Drug combinations for the treatment of pancreatic cancer

Abstract

The cancer therapeutics Minnelide, nab-paclitaxel, and gemcitabine were combined for the synergistic treatment of pancreatic cancer in cancer subjects. Cancer subjects treated daily with the combination experienced side effects. Therefore, described herein is a combination dosing regimen that reduces the number of side effects experienced by cancer subjects. The dosing regimen was established in a 28-day cycle, with Minnelide administered once daily on days 1-5, 8-12, and 15-19 of the cycle, and nab-paclitaxel and gemcitabine administered once daily on days 1, 8, and 15 of the cycle. This described dosing regimen was shown to be well tolerated in clinical trials.

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 / 489,221, filed March 9, 2023, which is incorporated herein by reference. [Background technology]

[0002] Minnelide™ is a prodrug that rapidly releases the active compound, triptolide, when exposed to phosphatases in the bloodstream. Triptolide is a diterpene that has been shown to inhibit tumor cell proliferation and induce apoptosis in vitro and in animal models of cancer, including human breast tumors (Shamon et al., Cancer Lett. 1997;112:113-7), cholangiocarcinoma cells (Tengchaisri et al., Cancer Lett. 1998;133:169-75), and xenografts of several different tumor types, including melanoma, breast cancer, bladder cancer, gastric carcinoma (Yang et al., Mol Cancer Ther. 2003;2:65-72), pancreatic tumors (Phillips et al., Cancer Res. 2007;67(19):9407-16), and neuroblastoma (Antonoff et al., Surgery. 2009;146:282-90).

[0003] The antitumor effects of triptolide are the result of inhibiting heat shock protein (HSP) 70 expression and inducing apoptosis in tumor cells. The mechanism of action of triptolide's inhibition of HSP70 expression is not fully understood, but it has been shown to induce caspase activation (Choi et al., Biochem Pharmacol. 2003;66:273-80; 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;108:630-7).

[0004] In MIA-PaCa2 and PANC-1 pancreatic cancer cell lines, cytochrome c release from mitochondria to the cytosol and caspase-3 activity were significantly increased after incubation with triptolide (TPL), suggesting that the mitochondrial apoptotic pathway is responsible for TPL-induced cell death in these cells (Phillips et al., Cancer Res. 2007;67(19):9407-16). Further studies showed that TPL-induced inhibition of HSP70 in pancreatic tumors was mediated by its inhibition of the transcriptional activity of specific protein 1 (Sp1) (Banerjee et al., Biol Chem. 2013 Nov 22;288(47)).

[0005] Sp1 is a transcription factor that regulates multiple pro-survival pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and heat shock factor 1 (HSF1). Inhibition of Sp1 transcriptional activity downregulates NF-kB activity, thereby increasing apoptosis. Furthermore, studies have shown that the activation of HSF1 (a key transcription factor for HSP70) is also regulated via Sp1 and NF-kB activity.

[0006] In addition to affecting tumor cells, Minnelide also depleted the extracellular matrix (ECM) of pancreatic tumors by downregulating hyaluronan (HA) synthesis and preventing collagen cross-linking, which in turn improved vasculature and drug delivery to tumors.

[0007] Furthermore, TPL induces autophagic cell death in some tumor types, including the metastatic tumor lines S2-013, S2-VP10, and Hs766T. TPL-induced autophagy requires autophagy-specific genes (atg5 or beclin 1) and is associated with inactivation of the protein kinase B (Akt) / mammalian target of rapamycin / p70S6K pathway and upregulation of the extracellular signal-related kinase (ERK) 1 / 2 pathway.

[0008] The study showed that at a dose of 0.2 mg / kg, Minnelide disrupted transforming growth factor β (TGFβ) signaling in cancer-associated fibroblasts (CAFs), preventing tumor-stroma crosstalk and reducing tumorigenic signaling in tumor epithelial cells.

