Drug combination for the treatment of gastric cancer

Abstract

To provide a combination for gastric cancer therapy which brings about enhanced therapeutic effects and reduced side effects.SOLUTION: Gastric cancer patients treated daily with the combination of the minelide prodrug and paclitaxel experienced significant negative side effects and cancer progression. Combination therapy of paclitaxel with a minelide prodrug administered according to the new regimen resulted in significantly improved therapeutic outcomes. The new dosing regimen comprises a 28-day cycle in which the minelide prodrug is administered once daily on days 1-5, 8-12, and 15-19 of the cycle, and paclitaxel is administered once daily on days 1, 8, and 15 of the cycle. The new dosing regimen was shown to be effective for treating gastric cancer and well tolerated in human patients.SELECTED DRAWING: Figure 5A

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 489,205, filed March 9, 2023, and the benefit of PCT / US2023 / 015809, filed March 21, 2023, which applications are incorporated herein by reference. [Background technology]

[0002] Background of the Invention Triptolide is a diterpene isolated from a Chinese herb that possesses potent antitumor, immunosuppressant, and anti-inflammatory properties. However, its clinical potential is greatly hindered by its limited aqueous solubility, oral bioavailability, and multi-organ toxicity. The prodrug Minnelide™ (14-O-phosphonooxymethyl triptolide disodium salt) is rapidly converted to triptolide upon exposure to phosphatases in the bloodstream. The Minnelide prodrug has higher aqueous solubility and lower organ toxicity than triptolide. Triptolide has been shown to inhibit tumor cell growth and induce apoptosis in vitro and in animal models of cancer, including xenografts of several different tumor types, including human breast tumors (Shamon et al., Cancer Lett. 1997;112:113-117), cholangiocarcinoma cells (Tengchaisri et al., Cancer Lett. 1998;133:169-175), melanoma, breast cancer, bladder cancer, gastric cancer (Yang et al., Mol Cancer Ther. 2003;2:65-72), pancreatic tumors (Phillips et al., Cancer Res. 2007;67(19):9407-9416), and neuroblastoma (Antonoff et al., Surgery. 2009;146:282-290). The higher aqueous solubility of the Minnelide prodrug compared to triptolide is beneficial for managing drug dosage and safety.

[0003] The antitumor effects of triptolide are the result of inhibition of heat shock protein (HSP) 70 expression and induction of apoptosis in tumor cells. Although the mechanism of action of triptolide's inhibition of HSP70 expression has not been fully elucidated, it has been shown to induce caspase activation (Choi et al., Biochem Pharmacol. 2003;66:273-280; Liu et al., Biochem Biophys Res Commun. 2004;319:980-6; Wang et al., J Mol Med. 2006;84:405-15; Carter et al., Blood. 2006;108:630-637).

[0004] In gastric cancer, triptolide has been shown to inhibit cell proliferation and induce apoptosis by stimulating the expression of p53 and p21(waf1 / cip1) (Jiang et al., Oncogene. 2001 Nov 29;20(55):8009-18). Triptolide has also been shown to be effective in inhibiting colony formation and tumor regression in animal models (Yang et al., Mol Cancer Ther. 2003;2:65-72). Other studies have also shown that triptolide inhibits NF-kB in gastric cancer, thereby inducing cell death (Chang et al., Anticancer Res. 2007 Sep-Oct;27(5A):3411-7). Minnelide prodrug, a water-soluble prodrug of triptolide, inhibits Sp1, reduces HSP70, and induces cell death in gastric cancer cell lines MKN28 and MKN45 (Arora et al., PLoS One. 2017 Feb 13;12(2):e0171827). Sp1 is a transcription factor that, like HSF1, regulates multiple pro-survival pathways. Inhibition of Sp1 transcriptional activity downregulates HSF1 activity, thereby reducing HSP70 and inducing cell death (Arora et al., PLoS One. 2017 Feb 13;12(2):e0171827).

[0005] The Minnelide prodrug, when "activated" by co-incubation with alkaline phosphatase, was determined to be as potent as triptolide in reducing the viability of pancreatic tumor cell lines in vitro. The "activated" Minnelide prodrug also reduced the proliferation of ovarian cancer cells in vitro in a concentration-dependent manner (50-200 nM). Daily intraperitoneal administration of Minnelide prodrug at doses of both 0.2 mg / kg and 0.4 mg / kg significantly reduced tumor weight and volume in subcutaneous gastric cancer models using the cell lines MKN45 and MKN28I-N-87.

[0006] Combination therapy is a therapeutic intervention in which two or more therapies are administered to a patient. Examples of combination therapy include a treatment regimen involving the administration of several separate tablets, each containing a specific drug, or the administration of a single tablet containing several drugs. For example, chemotherapy in addition to immunotherapy. One example is treating breast or pancreatic cancer with a combination of immunotherapy and chemotherapy drugs such as cisplatin and taxol. The combination of 0.2 mg / kg of Minnelide prodrug and 100 mg / kg of irinotecan was found to be more effective in causing regression of subcutaneous NCO-N-87 tumors in a mouse model of gastric cancer than either drug alone.

[0007] In summary, the results of the Minnelide prodrug pharmacology program demonstrate that the Minnelide prodrug has potent antitumor activity against pancreatic, gastric, and ovarian tumor cells in vitro (when "activated" with alkaline phosphatase to release triptolide), and when administered by oral or IP routes alone or in combination with various "standard of care" agents in models of pancreatic and ovarian cancer, significantly improved animal survival and significantly reduced tumor volume and weight. These results support the rationale for the evaluation of the Minnelide prodrug in cancer patients as a single agent or in combination with other therapies.

[0008] When clinical development of the Minnelide prodrug began with an intravenous drug product, IND-enabling toxicity studies were conducted in both rats and dogs using the intravenous route of administration. The results of these studies supported first-in-human clinical trials involving intravenous administration of the Minnelide prodrug to patients with advanced solid tumors. To support the clinical development of a new oral solid dosage form (capsules) of the Minnelide prodrug, exploratory and definitive toxicity studies were conducted with the Minnelide prodrug in solution by oral gavage in dogs. Collectively, the results of the intravenous and oral toxicity studies conducted with the Minnelide prodrug indicate that the target organ profile of the Minnelide prodrug is consistent in both species (rats and dogs) when administered by either route (intravenous or oral). In each definitive toxicity study conducted with the Minnelide prodrug, adverse and largely irreversible histopathological effects were observed in reproductive tract tissues of both males and females. Additional effects on primary and / or secondary lymphoid tissues were observed in some studies. No adverse histopathological effects were observed in the gastrointestinal tract of dogs administered Minnelide prodrug by oral gavage for up to 28 consecutive days.

[0009] Although oral Minnelide prodrugs are easier to administer than intravenous formulations, they continue to have toxicity at high doses (hence dose-limiting toxicity (DLT)) and side effects at high dose levels. Thus, there is a need for safer methods of administering Minnelide prodrugs, and for combination therapies of other drugs with Minnelide prodrugs that increase the effectiveness of the combination therapy while limiting the toxicity of the individual drugs used in the therapy. Furthermore, despite the availability of known antitumor agents, there is a continuing need for new treatment regimens that are more effective and better tolerated by patients. Summary of the Invention

[0010] The Minnelide™ prodrug was determined to have potent antitumor activity against pancreatic and ovarian tumor cells in vitro (when "activated" with alkaline phosphatase to release triptolide), and when administered daily in models of pancreatic and ovarian cancer, significantly improved animal survival and reduced tumor volume and weight.

[0011] [ka]

[0012] Gastric cancer is the most prevalent cancer in Korea and worldwide. Minnelide prodrugs have demonstrated efficacy in various cancers, including gastric cancer, in several preclinical models, and in human clinical trials in the United States. Minnelide prodrugs in combination with paclitaxel have demonstrated significant antitumor activity in preclinical models of pancreatic cancer and in ongoing clinical trials for pancreatic and breast cancer in the United States. Herein, we evaluated the efficacy of Minnelide prodrugs in combination with paclitaxel in a subcutaneous mouse model of gastric cancer and in human clinical trials. Results indicate that Minnelide prodrugs and paclitaxel, alone or in combination, have no significant adverse effects when administered appropriately, and treating mice with a low-dose combination of Minnelide prodrug and paclitaxel resulted in a significant reduction in tumor burden compared with Minnelide prodrug or paclitaxel alone. Further tumor analysis demonstrated that the combination therapy not only successfully reduced tumor growth in the animal model used in this study, but also promoted tumor regression. This study therefore demonstrates that the combination of Minnelide prodrug and paclitaxel, administered appropriately, is an effective treatment for gastric cancer.

