditions. Therefore, the Tmax of entinostat is increased when entinostat is administered under feeding conditions.

One embodiment provides a method of treating breast cancer in a patient in need, the method comprising oral administration of exemestane and entinostat, wherein the entinostat is administered to a fasting patient. ..

One embodiment provides a method of treating non-small cell lung cancer in a patient in need, the method comprising oral administration of erlotinib and entinostat, wherein the entinostat is applied to a fasting patient. Be administered.

One embodiment provides a method of treating cancer in a patient in need, the method comprising oral administration of entinostat, wherein the method is compared to administration of entinostat under fasting conditions. Administration of entinostat under fasting conditions results in an increase in Cmax, and the ratio of Cmax after administration under fasting conditions to Cmax after administration under fasting conditions is at least about 2: 1.

One embodiment provides a method of treating a patient's cancer in need, which method comprises oral administration of entinostat, which is here as compared to administration of entinostat under fasting conditions. Administration of entinostat under dietary conditions results in an increase in Tmax, and the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 2: 1.

<Built-in by reference>
All publications, patents, and patent applications described herein are to the same extent as if the individual publications, patents, or patent applications were specifically and individually indicated to be incorporated by reference. Incorporated herein by reference to. Patent Application PCT International Patent Application PCT / US2012 / 053551; US Patent Application No. 14 / 342,354; and US Patent Application Publication No. 2013/0150386 are incorporated herein by reference.

The novel features of the present invention are specified, in particular, within the appended claims. A better understanding of the features and advantages of the present invention can be obtained by reference to the detailed description below, which specifies specific examples, and the accompanying drawings below, in which the principles of the present invention are utilized.
Provided is a pharmacokinetic analysis of the dietary efficacy study described in Example 1. Provided is a pharmacokinetic analysis of the dietary efficacy study described in Example 1.

The present specification provides a method for treating breast cancer based on the administration of histone deacetylase (HDAC) inhibitor and aromatase inhibitor. The method comprises the step of administering the HDAC inhibitor without food. Treatment methods can incorporate patient selection based on the level of protein lysine acetylation observed during treatment. The method may further comprise treatment in which administration of the HDAC inhibitor and aromatase inhibitor is supplemented by one or more therapeutic agents or treatments.

Provided herein are methods of treating lung cancer based on the administration of HDAC inhibitors and epidermal growth factor receptor (EGFR) inhibitors. The method comprises the step of administering the HDAC inhibitor without food. The method may further comprise treatment in which administration of the HDAC inhibitor and the EGFR inhibitor is supplemented by one or more therapeutic agents or treatments.

One embodiment provides a method of treating cancer in a patient in need, the method comprising oral administration of entinostat, wherein the method is compared to administration of entinostat under fasting conditions. Administration of entinostat under fasting conditions results in an increase in Cmax, and the ratio of Cmax after administration under fasting conditions to Cmax after administration under fasting conditions is at least about 2: 1. Another embodiment provides a method of treating cancer in which the ratio of Cmax after administration under fasting conditions to Cmax after administration under fasting conditions is at least about 3: 1. Another embodiment provides a method of treating cancer in which the ratio of Cmax after administration under fasting conditions to Cmax after administration under fasting conditions is at least about 4: 1. Another embodiment provides a method of treating cancer in which the ratio of Cmax after administration under fasting conditions to Cmax after administration under fasting conditions is at least about 5: 1. Another embodiment provides a method of treating cancer in which the ratio of Cmax after administration under fasting conditions to Cmax after administration under fasting conditions is at least about 6: 1. Another embodiment provides a method of treating cancer in which the ratio of Cmax after administration under fasting conditions to Cmax after administration under fasting conditions is at least about 7: 1. Another embodiment provides a method of treating the cancer, the cancer being lung cancer. Another embodiment provides a method of treating the cancer, the cancer being non-small cell lung cancer. Another embodiment provides a method of treating cancer, the cancer being breast cancer. Another embodiment provides a method of treating cancer, further comprising oral administration of an EGFR inhibitor. Another embodiment provides a method of treating cancer and the EGFR inhibitor is erlotinib. Another embodiment provides a method of treating cancer, in which erlotinib is administered at a different time than entinostat. Another embodiment provides a method of treating cancer, in which the patient has not consumed food within 2 hours prior to administration of erlotinib. Another embodiment provides a method of treating cancer, in which the patient does not consume food within 1 hour after administration of erlotinib. Another embodiment provides a method of treating cancer, in which about 150 mg of erlotinib is administered. Another embodiment provides a method of treating cancer, in which erlotinib is administered once daily. Another embodiment provides a method of treating cancer, further comprising oral administration of an aromatase inhibitor. Another embodiment provides a method of treating cancer and the aromatase inhibitor is exemestane. Another embodiment provides a method of treating cancer, in which exemestane is administered at a different time than entinostat. Another embodiment provides a method of treating cancer, in which exemestane is administered postprandial. Another embodiment provides a method of treating cancer, where exemestane is administered with a meal. Another embodiment provides a method of treating cancer, in which about 25 mg of exemestane is administered. Another embodiment provides a method of treating cancer, in which exemestane is administered once daily. Another embodiment provides a method of treating the cancer, in which the patient is administered about 10 mg of entinostat. Another embodiment provides a method of treating the cancer, in which the patient is administered about 5 mg of entinostat. Another embodiment provides a method of treating the cancer, in which the patient is administered about 1 mg to about 20 mg of entinostat. Another embodiment provides a method of treating cancer, in which the patient has not consumed food within 2 hours prior to administration of entinostat under fasting conditions. Another embodiment provides a method of treating cancer, in which the patient has not consumed food within 1 hour prior to administration of entinostat under fasting conditions. Another embodiment provides a method of treating cancer, in which the patient does not consume food within 2 hours after administration of entinostat under fasting conditions. Another embodiment provides a method of treating cancer, in which the patient does not consume food within 30 minutes after administration of entinostat under fasting conditions. Another embodiment provides a method of treating cancer, in which the patient consumes a high-fat diet under feeding conditions.

One embodiment provides a method of treating a patient's cancer in need, which method comprises oral administration of entinostat, which is here as compared to administration of entinostat under fasting conditions. Administration of entinostat under dietary conditions results in an increase in Tmax, and the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 2: 1. Another embodiment provides a method of treating cancer in which the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is from about 2: 1 to about 5: 1. Another embodiment provides a method of treating cancer in which the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is from about 5: 1 to about 8: 1. Another embodiment provides a method of treating cancer in which the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is from about 8: 1 to about 12: 1. Another embodiment provides a method of treating cancer in which the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is from about 12: 1 to about 15: 1. Another embodiment provides a method of treating the cancer, the cancer being lung cancer. Another embodiment provides a method of treating the cancer, the cancer being non-small cell lung cancer. Another embodiment provides a method of treating cancer, the cancer being breast cancer. Another embodiment provides a method of treating cancer, further comprising oral administration of an EGFR inhibitor. Another embodiment provides a method of treating cancer and the EGFR inhibitor is erlotinib. Another embodiment provides a method of treating cancer, in which erlotinib is administered at a different time than entinostat. Another embodiment provides a method of treating cancer, in which the patient has not consumed food within 2 hours prior to administration of erlotinib. Another embodiment provides a method of treating cancer, in which the patient does not consume food within 1 hour after administration of erlotinib. Another embodiment provides a method of treating cancer, in which about 150 mg of erlotinib is administered. Another embodiment provides a method of treating cancer, in which erlotinib is administered once daily. Another embodiment provides a method of treating cancer, further comprising oral administration of an aromatase inhibitor. Another embodiment provides a method of treating cancer and the aromatase inhibitor is exemestane. Another embodiment provides a method of treating cancer, in which exemestane is administered at a different time than entinostat. Another embodiment provides a method of treating cancer, in which exemestane is administered postprandial. Another embodiment provides a method of treating cancer, where exemestane is administered with a meal. Another embodiment provides a method of treating cancer, in which about 25 mg of exemestane is administered. Another embodiment provides a method of treating cancer, in which exemestane is administered once daily. Another embodiment provides a method of treating the cancer, in which the patient is administered about 10 mg of entinostat. Another embodiment provides a method of treating the cancer, in which the patient is administered about 5 mg of entinostat. Another embodiment provides a method of treating the cancer, in which the patient is administered about 1 mg to about 20 mg of entinostat. Another embodiment provides a method of treating cancer, in which the patient has not consumed food within 2 hours prior to administration of entinostat under fasting conditions. Another embodiment provides a method of treating cancer, in which the patient has not consumed food within 1 hour prior to administration of entinostat under fasting conditions. Another embodiment provides a method of treating cancer, in which the patient does not consume food within 2 hours after administration of entinostat under fasting conditions. Another embodiment provides a method of treating cancer, in which the patient does not consume food within 30 minutes after administration of entinostat under fasting conditions. Another embodiment provides a method of treating cancer, in which the patient consumes a high-fat diet under feeding conditions.

To facilitate understanding of the disclosures described herein, many terms are defined below.

As used herein, "abnormal cell proliferation" refers to cell proliferation independent of normal regulatory mechanisms (eg, loss of contact inhibition), including abnormal cell proliferation and proliferation of abnormal cells.

As described herein, "neoplasty" is the abnormal, unregulated, and disorganized proliferation of cells that distinguish normal cells by autonomous proliferation and somatic mutations. As newborn cells proliferate and divide, they convey gene mutations and proliferative characteristics to progeny cells. A neoplasm, or tumor, is an accumulation of newborn cells. In some embodiments, the tumor can be benign or malignant.

"Metastasis" refers to the transmission of tumor cells through lymphatic vessels or blood vessels, as used herein. Metastasis also refers to the migration of tumor cells by direct dilation through the serosal or subarachnoid space, or other space. Through the process of metastasis, the migration of tumor cells to other areas of the body establishes neoplasms in areas away from the original site of development.

As discussed herein, "angiogenesis" is prominent in tumor formation and metastasis. Angiogenic factors have been found to be associated with various solid tumors such as rhabdomyosarcoma, retinoblastoma, Ewing's sarcoma, neuroblastoma, and osteosarcoma. Tumors cannot expand without a blood supply to provide nutrients and remove cell waste. Tumors of significant angiogenesis include benign tumors such as renal cell carcinoma, hepatocellular carcinoma, and acoustic neuroma, as well as solid tumors such as neurofibromatosis. Angiogenesis is associated with blood-born tumors such as leukemia. Angiogenesis is thought to play a role in bone marrow abnormalities that cause leukemia. Prevention of angiogenesis can stop the growth of cancerous tumors and the resulting damage to the subject due to the presence of the tumor.

The term "subject" refers to an animal, including, but not limited to, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein when referring to a mammalian subject, such as a human subject.

The terms "treat," "treating," and "treatment" are alleviating or suppressing a disorder, disease, or disease; or related to a disorder, disease, or disease. It means alleviating or suppressing one or more of the symptoms; or including alleviating or eradicating the cause of the disorder, disease, or the disease itself.

The term "therapeutically effective amount" refers to an amount of compound sufficient to prevent or to some extent alleviate the progression of one or more symptoms of a disorder, disease, or disease to be treated when administered. The term "therapeutically effective amount" is also sufficient to elicit the biological or medical response of cells, tissues, systems, animals, or humans sought by researchers, veterinarians, doctors, or clinicians. Refers to the amount of compound.

The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier", or "physiologically acceptable excipient" are liquid or solid. Refers to a pharmaceutically acceptable material, composition, or vehicle, such as a filler, diluent, excipient, solvent, or encapsulating material. Each component must be "pharmaceutically acceptable" in the sense that it is compatible with the other components of the pharmaceutical formulation. It is also used in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, corresponding to a reasonable benefit-risk ratio. Must be suitable. Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handjob , Eds. , The Pharmaceutical Press and the American Pharmaceutical Association: 2005; Handbook of Pharmaceutical Ads, 3rd Edition; Ash. , Gower Publicing Company: 2007; Pharmaceutical Preformation and Formulation, Gibson Ed. , CRC Press LLC: Boca Raton, FL, 2004).

The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein with other chemical components such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to the living body. The techniques for administering a compound are present in the art, including, but not limited to, oral administration, infusion, aerosol administration, parenteral administration, and topical administration. The pharmaceutical composition is also produced by reacting the compound with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid. You can get it.

The terms "fasting," "fasted," or "without food" generally refer to at least about 30 minutes prior to administration of the therapeutic agents described herein. It is defined to mean a state of ingestion of food during a period of at least about 30 minutes after administration of the therapeutic agents described herein. In some examples, food is not ingested from at least about 2 hours before administration of the therapeutic agent described herein to at least about 1 hour after administration of the therapeutic agent described herein. In some examples, food is not ingested from at least about 1 hour before administration of the therapeutic agent described herein to at least about 1 hour after administration of the therapeutic agent described herein. In some examples, food is not ingested from at least about 1 hour before administration of the therapeutic agent described herein to at least about 2 hours after administration of the therapeutic agent described herein.

The term "feeding condition" refers to the condition of eating. In some examples, the food is a high-fat or high-calorie diet. A high calorie diet may include, but is not limited to, a diet comprising 500 calories or more, about 300 to 800 calories, about 500 to about 1,000 calories, and about 800 to about 1,500 calories. In some examples, a high-fat diet is from, but is not limited to, the fat content of daily caloric intake of about 20% to about 50%, about 30% to about 60%, and about 40% to about 70%. Contains calories. In some embodiments, the diet is not high in fat. In some embodiments, the diet is not high in calories.

The term "bioavailability" generally means the rate and extent at which the active ingredient is absorbed from the therapeutic agent and becomes available at the site of action. In the oral dosage form, bioavailability involves the process by which the active ingredient is released from the oral dosage form and transferred to the site of action. Quantitatively, the term "oral bioavailability" or "% F" is _{defined as AUC oral} / AUC _iv , where AUC _oral is the AUC determined after oral administration and AUC _iv is determined after iv administration. It is AUC.

"AUC" refers to the area under the drug concentration curve. "AUC ^0-t " refers to the region below the drug concentration curve from zero to time t. "AUClass" refers to the region below the drug concentration curve from zero to the last data point on the drug concentration curve. "AUC ^0-∞ " or "AUCinf" refers to the region below the drug concentration curve from zero to infinite time.

“T _1/2 ” refers to the exclusion half-life of the indicated species. “T _max ” refers to the time of maximum concentration of the indicated species. "C _max " refers to the maximum concentration of the indicated species.