[0009] The tumor microenvironment in pancreatic ductal adenocarcinoma is highly heterogeneous, fibrotic, hypovascular, and characterized by extensive fibrosis, maintained by tumor cells, CAFs, and other stromal cells. A growing number of studies implicate the role of regulatory DNA elements called super-enhancers (SEs) in maintaining cell-type-specific gene expression networks in both normal and cancer cells.

[0010] Using chromatin activation marks, Noel et al. (Oncogenesis. 2020 Nov 9;9(11):100) first mapped the SE network in pancreatic CAFs and epithelial tumor cells and observed that they possess distinct SE profiles. Next, they investigated the role of TPL, a natural compound with antitumor activity, in modulating cell-type-specific SE signatures in pancreatic ductal adenocarcinoma (PDAC). They observed that TPL, which is cytotoxic to both pancreatic tumor cells and CAFs, disrupted SEs in a manner that resulted in the downregulation of SE-associated genes (e.g., BRD4, MYC, RNA Pol II, and collagen 1) in both cell types at the mRNA and protein levels. Their observations suggest that TPL acts as an SE interactor, eliciting its antitumor activity through SE disruption and potentially reprogramming cellular crosstalk and signaling in PDAC.

[0011] Based on those findings, epigenetic reprogramming of transcriptional regulation using SE-modulating compounds such as TPL may provide a means for effective treatment options for pancreatic cancer patients.

[0012] Despite the availability of antitumor agents, there is an urgent need to develop treatment strategies that can not only target tumor cells but also modulate stromal cells. Therefore, new therapeutic agents and treatment regimens that are well tolerated and more effective are desirable. Summary of the Invention

[0013] Minnelide™ (structure shown below) (when "activated" with alkaline phosphatase to release triptolide) has been determined to have potent antitumor activity against pancreatic and ovarian tumor cells in vitro, and when administered daily in models of pancreatic and ovarian cancer, markedly improved animal survival and significantly reduced tumor volume and tumor burden.

[0014] [ka]

[0015] Accordingly, the present disclosure provides a method for treating pancreatic cancer in a cancer-affected subject, comprising administering to the cancer patient during a 28-day cycle: a) about 0.25 mg to about 2.0 mg of Minnelide according to a first regimen administered once daily on days 1 to 5, 8 to 12, and 15 to 19 of the cycle; b) nab-paclitaxel approximately 75 mg / m according to a second regimen administered once daily on days 1, 8, and 15 of the cycle. 2 ~about 125mg / m 2 ; and c) gemcitabine approximately 600 mg / m according to the second regimen of this cycle 2 ~about 1000mg / m 2 administering a therapeutically effective combination of This cycle is repeated one or more times, and the combination effectively treats pancreatic cancer. A method is provided.

[0016] The described technology provides the use of the compositions described herein for use in medical therapy. The medical therapy can treat cancer, for example, breast cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer, or colon cancer. The present invention also provides the use of the compositions described herein for the manufacture of a medicament for treating a disease in a mammal, for example, cancer in a human. The medicament can include a pharmaceutically acceptable diluent, excipient, or carrier.

[0017] The following drawings form part of the present specification and are included to further demonstrate certain embodiments or various aspects of the present invention. In some cases, embodiments of the present invention may be best understood by reference to the accompanying drawings in combination with the detailed description presented herein. The specification and accompanying drawings may emphasize certain examples or certain aspects of the present invention. However, those skilled in the art will understand that some of the examples or aspects may be used in combination with other examples or aspects of the present invention. [Brief explanation of the drawings]

[0018] [Figure 1A-B] Mean tumor volume (A) and tumor burden (B) 28 days after initiation of once-daily oral treatment with gemcitabine / abraxane with or without minnelide in the orthotopic S2-VP10 pancreatic tumor model. DETAILED DESCRIPTION OF THE INVENTION