[0013] Accordingly, the present disclosure provides a method for treating gastric cancer in a cancer patient, the method comprising: a) about 0.25 mg to about 2.0 mg of Minnelide prodrug according to a first dosing regimen, wherein a dose is given once daily on days 1-5, 8-12, and 15-19 of a cycle; and b) about 60 mg / m according to a second dosing regimen 2 ~about 100mg / m 2 Paclitaxel of the formula (I) wherein a dose is given once daily on days 1, 8, and 15 of a cycle. to a cancer patient during a 28-day cycle, The 28-day cycle is repeated one or more times and the combination effectively treats gastric cancer.

[0014] The described technology provides for the use of the compositions described herein for use in medical therapy. The medical therapy can be treating cancer, for example, gastric cancer, breast cancer, colon cancer, lung cancer, pancreatic cancer, or prostate cancer. The invention also provides for the use of the compositions described herein for the manufacture of a medicament for treating a disease in an animal, for example, cancer in a human.

[0015] The following drawings form part of the specification and are included to further demonstrate certain embodiments or various aspects of the present invention. In some cases, embodiments of the present invention can be best understood by referring to the accompanying drawings in combination with the detailed description presented herein. The description and accompanying drawings may highlight certain specific examples or particular aspects of the invention. However, one skilled in the art will understand that some of the examples or aspects can be used in combination with other examples or aspects of the invention. [Brief explanation of the drawings]

[0016] [Figure 1] Figure 1. Tumor progression in mice treated with Minnelide prodrug or Minnelide prodrug in combination with paclitaxel. [Figure 2] Figure 2A-I. Regimen B: Graph showing cell count (1000 / dl) vs. dosing cycle / visit day for subject ID number. (A-D) Paclitaxel 60 mg / m² + Minnelide prodrug 0.25 mg / day for 21 days. (E-I) Paclitaxel 80 mg / m² + Minnelide prodrug 0.25 mg / day for 21 days. [Figure 3]Figure 3A-G. Graphs showing cell counts (1000 / dl) versus dosing cycles / day for subject ID number. (A-C) Paclitaxel 80 mg / m² + Minnelide prodrug 0.50 mg / day on days 1-5, 9-12, and 12-15. (D-G) Paclitaxel 80 mg / m² + Minnelide prodrug 0.75 mg / day on days 1-5, 9-12, and 12-15. [Figure 4] FIG. 4. Flow chart showing placement of patients into cohort groups in Example 5. [Figure 5A] Figure 5A. Regimen C: Best percent change in tumor size from baseline. Each bar represents an individual patient. "Best change from baseline" represents the change in the sum of the tumor diameters of the target lesions. BOR, best overall response; PD, progressive disease; PR, partial response; SD, stable disease. [Figure 5B] Figure 5B. Regimen B: Best percent change in tumor size from baseline. Each bar represents an individual patient. "Best change from baseline" represents the change in the sum of the tumor diameters of the target lesions. BOR, best overall response; PD, progressive disease; PR, partial response; SD, stable disease. [Figure 6A] Figure 6A. Regimen B treatment exposure and response over time based on investigator assessment by RECIST v1.1. [Figure 6B] Figure 6B. Regimen C treatment exposure and response over time based on investigator assessment by RECIST v1.1. [Figure 7] Figure 7. Graph of preclinical study results in mice showing the increase and decrease in tumor volume (mm3) from days 1 to 22. [Figure 8] Figure 8. Results of Regimen A for number of cycles per patient and best percent change in tumor size from baseline. DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description The results of this study demonstrate that combination therapy of low-dose Minnelide prodrugs and paclitaxel (the drug's standard therapeutic dose) unexpectedly synergized tumor growth reduction compared to the single agents in a mouse model of gastric cancer (Figure 1). Further analysis of the tumors demonstrated that the combination therapy not only reduced tumor growth but also promoted tumor regression in the animal model used in this study. Therefore, these studies demonstrate that the combination of Minnelide prodrugs and paclitaxel is an effective therapy for cancer, particularly gastric cancer.

[0018] Further information and data supporting the present invention can be found in US Pat. No. 8,507,552 (Georg) and US Pat. No. 9,150,600 (Georg), which are incorporated herein by reference.

[0019] definition The following definitions are included to provide a clear and consistent understanding of the specification and claims. As used herein, the listed terms have the following meanings. All other terms and phrases used herein have their ordinary meanings as understood by one of ordinary skill in the art. Such ordinary meanings may be obtained by consulting a technical dictionary such as Hawley's Condensed Chemical Dictionary, 14th Edition, by R.J. Lewis, John Wiley & Sons, New York, NY, 2001.

[0020] References in the specification to "one embodiment," "embodiment," etc. indicate that the described embodiment may include a particular aspect, property, structure, moiety, or characteristic, but not all embodiments necessarily include that aspect, property, structure, moiety, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referenced in other parts of the specification. Furthermore, when a particular aspect, property, structure, moiety, or characteristic is described in connection with an embodiment, it is within the knowledge of one of ordinary skill in the art to affect or combine such aspect, property, structure, moiety, or characteristic with other embodiments, whether or not explicitly stated.

[0021] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds, and thus, reference to compound X includes a plurality of compound X. It is further noted that the claims may be drafted to exclude optional elements. As such, this statement is intended to serve as a predicate for the use of exclusive terminology, such as "solely," "only," and the like, in connection with the recitation of any element described herein and / or the use of a "negative" limitation on claim elements.

[0022] The term "and / or" means any one of the items, any combination of the items, or all of the items with which the term is associated. The phrases "one or more" and "at least one" are readily understood by those of ordinary skill in the art, particularly when read in the context of their usage. For example, the phrase can mean 1, 2, 3, 4, 5, 6, 10, 100, or any upper limit that is about 10, 100, or 1000 times higher than the recited lower limit. For example, one or more substituents on a phenyl ring can refer to 1 to 5, or 1 to 4, e.g., when the phenyl ring is disubstituted.

[0023] As will be understood by one of ordinary skill in the art, all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and the like, are approximate and are understood to be optionally modified in all instances by the term "about." These values ​​may vary depending on the desired properties the artisan seeks to obtain using the teachings of the descriptions herein. It is also understood that such values ​​inherently encompass variations resulting from the standard deviation found in their respective testing measurements. When values ​​are expressed as approximations by use of the antecedent "about," it will be understood that the particular value without the modifier "about" also forms a further aspect.

[0024] The terms "about" and "approximately" are used interchangeably. Both phrases may refer to a variation of ±5%, ±10%, ±20%, or ±25% of the specified value. For example, "about 50" percent may, in some embodiments, have a variation of 45 to 55 percent, or as otherwise defined by a particular claim. In the case of integer ranges, the term "about" may include one or two integers greater than and / or less than the integers recited at both ends of the range. Unless otherwise indicated herein, the terms "about" and "approximately" are intended to include values ​​near the recited range, e.g., percentages by weight, that are equivalent in terms of the functionality of the individual components, compositions, or embodiments. The terms "about" and "approximately" can also modify the endpoints of the recited ranges, as described above in this paragraph.

[0025] As will be understood by those skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible subranges and combinations of those subranges, as well as the individual and specific integer values ​​comprising the ranges. Therefore, it is understood that each unit between two specified units is also disclosed. For example, if 10 to 15 is disclosed, then 11, 12, 13, and 14 are also disclosed individually and as part of a range. A recited range (e.g., weight percentage or carbon group) includes each specific value, integer, decimal, or identity within the range. Any range listed can be readily recognized as fully descriptive and allows for division of the same range into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily divided into a lower third, middle third, and upper third, etc. As will also be understood by those skilled in the art, all terms such as "up to," "at least," "more than," "less than," "greater than," "or more," etc., are inclusive of the recited numbers, and such terms refer to ranges that can then be divided into subranges, as described above. Similarly, all ratios recited herein also include all subratios falling within the broader ratio. Accordingly, specific values ​​recited for radicals, substituents, and ranges are for illustrative purposes only, and they do not exclude other defined values ​​for radicals and substituents or other values ​​within defined ranges. It will be further understood that the endpoints of each range are significant in relation to, and independently of, the other endpoint.