<Treatment for breast cancer>
<Histone deacetylase>
HDACs are a family containing at least 18 enzymes, grouped into three categories (Classifications I, II, and III). Category I HDACs include, but are not limited to, HDCs 1, 2, 3, and 8. Class I HDACs can be found in the nucleus and are thought to be involved in transcriptional regulatory inhibitors. Category II HDACs include, but are not limited to, HDACs 4, 5, 6, 7, and 9 and can be found in both the cytoplasm and nucleus. Class III HDACs are considered to be NAD-dependent proteins and include, but are not limited to, members of the Sirtuin family of proteins. Unrestricted examples of sirtuin proteins include SIRT1-7. As used herein, the term "selective HDAC" refers to HDAC inhibitors that do not interact with all three HDAC classifications.

<HDAC inhibitor>
HDAC inhibitors can be broadly classified into pan HDAC inhibitors and selective HDAC inhibitors. There is a great deal of structural diversity of known HDAC inhibitors, but they share a common feature: the part that interacts with the enzyme active site, and the side chains that are located inside the pathway leading to the active site. This can be seen with hydroxamate such as SAHA if the hydroxamate group is thought to interact with the active site. In the case of depsipeptides, the intracellular reduction of disulfide bonds is thought to create free thiol groups (interacting with the active site) attached to the 4-carbon alkenyl chain. The difference between HDAC inhibitors lies in the way they interact with the edges of HDAC channels at the opposite end of the pathway to the active site. It is believed to occupy some observed differences in HDAC selectivity between pan-HDAC inhibitors such as SAHA and selective HDAC inhibitors such as depsipeptides, at least in part. This interaction between the inhibitor and the edge of the channel. A particularly preferred HDAC inhibitor is entinostat. Entinostat has the chemical name N- (2-aminophenyl) -4- [N- (pyridine-3-yl) methoxycarbonylamino-methyl] -benzamide and the chemical structure shown below.

<Aromatase>
Estrogen is one of the female hormones and has many functions in the body. It was found that about 80% of breast cancer tumors overexpress estrogen receptors and respond positively to the presence of estrogen. In postmenopausal women, follicular hormone production is reduced and plasma estrogen levels are generally lower than in premenopausal women.

The residual source of estrogen in postmenopausal women is the synthesis of estrogen from androgens, which is catalyzed by aromatase. Inhibition of aromatase activity must cause reduced levels of estrogen and, therefore, reduced growth of breast cancer tumors that respond positively to the presence of estrogen. Aromatase is an enzyme of the cytochrome P450 family and a product of the CYP19 gene. The chemical function of aromatase is to convert testosterone to estradiol and androstenedione to estrone.

<Aromatase inhibitor>
Aromatase inhibitors reduce the body's estrogens by blocking the enzyme aromatase from converting androgens to estrogens. In the treatment of early-stage breast cancer, certain aromatase inhibitors can be used in place of tamoxifen or as adjuvant therapy more than 2 years after tamoxifen. In the treatment of metastatic breast cancer, aromatase inhibitors are being tested in clinical trials to compare them with hormone therapy with tamoxifen.

As described herein, an "aromatase inhibitor" is a molecule that inhibits the activity of an aromatase enzyme. Compounds that are inhibitors of aromatase are readily available to those of skill in the art using methods such as, for example, standard pharmacological testing procedures that measure inhibition of conversion of 1,2-3H-androstenedione to estrone. Can be identified.

Briefly, microsome fractions are prepared from human placenta by the methods as described in "Thompson and Chem., Vol. 249, p. 5364 (1974)". The resulting microsome preparation is lyophilized and stored at −40 ° C. Microsomes of human placenta was added to ^1,2-3 H- androstenedione, are incubated at 37 ° C. 20 min. The amount of aromatization of labeled substrate is detected by the ^{3 H} 2 _O losses to the incubation medium. The substrate is removed by chloroform extraction followed by adsorption to charcoal in the suspension. Charcoal is removed by centrifugation and the steroid free medium is counted in a liquid scintillation counter. The composition is tested for aromatase inhibitory activity by adding to the incubation medium prior to the addition of microsomes. The relative cpm obtained with or without the composition is used to calculate the percent inhibition of androstenedione aromatization for estrone. The IC ₅₀ value, aromatization of androstenedione is reduced to 50% of control values for estrone, it can be determined graphically as the concentration of the test composition.

Subcutaneous fat is a major site of aromatase activity and it has been suggested that plasma estrogen levels correlate with body volume index (Longcope et al, Metabolism 1986, 35, 235-7). It has been suggested that during menopause, plasma estrogen levels drop from about 110 pg / mL to sufficiently low levels of about 7 pg / mL. However, in postmenopausal women, the concentration of estradiol internal tumors was found to be about 10-fold higher than that of plasma, probably due to intratumoral aromatase activity.

Inhibition of aromatase as a treatment option for breast cancer has been studied with several outcomes. Currently, three aromatase inhibitors are approved in the US market for the treatment of breast cancer at various stages in postmenopausal women. Letrozole (Femara®) is an extended adjuvant treatment of early-stage breast cancer in postmenopausal women with 5 years prior to tamoxifen treatment, hormone receptor-positive (or unknown) locally advanced or metastasized. Various treatment options are presented, including treatment of postmenopausal women with sexual breast cancer and treatment of advanced breast cancer in postmenopausal women whose disease progression occurs after receiving antiestrogen treatment.

Anastrozole (Arimidex®) is an adjuvant treatment for postmenopausal women with hormone receptor-(+) early-stage breast cancer, hormone receptor-(+) locally advanced (or unknown) or Various treatment options are presented, including first-line treatment for postmenopausal women with metastatic breast cancer and treatment for advanced breast cancer in postmenopausal women whose disease progression occurs after receiving tamoxifen treatment.

Exemestane (Aromasin®) is an estrogen receptor that has been treated with tamoxifen for 2-3 years-(+) after receiving adjuvant treatment and tamoxifen treatment for postmenopausal women with early-stage breast cancer Various treatment options are presented, including treatment of advanced breast cancer in postmenopausal women with disease progression.

これら薬物は、２つの分類にグループ分けされる：（タイプ１）エキセメスタンはステロイド化学構造に基づき、（タイプ２）レトロゾールとアナストロゾールは非ステロイド性化学構造に基づく。臨床試験は、レトロゾールが、進行したＥＲ（＋）の疾患の処置においてタモキシフェンよりも優れていることを示した。初期の疾患において、アナストロゾールによるアジュバント療法は、再発のリスクを減らすことにおいてタモキシフェンによる治療よりも優れているように思われる。近年の臨床試験結果は、乳癌処置のためのケアの標準として、タモキシフェンに取ってかわるアロマターゼ阻害剤に繋がった。

These drugs are grouped into two categories: (Type 1) exemestane is based on steroidal chemical structure, and (Type 2) letrozole and anastrozole are based on non-steroidal chemical structure. Clinical trials have shown that letrozole is superior to tamoxifen in the treatment of advanced ER (+) disease. In early-stage disease, adjuvant therapy with anastrozole appears to be superior to treatment with tamoxifen in reducing the risk of recurrence. Recent clinical trial results have led to an aromatase inhibitor replacing tamoxifen as a standard of care for the treatment of breast cancer.

<Breast cancer>
Breast cancer continues to be the most frequently diagnosed cancer among women in the United States today. One in eight women in the United States is at risk of developing breast cancer. Age, family history, diet, and genetic factors were identified as risk factors for breast cancer. Breast cancer is the second leading cause of death in women.

<HER2 / neu positive breast cancer>
Cancers associated with HER2 / neu overexpression include breast cancer, ovarian cancer, endometrial cancer, prostate cancer, gastric cancer, salivary adenocarcinoma, pancreatic cancer, colonic rectal cancer, oral cancer, and non-small cell lung cancer. Breast cancer has been the focus of anti-HER2 / neu treatments.

Approximately 25-30 percent of breast cancers have amplification of the HER2 / neu gene or overexpression of its protein product. Overexpression of this receptor in breast cancer is associated with increased disease recurrence and a worsening prognosis.

<Hormone-positive cancer>
Many breast cancers require the growth of the hormone estrogen. In menopausal women, the main source of estrogen is through the conversion of androgens to estrogen. As mentioned above, this process is carried out by the aromatase enzyme.

<Triple Negative Breast Cancer>
In the treatment of triple-negative breast cancer in which the cancer is estrogen receptor negative, progesterone receptor negative, and HER2 negative, the compositions and treatments described herein can be combined with other therapeutic agents. Such agents are, by way of example, cetuximab, paclitaxel, docetaxel, taxane formulations such as Abraxane® (ABI-007), paclitaxel-cremohole EL, paclitaxel polygourmet, and emulsions capable of injecting paclitaxel. (PIE) is included. These combinations may be convenient if there are cancers associated with HER2 overexpression but are not detected due to technical limitations in the tests used to quantify HER2 expression.

Hormone therapy is a central pillar in the treatment of estrogen receptor-positive (ER +) breast cancer (BC). Due to both clinical activity and the characteristics and tolerability of the overall favorable side effects of hormonal agents, the standard of care typically requires a switch to chemotherapy for the progression of either resistance and / or visceral crisis. It is involved in the sequencing of hormonal agents. In postmenopausal women, aromatase inhibitors (AIs) are a preferred class of anti-estrogen therapies that function by interfering with endogenous estrogen synthesis. Exemestane irreversibly binds to and inactivates aromatase enzymes by the effects demonstrated in the post-progressive metastatic setting on letrozole or anastrozole; i.e., non-steroidal AI, NSAI; to, is the AI of steroid (Chia S, Gradishar W, Mauriac L, et al: Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancel: fruits from EFECT. J Clin Oncol 26: 1664-1670, 2008).

The development of resistance to hormone therapy in advanced BC represents a significant challenge. Estimated mechanisms of resistance include estrogen-independent growth, sensitivity to low estrogen concentrations, cyclin D1 overexpression, constitutive nuclear factor Kappa B (NFκB) activation, growth factor signaling pathway upregulation, and estrogen receptor. Includes down-regulation of body alpha (ERα) expression. These pathways and mechanisms provide possible targets for therapeutic intervention. Entinostat is a novel oral inhibitor of histone deacetylase (HDAC) with high specificity for Class 1 HDAC and unique pharmacological properties that allow weekly dosing. HDAC inhibition causes an increase in protein lysine acetylation in tumors and peripheral blood erythrocytes that act as substitutable pharmacodynamic markers of activity. The specificity of entinostat classification 1 is that it is approved by the United States (US) Food and Drug Administration (FDA) for HDAC inhibitors (HDACi) vorinostat (Zolinza®) and romidepsin (Istodax). Distinguish from registered trademark)). Prior to clinical practice, entinostat demonstrated inhibition of ERα-positive tumor growth and restoration of hormone sensitivity as a result of down-regulation of the estrogen-independent growth factor signaling pathway, standardization of ERα levels, and increased levels of aromatase enzymes. did. . (Sabnis GJ, Goloubeva O, Chumsri S, et al: Functional activation of the estrogen receptor-α and aromatase by the HDAC inhibitor entinostat sensitizes ER-negative tumors to letrozole Cancer Res 71: 1893-903, 2011; Sabnis GJ, Kazi A, Goloubeva O, Brodie AMH. HDAC Inhibitor Entinostat Restores Responsiveness of Letrozole Resistant MCF-7Ca Xenografts to AIs through Modulation of Her 2. Presented at the 33rd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-12, 2010 ). The results of the specific clinical trials described herein show that the combination of entinostat and exemestane in ER + breast cancer inhibits the mechanism of hormone therapy resistance and thereby cells against anti-estrogen treatment with exemestane. Demonstrate to sensitize.

<Additional therapy>
Additional treatments available for breast cancer that may be conveniently utilized in combination with the treatments disclosed herein include, but are not limited to, tyrosine kinase inhibitors as radiation therapy, chemotherapy, antibody therapy, and adjuvant therapy. Including.

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them growing. Chemotherapy is a cancer treatment that uses a drug to stop the growth of cancer cells, either by killing the cells or by stopping their division. When chemotherapy is obtained by mouth or injected into a blood vessel or muscle, the drug can enter the bloodstream and reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into body cavities such as the spine, organs, or abdomen, the drug primarily affects cancer cells in those areas (topical chemotherapy). The method in which chemotherapy is given depends on the type and stage of the cancer being treated.

Different chemotherapeutic agents are known in the art for the treatment of breast cancer. Cytoxic agents used in the treatment of breast cancer are doxorubicin, cyclophosphamide, methotrexate, 5-fluorouracil, mitomycin C, mitoxanthrone, paclitaxel, taxane preparations (Abraxane®, for example). (ABI-007), paclitaxel-cremohole EL, paclitaxel polygourmetox, and paclitaxel injectable emulsion (PIE), etc.), gemcitabine, docetaxel, capecitabin, and epirubicin.

Other chemotherapy treatments for breast cancer include vincristine, carboplatin (eg Paraplatin®), carmustin (eg BCNU®), chlorambusil (eg Leukeran®), cisplatin (eg Platinol®), Cyclophosphamide infusion (eg, Cytoxan®), oral cyclophosphamide (eg, Cytoxan®), dacarbazine (eg, DTIC®), ifofamide (eg, ifex®), romustine ( For example CCNU®), mechloretamine (eg nitrogen mustard, Mustarden®), melfaran (eg Alkeran®), procarbazine (eg Matulane®), bleomycin (eg Vincristine®). )), Doxorubicin (eg Adriamycin®, Rubex®), Epirubicin, Idalbisin (eg Idamycin®), Mitoxanthron (eg Novantrone®), Gemcitabine (eg Gemzar®). )), Oral mercaptopurine (eg Purinesol®), Metotrexate, Pentostatin IV (eg Nipent®), Oral thioguanine (eg Lanvis®), Oral etoposide (eg VP-16, VePesid (eg VP-16, VePesid) Registered Trademarks), Etopophos-Etoposide IV (eg VP-16, VePesid®, Etopophos), Vincristine (eg Velban®), Vincristine (eg Oncovin®), Vinorelbin (eg Navelbine®) Includes treatment with one or more of dexamethasone (eg Decadron®), methylprednisolone (eg Medrol®), and prednison (eg Deltasone®).