[0019] Preclinical studies of Minnelide were conducted in mice. Female athymic nude mice (NCI nu / nu; 4–6 weeks old) were anesthetized with xylazine / ketamine and implanted with S2-VP10 tumor cells embedded in Matrigel into the pancreatic tail (3 × 10 cells / mouse). Twelve days after tumor implantation (day 0), animals were randomized (10 animals / group) to receive saline, nab-paclitaxel plus gemcitabine (Gem / Abx; 250 / 25 mg / kg), or Minnelide plus nab-paclitaxel plus gemcitabine (Minn / Gem / Abx; 0.15 / 250 / 25 mg / kg or 0.21 / 250 / 25 mg / kg). Minnelide was administered once daily (QD) by oral gavage (PO). Treatment continued until day 28, at which time the animals were euthanized.

[0020] Treatment with Gem / Abx resulted in a reduction in tumor volume and tumor burden compared to saline-treated (vehicle) controls at day 28. The addition of Minnelide at doses of 0.15 mg / kg or 0.21 mg / kg further reduced tumor volume and tumor burden compared to Gem / Abx treatment alone (Figure 1).

[0021] Overall, in the orthotopic S2-VP10 pancreatic tumor model, daily oral treatment with Minnelide reduced tumor volume and tumor burden when administered concomitantly with Gem / Abx treatment compared with Minnelide or Gem / Abx treatment alone.

[0022] Additional information and data supporting the present invention can be found in U.S. Provisional Patent Application No. 63 / 489,205, filed March 9, 2023 by the inventors, and U.S. Patent Nos. 9,150,600 and 8,507,552, which applications and patents are incorporated herein by reference in their entireties.

[0023] definition The following definitions are included to provide a clear and consistent understanding of the specification and claims. As used herein, the described terms have the following meanings. All other terms and phrases used herein have their ordinary meanings as understood by those of ordinary skill in the art. Such ordinary meanings can be obtained by reference to a specialized dictionary, such as Hawley's Practical Dictionary of Chemistry, 14th Edition, by R.J. Lewis, John Wiley & Sons, New York, NY, 2001.

[0024] References herein to "one embodiment," "an embodiment," and the like indicate that the described embodiment may include a particular aspect, attribute, structure, portion, or feature, but not all embodiments necessarily include that aspect, attribute, structure, portion, or feature. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referenced elsewhere in this specification. Furthermore, when a particular aspect, attribute, structure, portion, or feature is described in connection with one embodiment, it is within the knowledge of one skilled in the art to extend or combine such aspect, attribute, structure, portion, or feature with other embodiments, whether or not explicitly stated.

[0025] 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 "a compound X" includes a plurality of compounds X. It is further noted that the claims may be drafted to exclude any and all optional elements. As such, this statement is intended to serve as a predicate based on the use of exclusive terminology, such as "solely," "only," etc., in connection with any element described herein and / or the use of a recitation or "negative" limitation of a claim element.

[0026] The term "and / or" means any one of the items, any combination of the items, or all of the items with which it 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 use. For example, the phrase can mean 1, 2, 3, 4, 5, 6, 10, 100, or any upper limit that is approximately 10-fold, 100-fold, or 1000-fold higher than the stated lower limit. For example, the number of substituents on a phenyl ring can be 1 to 5, or 1 to 4, for example, when the phenyl ring is disubstituted.

[0027] 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 approximations and, in some cases, are understood to be modified in all instances by the term "about." These values ​​may vary depending upon the desired properties one of ordinary skill in the art seeks to obtain using the teachings set forth herein. It is also understood that such values ​​inherently contain 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.