[0026] The present disclosure provides ranges, limits, and deviations for variables such as volume, mass, percentages, and ratios. It will be understood by those skilled in the art that ranges such as "number 1" to "number 2" imply a continuous range of numbers, including integers and decimals. For example, 1 to 10 means 1, 2, 3, 4, 5, ..., 9, 10. It also means 1.0, 1.1, 1.2, 1.3, ..., 9.8, 9.9, 10.0, and also 1.01, 1.02, 1.03, etc. When a disclosed variable is a number smaller than "number 10," it implies a continuous range, including integers and decimals smaller than "number 10," as described above. Similarly, when a disclosed variable is a number larger than "number 10," it implies a continuous range, including integers and decimals larger than "number 10." These ranges may be modified by the term "about," the meaning of which is explained above.

[0027] The listing of a), b), c), ... or i), ii), iii), etc. in a list of compounds or steps does not imply a particular order unless explicitly stated.

[0028] Those skilled in the art will also readily recognize that when members are grouped in a common manner, such as a Markush group, the invention encompasses not only the entire group listed as a whole, but also each member of the group individually and all possible subgroups of the main group. Moreover, for all purposes, the invention encompasses not only the main group, but also main groups in which one or more group members are absent. The invention therefore contemplates the explicit exclusion of any one or more members of a recited group. Thus, qualifications may be applied to any of the disclosed categories or embodiments, whereby any one or more recited elements, species, or embodiments may be excluded from such category or embodiment, for example, by use in an explicit negative limitation.

[0029] The term "contacting" refers to the act of touching, contacting, or bringing into immediate proximity or close proximity, including at the cellular or molecular level, for example, in solution, in a reaction mixture, in vitro, or in vivo, to cause a physiological reaction, a chemical reaction, or a physical change.

[0030] An "effective amount" refers to an amount effective to treat a disease, disorder, and / or condition, or to cause a recited effect. For example, an effective amount can be an amount effective to reduce the progression or severity of the condition or symptom being treated. Determination of a therapeutically effective amount is well within the capabilities of one of ordinary skill in the art. The term "effective amount" is intended to include, for example, an amount of a compound described herein, or an amount of a combination of compounds described herein, that is effective to treat or prevent a disease or disorder, or to treat a symptom of a disease or disorder, in a host. Thus, an "effective amount" generally refers to an amount that provides a desired effect.

[0031] Alternatively, the terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of an agent or composition or combination of compositions administered to relieve to some extent one or more symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case can be determined using techniques such as a dose escalation study. Doses can be administered in one or more administrations. However, the precise determination of what will be considered an effective dose will depend on individual factors for each patient, including, but not limited to, the patient's age, size, type or extent of disease, stage of disease, route of administration of the composition, type or extent of capture therapy used, ongoing disease process, and type of treatment desired (e.g., aggressive versus conventional treatment).

[0032] The terms "treating," "treat," and "treatment" include (i) preventing the occurrence of a disease, pathological, or medical condition (e.g., prophylaxis); (ii) inhibiting or arresting the development of a disease, pathological, or medical condition; (iii) alleviating a disease, pathological, or medical condition; and / or (iv) alleviating symptoms associated with a disease, pathological, or medical condition. As such, the terms "treat," "treatment," and "treating" can extend to prophylaxis and can include preventing, prevention, preventing, reducing, halting, or reversing the progression or severity of the disease state or symptom being treated. Thus, the term "treatment" can include medical, therapeutic, and / or prophylactic administration, as appropriate.

[0033] As used herein, "subject" or "patient" refers to an individual who has or is at risk for symptoms of a disease or other malignancy. A patient can be human or non-human and can include, for example, animal strains or species used as "model systems" for research purposes, such as the mouse model described herein. Similarly, a patient can include either an adult or juvenile (e.g., a child). Furthermore, a patient can refer to any organism, preferably a mammal (e.g., human or non-human), that may benefit from the administration of the compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the class Mammalia: non-human primates such as humans, chimpanzees, and other ape and monkey species; livestock animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-humans include, but are not limited to, birds, fish, and the like. In one embodiment of the methods provided herein, the mammal is a human.

[0034] As used herein, the terms "providing," "administering," and "introducing" are used interchangeably herein and refer to the placement of a disclosed compound into a subject by a method or route that results in at least partial localization of the compound at a desired site. The compound may be administered by any suitable route that results in delivery to the desired location in the subject.

[0035] The compounds and compositions described herein may be administered with additional compositions to prolong the stability and activity of the composition, or in combination with other therapeutic agents.

[0036] The terms "inhibit," "inhibiting," and "inhibition" refer to slowing, stopping, or reversing the growth or progression of a disease, infection, condition, or cell population. Inhibition can be, for example, greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99% compared to the growth or progression that occurs in the absence of treatment or contact.

[0037] As used herein, the term "substantially" is a broad term and is used in its ordinary sense, including, but not limited to, most, but not necessarily completely specified. For example, the term can refer to a numerical value that may not be 100% complete. The complete numerical value may be about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, or about 20% less.

[0038] Whenever the term "comprising" is used herein, the alternative of using the terms "consisting of" or "consisting essentially of" is contemplated. As used herein, "comprising" is synonymous with "including," "comprising," or "characterized by" and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the element of the embodiment. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the embodiment. In each instance herein, any of the terms "comprising," "essentially consisting of," and "consisting of" may be substituted for either of the other two terms. The disclosure illustratively set forth herein may suitably be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein.

[0039] The term "adverse event" refers to any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related.

[0040] The term "serious adverse event" refers to death, a life-threatening adverse event, hospitalization or prolongation of an existing hospitalization, a persistent or significant incapacity or substantial interruption in the ability to perform normal life functions, or a congenital anomaly / birth defect. A significant medical event that does not result in death, is life-threatening, or may require hospitalization may be considered serious if such a medical event includes allergic bronchospasm requiring intensive care in the emergency room or at home, a blood disorder or seizure that does not result in hospitalization, or the development of drug dependency or drug abuse, etc.

[0041] The term "dosing regimen" refers to a course of medical treatment over a certain period of time. The dosing regimens described herein include one or more sub-dosing regimens, such as a first dosing regimen, a second dosing regimen, etc., that constitute the overall medical dosing regimen. The treatment period can be one or more days, one or more weeks, one or more months, etc., and this period can be repeated periodically one or more times. For example, the period defining the length of a cycle that can be repeated can be 28 days. The dosing regimen can be a 28-day cycle in which compound A is administered on a specified day of the cycle that defines the first dosing regimen, and compound B is administered on another specified day of the cycle that defines the second dosing regimen, which collectively defines the overall dosing regimen.

[0042] Minnelide prodrug (MINNELIDE, or Minnelide™ prodrug) is also known as 14-O-phosphonooxymethyl triptolide disodium salt, which has the IUPAC chemical name disodium; [(1S,2S,4S,5S,7S,8R,9R,11S,13S)-1-methyl-17-oxo-7-propan-2-yl-3,6,10,16-tetraoxaheptacyclo[11.7.0.0] 2,4 .0 2,9 .0 5,7 .0 9,11 .0 14,18 ]icos-14(18)-en-8-yl]oxymethyl phosphate. This neutral compound and its pharmaceutically acceptable salt forms are referred to herein as the Minnelide prodrug or Compound 1.

[0043] Embodiments of the Technology The present disclosure provides a method for treating cancer in a cancer patient, the method comprising: a) about 0.25 mg to about 2.0 mg of Minnelide prodrug according to a first dosing regimen, wherein a dose is given once daily on days 1-5, 8-12, and 15-19 of a cycle; and b) about 60 mg / m according to a second dosing regimen 2 ~about 100mg / m 2 Paclitaxel of the formula (I) wherein a dose is given once daily on days 1, 8, and 15 of a cycle. to a patient with gastric cancer in a 28-day cycle, The 28-day cycle is repeated one or more times and the combination effectively treats the cancer.

[0044] In various embodiments, a cancer patient is administered about 0.25 mg to about 1.25 mg of a Minnelide prodrug according to a first dosing regimen. In various embodiments, according to the first dosing regimen, a cancer patient is administered a milligram amount of a Minnelide prodrug that is about 0.15 mg, 0.25 mg, 0.35 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, or about 6.0 mg.