Monoclonal antibody therapy is a cancer treatment that uses laboratory-produced antibodies from a single immune system cell. These antibodies can identify substances on cancer cells, or conventional substances that can help cancer cells grow. Antibodies attach to substances, kill cancer cells, block the growth of cancer cells, or maintain their spread. Monoclonal antibodies are given by infusion. They can be used alone or to carry drugs, toxins, or radioactive substances directly to cancer cells. Monoclonal antibodies are also used as adjuvant therapy in combination with chemotherapy.

Trastuzumab (Herceptin®) is a monoclonal antibody that blocks the effect of the growth factor protein HER2, which sends growth signals to breast cancer cells.

Trastuzumab causes a clinical response as a single drug and improves survival when added to chemotherapy for advanced HER2-positive breast cancer. However, some patients do not respond to trastuzumab and eventually develop clinical resistance. The mechanism of endogenous and acquired trastuzumab resistance is poorly understood. One study utilizing cell line-based methods to delineate resistance-related genetic and protein modulations has been reported (D. Tripathy et al Journal of Clinical Oncology, 2005 Vol 23, No 16S, 3121). ). These researchers studied two HER2-positive breast cancer cell lines (BT474 and SKBR3) that were continuously passaged in the presence of trastuzumab until in vitro resistance was documented. Resistant cell lines emerged after 12 months and showed a growth rate more than 3-fold faster in the absence of trastuzumab. After trastuzumab _exposure, G 0 / _{G 1} phase arrest, few with cells (3 vs. 14%) than in S phase was observed to be susceptible compared to the resistant cells (84 vs 68%). Resistant cell lines showed less gene expression changes with trastuzumab, as well as up-regulation of the chemokine receptor CXCR4 and mitotic checkpoint regulators, and down-regulation of PTEN compared to sensitive cells.

Additional exemplary treatments that can be conveniently combined with the compositions and treatments disclosed herein are capecitabine, docetaxel, epirubicin, epothilone A, B, or D, goseleline acetate, paclitaxel, It may include administration of a drug, including but not limited to lapatinib, in combination with pamidronate, bevacizumab, or trastuzumab.

In some embodiments, the chemotherapy comprises the step of administering to the subject one or more of doxorubicin, cyclophosphamide, paclitaxel, lapatinib, capecitabine, trastuzumab, bevacizumab, gemcitabine, eribulin, or nab-paclitaxel. Including therapy.

<Treatment method for breast cancer>
One embodiment provides a method of treating a patient's breast cancer, which method measures (i) the level of protein lysine acetylation prior to administration of an entinostat-aromatase inhibitor combination therapy. ii) Entinostat-aromatase inhibitor combination therapy, (iii) entinostat-aromatase inhibitor combination therapy followed by protein lysine acetylation level measurement, (iv) entinostat -A step of comparing the level of protein lysine acetylation after aromatase inhibitor combination therapy with the level of protein lysine acetylation before entinostat-aromatase inhibitor combination therapy, and (v). When the level of protein lysine acetylation after the combination therapy of entinostat-aromatase inhibitor is higher than the level of protein lysine acetylation before the combination therapy of entinostat-aromatase inhibitor. Includes the step of continuing treatment with a combination therapy of tinostat-aromatase inhibitors. In some examples, entinostat is administered to fasting patients.

One embodiment provides a method of treating a patient's breast cancer, the method of (i) performing a combination therapy of an entinostat-aromatase inhibitor, and (ii) pretreatment protein lysine acetylation levels. Includes a step of determining changes in protein lysine acetylation levels during the treatment as compared to. In some examples, entinostat is administered to fasting patients.

One embodiment provides a method of treating breast cancer in a patient, wherein the method is (i) determining the level prior to protein lysine acetylation, (ii) entinostat-aromatase inhibitor combination therapy. And (iii) determine the level of protein lysine acetylation during treatment. In some examples, entinostat is administered to fasting patients.

It is desirable to increase the oral bioavailability of therapeutic agents such as entinostat in order to increase the range of therapeutic effects on the patient. In general, food has a variable effect on the bioavailability of therapeutic agents. Interactions between therapeutic agents and food may result in decreased, delayed, or increased systemic drug availability. Food may interact with the therapeutic agent in the following steps: (i) before and during gastrointestinal absorption; (ii) in distribution; (iii) in metabolism; and (iv) in excretion. In one embodiment, the bioavailability of entinostat is reduced when administered with food.

Food can affect peak exposure (Cmax) and time to peak exposure (Tmax) by delaying gastric emptying and prolonging intestinal transit time. In some examples, food affects total exposure, or the region below the concentration time curve (AUC). In some embodiments, the Cmax is even higher when the entinostat is administered without food, as compared to the Cmax when the entinostat is administered with food. In some embodiments, the ratio of Cmax after administration of entinostat under fasting conditions to Cmax after administration of entinostat under fasting conditions is at least about 2: 1. In one embodiment, the ratio of Cmax after administration of entinostat under fasting conditions to Cmax after administration of entinostat under fasting conditions is at least about 3: 1. In one embodiment, the ratio of Cmax after administration of entinostat under fasting conditions to Cmax after administration of entinostat under fasting conditions is at least about 4: 1. In one embodiment, the ratio of Cmax after administration of entinostat under fasting conditions to Cmax after administration of entinostat under fasting conditions is at least about 5: 1. In one embodiment, the ratio of Cmax after administration of entinostat under fasting conditions to Cmax after administration of entinostat under fasting conditions is at least about 6: 1. In one embodiment, the ratio of Cmax after administration of entinostat under fasting conditions to Cmax after administration of entinostat under fasting conditions is at least about 7: 1.

In some embodiments, the Tmax is even lower when the entinostat is administered without food, as compared to the Tmax when the entinostat is administered with food. In some embodiments, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 2: 1. In one embodiment, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 3: 1. In one embodiment, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 4: 1. In one embodiment, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 5: 1. In one embodiment, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 6: 1. In one embodiment, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 7: 1. In one embodiment, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 8: 1. In one embodiment, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 9: 1. In one embodiment, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 10: 1. In one embodiment, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 11: 1. In one embodiment, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 12: 1. In one embodiment, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 13: 1. In one embodiment, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 14: 1. In one embodiment, the ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is at least about 15: 1.

In some embodiments, exemestane is administered at a different time than entinostat. In one embodiment, exemestane is administered postprandial. In one embodiment, exemestane is administered with a meal.

In another embodiment, the step of determining changes in protein lysine acetylation levels during treatment is about 2 days after treatment, about 5 days after treatment, about 7 days after treatment, about 15 days after treatment, or about treatment. Provided is a method performed after about 21 days.

Another embodiment provides a method in which the protein lysine acetylation level is obtained from a tissue sample selected from B cells, T cells, or monocytes.

Another embodiment provides a method in which the aromatase inhibitor is exemestane. Another embodiment provides a method in which the aromatase inhibitor is anastrozole. Another embodiment provides a method in which the aromatase inhibitor is letrozole. Another embodiment provides a method in which an aromatase inhibitor is administered daily. Another embodiment provides a method in which the aromatase inhibitor is exemestane and is administered daily. Another embodiment provides a method in which entinostat is administered every 7 days in a 28-day cycle. Another embodiment provides a method in which entinostat is administered every 14 days in a 28-day cycle. Another embodiment provides a method in which the entinostat-aromatase inhibitor combination therapy comprises oral administration of entinostat every 7 days in a 28-day cycle, and daily oral administration of exemestane. Another embodiment provides a method in which the entinostat-aromatase inhibitor combination therapy comprises oral administration of entinostat every 14 days in a 28-day cycle, and daily oral administration of exemestane. Another embodiment provides a method in which entinostat is administered to a fasting patient every 7 days in a 28-day cycle. Another embodiment provides a method in which entinostat is administered to a fasting patient every 14 days in a 28-day cycle. Another embodiment is a method in which the entinostat-aromatase inhibitor combination therapy comprises oral administration of entinostat to fasting patients every 7 days in a 28-day cycle, and daily oral administration of exemestane. provide. Another embodiment is a method in which the entinostat-aromatase inhibitor combination therapy comprises oral administration of entinostat to fasting patients every 14 days in a 28-day cycle, and daily oral administration of exemestane. provide.

Another embodiment provides a method in which the step of determining protein lysine acetylation levels during treatment is performed more than once. Another embodiment provides a method in which the step of determining protein lysine acetylation levels during treatment is performed once.

Another embodiment provides a method further comprising selecting a patient for further treatment when the level of protein lysine acetylation levels increases during treatment.

Another embodiment provides a method further comprising selecting a patient for further treatment if the level of protein lysine acetylation levels increases during the first week of treatment. Another embodiment provides a method further comprising selecting a patient for further treatment if the level of protein lysine acetylation levels increases during the first and second weeks of treatment.

One embodiment provides a method of selecting a patient for additional entinostat-aromatase inhibitor combination therapy, which treats protein lysine acetylation levels in tissue samples obtained after initiation of treatment. Includes a step to compare with the protein lysine acetylation level determined prior to initiation.

One embodiment provides a method of selecting a patient for additional entinostat-aromatase inhibitor combination therapy, which treats protein lysine acetylation levels in tissue samples obtained after initiation of treatment. Including the step of comparing with the protein lysine acetylation level determined before the start, where the increase in the protein lysine acetylation level after the start of treatment indicates that the patient will benefit from further treatment.

Another embodiment provides a method in which the protein lysine acetylation level in a tissue sample obtained after the start of treatment is determined more than once. Another embodiment provides a method in which an increase in protein lysine acetylation levels occurs over a week after the start of treatment. Another embodiment provides a method for determining protein lysine acetylation levels after the start of treatment on days 2, 8, and 15.

Another embodiment provides a method in which the increase is from about 10% to about 500%. Another embodiment provides a method in which the increase is from about 10% to about 400%. Another embodiment provides a method in which the increase is from about 10% to about 300%. Another embodiment provides a method in which the increase is from about 10% to about 200%. Another embodiment provides a method in which the increase is from about 10% to about 100%. Another embodiment provides a method in which the increase is about 10%, about 20%, about 30%, about 40%, about 50%, or about 60%. Another embodiment provides a method in which the increase is about 25%, about 50%, about 75%, about 100%, about 125%, or about 150%.

Another embodiment provides a method in which tissue samples are selected from B cells, T cells, or monocytes.

Another embodiment provides a method in which tissue samples obtained after the start of treatment are obtained at least 2 days after the start of treatment. Another embodiment provides a method in which tissue samples obtained after the start of treatment are obtained between the 2nd and 28th days after the start of treatment. In another embodiment, the tissue sample obtained after the start of treatment is 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days after the start of treatment. , 13 days later, 14 days later, or 15 days later.

One embodiment provides a method of selecting patients for additional entinostat-aromatase inhibitor combination therapy, which method results in a percentage change in protein lysine acetylation levels in tissue samples obtained after initiation of treatment. Includes the step of comparing the protein lysine acetylation level determined prior to the start of treatment, where a percentage reduction in the protein lysine acetylation level after the start of treatment of about 5% to about 50% is added to the patient. Indicates that you will not benefit from the treatment.

One embodiment provides a method of treating breast cancer that exhibits resistance prior to treatment with an aromatase inhibitor, the method comprising administering to a patient a combination comprising an entinostat and an aromatase inhibitor. The patient did not demonstrate complete, partial or stable disease for more than 6 months during pretreatment with an aromatase inhibitor. In some examples, entinostat is administered to fasting patients.

Another embodiment provides a method by which the patient returns to its original state during treatment within 6 months or within 6 months of completion of the previous non-steroidal aromatase inhibitor given as adjuvant therapy. ..

Another embodiment provides a method in which a patient demonstrates a progressive disease at least 3 months after treatment with a previous non-steroidal aromatase inhibitor.

Another embodiment provides a method in which breast cancer is ER-positive.

Another embodiment provides a method in which the aromatase inhibitor administered in combination with entinostat is letrozole. Another embodiment provides a method in which the aromatase inhibitor administered in combination with entinostat is anastrozole. Another embodiment provides a method in which the aromatase inhibitor administered in combination with entinostat is exemestane.

Another embodiment provides a method in which the entinostat and the aromatase inhibitor are administered sequentially or simultaneously. Another embodiment provides a method in which an entinostat and an aromatase inhibitor are administered simultaneously. Another embodiment provides a method in which the aromatase inhibitor is first administered. Another embodiment provides a method in which an aromatase inhibitor is administered daily and entinostat is administered cyclically. Another embodiment provides a method in which entinostat is administered weekly and an aromatase inhibitor is administered daily. Another embodiment provides a method by which entinostat is introduced into an aromatase inhibitor that continues during treatment.

Another embodiment provides a method further comprising the step of giving the subject one or more treatments with a combination of entinostat and an aromatase inhibitor selected from the group consisting of: letrozole: , Anastrozole, or exemestane, or pharmaceutically acceptable salts, solvates, or prodrugs thereof.

Another embodiment provides a method in which one or more therapies comprises one or more of radiation therapy, chemotherapy, high dose chemotherapy by stem cell transplantation, and monoclonal antibody therapy. Another embodiment provides a method in which radiation therapy involves internal and / or external radiation therapy. Another embodiment comprises the step of chemotherapy administering to a subject one or more of doxorubicin, cyclophosphamide, paclitaxel, lapatinib, capecitabine, trastuzumab, bevacizumab, gemcitabine, eribulin, or nab-paclitaxel. provide.

One embodiment provides a method of treating breast cancer in a patient in need, the method comprising oral administration of exemestane and entinostat, wherein the entinostat is administered to a fasting patient. .. Another embodiment provides a method of treating breast cancer, where the Tmax of entinostat is less than 1 hour after administration. Another embodiment provides a method of treating breast cancer, where the Tmax of entinostat is less than 90 minutes after administration. Another embodiment provides a method of treating breast cancer, where the Tmax of entinostat is less than 2 hours after administration. Another embodiment provides a method of treating breast cancer, where the Tmax of entinostat is between 30 minutes and 2 hours after administration. Another embodiment provides a method of treating breast cancer, where the Cmax of entinostat is at least 150 ng / mL after oral administration of entinostat. Another embodiment provides a method of treating breast cancer, where the Cmax of entinostat is at least 125 ng / mL after oral administration of entinostat. Another embodiment provides a method of treating breast cancer, where the Cmax of entinostat is at least 100 ng / mL after oral administration of entinostat. Another embodiment provides a method of treating breast cancer, where the Cmax of entinostat is at least 80 ng / mL after oral administration of entinostat. Another embodiment provides a method of treating breast cancer, where the Cmax of entinostat is at least 50 ng / mL after oral administration of entinostat. Another embodiment provides a method of treating breast cancer, in which about 5 mg of entinostat is administered. Another embodiment provides a method of treating breast cancer, in which about 10 mg of entinostat is administered. Another embodiment provides a method of treating breast cancer in which about 1 mg to about 20 mg of entinostat is administered. Another embodiment provides a method of treating breast cancer, in which the entinostat is administered once a week. Another embodiment provides a method of treating breast cancer, in which the entinostat is administered during a 28-day cycle. Another embodiment provides a method of treating breast cancer, in which the patient has not consumed food within 2 hours prior to administration of entinostat. Another embodiment provides a method of treating breast cancer, in which the patient has not consumed food within 1 hour prior to administration of entinostat.