[0028] The terms "about" and "approximately" are used interchangeably. These two terms can refer to a variation of ±5%, ±10%, ±20%, or ±25% of the specified value. For example, "about 50" percent can, in some embodiments, retain a variation of 45 to 55 percent, or as otherwise defined by the particular claim. In integer ranges, the term "about" can include one or two integers greater than and / or less than the stated integer at either end of the range. Unless otherwise specified herein, the terms "about" and "approximately" are intended to include values, e.g., weight percent, proximate to the stated range that are equivalent in terms of the functionality of the individual component, composition, or embodiment. The terms "about" and "approximately" can also modify the endpoints of a stated range, as described earlier in this paragraph.

[0029] As will be understood by those skilled in the art, for all purposes, particularly in terms of providing a written description, all ranges stated herein also encompass any and all possible subranges and combinations of those subranges, as well as the individual values, particularly integers, comprising that range. Therefore, it is understood that each unit between two specific units is also disclosed. For example, if 10 to 15 is disclosed, 11, 12, 13, and 14 are also disclosed individually and as part of a range. A stated range (e.g., weight percent or carbon group) includes each specific integer, decimal, or unit within that range. Any stated range is fully described and readily recognizable as divisible into at least equal halves, thirds, quarters, fifths, or tenths of that same range. As a non-limiting example, each range discussed herein can be readily divided into a lower third, middle third, and upper third, etc. Also, as will be understood by those skilled in the art, all terms, such as "up to," "at least," "greater than," "less than," "more than," or "more than," are inclusive of the stated number, and such terms refer to ranges that can be subsequently divided into subranges as discussed above. Similarly, all ratios stated herein also include all subratios falling within the broader ratio. Thus, the specific values ​​stated for radicals, substituents, and ranges are exemplary only and do not exclude other defined values ​​for radicals and substituents or other values ​​within the defined ranges. Furthermore, it will be understood that both endpoints of each range are significant both in relation to and independently of the other endpoint.

[0030] The present disclosure provides ranges, limits, and deviations for variables, such as volume, mass, percentages, and ratios. It is understood by those of ordinary skill in the art that ranges such as "number 1" to "number 2" refer to continuous ranges of numbers, including integers and fractions. For example, 1 to 10 refers to 1, 2, 3, 4, 5, ..., 9, 10. This also refers to 1.0, 1.1, 1.2, 1.3, ..., 9.8, 9.9, 10.0, as well as 1.01, 1.02, 1.03, etc. When a disclosed variable is a number less than "number 10," this refers to a continuous range, including integers and fractions less than "number 10," as discussed above. Similarly, when a disclosed variable is a number greater than "number 10," this refers to a continuous range, including integers and fractions greater than "number 10." These ranges may be modified by the term "about," the meaning of which is defined above.

[0031] The enumeration of a), b), c), ... or i), ii), iii), etc. in a list of ingredients or steps does not imply any particular order unless explicitly stated.

[0032] Those skilled in the art will also readily recognize that when numbers are grouped together in a common manner, such as in a Markush group, the invention encompasses not only the entire group described as a whole, but also each individual member of the group and all possible subgroups of the main group. Moreover, regardless of its purpose, the invention encompasses not only the main group but also the absence of one or more group members from the main group. As such, the invention presumes the explicit exclusion of any one or more members of a stated group. Thus, exclusionary clauses may be applied to any of the disclosed categories or embodiments, whereby any one or more stated elements, species, or embodiments may be excluded from such category or embodiment, for example, for use in an explicit negative limitation.

[0033] The term "contacting" refers to the act of touching, coming into contact, abutting or bringing into close proximity, including at the cellular or molecular level, e.g., in solution, in a reaction mixture, in vitro, or in vivo, e.g., to cause a physiological response, a chemical reaction, or a physical change.

[0034] An "effective amount" refers to an amount effective to treat a disease, disorder, and / or condition or to cause a stated 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 symptoms of a disease or disorder in a host. Thus, an "effective amount" generally refers to an amount that provides a desired effect.

[0035] Alternatively, the term "effective amount" or "therapeutically effective amount," as used herein, refers 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. This may result in 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 necessary to provide a clinically significant reduction in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study. This dose may be administered in one or more administrations. However, the precise determination of what constitutes an effective amount may be based 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 replacement therapy used, ongoing disease course, and type of treatment desired (e.g., active vs. conventional therapy).