[0045] In various embodiments, the cancer patient receives about 50 mg / m according to the second dosing regimen. 2 ~about 100mg / m 2 In various embodiments, according to the second dosing regimen, the cancer patient receives about 5 mg / m paclitaxel. 2 , 10 mg / m 2 , 15 mg / m 2 , 20 mg / m 2 , 25 mg / m 2 , 30 mg / m 2 , 35 mg / m 2 , 40 mg / m 2 , 45 mg / m 2 , 50 mg / m 2 , 55 mg / m 2 , 60 mg / m 2 , 65 mg / m 2 , 70 mg / m 2 , 75 mg / m 2 , 80 mg / m 2 , 85 mg / m 2 , 90 mg / m 2 , 95 mg / m 2 , 100 mg / m2 , 125 mg / m 2 , 150 mg / m 2 , 175 mg / m 2 , or about 200 mg / m 2 milligrams of paclitaxel.

[0046] In some embodiments, cancer patients receive about 0.25 mg of Minnelide according to a first dosing regimen and about 60 mg / m according to a second dosing regimen. 2 Patients are given paclitaxel.

[0047] In some embodiments, cancer patients receive about 0.25 mg of Minnelide according to a first dosing regimen and about 80 mg / m according to a second dosing regimen. 2 Patients are given paclitaxel.

[0048] In some embodiments, cancer patients receive about 0.5 mg of Minnelide according to a first dosing regimen and about 80 mg / m according to a second dosing regimen. 2 Patients are given paclitaxel.

[0049] In some embodiments, cancer patients receive about 0.75 mg of Minnelide according to a first dosing regimen and about 80 mg / m according to a second dosing regimen. 2 Patients are given paclitaxel.

[0050] In some embodiments, cancer patients receive about 1 mg of Minnelide according to a first dosing regimen and about 80 mg / m according to a second dosing regimen. 2 Patients are given paclitaxel.

[0051] In some embodiments, cancer patients receive about 1.25 mg of Minnelide according to a first dosing regimen and about 80 mg / m according to a second dosing regimen. 2 Patients are given paclitaxel.

[0052] In some embodiments, cancer patients receive about 1.5 mg of Minnelide according to a first dosing regimen and about 80 mg / m according to a second dosing regimen. 2Patients are given paclitaxel.

[0053] In some embodiments, cancer patients receive about 1.75 mg of Minnelide according to a first dosing regimen and about 80 mg / m according to a second dosing regimen. 2 Patients are given paclitaxel.

[0054] In some embodiments, cancer patients receive about 2 mg of Minnelide according to a first dosing regimen and about 80 mg / m according to a second dosing regimen. 2 Patients are given paclitaxel.

[0055] In various embodiments, the Minnelide prodrug is administered orally or intravenously, preferably orally. In various embodiments, the paclitaxel is administered intravenously or orally, preferably intravenously.

[0056] In various embodiments, the cancer patient also has one or more of pancreatic cancer, ovarian cancer, liver cancer, lung cancer, breast cancer, bladder cancer, and skin cancer. In some embodiments, the cancer patient has been diagnosed with advanced gastric cancer (AGC). The method can effectively treat cancer patients suffering from gastric cancer or gastric cancer and one or more of pancreatic cancer, ovarian cancer, liver cancer, lung cancer, breast cancer, bladder cancer, and skin cancer.

[0057] In various embodiments, the cancer patient is a human. In various embodiments, the cancer patient is a female human or a male human. In other embodiments, the cancer patient is a young female human or a young male human.

[0058] In various embodiments, the combination effectively treats cancer without causing a decrease in the cancer patient's complete blood count by more than 25%, 20%, 15%, 10%, or 5% from baseline. In various embodiments, the combination effectively treats cancer without causing a decrease in the cancer patient's platelet count or absolute neutrophil count by more than 25%, 20%, 15%, 10%, or 5% from baseline.

[0059] In various embodiments, the cancer patient has a tumor that continues to progress after receiving paclitaxel chemotherapy, and in various embodiments described herein, the cancer patient's tumor has a greater than 30% reduction in diameter after two, three, four, five or more 28-day cycles.

[0060] In some embodiments, the methods described herein are used to treat cancers that have become refractory or that are resistant or unresponsive to other methods of cancer treatment, hi various embodiments, the cancer is gastric cancer, e.g., advanced gastric cancer (AGC).

[0061] In one specific embodiment, the present invention provides a method for treating advanced gastric cancer in a cancer patient whose tumor has continued to progress after receiving paclitaxel chemotherapy, the method comprising: a) about 0.5 mg to about 1.5 mg of Minnelide according to a first dosing regimen, wherein a dose is given once daily on days 1-5, 8-12, and 15-19 of a cycle; b) about 70 mg / m according to a second dosing regimen 2 ~about 90mg / m 2 Paclitaxel of the formula (I) wherein a dose is given once daily on days 1, 8, and 15 of a cycle. during a 28-day cycle to a cancer patient diagnosed with advanced gastric cancer, The 28-day cycle is repeated two or more times, thereby achieving disease stability or disease regression of the advanced gastric cancer. In various embodiments, the combination effectively treats gastric cancer without causing the cancer patient's whole blood count to fall by more than 25% from baseline, and the combination effectively treats gastric cancer without causing the cancer patient's platelet count or absolute neutrophil count to fall by more than 25% from baseline.

[0062] Classification of adverse events by severity The severity of each adverse event (AE) followed the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) guidelines and is summarized as follows: Grade 1: An AE that is a temporary or mild discomfort that does not interfere with the patient's daily activity performance or function; medical intervention / treatment may be required. Grade 2: An AE of sufficient severity that it may cause moderate discomfort to the patient; may affect the patient's performance or function in daily activities; generally does not impair the patient's ability to continue in the study; and / or may require therapeutic intervention. Grade 3: An AE event that significantly affects the patient's performance or function in daily activities, generally causing severe discomfort, generally necessitating a change or discontinuation of study drug administration, and / or requiring therapeutic intervention, generally with the possibility of hospitalization. Grade 4: An AE that is considered life-threatening, resulting in significant impairment or incapacity and / or likely to result in hospitalization, representing the worst possible outcome of the event. Grade 5: Death related to an AE.

[0063] Clinical experience Intravenous Minnelide Prodrug. A Phase 1, multicenter, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of Minnelide prodrug given intravenously daily for 21 days, followed by a 7-day rest schedule in patients with advanced gastrointestinal tumors. A second dosing schedule of Minnelide prodrug given QD intravenously for 5 days, followed by 2 days off for 3 weeks, followed by a 7-day rest period, was also investigated during this study.

[0064] A total of 45 patients were enrolled in the Phase 1 trial, but 3 patients did not receive the study drug. The remaining 42 patients received the drug. The primary reason for treatment discontinuation was disease progression. Six deaths occurred in the trial, occurring after completion of study drug and within the 30-day follow-up period. Deaths occurring during the trial were found to be unrelated to the study drug and related to progression of the patient's disease (pancreatic cancer / gastric cancer). One patient who died of respiratory failure was also found to be unrelated to the use of study drug.

[0065] Three patients discontinued study drug due to the occurrence of treatment-emergent adverse events (TEAEs). All were considered grade 3, and two of these TEAEs were considered likely related to the use of study drug. These two cases were also considered DLTs. A total of 28 serious adverse events occurred in 17 patients, six of which were found to be related to study drug.

[0066] The most commonly reported TEAEs (>20%), regardless of causality, included hypoalbuminemia, anemia, hypoproteinemia, fatigue, neutropenia, leukopenia, thrombocytopenia, nausea, hypocalcemia, diarrhea, hyperphosphatemia, constipation, vomiting, hyponatremia, lymphopenia, abdominal pain, dehydration, hyperglycemia, peripheral edema, hypophosphatemia, and headache.

[0067] All 32 patients had at least one adverse event (AE) considered related to the study drug. Grade 3 and 4 AEs of short duration of neutropenia were observed at all doses and were determined to be drug-related. Neutropenia resolved within several days without treatment. Neutropenia fever and neutropenic infection were observed in three patients and were determined to be drug-related. Grade 3 and 4 anemia and thrombocytopenia were observed in 22% of patients and were determined to be drug-related. Other adverse reactions of any grade potentially related to the drug included nausea, vomiting, diarrhea, constipation, anorexia, stomatitis, cerebellar toxicity, embolism, and dyspnea, which occurred in 3% or fewer patients.