Another embodiment provides a method of treating breast cancer, in which the patient does not consume food within 2 hours after administration of entinostat. Another embodiment provides a method of treating breast cancer, in which the patient does not consume food within 30 minutes after administration of entinostat. Another embodiment provides a method of treating breast cancer, in which exemestane is administered at a different time than entinostat. Another embodiment provides a method of treating breast cancer, in which exemestane is administered postprandial. Another embodiment provides a method of treating breast cancer, where exemestane is administered with a meal. Another embodiment provides a method of treating breast cancer, in which about 25 mg of exemestane is administered once daily.

<Treatment for lung cancer>
<Epidermal Growth Factor Receptor>
Over the past few years, there has been increased knowledge of molecular mechanisms and cell transformations related to cancer behavior. More interest has been generated as the development of process-specific targeted therapies has been associated with the carcinogenicity of many types of cancers. During the 1990s, it was discovered that epidermal growth factor receptor (EGFR) played an important role in tumor ecology and behavior. EGFR stimulation activates intracellular signaling and cascades that affect cell proliferation and recruitment, angiogenesis, and other mechanisms. Normal cells are affected by external factors, and in tumor cells, the activation of cell proliferation mediated by this receptor no longer requires external stimuli, but acts independently and autonomously. Found. In the case of NSCLC, overexpression of this receptor, as well as specific somatic mutations (which can affect prognosis) in the intracellular domain with tyrosine kinase activity (between exons 18 and 21) It has been shown to be significantly associated with gradual, survival, and chemotherapy responses. These data lead to the development and study of various substances, which inhibit the tyrosine kinase intracellular domain (tyrosine kinase inhibitor, TKI) of EGFR (eg, gefitinib and erlotinib), EGFR (eg, cetuximab, etc.). Includes Erlotix®) and monoclonal antibodies directed to the extracellular domain of small molecules. Preliminary results of randomized clinical trials conducted with these TKIs show that their use in patients with advanced disease is effective, especially in female patients who are abstinent, of Asian descent, and Significantly increases survival of patients with EGFR mutations found fairly often in subgroups of patients with histological subtypes of adenocarcinoma (especially in the presence of bronchiolar alveolar epithelial cancer) .. Among these results, this phenomenon was noted (Lazarus effect), with approval of erlotinib for second-line and third-line treatment of NSCLC patients in the United States and Europe; and for patients with EGFR mutations. Some were so impressive that they led to the approval of gefitinib in Europe (del Mello, et al., World J Clinc Oncol, Vol. 2, p. 367 (2011)).

EGFR, also known as ErbB1 or Her1, is a transmembrane glycoprotein encoded by a gene located on chromosome 7 (7p12.1-12.3). EGFR contains 1186 amino acids (a.a.) and 26 exons. Exons 1-14 encode the extracellular domain, exon 15 encodes the transmembrane domain, and exons 16-26 encode the intracellular domain. This glycoprotein belongs to the ErbB receptor family, which also consists of ErbB2 (HER2 / neu), ErbB3 (HER3), and ErbB4 (HER4). Each of these proteins is structurally composed of an extracellular domain, a hydrophobic transmembrane domain, and an intracellular domain with endogenous tyrosine kinase (TK) activity (excluding ErbB3). These receptors exist as inactive monomers and are activated by extracellular domain-mediated interactions with EGF family growth factors. The binding of the ErbB receptor molecule to one of these ligands leads to its interaction with other monomers of the same family (receptor dimerization). This dimerization can occur between two identical receptors (homodimerization, eg ErbB1-ErbB1) or between two different receptors (heterodimerization, eg ErbB1-ErbB3). ), May occur. The irritation caused by the specific ligand causes a unique pattern of dimerization, which is also specific to the tissue / tumor in which the phenomenon occurs. Receptor dimerization leads to autophosphorylation by activation of TK and a cascade of intracellular biochemical processes, the processes of proliferation, differentiation, apoptosis, and cell migration. As such, it regulates such diverse activities.

<E-cadherin>
Cadherin-1, CAM 120/80, or epithelial cell cadherin (E-cadherin), also known as ubomorrin, is a protein encoded by the CDH1 gene in humans. E-cadherin is a classic member of the cadherin superfamily. E-cadherin consists of an extracellular domain, a transmembrane domain, an intracellular domain that binds p120-catenin and beta-catenin, and five extracellular cadherin repeats (EC1-EC5) in the highly conserved cytoplasmic tail. It is a calcium-dependent intercellular adhesive sugar protein. The intracellular domain contains beta-catenin binding and, therefore, a highly phosphorylated region that is essential for E-cadherin function. Beta-catenin can also bind to alpha-catenin. Alpha-catenin is involved in the regulation of actin-containing cytoskeletal filaments. In epithelial cells, the junctions between cells containing E-cadherin are usually adjacent to actin-containing filaments of the cytoskeleton.

Mutations in this gene are associated with cancers of the stomach, breast, colorectal, thyroid, and ovaries. Loss of function or expression is thought to contribute to the progression of cancer and metastasis. Down-regulation of E-cadherin weakens the strength of cell adhesion within the tissue, resulting in increased cell motility. This may then allow cancer cells to cross the basement membrane and invade surrounding tissues.

<Method of determining E-cadherin level>
E-cadherin protein levels can be measured quantitatively by ELISA. Several E-cadherin ELISA kits, such as the E-cadherin EIA kit provided by TaKaRA, use a two-step incubation method to detect human E-cadherin in two mouse monoclonal E-. A solid-phase sandwich ELISA that utilizes a cadherin antibody, one coated on a plate and the other POD-labeled. In the first step, the sample is incubated in an antibody-coated microtiter plate. During the second step, the plates are washed and incubated with POD-labeled E-cadherin antibody. Substrate addition results in a reaction between the POD and the substrate (H2O2, TMBZ) resulting in color development. The amount of soluble e-cadherin in a sample is determined by measuring absorption using an EIA plate reader. The concentration of the exact soluble e-cadherin sample can be determined by comparing their specific absorption with the absorption obtained for the standard plotted on the standard curve. In some embodiments, E-cadherin protein levels can be measured quantitatively by ELISA.

E-cadherin protein levels can be detected by immunohistochemistry. To detect E-cadherin levels in immersed fixed cells, cells were subjected to human E-cadherin antigen affinity purified polyclonal antibody (R & D Systems® Catalog # AF648) at room temperature for 3 hours at 10 μg / mL Incubate. Cells were then stained using Northern Lights ™ 557-conjugated anti-goat IgG secondary antibody (R & D Systems® Catalog # NL001) and counterstained with DAPI. E-cadherin and DAPI are visualized using a fluorescence microscope and a filter set appropriate for the label used. In some embodiments, E-cadherin protein levels are detected by immunohistochemistry.

Protein levels of E-cadherin can be detected by immunocytochemistry. Cover glass for immunocytochemistry (ICC) can be prepared using gelatin. In some embodiments, the method of preparing a cover glass for ICC is a) a step of placing a sterile cover glass in the wells of a 24-well plate, b) a step of adding 400 μL of gelatin coating solution, and. c) The step of incubating the cover glass at room temperature for 10 minutes is included. The gelatin coating solution is then removed and the cover glass is air dried for 15 minutes. Dry cover glass can be stored at room temperature until use. Once the coverslip is prepared, the cells can be prepared and fixed as follows. Cells are cultured by adding 500 μL culture medium containing approximately 5000 cells to the wells of a cell culture plate containing a gelatin-coated cover glass. When the cells reach the desired density / age, the culture medium is removed from each well and washed twice with PBS. Add 300-400 μL of 2-4% formaldehyde fixative to each well and incubate for 20 minutes at room temperature. The wells are washed twice with PBS and covered with 400 μL wash buffer. Cover glasses can be stored at 2-8 ° C. for 3 months, or they may be immediately stained. Once the cells are prepared, they can be stained for ICC as follows. The cover glass containing the immobilized cells is washed twice in 400 μL wash buffer. Remove the blocking buffer. Rinse is not mandatory. Dilute the non-conjugated primary antibody (or fluorescently conjugated primary antibody) in dilution buffer according to the manufacturer's instructions. Incubation with R & D Systems antibody for 1 hour at room temperature is recommended for fluorescent ICC staining of cells on cover glass. Alternatively, incubate overnight at 2-8 ° C. Wash twice in 400 μL wash buffer. If a primary antibody having the fluorescent conjugate directly is used, proceed to step 8. Dilute the secondary antibody in dilution buffer according to the manufacturer's instructions. Add 400 μL to the wells and incubate in the dark for 1 hour at room temperature. From this step, the sample in front should be protected from light. Rinse twice in 400 μL detergent buffer. Sufficiently add 300 μL of diluted DAPI solution to each well and incubate for 2-5 minutes at room temperature. DAPI binds to DNA and is a convenient counterstain of the nucleus. DAPI has an absorption maximum of 358 nm and emits blue fluorescence with an emission maximum of 461 nm. Rinse once with PBS and once with water. Carefully, the cover glass was removed from the wells and blotted to remove any excess water. Dispense 1 drop of anti-fading encapsulant per cover glass onto the microscope slide. Mount the cover glass with the cells facing the microscope slide. Visualize using a fluorescence microscope and filter set suitable for the label used. The slides can be stored in the slide box at <-20 ° C. for later testing. In some embodiments, the level of E-cadherin protein is detected by immunohistochemistry.

The expression of the E-cadherin gene can be determined by measuring the methylation of E-cadherin. E-cadherin methylation kits, such as the CpG WIZ® E-cadherin amplification kit provided by Millipore®, provide methylation status of the E-cadherin promoter by methylation-specific PCR (MSP). judge. The kit contains primers that target regions of the promoter with the most different sequences after sodium bisulfite treatment. The parameters of the PCR are identified so that the entire primer set in the kit is amplified under the same conditions. Samples of control genomic DNA for E-cadherin (methylated and unmethylated) are also included. In some embodiments, the expression of the E-cadherin gene can be determined by measuring the methylation of E-cadherin.

One embodiment provides a method of treating cancer in a patient who has not been treated with an EGFR inhibitor, which has progressed with conventional treatment, wherein the patient exhibits high expression levels of E-cadherin, the method of which is entinostat. Includes the step of administering to the patient a combination comprising and EGFR inhibitor. Another embodiment provides a method in which high expression levels of E-cadherin are characterized by determination of ELISA, immunohistochemistry, immunocytochemistry, or methylation levels of E-cadherin. Another embodiment provides a method in which high expression levels of E-cadherin are determined by immunohistochemistry. Another embodiment provides a method of determining high expression levels of E-cadherin by immunohistochemistry and scoring as +3.

<Lung cancer>
Lung cancer is a leading cause of cancer death in both women and men in the United States and around the world. Lung cancer has surpassed breast cancer as the leading cause of cancer death in women. In 2010, it was estimated that 157,300 people (more than colorectal, breast, and prostate cancers and their combination) would die of lung cancer in the United States. Only about 2% of patients diagnosed with lung cancer that has spread to other parts of the body are alive 5 years after diagnosis, but the survival rate of lung cancer diagnosed at the earliest stages is higher. Approximately 49% of patients survive for more than 5 years.

Cancer develops when normal cells are transformed and grow and proliferate uncontrolled. The cells form a mass or tumor that is different from the surrounding tissue in which the tumor originates. Tumors are dangerous because they deprive normal cells of oxygen, nutrients, and space, thus infiltrating and destroying or reducing the ability of normal tissue to function.

Most lung tumors are malignant. This means that they can infiltrate the surrounding normal tissue, destroy it and spread throughout the body. Tumors can spread to nearby lymph nodes or through blood flow to other organs. This process is called metastasis. When lung cancer metastasizes, tumors in the lung are called primary tumors, and tumors in other parts of the body are called secondary or metastatic tumors.

Some tumors in the lung are metastases from cancer elsewhere in the body. The lungs are a common site for metastases. In that case, the cancer is not considered to be lung cancer. For example, if prostate cancer spreads through the bloodstream to the lungs, it is metastatic prostate cancer (secondary cancer) in the lungs and is not called lung cancer.

Lung cancer includes a group of different types of tumors. Lung cancer is usually divided into two major groups, which account for about 95% of all cases. The division within the group is based on the type of cells that make up the cancer. Two major types of lung cancer are characterized by tumor cell size when viewed under a microscope. They are called small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC contains several subtypes of tumor. SCLC is less common, but it grows faster and is more likely to metastasize than NSCLC. Often, SCLC has already spread to other parts of the body when cancer is diagnosed. About 5% of lung cancers are rare cell types, including carcinoid tumors, lymphomas and others. As used herein, the term "lung cancer" includes, but is not limited to, SCLC, NSCLC, carcinoid tumors, lymphomas, and various subtypes thereof.

<Non-small cell lung cancer>
NSCLC is a lung cancer that is not of the small cell carcinoma (swallow cell carcinoma) type. The term "non-small cell lung cancer" applies to various types of bronchiogenic carcinomas (resulting from bronchial lining). Examples of specific types of NSCLC include, but are not limited to, adenocarcinomas, squamous cell lung cancers, and large cell lung cancers (ie, large cell undifferentiated carcinomas).

Adenocarcinoma is a cancer that develops on the lining or internal surface of an organ. Adenocarcinoma is the most common type of lung cancer, accounting for 30% -40% of all cases of lung cancer. A subtype of adenocarcinoma is called bronchoalvolar cell carcinoma, which produces a pneumonia-like appearance on chest X-rays.