[0036] The terms "treating," "treat," and "treatment" include (i) preventing a disease, pathological condition, or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting or arresting the development of a disease, pathological condition, or medical condition; (iii) alleviating a disease, pathological condition, or medical condition; and / or (iv) alleviating symptoms associated with a disease, pathological condition, or medical condition. Thus, the terms "treat," "treatment," and "treating" can extend to prophylaxis and can include preventing, prophylaxis, preventing, lowering, stopping, or reversing the progression or severity of the condition or symptom being treated. Thus, the term "treatment" can include medical, therapeutic, and / or prophylactic administration, as appropriate.

[0037] As used herein, "subject" or "patient" refers to an individual who has or is at risk for a disease or other malignancy. A patient may be human or non-human and may include, for example, animal strains or species used as "model systems" for research purposes, such as the mouse model described herein. Similarly, a patient may include either an adult or a minor (e.g., a child). Furthermore, a patient may refer to any living 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: humans, non-human primates such as chimpanzees, and other ape and monkey species; domestic 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-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods provided herein, the mammal is a human.

[0038] As used herein, the terms "providing," "administering," and "introducing" are used interchangeably herein and refer to placing a compound of the present disclosure in a subject by a method or route that results in the compound being at least partially localized at a desired site. The compound may be administered by any suitable route that results in delivery to the desired location in the subject.

[0039] 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 drugs.

[0040] 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 growth or progression that occurs in the absence of treatment or contact.

[0041] 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 all, of what is specified. For example, the term may refer to a value that may not be 100% of the complete value. The complete 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.

[0042] Whenever the term "comprising" is used herein, the option of using the terms "consisting of" or "consisting essentially of" instead is contemplated. As used herein, "comprising" is synonymous with "including," "containing," 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," "consisting essentially of," and "consisting of" can be replaced with either of the other two terms. Illustratively, the present disclosure described herein may suitably be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein.

[0043] The term "adverse event" refers to any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered drug-related.

[0044] The term "serious adverse event" refers to death, a life-threatening adverse event, hospitalization or prolongation of an existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to perform normal life functions, or a congenital anomaly / birth defect. Significant medical events that do not result in death, are not potentially life-threatening, or do not require hospitalization may be considered serious if such medical events include allergic bronchospasm requiring intensive care in the emergency room or at home, blood disorders or seizures that do not result in hospitalization, or the development of drug dependence or abuse.

[0045] The term "regimen" refers to a series of medical treatments over a period of time. The regimens described herein include one or more sub-regimens, such as a first regimen, a second regimen, etc., that make up the overall medical treatment regimen. The duration of treatment can be one or more days, one or more weeks, one or more months, etc., and this period can be repeated cyclically one or more times. For example, the period can be 28 days, defining the length of the cycle that can be repeated. The regimen can be a 28-day cycle, with compound A being administered on a specific day of this cycle to define the first regimen, and compound B being administered on another specific day of this cycle to define the second regimen, which together define the overall regimen.

[0046] The IUPAC chemical name for the compound MINNELIDE or Minnelide™ drug is 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. Minnelide and other pharmaceutically acceptable salt forms thereof are referred to herein as Compound 1.

[0047] Classification of adverse events by severity. The severity of each adverse event (AE) follows the guidelines of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). A brief summary is given below: Grade 1: An AE that is transient or mild discomfort and does not interfere with the patient's ability to perform daily activities or function; medical intervention / treatment may be required. Grade 2: An AE that is sufficiently severe to potentially cause the patient moderate discomfort; possibly affects the patient's ability to perform daily activities or function; generally does not impair the patient's ability to continue in the study; and / or possibly requires therapeutic intervention. Grade 3: An AE event that generally causes severe discomfort, significantly affects the patient's ability to perform daily activities or function, generally requires a change or discontinuation of the study drug dose, and / or generally requires therapeutic intervention with the possibility of hospitalization. Grade 4: An AE that is considered life-threatening and represents the worst possible outcome of the event, resulting in significant impairment or incapacity and / or potential hospitalization. Grade 5: Death related to an AE.