[0068] Oral Minnelide prodrug. A phase 1, multicenter, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of Minnelide™ capsules given alone or in combination with protein-bound paclitaxel in patients with advanced solid tumors. A total of 44 patients were enrolled in the phase 1 study, 32 receiving the monotherapy regimen and 12 receiving the combination regimen. The primary reason for treatment discontinuation was disease progression. Nine patients died in the study; seven of these deaths were assessed as unrelated to the Minnelide prodrug and occurred after completion of study drug. One patient on the 1.25 mg monotherapy regimen died of G5-associated sepsis. One patient on the combination regimen with the 0.25 mg Minnelide prodrug died of G5 sepsis, which was determined to be unrelated to the Minnelide prodrug after review and consideration of the pharmacokinetic data.

[0069] Four patients discontinued the study drug due to treatment-emergent adverse events (TEAEs): two were considered grade 5, one was considered grade 3, and one was considered grade 2. One TEAE was considered likely related to the use of the study drug, and the other three were probably related (two grade 5 sepsis, one grade 3 hypokalemia, and one grade 2 neutrophil count decrease). Three SAEs were considered dose-limiting toxicities (DLTs). These events included two events of sepsis and one event of influenza A pneumonia. A total of 28 serious adverse events occurred in 17 patients, and four were found to be related to the study drug.

[0070] Minnelide prodrug 0.25 mg + protein-bound paclitaxel 80 mg / m 2 or 100 mg / m 2 Adverse events were classified according to the response observed at any dose. The most commonly reported TEAEs (>20%), regardless of causality, included anemia, abdominal pain, constipation, vomiting, diarrhea, nausea, fatigue, hypokalemia, and hypoalbuminemia. Twenty-seven patients had at least one AE considered related to study drug. Minnelide prodrug 0.25 mg + protein-bound paclitaxel 80 mg / m 2 or 100 mg / m2 Grade 3 to 5 TEAEs reported for either dose were: Grade 3 adverse events: cellulitis 2%, hypokalemia 9%, hypotension 2%, hypophosphatemia 2%, leukopenia 2%, nausea 2%, neutropenia 25%, sepsis 2%, thrombocytopenia 2%, vomiting 2%, weight loss 2%. Grade 4 adverse events: Aeromonas infection 2%, lactic acidosis 2%, leukopenia 2%, lymphopenia 2%, multiple organ dysfunction syndrome 2%, neutropenia 9%. Grade 5 adverse event: sepsis 5%. Ten patients with either pancreatic or breast cancer were treated during the Minnelide prodrug + protein-bound paclitaxel regimen. Two patients had a partial response, six patients had stable disease, one patient had progressive disease, and one patient had dose-limiting toxicity.

[0071] Dose-escalation study The purpose of dose escalation was to define the safety and toxicity characteristics (e.g., maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs)) of Minnelide™ Capsules as monotherapy in advanced gastric cancer (regimen A) and in combination with paclitaxel in gastric cancer (regimen B and C). Regimen A (Monotherapy). Minnelide™ capsules were given orally as a single agent once daily for 21 days, followed by a 7-day washout period. One cycle was 28 days long. Minnelide™ capsules were given to patients in the fasting state. Regimen B (Combination): Minnelide™ capsules were given orally once daily for 21 days in combination with paclitaxel given intravenously on days 1, 8, and 15. One cycle was 28 days. Minnelide™ capsules were given to patients in the fasting state. Regimen C (Combination). Minnelide™ capsules were given orally once daily on days 1-5, 8-12, and 15-19 in combination with paclitaxel given intravenously on days 1, 8, and 15. One cycle was 28 days. Minnelide™ capsules were given to patients in the fasting state.

[0072] Dose-limiting toxicity Dose-limiting toxicities (DLTs) were assessed during cycle 1 of treatment. Toxicity was graded and documented according to the NCI CTCAE guidelines (see above). Dose reductions were not permitted during cycle 1. DLTs were: Grade 4 neutropenia lasting 5 days or more, Grade 4 neutropenia with growth factor use, or Grade 3 or 4 neutropenia accompanied by fever and / or infection; Grade 4 thrombocytopenia (or grade 3 with bleeding); Grade 3 or 4 treatment-related non-hematologic toxicity (grade 3 nausea, vomiting, or diarrhea lasting more than 72 hours despite maximal therapy represents a DLT); or Dose delays of more than 2 weeks due to treatment-emergent AEs or related severe laboratory abnormalities Adverse events considered to be related to the study drug, including:

[0073] Exam Eligibility Inclusion Criteria Eligible patients signed an IRB-approved informed consent and met the following inclusion criteria: 1.Patients with histologically confirmed advanced gastric cancer (AGC). 2. Tumor progression after standard / approved chemotherapy or for which no approved treatment is available. 3. ≥1 measurable metastatic tumor per RECIST v1.1 criteria. 4. Karnofsky performance 70% (cares for self but cannot carry on normal activities). 5. Life expectancy of at least 3 months. 6. 19 years of age or older. 7. Negative pregnancy test (if female). 8. Acceptable liver function: bilirubin ≤ 1.5 times the upper limit of normal (ULN); aspartate aminotransferase (AST), serum glutamic oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT), serum glutamic pyruvic transaminase (SGPT), and alkaline phosphatase ≤ 2.5 times the upper limit of normal (≤ 5 times the ULN is permitted if liver metastases are present); albumin ≥ 3.0 g / dL. 9. Acceptable renal function: Serum creatinine within the normal range or 60 mL / min / 1.73 m for patients with creatinine levels above the institutional normal range. 2 or greater calculated creatinine clearance. 10. Acceptable hematological status: 1,500 cells / mm for monotherapy 3 or more than 2000 cells / mm in combination with paclitaxel 3 Absolute neutrophil count of 100,000 or more (plt / mm 3 ) or higher platelet count; hemoglobin greater than 9g / dL. 11. Urinalysis: No clinically significant abnormalities. 12. Acceptable coagulation status: Prothrombin time (PT) ≤ 1.5x institutional ULN. Partial thromboplastin time (PTT) ≤ 1.5x institutional ULN. 13. Females and males of childbearing potential must agree to use adequate contraception, and for males and females of childbearing potential, throughout the study and until 90 days after the last IP dose for males, or until 6 months after the last IP dose for females, or until 6 months after the last IP dose of paclitaxel for both sexes.

[0074] Discontinuation of Minnelide prodrug administration Decreases in blood counts are usually seen within the first 5-7 days of starting the Minnelide prodrug and resolve within 4-8 days of withdrawal.

[0075] CBC with differential was performed on days 1, 8, 15, 22, and more frequently when clinically indicated. 3<100,000 cells / mm3 (Grade 3 or higher) or platelets <100,000 cells / mm3 3 Patients were admitted for close monitoring whenever the ANC level was below 1500 mmHg. 3 or greater than 100,000 cells / mm 3 It won't restart until it's over.

[0076] The following examples are intended to illustrate the above invention and should not be construed as narrowing its scope in any way. Those skilled in the art will readily recognize that these examples suggest that the present invention can be practiced in many other ways. It should be understood that many variations and modifications can be made while remaining within the scope of the present invention.

[0077] Example Example 1. Gastric Cancer Therapy Regimen A (Monotherapy) Minnelide™ Capsules were administered orally once daily for 21 days as monotherapy, followed by a 7-day washout period. Dose escalation for Regimen A followed Table 1. At each dose level, a first patient was treated. If the patient did not develop CTCAE V4.03 Grade 3 or higher toxicity after one week of treatment, the second and third patients could receive the same dose of Minnelide™ Capsules (capsules containing the Minnelide prodrug). If the second and third patients did not experience CTCAE V4.03 Grade 3 or higher toxicity after a minimum of three weeks of treatment, dose escalation proceeded to dose level 2.

[0078] If a DLT is observed in 1 in 3 patients at the first dose level, up to 3 additional patients will be enrolled and treated at that dose level. If 2 patients have a DLT at this dose level, dosing will be reduced to 1 / 2 of dose level 1. If 1 in 6 patients has a DLT, dosing will be increased to the second dose level. If 2 or more of up to 6 patients at the second dose level have a DLT, the previous dose (dose level 1) will be identified as the MTD. If 1 or less of 6 patients have a DLT, dose level 2 will be identified as the MTD.