Squamous epithelial carcinoma is a cancer that begins in squamous cell. Squamous epithelial cells are flat cells that look like fish scales under a microscope. Squamous epithelial cells are found on the surface of the skin, the lining of the body's luminal organs, and the tissues that form the passages of the airways and gastrointestinal tract. Squamous epithelial cell carcinoma can occur in any of these tissues. Squamous epithelial cell carcinoma is the second most common type of lung cancer, accounting for about 30% of all cases.

Large cell carcinoma shows no evidence of scaly or glandular maturation. Therefore, these tumors are often diagnosed by default if all other possibilities are ruled out. These tumors lack any diagnostic features to suggest their diagnosis prior to biopsy. They tend to grow rapidly and metastasize early and are strongly associated with smoking. Large cell tumors are large, bulky, well-defined, pink-gray masses, usually with extensive bleeding and necrosis. They generally have central necrosis but rarely cavity. They tend to appear in the central to marginal lung region. They may expand locally to be associated with segmental or subsegmental bronchi. A variant of large cell carcinoma is a giant cell carcinoma. This subtype is particularly active and has a very poor prognosis. These tumors generally appear as large marginal masses with a component of localized necrosis. Without direct enlargement, they do not participate in the large airways. Large cell carcinoma accounts for 10% -20% of all cases of lung cancer.

<Small cell lung cancer>
SCLC is also called swallow cell lung cancer and is a type of lung cancer in which cells appear small and round under a microscope. SCLC is considered to be different from other lung cancers because of their clinical and biological characteristics. Small cell lung cancer exhibits vigorous behavior with rapid growth, early spread to the distal site, sensitive sensitivity to chemotherapy and radiation, and habitual association with different paraneoplastic syndromes. Small cell carcinoma occurs around the bronchi and invades the bronchial submucosa. Extensive metastases occur early in the course of the disease and commonly spread to the septal lymph nodes, liver, bones, adrenal glands, and brain. In addition, the production of various peptide hormones leads to a wide range of paraneoplastic syndromes; the most common of these are the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and the syndrome of ectopic adrenocorticotropic hormone (ACTH) production. is there. In addition, autoimmune events can lead to various neurological syndromes such as Lambert-Eaton syndrome. SCLC accounts for 20% of all cases.

<Carcinoid tumor>
Carcinoid tumors are tumors that secrete large amounts of serotonin hormone. Carcinoid tumors are also called argyrophilic tumors. Tumors usually develop in the gastrointestinal tract anywhere between the stomach and rectum (predominant sites are in the appendix) and can metastasize to the liver from there. In the liver, tumors produce large amounts of serotonin and release it into the bloodstream throughout the body. The result is called carcinoid syndrome. The result is called carcinoid syndrome. It is directly due to serotonin, flushing and blushing, swelling of the face (especially around the eyes), flat-skinned hemangiomas (small collections of enlarged blood vessels), diarrhea, bronchial spasms, tachycardia, hypotension, and Includes tricuspid and pulmonary valve stenosis (tricuspid and pulmonary valve stenosis of the heart), often accompanied by reflux. One or more of the following four treatments are used for cartinoid tumors: surgery (to remove the cancer); radiation therapy (using high-dose X-rays to kill the cancer cells) Biological therapy (using the body's natural immune system to fight cancer); chemotherapy (using drugs that kill cancer cells). Carcinoid tumors are considered to be a type of endocrine tumor because they secrete the hormone (serotonin). They can occur as part of certain genetic disorders such as type 1 multiple endocrine neoplasms (MEN) and type 1 neurofibromatosis (NF1 or von Recklinghausen's disease). Carcinoid tumors account for 1% of all cases.

<Lymphoma>
Lymphoma is a type of cancer that involves cells of the immune system called lymphocytes and primarily represents the cells involved in the body's lymphatic system. Lymphoma is a malignant transformation of B or T cells or a subtype thereof. Lymphomas fall into one of two main categories: Hodgkin lymphoma (HL, formerly known as Hodgkin's disease) and all other lymphomas (non-Hodgkin's lymphoma or NHL). These two types occur in the same place and may be associated with the same symptoms and often have similar appearances on physical examination. However, they are easily identifiable via microscopic examination. Hodgkin's disease develops from the genealogy of certain abnormal B lymphocytes. NHL may be derived from either abnormal B cells or T cells and is determined by a unique genetic marker. There are five subtypes of Hodgkin's disease and about 30 subtypes of non-Hodgkin's lymphoma. The classification of lymphomas is complex because there are so many different subtypes of lymphoma (it includes both microscopic images as well as genetic and molecular markers). Although many of the NHL subtypes appear to be similar, they are functionally completely different and respond to different treatments with different potential cures. The HL subtypes differ under the microscope and the classification is based on the differences under the microscope as well as the extent of the disease.

<EGFR inhibitor>
EGFR inhibitors interfere with signal transduction in target cells via epidermal growth factor receptor (EGFR). Certain EGFR inhibitors, such as erlotinib, have been approved for the treatment of metastatic NSCLC. EGFR inhibitors such as gefitinib have been approved for advanced NSCLC. In addition, several EGFR inhibitors are being tested in clinical trials for the treatment of NSCLC and additional lung cancer.

As described herein, an "EGFR inhibitor" is a molecule that inhibits the activity of the EGF receptor. Compounds that are inhibitors of EGFR can be readily identified by those of skill in the art using methods such as, for example, the EGFR kinase assay in which ADP is formed from a kinase reaction.

Inhibition of EGFR as a treatment option for lung cancer has been studied with several outcomes. Currently, three EGFR inhibitors, erlotinib, gefitinib and cetuximab, have been approved for commercialization in the United States for the treatment of lung cancer.

Erlotinib (Tarceva®) is approved for the treatment of metastatic non-small cell lung cancer and pancreatic cancer that cannot be surgically removed or has metastasized. This small molecule drug inhibits the tyrosine kinase activity of EGFR.

Gefitinib (Iressa®) has been approved for the treatment of patients with advanced non-small cell lung cancer. This small molecule drug is restricted to use in patients who are currently or previously benefiting from gefitinib treatment in the view of the physician treating the patient. Gefitinib inhibits the tyrosine kinase activity of the epidermal growth factor receptor (EGFR), which is overproduced by many types of cancer cells.

Cetuximab (Erbitux®) is a monoclonal antibody approved for the treatment of patients with head and neck squamous cell carcinoma or colorectal cancer. The treatment binds to the outer part of EGFR, thereby preventing the receptor from being activated by growth signals, which can inhibit signaling and lead to antiproliferative effects.

Additional examples of EGFR inhibitors include, but are not limited to, panitumumab, vandetanib, lapatinib, canertinib, afatinib, necitumumab, nimotzumab, PF299804, RO508934, ABT-806 and AP26113.

Panitumumab (Vectibix®) is approved for the treatment of patients with metastatic colon cancer. This monoclonal antibody is attached to EGFR and prevents it from sending growth signals.

Vandetanib (Caprelsa®) is approved for the treatment of patients with metastatic medullary thyroid cancer who are unsuitable for surgery. This small molecule drug can bind to several tyrosine kinase enzymes, including EGFR, some receptors for vascular endothelial growth factor (VEGF), and RET, and interfere with proliferative activity.

Lapatinib (Tykerb®) has been approved for the treatment of certain types of advanced or metastatic breast cancer. This small molecule drug inhibits several tyrosine kinases, including the tyrosine kinase activity of HER-2. Lapatinib treatment prevents the HER-2 signal from activating cell proliferation.

Canertinib is an orally bioavailable irreversible pan-ErbB tyrosine kinase inhibitor that targets EGFR, HER-2, ErbB-3 and ErbB-4. It effectively inhibits the growth of esophageal squamous cell carcinoma, which involves inhibition of both MAPK and AKT phosphorylation and co-expresses both EGFR and HER2. In vitro studies of human cancer cell lines show that canertinib results in a rapid, potent, persistent inhibition of tyrosine kinase activity.

Afatinib is irreversible EGFR / HER2. In a cell-free in vitro kinase assay, afatinib showed potent activity against wild and mutant forms of EGFR and HER2, similar to the efficacy of gefitinib for EGFR of L858R, but of gefitinib resistant L858R-T790M It exhibits about 100-fold more activity than against the EGFR double mutant. Afatinib was effective in inhibiting the survival of wild-type (H1666) or L858R / T790M (NCI-H1975) EGFR-bearing lung cancer cell lines. It was evaluated in a standard xenograft model of the epidermal cancer cell line A431. Daily oral treatment with 20 mg / kg afatinib for 25 days resulted in dramatic tumor regression of 2% in cumulative treatment / control tumor volume ratio (T / C ratio). Afatinib, like lapatinib and neratinib, is a next-generation tyrosine kinase inhibitor (TKI) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinase. Afatinib is active not only against EGFR mutations that have been targeted by first-generation TKIs, such as erlotinib or gefitinib, but also against those that are not sensitive to these standard therapies. It is investigated for breast cancer, as well as other cancers caused by EGFR and Her2, due to its additional activity against Her2.

Nesitumumab is a fully human IgG1 monoclonal antibody directed against epidermal growth factor receptor (EGFR) with potential antineoplastic drug activity. Nesitumumab binds and blocks the ligand binding site of EGFR, thereby interfering with receptor activation and subsequent dimerization. This leads to inhibition of the EGFR-dependent downstream pathway and therefore inhibition of EGFR-dependent tumor cell proliferation and metastasis.

Nimotuzumab is a humanized monoclonal antibody directed against the epidermal growth factor receptor (EGFR) with potential antineoplastic drug activity. Nimotuzumab binds to and inhibits EGFR, which results from the inhibition of growth of overexpressing tumor cells. This drug may work synergistically with radiation therapy.

PF299804 is a potent irreversible inhibitor of human epidermal growth factor receptor (HER) -1 / EGFR, -2, and -4 tyrosine kinases (TK) in preclinical models of E-sensitivity and resistance. Active. PF299804 had clinical activity in Phase I / II trials in EGFR TK inhibitor resistant NSCLC.

RO508934 is a sugar-engineered anti-EGFR IgG1 mAb that exhibits increased binding affinity for all FcγRIIIa variants expressed on immune effector cells. RO5083945 showed significantly improved cell death in ADCC-based assays compared to cetuximab and panitumumab, showing high activity in the in vivo model. Therefore, RO508934 has the potential to exhibit clinical activity in patients with solid tumors, including KRAS mutant CRC.

ABT-806 is a humanized monoclonal antibody (MoAb) against the human epidermal growth factor receptor (EGFR) with antitumor activity. MoAb ABT-806 targets the EGFR-deficient mutant de2-7 EGFR, which is expressed in cells similar to wild-type EGFR and overexpresses the receptor, and is therefore activated and subsequently dilated. Preventing somatization and reducing receptor activation and dimerization results in inhibition of signaling and antiproliferative effects. This MoAb targets cells that express aberrant EGFR, making it an ideal candidate for the production of radioisotope or toxin conjugates.

AP26113 is an orally administrable inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) with potential antitumor activity. The ALK / EGFR dual inhibitor AP26113 binds to and inhibits ALK kinase and ALK fusion proteins, as well as EGFR and variants. This leads to inhibition of ALK and EGFR kinases, their signaling pathways, and ultimately inhibition of tumor cell growth in susceptible tumor cells. AP2611 also appears to overcome mutation-based resistance. ALK belongs to the insulin receptor superfamily and plays an important role in the development of the nervous system. ALK dysregulation and gene rearrangement are associated with a series of tumors. EGFR is overexpressed in various cancer cell types.

<Additional therapy>
Additional treatments available for lung cancer that may be advantageously utilized in combination with the therapies disclosed herein include, but are not limited to, tyrosine kinase inhibitors as radiation therapy, chemotherapy, antibody therapy, and adjuvant therapy. Including.

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them growing. Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping their division. When chemotherapy is obtained by mouth or injected into a blood vessel or muscle, the drug can enter the bloodstream and reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into body cavities such as the spine, organs, or abdomen, the drug primarily affects cancer cells in those areas (topical chemotherapy). The method in which chemotherapy is given depends on the type and stage of the cancer being treated.

Different chemotherapeutic agents are known in the art for the treatment of lung cancer. Cytoxic agents used to treat lung cancer include carboplatin (eg, ParaplatinR, Paraplat (registered commercial)), cisplatin (eg, Platinol (registered commercial), Platinol-Aq (registered commercial)), crizotinib ( For example, Xalkori (registered commercial), etopocid (eg Toposar (registered commercial), VePesid (registered commercial)), methotrexate (eg Etopophos (registered commercial)), gemcitabine hydrochloride (eg Gemzar (registered commercial)), gemcitabine cisplatin. , Methotrexate (eg Abitrexate (registered commercial), Folex (registered commercial), Folex Pfs (registered commercial), Cisplatin, Lpf (registered commercial), Mixate (registered commercial), Mixate-Aq (registered commercial)), Paclitaxel (eg Taxol) (Registered Commercial)), pemethrexed disodium (eg Alimta (Registered Commercial)) and topotecan hydrochloride (eg Hycamtin (Registered Commercial)).

Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the laboratory from a single immune system cell. These antibodies can identify substances on cancer cells, or normal substances that help cancer cells grow. Antibodies attach to substances, kill cancer cells, block the growth of cancer cells, or maintain their spread. Monoclonal antibodies are given by infusion. They can be used alone or to carry drugs, toxins, or radioactive substances directly to cancer cells. Monoclonal antibodies are also used as adjuvant therapy in combination with chemotherapy.

Bevacizumab (AvastinR) is a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), a cytokine that supports angiogenicity. Bevacizumab binds to VEGF and inhibits VEGF receptor binding, thereby preventing the growth and maintenance of tumor blood vessels. Bevacizumab is currently used to treat certain types of colorectal cancer, lung cancer, breast cancer and kidney cancer and glioblastoma.

Additional exemplary treatments that may be advantageously combined with the compositions and treatments disclosed herein are capecitabine, docetaxel, epirubicin, epothilone A, B, or D, goseleline acetate, paclitaxel, paclitaxel, In combination with bevacizumab, or trastuzumab, administration of agents including, but not limited to, lapatinib may be included.

In some embodiments, the chemotherapy comprises the step of administering to the subject one or more of doxorubicin, cyclophosphamide, paclitaxel, lapatinib, capecitabine, trastuzumab, bevacizumab, gemcitabine, eribulin, or nab-paclitaxel. Including therapy.