[0048] An embodiment of the technology. The present disclosure provides a method for treating cancer in a subject suffering from cancer, comprising administering to the cancer patient during a 28 day cycle: a) about 0.25 mg to about 2.0 mg of Minnelide according to a first regimen administered once daily on days 1 to 5, 8 to 12, and 15 to 19 of the cycle; b) nab-paclitaxel approximately 75 mg / m according to a second regimen administered once daily on days 1, 8, and 15 of the cycle. 2 ~about 125mg / m 2 ; and c) gemcitabine approximately 600 mg / m according to the second regimen of this cycle 2 ~about 1000mg / m 2 administering a therapeutically effective combination of This cycle is repeated one or more times, and the combination effectively treats the cancer. A method is provided.

[0049] In various embodiments, a subject with cancer is administered about 0.25 mg to about 1.00 mg of Minnelide according to a first regimen. In various embodiments, according to the first regimen, a subject suffering from cancer is administered a milligram amount of Minnelide 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.

[0050] In various embodiments, the cancer-afflicted subject is administered about 50 mg / m paclitaxel according to the second regimen. 2 ~about 100mg / m 2 In various embodiments, according to the second regimen, the cancer-afflicted subject is administered about 5 mg / m 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 / m 2, 125 mg / m 2 , 150 mg / m 2 , 175 mg / m 2 , or approximately 200 mg / m 2 milligrams of paclitaxel is administered.

[0051] In some embodiments, a subject suffering from cancer is administered about 0.25 mg of Minnelide according to a first regimen and about 75 mg / m of nab-paclitaxel according to a second regimen. 2 and gemcitabine approximately 600 mg / m 2 is administered.

[0052] In some embodiments, a subject suffering from cancer is administered about 0.25 mg of Minnelide according to a first regimen and about 100 mg / m nab-paclitaxel according to a second regimen. 2 and gemcitabine approximately 800 mg / m 2 is administered.

[0053] In some embodiments, a subject suffering from cancer is administered about 0.25 mg of Minnelide according to a first regimen and about 125 mg / m of nab-paclitaxel according to a second regimen. 2 and gemcitabine approximately 1000 mg / m 2 is administered.

[0054] In some embodiments, a subject suffering from cancer is administered about 0.50 mg of Minnelide according to a first regimen and about 125 mg / m of nab-paclitaxel according to a second regimen, respectively. 2 and gemcitabine approximately 1000 mg / m 2 is administered.

[0055] In some embodiments, a subject suffering from cancer is administered about 0.75 mg of Minnelide according to a first regimen and about 125 mg / m of nab-paclitaxel according to a second regimen, respectively. 2 and gemcitabine approximately 1000 mg / m 2 is administered.

[0056] In some embodiments, a subject suffering from cancer is administered about 1.00 mg of Minnelide according to a first regimen and about 125 mg / m of nab-paclitaxel according to a second regimen. 2 and gemcitabine approximately 1000 mg / m 2 is administered.

[0057] In some embodiments, a subject suffering from cancer is administered about 1.25 mg of Minnelide according to a first regimen and about 125 mg / m of nab-paclitaxel according to a second regimen. 2 and gemcitabine approximately 1000 mg / m 2 is administered.

[0058] In some embodiments, a subject suffering from cancer is administered about 1.50 mg of Minnelide according to a first regimen and about 125 mg / m of nab-paclitaxel according to a second regimen. 2 and gemcitabine approximately 1000 mg / m 2 is administered.