[0079] [Table 1]

[0080] Example 2. Gastric Cancer Therapy Regimen B (Combination) Minnelide™ capsules were administered orally once daily for 21 days in combination with paclitaxel administered intravenously on days 1, 8, and 15. Once dose level 1 in regimen A (monotherapy) was cleared, dose escalation in regimen B (combination) began according to Table 2. At each dose level, the first patient was treated. If the patient did not develop CTCAE V4.03 grade 3 or higher toxicity after 1 week of treatment, the second and third patients could receive the same dose of Minnelide™ capsules and paclitaxel. Paclitaxel was administered at an initial dose of 60 mg / m 2 80 mg / m if no DLTs were observed in 3 patients 2 increased to 80 mg / m 2 and the dose levels for escalation of the Minnelide prodrug will proceed as summarized in Table 2. Escalation will proceed according to the parameters described for Regimen A.

[0081] [Table 2]

[0082] Example 3. Gastric Cancer Therapy Regimen C (Combination) Minnelide™ capsules were administered orally once daily on days 1-5, 8-12, and 15-19 in combination with paclitaxel administered intravenously on days 1, 8, and 15. Dose escalation for Regimen C (combination) was initiated according to Table 3. At each dose level, the first patient was treated. If no patient developed CTCAE V4.03 grade 3 or higher toxicity after 1 week of treatment, the second and third patients received the same dose of Minnelide™ capsules and paclitaxel. Paclitaxel was administered at 80 mg / m 2 if no DLTs were observed in three patients. 2 80 mg / m 2 The dose will be maintained at 0.05 and dose levels for escalation of the Minnelide prodrug will proceed as summarized in Table 3. Paclitaxel adjustments will be considered from cycle 2 onwards after safety evaluation.

[0083] [Table 3]

[0084] Example 4. Disease Assessment (See Table 4 below) Target Lesions. Response criteria for target lesions are shown in Table 5. All measurable lesions, with a maximum of two lesions per organ and five lesions total, representing all involved organs, were identified as target lesions and recorded and measured at baseline. Target lesions were selected based on their size (lesions with the longest diameter), were representative of all involved organs, and were suitable for reproducible repeated measurements. All measurements were recorded using calipers when clinically assessed.

[0085] The sum of the diameters for all target lesions (longest for non-nodal lesions and short axis for nodal lesions) was calculated and reported as the baseline sum diameter, which was used as a reference to further characterize objective tumor regression in the measurable extent of disease. When lymph nodes were included in the sum, only the short axis contributed.

[0086] [Table 4] JPEG2026009993000007.jpg48159

[0087] [Table 5]

[0088] Example 5. First-in-human Phase 1 study This study evaluated the safety and preliminary antitumor activity of the Minnelide prodrug, administered alone or in combination with paclitaxel to patients with advanced gastric cancer (AGC) (NCT 05566834).

[0089] Study design: This was an open-label, non-randomized, Phase 1 study conducted at Samsung Medical Center (SMC) in Korea. The study consisted of three dosing regimens: Minnelide prodrug monotherapy (Regimen A) and combination therapy (Minnelide prodrug plus paclitaxel), which was further divided into Regimen B and C.

[0090] [Table 6]

[0091] Patients. Adult (≥20 years) Korean patients with histologically confirmed advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who had failed initial standard therapy or were ineligible for standard therapy were eligible to participate in the study, regardless of HER2 status. Study treatment was discontinued if patients experienced radiologically determined progressive disease (PD) according to Investigator-Assessed Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), investigator-assessed clinical progression, or the development of unacceptable toxicity.

[0092] Treatment. In regimen A, 3 to 5 patients were treated with escalating doses of Minnelide prodrug alone to determine the maximum tolerated dose (MTD). Minnelide prodrug was administered orally (PO) once daily for 21 days, starting at 1 mg and escalating to 1.25 mg and 1.5 mg, followed by a 7-day washout period. One cycle was equal to 28 days, and Minnelide prodrug was administered to patients in the fasting state. In regimen B, 60 mg / m 2 Starting at 80 mg / m 2 The same dosing scheme was used for 0.25 mg Minnelide prodrug PO in combination with intravenous paclitaxel on days 1, 8, and 15 (Q4W) starting at 0.5 mg and titrating to 0.75 mg, 1.0 mg, and 1.25 mg. In Regimen C, patients received 80 mg / m2 intravenously on days 1, 8, and 15 (Q4W) in combination with Minnelide prodrug PO once daily on days 1-5, 8-12, and 15-19 starting at 0.5 mg and titrating to 0.75 mg, 1.0 mg, and 1.25 mg. 2 Patients were treated with 100 mg of paclitaxel. Dose-limiting toxicities (DLTs) were assessed during Cycle 1. Treatment continued until disease progression, death, unacceptable toxicity, or patient or investigator decision to discontinue treatment.

[0093] Results: In this phase 1 study, the primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Minnelide prodrug when administered alone or in combination with paclitaxel, and to establish recommended phase 2 doses (RP2Ds) for Minnelide prodrug alone and in combination with paclitaxel every 4 weeks. Secondary objectives were to evaluate evidence of antitumor activity of Minnelide prodrug alone and in combination with paclitaxel by objective radiographic assessment. Antitumor activity was assessed by objective response rate (ORR). Analyses of disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were performed.

[0094] Assessment. Adverse events were graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Tumor assessments were performed after cycles 2, 4, 6, and 8, and every four cycles thereafter, or as indicated. Responses were determined by the investigator using RECIST version 1.1. Objective response rate (ORR) was determined in patients with measurable disease at baseline and defined as a complete or partial response confirmed by repeat assessment 4 weeks or more later. Disease control rate (DCR) was defined as the proportion of patients who achieved complete remission, partial remission, or stable disease.

[0095] Statistical Methods. Safety analyses were performed on the safety-evaluable population, which included all patients who received any study drug. Safety was assessed by DLTs and AEs. Patients with missing baseline or response assessments were classified as non-responders. ORR and DCR were reported with exact 95% confidence intervals (CIs). PFS, OS, and DOR were estimated using the Kaplan-Meier method with 95% CIs. Safety data were summarized for clarity. Data for regimen A (Minnelide prodrug monotherapy), regimens B, and C (Minnelide prodrug and paclitaxel) are presented separately. Data analysis was performed on December 20, 2023, using the Statistical Package for Social Sciences for Windows (version 27.0; IBM Corp., Armonk, NY, USA).

[0096] result Patients. Between November 2, 2020, and October 18, 2023, 49 patients were screened; 36 (median age, 59 [range, 30-74]) met the eligibility criteria; 11 were treated with regimen A, 10 with regimen B, and 15 with regimen C (Figure 4 and Table 6). Study exclusions (n ​​= 13) were due to failure to meet inclusion criteria (n = 12) or refusal to participate in the study (n = 1). All 36 enrolled patients were included in the data analysis (Figure 4). Baseline demographic data and characteristics are summarized in Table 6.

[0097] Regimen A included six male and five female patients, all with an ECOG PS of 1, who had received a median of three prior cancer therapies (four [36%] had received prior immunotherapy). Regimen B included eight male and two female patients, who had received a median of three prior cancer therapies (three [30%] had received prior immunotherapy). Regimen C included eight male and seven female patients, who had received a median of two prior therapies, with eight (53%) having received prior immunotherapy. A total of six (17%) patients had HER2-positive tumors, and 19 (76%) had PD-L1 (CPS ≥ 1)-expressing tumors (Table 6). None of the patients had microsatellite instability-high tumors. In the combination treatment group, 80% of patients in Regimen B and 53.3% of patients in Regimen C had previously been treated with paclitaxel.

[0098] [Table 7] JPEG2026009993000011.jpg93159

[0099] At the data cutoff date (December 20, 2023), 32 patients (89%) had discontinued study treatment, and 4 patients were still receiving treatment. The primary reason for discontinuation was progressive disease. Five patients (2 in Regimen A, 2 in Regimen B, and 1 in Regimen C) did not complete cycle 1 (Figure 4), leaving 36 and 31 subjects evaluable for safety and antitumor activity, respectively.

[0100] Safety. Minnelide prodrug monotherapy regimen A had two dose-limiting toxicities (DLTs) (Minnelide prodrug 1.5 mg at dose level 3: grade 3 abdominal pain). No DLTs occurred with the combination of Minnelide prodrug and paclitaxel. The most common treatment-related AEs (TRAEs) were anorexia (18 / 36, 50%), abdominal pain (16 / 36, 44.4%), nausea (12 / 36, 33.3%), and neutropenia (11 / 36, 30.6%) (Table 7). The majority of TRAEs were grade 1 or 2. Grade 3 or higher TRAEs occurred in 16 patients; neutropenia (19.4%) was the most common, followed by abdominal pain (11.1%). There were four grade 5 AEs caused by progression of gastric cancer.