<Treatment method for lung cancer>
One embodiment provides a method of treating cancer in a patient who has not been treated with an EGFR inhibitor, which has progressed with conventional treatment, and the method is: (1) a step of determining the level of E-cadherin expression in a patient; It comprises (2) selecting a patient showing a high expression level of E-cadherin scored as +3; and (3) administering to the patient a combination containing an entinostat and an EGFR inhibitor. In some cases, entinostat is administered to fasting patients.

In some embodiments, the Cmax is higher when the entinostat is administered without food, as compared to the Cmax when the entinostat is administered with food. In some embodiments, the ratio of Cmax after entinostat administration under fasting conditions to Cmax after entinostat administration under fasting conditions is at least about 2: 1. In one embodiment, the ratio of Cmax after administration under fasting entinostat to Cmax after administration of entinostat under feeding conditions is at least about 3: 1. In one embodiment, the ratio of Cmax after administration under fasting entinostat to Cmax after administration of entinostat under feeding conditions is at least about 4: 1. In one embodiment, the ratio of Cmax after administration under fasting entinostat to Cmax after administration of entinostat under feeding conditions is at least about 5: 1. In one embodiment, the ratio of Cmax after administration under fasting entinostat to Cmax after administration of entinostat under feeding conditions is at least about 6: 1. In one embodiment, the ratio of Cmax after administration under fasting entinostat to Cmax after administration of entinostat under feeding conditions is at least about 7: 1.

In some embodiments, the Tmax when the entinostat is administered without food is lower than the Tmax when the entinostat is administered with food. In some embodiments, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 2: 1. In one embodiment, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 3: 1. In one embodiment, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 4: 1. In one embodiment, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 5: 1. In one embodiment, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 6: 1. In one embodiment, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 7: 1. In one embodiment, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 8: 1. In one embodiment, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 9: 1. In one embodiment, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 10: 1. In one embodiment, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 11: 1. In one embodiment, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 12: 1. In one embodiment, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 13: 1. In one embodiment, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 14: 1. In one embodiment, the ratio of Tmax after administration under fasting entinostat to Tmax after administration under fasting entinostat is at least about 15: 1.

In some embodiments, the EGFR inhibitor is administered at a different time than the entinostat. In one embodiment, the EGFR inhibitor is administered to a fasting patient.

Another embodiment provides a method in which the previous treatment is one chemotherapy.

Another embodiment provides a method in which the previous treatment is more than one chemotherapy.

Another embodiment provides a method in which high expression levels of E-cadherin are characterized by determination of ELISA, immunohistochemistry, immunocytochemistry, or methylation levels of E-cadherin. Another embodiment provides a method in which high expression levels of E-cadherin are determined by immunohistochemistry. Another embodiment provides a method of determining high expression levels of E-cadherin by immunohistochemistry and scoring as +3.

Another embodiment provides a method in which the cancer is lung cancer.

Another embodiment provides a method in which the cancer is non-small cell lung cancer.

Another embodiment provides a method in which the EGFR inhibitor is administered in combination and the entinostat is erlotinib.

Another embodiment provides a method in which the entinostat and the EGFR inhibitor are administered sequentially, either sequentially or simultaneously. Another embodiment provides a method in which the entinostat and the EGFR inhibitor are administered simultaneously. Another embodiment provides a method in which the EGFR inhibitor is first administered. Another embodiment provides a method in which the EGFR inhibitor is administered daily and the entinostat is administered cyclically. Another embodiment provides a method in which the EGFR inhibitor is administered daily and the entinostat is administered cyclically.

Another embodiment provides a method of treating cancer in an EGFR inhibitor-naive patient who has progressed with conventional therapy, wherein the patient exhibits high levels of E-cadherin expression and the method is entinostat. Includes the step of administering to a patient a combination containing a stat and an EGFR inhibitor.

Another embodiment provides a method of treating cancer in an EGFR inhibitor-naive patient who has progressed with conventional therapy, wherein the patient exhibits high levels of E-cadherin expression and the method is entinostat. It further comprises the step of administering one or more additional therapies to the subject in addition to the combination of stat and EGFR inhibitor. Another embodiment provides a method in which one or more therapies comprises one or more of radiation therapy, chemotherapy, high dose chemotherapy by stem cell transplantation, and monoclonal antibody therapy. Another embodiment provides a method in which radiation therapy comprises internal and / or external radiation therapy. Another embodiment comprises the step of chemotherapy administering to a subject one or more of doxorubicin, cyclophosphamide, paclitaxel, lapatinib, capecitabine, trastuzumab, bevacizumab, gemcitabine, eribulin, or nab-paclitaxel. provide. Another embodiment provides a method in which chemotherapy comprises administering to a subject one or more IGF-1R inhibitors. Another embodiment provides a method in which the IGF1R inhibitor is AEW541.

One embodiment provides a method of treating non-small cell lung cancer in a patient, the method comprising oral administration of erlotinib and entinostat, where the entinostat is administered to a fasting patient. Another embodiment provides a method of treating non-small cell lung cancer, where the Tmax of entinostat is less than 1 hour after administration. Another embodiment provides a method of treating non-small cell lung cancer, where the Tmax of entinostat is less than 90 minutes after administration. Another embodiment provides a method of treating non-small cell lung cancer, where the Tmax of entinostat is less than 2 hours after administration. Another embodiment provides a method of treating non-small cell lung cancer, where the Tmax of entinostat is between 30 minutes and 2 hours after administration. Another embodiment provides a method of treating non-small cell lung cancer, where the Cmax of entinostat is at least 150 ng / mL following oral administration of entinostat. Another embodiment provides a method of treating non-small cell lung cancer, where the Cmax of entinostat is at least 125 ng / mL following oral administration of entinostat. Another embodiment provides a method of treating non-small cell lung cancer, where the Cmax of entinostat is at least 100 ng / mL following oral administration of entinostat. Another embodiment provides a method of treating non-small cell lung cancer, where the Cmax of entinostat is at least 80 ng / mL following oral administration of entinostat. Another embodiment provides a method of treating non-small cell lung cancer, where the Cmax of entinostat is at least 50 ng / mL following oral administration of entinostat. Another embodiment provides a method of treating non-small cell lung cancer, wherein about 10 mg of entinostat is administered. Another embodiment provides a method of treating non-small cell lung cancer, wherein about 1 mg to about 20 mg of entinostat is administered. Another embodiment provides a method of treating non-small cell lung cancer, where entinostat is administered every 14 days. Another embodiment provides a method of treating non-small cell lung cancer, where the entinostat is administered monthly. Another embodiment provides a method of treating non-small cell lung cancer, where the patient has not consumed food within 2 hours prior to administration of entinostat. Another embodiment provides a method of treating non-small cell lung cancer, where the patient has not consumed food within 1 hour prior to administration of entinostat. Another embodiment provided a method of treating non-small cell lung cancer, where the patient did not consume food within 1 hour after administration of entinostat. Another embodiment provided a method of treating non-small cell lung cancer, where the patient did not consume food within 30 minutes after administration of entinostat. Another embodiment provides a method of treating non-small cell lung cancer, where erlotinib is administered at a different time than entinostat. Another embodiment provides a method of treating non-small cell lung cancer, where erlotinib is administered once daily to fasting patients. Another embodiment provides a method of treating non-small cell lung cancer, where the patient has not consumed food within 2 hours prior to administration of erlotinib. Another embodiment provides a method of treating non-small cell lung cancer, in which the patient does not consume food within 1 hour after administration of erlotinib. Another embodiment provides a method of treating non-small cell lung cancer, in which approximately 150 mg of erlotinib is administered.

<Oral preparation>
Oral formulations containing the pharmaceutical active ingredients described herein may include any conventionally used oral dosage form, including: tablets, capsules, pills, lozenges, lozenges, pastel. Agents, capsules, pellets, medicated chewing gums, berries, mixed powders, effervescent or non-foaming powders or pills, solutions, emulsions, suspensions, solutions, wafers, sprinkles, Elixirs, syrups, buccal forms, and oral liquids.
Capsules include pharmaceutically acceptable starch (eg, corn, potato, or tapioca starch), sugars, artificial sweeteners, powdered celluloses such as crystalline and microcrystalline celluloses, wheat flour, gelatin, rubbers, and the like. It may contain a mixture of the active compound and an inert filler and / or diluent. Useful tablet formulations are made by conventional compression, wet or dry granulation methods, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, crystalline cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone, Gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicate, calcium carbonate, glycine, dextrin, sucrose, sorbitol, calcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starch, And pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents or stabilizers, including powdered sugar, may be utilized. In some embodiments, the surface modifier comprises a nonionic and anionic surface modifier. For example, surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, setomacrogol emulsified wax, sorbitan ester, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, silicate. Contains aluminum magnesium and triethanolamine.
Oral formulations herein may utilize standard delayed or time-release formulations to alter the absorption of the active compound. Oral formulations can also consist of administration of the active ingredient in water or juice, including the appropriate solubilizer or emulsifier as required.

<Oral administration>
As described herein, the combination therapies described herein can be given simultaneously or in a staggered chemen, and the entinostat is with an EGFR inhibitor. Is given at different times during chemotherapy. This time difference can vary longer than minutes, hours, days, weeks, or between administrations of the two compounds. Therefore, the combination of terms does not necessarily mean that they are administered simultaneously or as a single dose, but each of the components is administered during the desired treatment period.
The drug can also be administered by different routes. As is typical of chemotherapy regimens, a series of chemotherapy can be repeated after a few weeks and modified according to the same time frame for administration of the two compounds or based on the patient's response.

In other embodiments, the pharmaceutical compositions provided herein may be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms are, but are not limited to, tablets, capsules, pills, lozenges, lozenges, pastel, cashiers, pellets, medicated chewing gums, granules, mixed powders, effervescent or non-foaming Includes powders or pills, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixyl agents, and syrups. In addition to the active ingredient, pharmaceutical compositions include, but are not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, fluidants, colorants, dye transfer inhibitors, sweeteners. , And one or more pharmaceutically acceptable carriers or excipients, including flavoring agents.

The binder or granulator gives the tablets stickiness to identify the tablets that remain intact after compression. Suitable binders or granulators are, but are not limited to, starches such as corn starch, potato starch, and pre-gelatinized starch (eg, STARCH 1500); gelatin; sucrose, glucose, dextrose, sugar, and lactos. Sugars such as acacia, alginic acid, alginate, Irish moss extract, Panwar rubber, ghatti rubber, isabgor starch mucus, carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone (PVP), Veegum, caramatsu arabogalactan, tragant powder, and guar gum. Natural and synthetic rubbers; celluloses such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); AVICEL-PH-101 , AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA) and other microcrystalline cellulose; and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. Including. Binders or fillers can be present in up to about 50 to about 99% by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, calcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dried starch, and powdered sugar. Certain diluents such as mannitol, lactose, sorbitol, sucrose, and inositol can give properties to some compressed tablets that allow chewing in the mouth. Such compressed tablets can be used as chewing tablets.

Suitable disintegrants are, but are not limited to, agar; bentonite; cellulose such as methyl cellulose and carboxymethyl cellulose; wood products; natural sponges; cation exchange resins; alginic acid; rubbers such as guar gum and Veegum HV; citrus starch; cross-carburizing such as croscarmellose. Bound cellulose; Cross-linked polymer such as crospovidone; Cross-linked starch; Calcium carbonate; Microcrystalline cellulose such as sodium starch glycolate; Polarylin potassium; Corn starch, potato starch, tapioca starch, and pre-covered with gelatin Includes starches such as starch; clay; polymers; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein will vary based on the type of formulation and will be readily identifiable to those skilled in the art. The pharmaceutical compositions provided herein may comprise from about 0.5 to about 15% by weight, or from about 1 to about 5% by weight, of the disintegrant.

Suitable lubricants are, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light oil; glycerin; sorbitol; mannitol; glycerin benate and glycols such as polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc. Hardened vegetable oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; Includes silica or silica gel such as R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain from about 0.1 to about 5% by weight of the lubricant.

Suitable flow promoters include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Colorants include approved and certified water-soluble FD & C pigments, water-insoluble FD & C pigments suspended on alumina white, and lake pigments, as well as mixtures thereof. Lake pigments are a combination of heavy metals by adsorption of water-soluble dyes to hydrated oxides, resulting in an insoluble form of the dye. Flavors include natural flavors extracted from plants such as fruits and synthetic mixtures of compounds that provide a pleasant taste, such as peppermint and methyl salicylate. Sweeteners include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers are gelatin, acacia, tragacanth, bentonite, and polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and tri. Contains surfactants such as ethanolamine oleate. Suspension and dispersants include sodium carboxymethyl cellulose, pectin, tragacant, Veegum, acacia, sodium carbomethyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl, and propylparaben, benzoic acid, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethanol, and syrup. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients can perform different functions even within the same formulation.

In a further embodiment, the pharmaceutical compositions provided herein are provided as compressed tablets, wet tablets, chewable lozenges, fast-dissolving tablets, nucleated tablets, or enteric coated tablets, sugar-coated tablets, or film-coated tablets. Can be done. Enteric-coated tablets are compressed tablets that withstand the action of gastric acid but are covered with a substance that dissolves or crumbles inside, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats (phenyl salicylate), wax, shellac, ammoniacal shellac, and cellulose phthalate acetate. Dragees are compressed tablets surrounded by sugar coatings, which can be beneficial in concealing unpleasant tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose phthalate acetate. The film coating gives the same general characteristics as sugar coating. Nucleated tablets are compressed tablets made with more than one compression cycle and include layered tablets and press-coated tablets or nucleated tablets.

The dosage form of the tablet alone or contains one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents, and / or colorants. In combination with, it can be prepared from the active ingredient in powdery, crystalline or granular form. Flavors and sweeteners are particularly useful in the composition of chewing tablets and lozenges.

The pharmaceutical compositions provided herein can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), consist of two sections, one of which slides over the other and thus completely encloses the active ingredient. Soft capsules (SEC) are soft, spherical shells such as gelatin shells, which are plasticized by the addition of glycerin, sorbitol, or similar polyols. The soft gelatin shell may contain preservatives to prevent the growth of microorganisms. Suitable preservatives are those described herein, including methylparaben and propylparaben, as well as sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in formulation form. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as disclosed in US Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. Capsules may also be covered as known to those of skill in the art to modify or sustain the dissolution of the active ingredient.