[0101] [Table 8] JPEG2026009993000013.jpg48159

[0102] Minnelide prodrug-related adverse events (AEs) are summarized in Table 8. The maximum tolerated dose (MTD) was 1.25 mg Minnelide prodrug PO once daily for 21 days every 4 weeks as monotherapy. The most common Minnelide prodrug-related treatment AEs experienced by patients in Regimen A were anorexia (54.5%), nausea (45.5%), and abdominal pain (27.3%). In the combination treatment regimens (B&C), abdominal pain (44.0%) and neutropenia (40.0%) occurred most frequently. Grade 3 or higher severe TRAEs were nausea (18.2%), vomiting (9.1%), abdominal pain (18.2%), and neutropenia (9.1%) in the Minnelide prodrug monotherapy group, whereas in the combination therapy group, 8.0% of patients experienced more than one Grade 3 or higher TRAE, and 24.0% of patients had Grade 3 or higher neutropenia (Table 8).

[0103] [Table 9]

[0104] Antitumor Activity. In combination regimen C, four patients (28.6%) experienced a partial response (PR), and six patients (42.9%) experienced stable disease (SD) (Figure 5A). Four patients (44.4%) in regimen A and three patients (37.5%) in regimen B experienced stable disease. In regimen A (monotherapy), nine patients with measurable disease completed at least one cycle of treatment, with a BOR of SD (44.4%) or PD (55.6%). The DCR was 44.4% (95% CI 13.7-78.8) (Figure 8) (Tables 9 and 10).

[0105] [Table 10]

[0106] [Table 11]

[0107] In regimen B, eight patients with measurable disease completed at least one cycle of treatment, with a BOR of 37.5% (SD) or PD (62.5%) (Figure 5B). The DCR was 37.5% (95% CI 8.5-75.5). In regimen C, 14 patients with measurable disease completed at least one cycle of treatment, with a BOR of 28.6% (PR), 42.9% (SD), or PD (28.6%). The ORR was 28.6% (95% CI 8.4-58.1), and the DCR was 71.4% (95% CI 41.9-91.6) (Table 11).

[0108] [Table 12]

[0109] In regimen B, two patients had SD of 6 months or more (Figure 6A). Of the six patients who showed SD in regimen C, paclitaxel 80 mg / m 2One patient receiving Minnelide 1.0 mg / day had prolonged stable disease for over 1 year with tumor size regression (Figure 6B). Two patients experienced prolonged PR (over 8 months). Four patients were still receiving paclitaxel and Minnelide at the time of submission.

[0110] The median PFS was 1.6 months (95% CI, 0.7-2.5) for regimen A, 1.6 months (95% CI, 1.2-2.0) for regimen B, and 4.5 months (95% CI, 0.2-8.8) for regimen C. The median OS was 5.3 months (95% CI, 0.0-13.2) for regimen A, 4.5 months (95% CI, 1.2-7.8) for regimen B, and 10.7 months (95% CI, 6.9-14.5) for regimen C (Table 12).

[0111] [Table 13]

[0112] In regimen B, median PFS was 1.3 months (95% CI 0.84-1.76) in patients previously treated with paclitaxel and 1.6 months (95% CI NE-NE) in patients not previously exposed to paclitaxel. Median OS was 3.6 months (95% CI 1.66-5.54) in patients previously treated with paclitaxel and 4.5 months (95% CI NE-NE) in patients not previously exposed to paclitaxel (n=2) (p=0.569).

[0113] In regimen C, median PFS and OS were 2.4 months (95% CI, 0.68-4.12) and 8.3 months (95% CI, 0.00-18.05), respectively, for patients previously treated with paclitaxel (n=8). In patients not previously exposed to paclitaxel (n=7), median PFS and OS were 5.4 months (95% CI, 5.20-5.61) and 14.3 months (95% CI, NE-NE) (p=0.295 for PFS; p=0.301 for OS). In the final two cohorts of regimen C, three patients not previously exposed to paclitaxel (n=4) had a confirmed ORR of 50.0%, a DCR of 75.0%, a median PFS of 5.3 months, and no median OS.

[0114] Importantly, Figure 5A demonstrates the synergistic effect of Regimen C Minnelide prodrug when administered in combination with paclitaxel, with 11 of 14 patients experiencing at least a 20% reduction in tumor growth, 9 experiencing a reduction in tumor size, and 5 of these 9 experiencing a significant reduction (30-60%) in tumor size. This surprising synergistic effect is also demonstrated in Figure 7 (a graph of preclinical results in mice), which shows (a) control subjects receiving vehicle, test mice receiving Minnelide prodrug alone at (b) 0.0026 mg / day and (c) 0.005 mg / day, and (d) paclitaxel alone, compared with (e) 0.0026 mg / day Minnelide prodrug in combination with 0.67 mg / day paclitaxel, and (f) 0.005 mg / day Minnelide prodrug in combination with 0.67 mg / day paclitaxel.

[0115] Consideration This phase 1 study evaluated the safety and efficacy of oral Minnelide prodrug monotherapy and combination therapy with paclitaxel in Korean patients with locally advanced or metastatic gastric cancer who had received multiple prior therapies. Two DLTs occurred at the 1.5 mg Minnelide prodrug monotherapy dose, and the 1.25 mg Minnelide prodrug dose was identified as the MTD. No DLTs were observed in patients treated with Minnelide prodrug plus paclitaxel, and the combination therapy was well tolerated.

[0116] The most common treatment-related AEs with Minnelide prodrug were anorexia, abdominal pain, neutropenia, and nausea. Grade 3 or higher AEs with Minnelide prodrug occurred in 27.8% of patients overall, followed by neutropenia (19.4%), abdominal pain (11.1%), and nausea (5.6%). The incidence of abdominal pain was observed, not significantly different from that observed with previous gastrectomy. The overall type and incidence of TRAEs were similar to those associated with Minnelide prodrug. The majority of TRAEs were grade 1 or 2, with the most common TRAEs being anorexia (18 / 36, 50%), abdominal pain (16 / 36, 44.4%), nausea (12 / 36, 33.3%), and neutropenia (11 / 36, 30.6%). Four grade 5 AEs caused by progression of gastric cancer were reported (3 in regimen A and 1 in regimen B).

[0117] Although no objective responses were observed with the single-agent Minnelide prodrug, some patients who had previously received at least two lines of chemotherapy experienced tumor regression. One patient who had previously failed four lines of therapy, including immunotherapy, experienced stable disease for 5.4 months.

[0118] The addition of paclitaxel to the Minnelide prodrug was shown to improve response rates and provide prolonged PFS and OS compared with the Minnelide prodrug alone. Particularly in regimen C, Minnelide prodrug plus paclitaxel demonstrated promising antitumor activity, with a confirmed ORR of 28.6% and a DCR of 71.4%; the median PFS was 4.5 months (95% CI 0.2-8.8), and the median OS was 10.7 months (95% CI 6.9-14.5). This is comparable to the median PFS of 4.4 months and median OS of 9.6 months for paclitaxel plus ramucirumab, the most commonly used second-line standard of care for AGC.

[0119] Furthermore, the Minnelide prodrug in combination with paclitaxel (regimens B and C) demonstrated a disease control rate of 43.8% (7 / 16) in patients previously treated with paclitaxel (n=16). These findings indicate that administering the Minnelide prodrug in combination with paclitaxel can overcome resistance and reverse sensitivity to paclitaxel, as previously reported (Wang et al., J. Clin. Oncol. 32 (2014)).

[0120] The results of this phase 1 trial are limited by the poor prognosis of the study population, along with the fact that many patients had received multiple prior chemotherapy regimens.

[0121] To the inventors' knowledge, this is the first study of the Minnelide prodrug, with and without paclitaxel, for the treatment of patients with AGC whose disease has progressed on previous therapy. Oral administration of the Minnelide prodrug alone at a dose of 1.25 mg demonstrated tolerability with limited single-agent efficacy. Furthermore, the combination of the Minnelide prodrug with paclitaxel as salvage therapy in patients with AGC demonstrated meaningful clinical efficacy with a manageable safety profile. These data support the use of the Minnelide prodrug alone and in combination with paclitaxel and / or chemotherapy and immunotherapy in cancer, particularly advanced gastric cancer.

[0122] The following paragraphs, listed consecutively from 1 to 15, provide various further aspects of the present invention. In one embodiment, in the first paragraph, the present disclosure provides: 1. A method for treating gastric cancer in a cancer subject, comprising: a) about 0.25 mg to about 2.0 mg of Minnelide according to a first dosing regimen, wherein a dose is given once daily on days 1-5, 8-12, and 15-19 of a cycle; b) about 60 mg / m according to a second dosing regimen 2 ~about 80mg / m 2 Paclitaxel of the formula (I) wherein a dose is given once daily on days 1, 8, and 15 of a cycle. to a cancer subject during a 28-day cycle, The 28-day cycle is repeated one or more times, and the combination effectively treats gastric cancer. 2. The method of paragraph 1, wherein the cancer subject is administered about 0.5 mg to about 0.75 mg of Minnelide according to a first dosing regimen. 3. A cancer subject receives approximately 0.5 mg of Minnelide according to a first dosing regimen and approximately 60-80 mg / m according to a second dosing regimen. 2 3. The method of paragraphs 1-2, wherein the patient is administered paclitaxel. 4. A cancer subject receives approximately 0.25 mg of Minnelide according to a first dosing regimen and approximately 70-90 mg / m according to a second dosing regimen. 2 (e.g., about 80 mg / m 2 4. The method of any one of paragraphs 1 to 3, wherein paclitaxel of 5. A cancer subject receives approximately 0.50 mg of Minnelide according to a first dosing regimen and approximately 70-90 mg / m according to a second dosing regimen. 2 (e.g., about 80 mg / m 2 5. The method of any one of paragraphs 1 to 4, wherein paclitaxel of 6. A cancer subject receives approximately 0.75 mg of Minnelide according to a first dosing regimen and approximately 70-90 mg / m according to a second dosing regimen. 2 (e.g., about 80 mg / m 26. The method of any one of paragraphs 1 to 5, wherein paclitaxel of 7. A cancer subject receives approximately 1 mg of Minnelide according to a first dosing regimen and approximately 70-90 mg / m according to a second dosing regimen. 2 (e.g., about 80 mg / m 2 7. The method of any one of paragraphs 1 to 6, wherein paclitaxel of 8. A cancer subject receives approximately 1.25 mg of Minnelide according to a first dosing regimen and approximately 70-90 mg / m according to a second dosing regimen. 2 (e.g., about 80 mg / m 2 8. The method of any one of paragraphs 1 to 7, wherein paclitaxel of 9. The method of any of paragraphs 1-8, wherein Minnelide is administered orally. 10. The method of any of paragraphs 1-9, wherein paclitaxel is administered intravenously. 11. The method of any one of paragraphs 1-10, wherein the cancer patient has a tumor that has continued to progress after receiving paclitaxel chemotherapy, and / or the cancer patient's cancer tumor has reduced in diameter by more than 30% after five or more 28-day cycles. 12. The method of any one of paragraphs 1-11, wherein the subject further suffers from advanced gastric cancer, ovarian cancer, breast cancer, bladder cancer, skin cancer, or a combination thereof, and wherein the method effectively treats the cancer subject. 13. The method of any one of paragraphs 1 to 12, wherein the cancer subject is a human. 14. The method of any one of paragraphs 1-13, wherein the combination effectively treats gastric cancer without causing a decrease in the complete blood count of the cancer subject by more than 25% from baseline. 15. The method of any one of paragraphs 1-14, wherein the combination effectively treats gastric cancer without causing a decrease in platelet count or absolute neutrophil count of more than 25% from baseline in the cancer subject.

[0123] While specific embodiments have been described above with reference to the disclosed embodiments and examples, such embodiments are merely illustrative and do not limit the scope of the present invention. Modifications and changes can be made in accordance with the ordinary skill of those skilled in the art without departing from the present invention in its broader aspects, as defined in the following claims.

[0124] All publications, patents, and patent documents are incorporated herein by reference, as if individually incorporated by reference. No limitations inconsistent with the present disclosure are to be understood therefrom. The present invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the invention.

Claims

1. 1. A composition for use in a method of treating gastric cancer in a cancer patient, said composition comprising Minnelide or triptolide, said method comprising administering to said cancer patient a therapeutically effective combination of a) Minnelide or triptolide and b) paclitaxel during a 28 day cycle, said method comprising: a) administering Minnelide or Triptolide once daily on days 1-5, 8-12, and 15-19 of said 28-day cycle at a dose of about 0.15 mg / day to about 3.0 mg / day according to a first dosing regimen; and b) according to a second dosing regimen, about 60 mg / m ２ / day ~ approx. 100mg / m ２ / day on days 1, 8, and 15 of said 28-day cycle. Including, The 28-day cycle is repeated one or more times, and the combination effectively treats the gastric cancer.

2. 10. The composition of claim 1, wherein the method comprises administering Minnelide or Triptolide at a dose of about 0.25 mg / day to about 1 mg / day according to the first dosing regimen.

3. The method comprises administering Minnelide or Triptolide at a dose of about 0.25 mg / day to about 1 mg / day according to the first dosing regimen, and administering Minnelide or Triptolide at a dose of about 60 mg / m according to the second dosing regimen. ２ / day ~ 80mg / m ２ 10. The composition of claim 1, comprising administering paclitaxel at a dose of 0.05 mg / day.

4. The method comprises administering Minnelide or Triptolide at a dose of about 0.25 mg / day to about 0.35 mg / day according to the first dosing regimen, and administering Minnelide or Triptolide at a dose of about 80 mg / m according to the second dosing regimen. ２ 10. The composition of claim 1, comprising administering paclitaxel at a dose of 0.05 mg / day.

5. The method comprises administering Minnelide or Triptolide at a dose of about 0.35 mg / day according to the first dosing regimen, and administering Minnelide or Triptolide at a dose of about 80 mg / m according to the second dosing regimen. ２ 10. The composition of claim 1, comprising administering paclitaxel at a dose of 0.05 mg / day.

6. The method comprises administering Minnelide or Triptolide at a dose of about 0.5 mg / day according to the first dosing regimen, and administering Minnelide or Triptolide at a dose of about 80 mg / m according to the second dosing regimen. ２ 10. The composition of claim 1, comprising administering paclitaxel at a dose of 0.05 mg / day.

7. The method comprises administering Minnelide or Triptolide at a dose of about 0.8 mg / day according to the first dosing regimen, and administering Minnelide or Triptolide at a dose of about 80 mg / m according to the second dosing regimen. ２ 10. The composition of claim 1, comprising administering paclitaxel at a dose of 0.05 mg / day.

8. The composition of claim 1 , wherein the cancer patient has been diagnosed with advanced gastric cancer.

9. 10. The composition of claim 1, wherein the cancer tumor in the cancer patient is reduced in diameter by 30% or more after five or more 28-day cycles.

10. 10. The composition of claim 1, wherein said method comprises administering Minnelide or Triptolide orally and administering Paclitaxel intravenously.

11. 10. The composition of claim 1, wherein the cancer patient further suffers from breast cancer, bladder cancer, liver cancer, lung cancer, ovarian cancer, skin cancer, or a combination thereof, and the combination effectively treats the cancer patient.

12. 10. The composition of claim 1, wherein the combination effectively treats the gastric cancer without causing a 25% or greater decrease in the cancer patient's complete blood count from baseline.

13. 10. The composition of claim 1, wherein the combination effectively treats the gastric cancer without causing a 25% or greater decrease in the cancer patient's platelet count or absolute neutrophil count from baseline.

14. 1. A composition for use in a method for treating advanced gastric cancer in a cancer patient having a tumor that has continued to progress after receiving chemotherapy, said composition comprising Minnelide or triptolide, said method comprising administering to said cancer patient a therapeutically effective combination of a) Minnelide or triptolide and b) paclitaxel during a 28 day cycle, said method comprising: a) orally administering Minnelide or Triptolide once daily on days 1-5, 8-12, and 15-19 of said 28-day cycle at a dose of about 0.15 mg / day to about 1.5 mg / day according to a first dosing regimen; and b) according to a second dosing regimen, about 70 mg / m ２ / day ~ approx. 90mg / m ２ / day on days 1, 8, and 15 of said 28-day cycle. Including, The 28-day cycle is repeated two or more times, thereby achieving disease stability or disease remission of the advanced gastric cancer.

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