In other embodiments, the pharmaceutical compositions provided herein can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. The emulsion is a two-phase system, where one liquid is dispersed in the form of small globules through another liquid, which can be oil-in-water or water-in-oil. Emulsions may contain pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers, and preservatives. Suspensions may contain pharmaceutically acceptable suspending agents and preservatives. Alcoholic aqueous solutions are pharmaceutically acceptable acetals such as the lower alkyl aldehyde di (lower alkyl) acetal (the term "lower" means an alkyl having 1 to 6 carbon atoms) (eg, acetaldehyde diethyl acetal). It also contains a water-miscible solvent having one or more hydroxyl groups such as propylene glycol and ethanol. Elixil agents are clear, sweetened, water-alcoholic solutions. The syrup is a concentrated aqueous solution of sugar (eg, sucrose) and may also contain preservatives. With respect to the liquid dosage form, for example, the solution in polyethylene glycol can be diluted with a pharmaceutically acceptable liquid carrier (eg, water) in an amount conveniently sufficient to be measured for administration.

Other useful liquid and semi-solid dosage forms are, but are not limited to, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-. It comprises the active ingredient provided herein, including dimethyl ether, and dialkylated mono- or poly-alkylene glycol, where 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol. These preparations include butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, kephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, and bicarbonate. , Sodium metabisulfite, thiodipropionic acid and its esters, and one or more antioxidants such as dithiocarbamate.

The pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microparticles, or nanosystems. Micelle dosage forms can be prepared as described in US Pat. No. 6,350,458.

In other embodiments, the pharmaceutical compositions provided herein can be provided as non-foaming or effervescent, granules and powders as they are reconstituted into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-foaming granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in non-foaming granules or powders may include sources of organic acids and carbon dioxide.

Colorants and flavoring agents can be used in all of the above dosage forms.

The pharmaceutical compositions provided herein are immediate or immediate release, including delayed release, sustained release, pulsed release, controlled release, release dosage form, target release, and program release form. It can be formulated as a modified release formulation.

In a further embodiment, the pharmaceutical compositions provided herein can be co-prescribed with other active ingredients that do not impair the desired therapeutic effect, or with substances that complement the desired action.

Example 1
Phase 1 randomization to assess the effect of food on the pharmacokinetics of entinostat in postmenopausal women with locally recurrent or metastatic ER + breast cancer, and men and women with advanced non-small cell lung cancer. Open Label Study

<Protocol>
Title: Phase 1 evaluation of the effect of food on the pharmacokinetics of entinostat in postmenopausal women with locally recurrent or metastatic ER + breast cancer, and men and women with advanced non-small cell lung cancer. Random Open Label Research Phase of Research: Phase 1
Indications: Breast cancer; Non-small cell lung cancer Main purpose:
To evaluate the effect of food on the pharmacokinetics of entinostat in women with breast cancer and in men and women with non-small cell lung cancer (NSCLC).
Second purpose:
-Safety: To assess the safety and tolerability of entinostats in combination with exemestane or erlotinib, as measured by adverse events, laboratory parameters and ECG assessments.
Purpose of exploration:
-Determining the effect of food on the degree of change in lysine acetylation of proteins induced by entinostat administration.
-Evaluate the degree of acetylation in patients receiving entinostat so that it is related to plasma levels of entinostat and duration of treatment.
• Determine if addition of exemestane or erlotinib affects the degree of acetylation-induced changes induced by entinostat administration.

<Research design>
This is an entinostat, phase 1, random, open-label, two-period, two-sequence crossover study. Patients are randomized on the first day of cycle 1 (C1D1) in a 1: 1 ratio to receive 10 mg of entinostat with or without food. Patients who receive entinostat with food at C1D1 are randomized to receive a second concentration of 10 mg of entinostat without food on day 15 of cycle 1 (C1D15). Similarly, patients randomized to receive entinostat without food at C1D1 are randomized to receive a second concentration of entinostat 10 mg with food at CID15. Randomization is layered by gender. Each cycle in the study lasted 28 days. Blood samples are obtained as pre-dose and successive blood samples are obtained after each dose to assess pharmacokinetics. In addition, blood samples are drawn for assessment of entinostat acetylation.

For cycle 2 and all subsequent cycles, all patients receive 10 mg entinostat on days 1 and 15 of each cycle. Patients with breast cancer receive (po) 25 mg exemestane orally (qd) once daily from day 1 of cycle 2.
Patients with NSCLC will also receive 150 mg po erlotinib at qd from day 1 of cycle 2.

Patients are evaluated at screening and at pre-determined times during enrollment of studies using standard clinical and laboratory evaluations. Patients are also evaluated for tumor response after each 2 cycles. Tumor development is assessed by CT, MRI or other suitable radiological study. Patients continue to receive the appropriate cycle of study treatment until tumor progression or adverse events that require discontinuation of treatment occur, as determined by the investigator.
end point:
Primary pharmacokinetic endpoint Cmax, maximum plasma concentration Tmax, time of maximum plasma concentration AUClass, area below the plasma concentration-time curve from time zero to the latest measurable concentration

AUCinf, the area below the estimated time zero to infinite plasma concentration-time curve, λz, i.e. the final elimination rate constant, via the following AUClast + Clast / λz.
Pharmacodynamic secondary endpoint-Changes from baseline in protein lysine acetylation as measured by peripheral blood mononuclear cells

Safety endpoints • Occurrence of adverse reactions during treatment, serious adverse events, adverse events resulting from permanent cessation of study drug, and death within 30 days of the latest dose of study drug. Changes from baseline in laboratory, life signs and electrocardiogram results

Specimen size: Up to 28 patients (approximately 14 patients with breast cancer and 14 patients with NSCLC with a minimum of 4 male patients) are enrolled and 24 patients (approximately 12 per treatment sequence) Ensure that (person) completes cycle 1 of the research procedure. Outline of Subject Eligibility Criteria: Studies have confirmed estrogen receptor-positive (ER +) breast cancer histologically or cytologically at the time of initial diagnosis, and the disease is such that researchers determine that patients are candidates for exemestane. Register a postmenopausal woman who has progressed. In addition, adults with stage IIIb or IV, cytologically or histologically confirmed NSCLC who are eligible candidates for erlotinib treatment are enrolled. All patients must be at least 18 years of age with 0 or 1 Eastern Cooperative Oncology Group (ECOG) status.

Investigational new drug:
Entinostat is a synthetic small molecule having a molecular weight of molecular formula C21H20N4O3 and 376.41. Entinostats are classified as antitumor agents that specifically function as inhibitors of histone deacetylase by promoting the hyperacetylation of histones in nucleosomes. Entinostat is orally bioavailable and is supplied as a yellow coated tablet containing 5.0 mg of the active ingredient.
Research procedure:
One cycle is defined as a 28-day study procedure.
All patients: Cycle 1 only-Group A: 10 mg entinostat at po on day 1 under fasting conditions in the study and on day 15 under feeding conditions in the study.
Group B: 10 mg entinostat at po on day 1 under the study feeding conditions and on day 15 under the test fasting conditions.
Breast Cancer Patients Only: In Cycle 2 and all subsequent cycles.
-Exemestane 25 mg is administered once daily from the first day of cycle 2.
Entinostat is administered in po at a dose of 10 mg at least 2 hours after breakfast on days 1 and 15, followed by a fast for at least 1 hour.
NSCLC patients only: Cycle 2 and all subsequent cycle erlotinib 150 mg are administered once daily from day 1 of cycle 2.
Entinostat is administered in po at a dose of 10 mg at least 2 hours after breakfast on days 1 and 15, followed by a fast for at least 1 hour.

Pharmacokinetic assessment, all patients (cycle 1 only study day 1 and study day 15)
Patients are administered in one of two treatments according to randomization: 10 mg entinostat under the study feeding conditions, 10 mg entinostat under the study fasting conditions. All treatments are given as a single dose with 240 mL of water. Water is tolerated as desired in all treatment groups up to 2 hours before dosing, after which it is restricted up to 2 hours after dosing, except for fluid intake during breakfast in the feeding treatment group. Blood is collected to determine entinostat levels at the following times: before (within 60 minutes of administration) and thereafter, 0.25, 0.5, 1, 1.5, 2 After 3, 4, 6, 8, 10, 12, 24, 72, 120, 168, 240, and 336 hours. ECG is taken at -60 and -45 minutes before dosing and then 3 times as a PK blood sample. Holter monitors are used for the 1st and 15th days of cycle 1 from pre-dose to 12 hours after dosing.

Pharmacodynamic Evaluation, All Patients Cycle 1 Day 1 and Day 15 Studies Blood is obtained for determination of acetylation by entinostat at the following times: before dosing (60 minutes of dosing) Within), and then 12, 24, 168, and 336 hours after dosing.
Study on Day 1 of Cycle 3 Blood is collected on Day 1 of Cycle 3 for pre-dose determination of protein acetylation.
End of study evaluation Blood will be collected at the final study visit to determine protein acetylation.
Study period Patients continue to receive protocol treatment until they encounter progressive disease or unacceptable or intolerable toxicity.
Statistical consideration:

The Schuirmann two-sided test procedure for the interval hypothesis is used to compare feeding and fasting states for differences in mean bioavailability.
Differences in mean bioavailability are determined by the range of entinostat exposure based on _{AUC last} and C _max.

The next set of hypotheses is tested to compare fasting to feeding based on log-transformed data.

式中、μ_Ｆｅｄおよびμ_{Ｆａｓｔｅｄ}は、摂食および絶食条件それぞれについて、ＡＵＣ_ｌａｓｔ、ＡＵＣ_ｉｎｆ、またはＣ_ｍａｘの母集団の平均を表す。治療シーケンスあたり１２人の、評価可能な２４人の患者は、９０％の検出力および１型の誤差率５％で前記の摂食および絶食状態の間の平均バイオアベイラビリティの差を検知する必要がある。患者内の変動係数（ＣＶ）は２２％であると推定される。摂食および絶食条件の間の真の平均比率は１．０であると推定される。

In the formula, μ _Fed and μ _Fasted represent the mean of the population of _{AUC last} , AUC _inf , or C _max for each of the feeding and fasting conditions. Twelve, evaluable 24 patients per treatment sequence need to detect the difference in mean bioavailability between the above-mentioned feeding and fasting states with 90% detection power and a type 1 error rate of 5%. is there. The coefficient of variation (CV) within the patient is estimated to be 22%. The true average ratio between feeding and fasting conditions is estimated to be 1.0.

Patients are considered to be considered for PK analysis if they receive entinostats during each treatment period according to conditions clarified by randomization (ie, eating or fasting). Patients must also have sufficient plasma concentration-time data from each treatment period to provide a meaningful assessment of PK parameters (eg Cmax, AUClast).

Concentration-time data for individual patients are listed and displayed graphically on a linear and logarithmic scale. Concentration-time data are summarized descriptively in tabular and graph formats (linear and logarithmic scales). PK parameters estimated using the noncompartmental method are calculated using WinNonlin version 5.1 or later. Such estimates are listed and summarized descriptively in tabular and graph format.

For selected PK parameters (eg, Cmax, AUClast), comparisons between feeding and fasting conditions are made using a linear mixed-effects ANOVA model. The model includes terms related to the treatment (feeding, fasting), duration, and sequence as a fixed effect, and patients within the sequence as a random effect. The evaluation of bioequivalence is based on the classical (shortest) confidence interval approach, which is operably equivalent to the procedure of Schuirmann's two-sided test because of the interval hypothesis. Estimates from the ANOVA model are used to calculate the 90% confidence limit for the ratio of true mean AUC for feeding and fasting conditions. If the 90% confidence interval for the ratio (inverse transformation) is within the equivalent range of 80% and 125% of the total, we can conclude the bioavailability of average bioavailability.

The time to observed maximum plasma concentration of entinostats (Tmax) is summarized for feeding and fasting conditions using descriptive statistics and chart display. Differences in Tmax between individual patients between feeding and fasting conditions are calculated to provide symmetric nonparametric confidence intervals for median differences. Inference comparison of Tmax between feeding and fasting conditions is made using Wilcoxon signed rank test.

Changes in protein lysine acetylation (the main pharmacodynamic parameter of this study) are analyzed in the same or similar manner as above for PK analysis.
Joint analysis of PK by acetylation may be performed.

Safety data analysis is performed on all patients receiving at least one dose of entinostat. The analysis consists of clinical and laboratory parameters, and a summary of data on adverse events. Unless otherwise specified, safety analysis is performed by primary diagnosis. The number and percentage of patients with one or more adverse events are summarized by their relationship to individual study treatments and severity grades. Severity grade is determined using NCI-CTCAE (version 4.0). Adverse events are encoded using the International Pharmaceutical Glossary Terminology (MedDRA). Laboratory parameters are summarized using descriptive statistics by a data list of changes relative to baseline and clinically significant anomalies.
Vital signs and ECG data are summarized by changes from baseline values using descriptive statistics.

<Result>
The results of a study of food effects are presented herein. FIG. 1 shows an average concentration time profile following administration of entinostat 10 mg under fasting or feeding conditions. A summary of the pharmacokinetic parameters is shown in Table 1.

Co-administration of food and entinostat 10 mg results in delayed drug absorption and delayed Tmax (median TMAX = 0.76 hours under fasting conditions; median TMAX = 11 hours under fasting conditions). A significant reduction in maximum drug concentration (71% reduction in Cmax) was observed. Overall exposure was reduced by about 15 to 17 percent when entinostat was administered on a high-fat diet, estimated by AUClast and AUCINF. The mean elimination half-life of entinostat was estimated to be 140 hours under fasting conditions and 178 hours under feeding conditions. The high volatility of the half-life estimates in the feeding group (% CV = 70%) is likely due to the small sample size. Several individuals had a significantly prolonged t1 / 2 value in the Federal Bureau of Investigation. The median t1 / 2 suggests that the two groups are equivalent.

CONCLUSIONS: The effects of food are evident when entinostat and a high-fat diet are co-administered, resulting in delayed tmax and reduced Cmax and AUC.

<Example 2>
Methods for treating postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer by administration of entinostat and the non-steroidal aromatase inhibitor exemestane

The purpose of this study is to evaluate the safety and efficacy of entinostat in combination with exemestane in the treatment of advanced breast cancer.

The primary endpoint is to compare the effects of exemestane alone with exemestane plus entinostat so that it is determined from the date of randomization to the period of progression-free survival (PFS) measured. is there.

A secondary endpoint is the comparison of objective response rate (ORR) and clinical utility rate (CBR), which is combined with exemestane as measured by adverse events and laboratory safety parameters. To evaluate the safety and durability of chinostats.

Study design:

適格基準
研究に適格な年齢：１８歳以上
研究に適格な性別：女性
健康なボランティアの受け入れ：無し
包含基準：
・閉経後の女性患者
・組織学的にまたは細胞学的に確認されたＥＲ＋乳癌
・ＡＩによる以前の処置で再発したか進行した。
・転移性疾患は測定可能でなければならない。
・非標的病変に緩和的放射線を受けた患者は、登録前に処置完了後に２週間のウオッシュアウト期間を設けなくてはならない。
・患者は、以前のＡＩの開始前に受ける限りは、第１ラインの処置の一部として、１つの従来の化学療法を受けていてもよい。
・ＥＣＯＧパフォーマンスの状態：０から１
・実験室パラメータ：ａ）造血の成長因子の使用なしで、ヘモグロビン≧９．０ｇ／ｄＬ；血小板≧１００．０×１０^９／Ｌ；ＡＮＣ≧１．５×１０^９／Ｌ、ｂ）機関の標準の上限の２．５倍未満のクレアチニン、ｃ）機関の標準の上限の２．５倍未満のＡＳＴおよびＡＬＴ
・書面によるインフォームドコンセントを理解し、かつそれを与え、研究手順に準拠することができる
除外基準；
・アジュバント設定において、患者のために１２か月未満の後に非ステロイド性のＡＩによる処置において、再発する。
・転移性疾患を有する患者のための最近のＡＩによる、３ヶ月未満の治療後において、進行性の疾患
・急速な進行性であり、生命を脅かす転移
・測定可能な病変への任意の緩和的放射線治療
・エンチノスタット、またはバルプロ酸を含む他のＨＤＡＣ阻害剤による以前の処置
・ベンズアミドまたは試験薬の不活性の成分に対するアレルギー
・エキセメスタンの任意の活性または不活性成分に対するアレルギーの履歴
・適切な試験処置の遵守を妨げる任意の付随する医学的状態
・患者が現在別の治験薬の研究に登録されている（または研究薬物投与前３０日以内に完了した）。
・患者が現在、バルプロ酸、ゾリンザ（ボリノスタット）または他のＨＤＡＣ阻害剤、またはＤＮＡメチルトランスフェラーゼ阻害剤による処置、又は任意の全身性の抗癌処置（リュプロンは例外）を受けている。

Eligibility Criteria Study Eligible Age: 18+ Gender Eligible for Study: Female Acceptance of Healthy Volunteers: None Inclusion Criteria:
-Postmenopausal female patients-Histologically or cytologically confirmed ER + breast cancer-Relapsed or advanced with previous treatment with AI.
• Metastatic disease must be measurable.
Patients who have received palliative radiation to non-target lesions must have a two-week washout period after completion of treatment prior to enrollment.
-Patients may receive one conventional chemotherapy as part of the first line of treatment, as long as they receive it before the start of the previous AI.
-ECOG performance status: 0 to 1
- Laboratory parameters: a) without the use of growth factors of hematopoietic, hemoglobin ≧ 9.0 g / dL; platelet ^{≧ 100.0 × 10 9 /L;ANC≧1.5×10 9 /} L, b) organizations Creatinine less than 2.5 times the standard upper limit, c) AST and ALT less than 2.5 times the institutional standard upper limit
Exclusion criteria that can understand and give written informed consent and comply with research procedures;
-In the adjuvant setting, recurrence in treatment with non-steroidal AI after less than 12 months for the patient.
-Progressive disease-rapidly progressive, life-threatening metastasis-any palliative to measurable lesions after less than 3 months of treatment with recent AI for patients with metastatic disease Radiation therapy-Previous treatment with entinostat or other HDAC inhibitors including valproic acid-Allergy to the inactive component of benzamide or study drug-History of allergy to any active or inactive component of Exemestane-Appropriate Any incidental medical condition that interferes with study procedure compliance • The patient is currently enrolled in another study of the study drug (or completed within 30 days prior to administration of the study drug).
Patients are currently undergoing treatment with valproic acid, zorinza (vorinostat) or other HDAC inhibitors, or DNA methyltransferase inhibitors, or any systemic anti-cancer treatment (with the exception of Ruplon).

<Example 3>
Methods for treating patients with advanced non-small cell lung cancer with erlotinib by administering a combination of erlotinib and entinostat

Primary endpoint Disease control rate (complete remission, partial response, or disease that stabilizes for at least 3 months)

Secondary endpoint:
Exacerbation-free survival rate at 4 months Exacerbation-free survival rate at 2 months

Study design:

適格基準
研究の対象年齢：１８歳以上
研究の対象性別：両方
健康なボランティアの受け入れ：無し
選択基準：
・細胞学的または組織学的に確認された、ステージＩｌｌｂ（胸水）またはＩＶのＮＳＣＬＣ
・疾患は、少なくとも２つのスキャン（研究登録の４週間以内に行われた最新のもので、患者のスクリーニングのためのベースラインスキャンとして役立ち得る）に基づいて、エルロチニブ処置において進行している（処置に対して応答しないか、客観的反応後の再発のいずれか）。
・最新のがん処置に関連した任意の毒性から回復（ＣＴＣＡＥスケールでグレード１よりも、または以前のベースライン条件よりも大きくない毒性）
・従来のＣＴスキャンにより測定可能な≧２０ミリメートルの、またはスパイラルＣＴスキャンにより測定可能な≧１０ミリメートルの、少なくとも１つの病変
・０、１、又は２のＥＣＯＧパフォーマンススコアと、少なくとも３ヶ月の平均余命
・相関研究のために利用可能なパラフィン包埋腫瘍標本
・１８歳以上の男性または女性
・造血成長因子を使用せずに、ヘモグロビン≧９．０グラム／ｄＬ、血小板≧７５×１０^９／Ｌ；ＡＮＣ≧１．０×１０^９／Ｌ
・正常範囲内凝固試験
・機関の標準の上限の２倍未満のビリルビンおよびクレアチニン
・機関の標準の上限の３倍未満のＡＳＴおよびＡＬＴ
・機関の標準の範囲内のカリウム、マグネシウム、リン（補充が許されている）
・研究中（必要に応じて、男性と女性の両方）、およびエンチノスタットの最新服用の３カ月後に、認められた効果的な避妊法の使用希望する
・患者または法律上許容可能な代表が実行される（特別なスクリーニング試験を含む）の研究に固有の手順の前に、書面によるインフォームドコンセントを与えました
・研究に固有の任意の手順（特別なスクリーニング試験を含む）が実行される前に、患者または法的に許容可能な代表者は、書面によるインフォームドコンセントを与えた
除外基準：
・事前の幹細胞移植
・症候性のＣＮＳの関与
・ＨＤＡＣ阻害剤による事前処置
・非標的研究病変に対する放射線治療を除く、同時の抗癌治療、
・禁止薬物リストの薬（複数可）を現在摂取している
・登録前２８日以内の、治験薬による全身化学療法または処置
・バルプロ酸を現在使用している
・未処置または不安定な脳の転移、あるいは研究薬物投与の４週間以内にこの疾病のためにステロイドを摂取している
・現在アテクィブな二次悪性腫瘍、または硬化基底か扁平上皮細胞皮膚癌腫、上皮内子宮頚癌、または表在性膀胱癌以外の過去５年以内の任意の悪性腫瘍
・経口薬を飲み込むことができない、または胃腸の吸収不良の状態
・ＨＩＶ感染、またはアクティブなＢ型あるいはＣ型肝炎感染として知られ、ＩＶ抗生物質、抗ウイルス剤、または抗真菌剤を必要とする、未制御の感染症
・ＭＵＧＡスキャンで、ＥＣＧ（多焦点のＰＶＣ、ＳＴ−Ｔ波が心筋梗塞または急性虚血、５００ミリ秒よりも大きいＱＴｃと一致して変化する）、頻脈、または４０％未満の左心室駆出率における臨床的に有意な所見として定められる異常な心臓機能
・高血圧、糖尿病、または抑制された免疫系など、登録の３ヶ月以内での、別の深刻なまたは未制御の医学的状態
・ベンズアミドに対する既知の過敏症
・病的肥満
・現在妊娠中または授乳している女性
・現在、別の調査薬物の研究に登録されている患者（または２８日以内に完了している）
・研究やフォローアップの評価に利用できない患者
・試験参加のためのリスクを増加させるか、あるいは、書面にしたインフォームドコンセントを与え、および／または研究手順と要件に準拠する能力を損なわせる、医療の、精神科の、または行動の任意の種類の障害を有する患者。

Eligibility Criteria Study Target Age: 18+ Study Target Gender: Acceptance of Both Healthy Volunteers: None Selection Criteria:
Cytologically or histologically confirmed stage Illb (pleural effusion) or IV NSCLC
The disease is progressing in erlotinib treatment based on at least two scans, the latest performed within 4 weeks of study enrollment and which can serve as a baseline scan for patient screening (treatment). Either does not respond to or recurs after an objective response).
-Recovery from any toxicity associated with the latest cancer treatment (toxicity not greater than Grade 1 on the CTCAE scale or greater than previous baseline conditions)
At least one lesion with ≥20 mm measurable by conventional CT scans or ≥10 mm measurable with spiral CT scans-ECOG performance score of 0, 1, or 2 and average life expectancy of at least 3 months • Paraffin-embedded tumor specimens available for correlation studies • Male or female 18 years or older • Hemoglobin ≥ 9.0 g / dL, platelets ≥ 75 × 10 ⁹ / L without the use of hematopoietic growth factors; ANC ≧ 1.0 × 10 ⁹ / L
• Normal range coagulation test ・ Bilirubin and creatinine less than twice the upper limit of the institutional standard ・ AST and ALT less than three times the upper limit of the institutional standard
-Potassium, magnesium, phosphorus within the standard range of the institution (replenishment is allowed)
• During research (both male and female, if necessary), and 3 months after taking the latest dose of Entinostat, wish to use approved and effective contraceptive methods • Patients or legally acceptable representatives Written informed consent was given prior to the study-specific procedures performed (including special screening tests) -Any study-specific procedures (including special screening tests) are performed Previously, the patient or legally acceptable representative gave written informed consent Exclusion Criteria:
-Preliminary stem cell transplantation-Involvement of symptomatological CNS-Pretreatment with HDAC inhibitors-Simultaneous anti-cancer treatment, excluding radiation therapy for non-target research lesions,
-Currently taking any of the drugs on the prohibited drug list-Systemic chemotherapy or treatment with an investigational drug within 28 days prior to registration-Current use of valproic acid-Untreated or unstable brain Metastasis, or taking steroids for this disease within 4 weeks of study drug administration-Currently acute secondary malignancies, or sclerosing basal or squamous cell skin cancer, intraepithelial cervical cancer, or superficial Any malignant tumor within the last 5 years other than bladder cancer-Inability to swallow oral medications, or gastrointestinal malabsorption-known as HIV infection or active hepatitis B or C infection, IV antibiotics ECG (multifocal PVC, ST-T wave is greater than myocardial infarction or acute ischemia, 500 ms) on uncontrolled infection / MUGA scans requiring substances, antiviral agents, or antifungal agents Registrations such as abnormal cardiac function / hypertension, diabetes, or suppressed immune system defined as clinically significant findings in (varies consistent with QTc), tachycardia, or left ventricular ejection rate of less than 40% Within 3 months of another serious or uncontrolled medical condition, known hypersensitivity to benzamide, morbid obesity, currently pregnant or lactating women, currently enrolled in another research drug study Patients (or completed within 28 days)
Patients not available for study or follow-up evaluation • Medical care that increases the risk of participation in the study or provides written informed consent and / or impairs the ability to comply with study procedures and requirements Patients with any kind of disorder, psychiatric, or behavioral.

Claims (14)

A combination of exemestane and entinostat for use in the treatment of breast cancer in patients in need.
Exemestane and entinostat are orally administered
Here, entinostat is administered to a fasting patient and
Patients have not consumed food within 2 hours or 1 hour prior to administration of entinostat.
A combination drug characterized by that. The combination drug of exemestane and entinostat according to claim 1, wherein the Tmax of entinostat is less than 1 hour, less than 90 minutes, less than 2 hours, or between 30 minutes and 2 hours after administration. .. The claim that the Cmax of entinostat is at least 150 ng / mL, at least 125 ng / mL, at least 100 ng / mL, at least 80 ng / mL, or at least 50 ng / mL after oral administration of entinostat. The combination drug of exemestane and entinostat according to 1 or 2. The combination drug of exemestane and entinostat according to any one of claims 1 to 3, wherein about 5 mg, 10 mg, or 1 mg to 20 mg of entinostat is administered. The combination drug of exemestane and entinostat according to any one of claims 1 to 4, wherein the entinostat is administered once a week or during a cycle of 28 days. The combination of exemestane and entinostat according to any one of claims 1 to 5, wherein the patient has not ingested food within 2 hours or 1 hour before administration of entinostat. Medicine. The combination drug of exemestane and entinostat according to any one of claims 1 to 6, wherein exemestane is administered at a time different from that of entinostat. Exemestane is a combination drug of exemestane and entinostat according to any one of claims 1 to 7, which is administered after a meal or with a meal. The combination drug of exemestane and entinostat according to any one of claims 1 to 8, wherein 25 mg of exemestane is administered once a day. A composition comprising entinostat for use in a method of treating cancer in a patient in need, said method comprising oral administration of entinostat .
Here, the administration of entinostat under fasting conditions results in an increase in Tmax as compared to the administration of entinostat under fasting conditions, with respect to Tmax after administration under fasting conditions. The ratio of Tmax after administration of is at least about 2: 1 and the patient is fasting and has not consumed food within 2 hours or 1 hour prior to administration of entinostat.
A composition comprising entinostat. That the ratio of Cmax after administration under fasting conditions to Cmax after administration under feeding conditions is at least about 3: 1, 4: 1, 5: 1, 6: 1, or 7: 1. The composition comprising the entinostat according to claim 10. The ratio of Tmax after administration under fasting conditions to Tmax after administration under fasting conditions is 2: 1 to 5: 1, 5: 1 to 8: 1, 8: 1 to 12: 1, or 12: The composition comprising the entinostat according to claim 10, wherein the composition is 1 to 15: 1. The composition comprising entinostat according to claim 10, wherein the patient has not ingested food within 2 hours or 1 hour before administration of entinostat in a fasted state. The composition comprising entinostat according to claim 10, wherein the patient ingests a high-fat diet under feeding conditions.

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