[0059] In some embodiments, a subject suffering from cancer is administered about 1.75 mg of Minnelide according to a first regimen and about 125 mg / m of nab-paclitaxel according to a second regimen. 2 and gemcitabine approximately 1000 mg / m 2 is administered.

[0060] In some embodiments, a subject suffering from cancer is administered about 2.00 mg of Minnelide according to a first regimen and about 125 mg / m of nab-paclitaxel according to a second regimen. 2 and gemcitabine approximately 1000 mg / m 2 is administered.

[0061] In some embodiments, a subject suffering from cancer is administered about 1.25 mg of Minnelide according to a first regimen and about 125 mg / m of nab-paclitaxel according to a second regimen. 2 and gemcitabine at approximately 1000 mg / m2.

[0062] In some embodiments, a subject suffering from cancer is administered about 1.50 mg of Minnelide according to a first regimen and about 125 mg / m of nab-paclitaxel according to a second regimen. 2 and gemcitabine approximately 1000 mg / m 2 is administered.

[0063] In some embodiments, a subject suffering from cancer is administered about 1.75 mg of Minnelide according to a first regimen and about 125 mg / m of nab-paclitaxel according to a second regimen. 2 and gemcitabine approximately 1000 mg / m 2 is administered.

[0064] In some embodiments, a subject suffering from cancer is administered about 2.00 mg of Minnelide according to a first regimen and about 125 mg / m of nab-paclitaxel according to a second regimen. 2 and gemcitabine approximately 1000 mg / m 2 is administered.

[0065] In some embodiments, Minnelide is administered orally. In some embodiments, Minnelide is administered intravenously. In various embodiments, nab-paclitaxel is administered intravenously or orally. In various embodiments, gemcitabine is administered intravenously or orally. In various embodiments, nab-paclitaxel is administered intravenously simultaneously with or sequentially to gemcitabine. In various embodiments, gemcitabine is administered intravenously simultaneously with or sequentially to nab-paclitaxel.

[0066] In various embodiments, the cancer is gastric cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, skin cancer, or a combination thereof. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the method effectively treats a cancer-affected subject who is suffering from or suffering from gastric cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, skin cancer, or a combination thereof.

[0067] In various embodiments, the cancer-afflicted subject is a human. In various embodiments, the cancer-afflicted subject is a female human or a male human.

[0068] In various embodiments, the combination effectively treats cancer without causing a decrease in the complete blood count of the cancer subject by 25%, 20%, 15%, 10%, or 5% or more from baseline. In various embodiments, the combination effectively treats cancer without causing a decrease in the platelet count or absolute neutrophil count of the cancer subject by 25%, 20%, 15%, 10%, or 5% or more from baseline.

[0069] In some embodiments, the methods described herein are used to treat cancers that have become refractory or that are resistant or unresponsive to other cancer therapies. In some embodiments, the pancreatic cancer is a cancer that has become refractory, resistant, or unresponsive to other cancer therapies. In some embodiments, the pancreatic cancer is metastatic adenocarcinoma of the pancreas.

[0070] Clinical experience. Intravenous Minnelide. A Phase 1, multicenter, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of Minnelide administered intravenously daily for 21 days, followed by a 7-day rest period, in patients with advanced GI tumors. A second dosing schedule of Minnelide administered intravenously QD for 5 days, followed by a 2-day rest period for 3 weeks, followed by a 7-day rest period, was also investigated during this study.

[0071] A total of 45 patients were enrolled in the phase 1 trial, but three patients did not receive the study drug. The remaining 42 patients received treatment in the study. The primary reason for treatment discontinuation was disease progression. Six deaths occurred in the study after study drug completion and occurred within the 30-day follow-up period. Deaths occurring in the study were not found to be related to the study drug but were instead related to the progression of the patient's disease (pancreatic / gastric cancer). One patient died from respiratory failure, which was also not found to be related to the use of the study drug.

[0072] Three patients discontinued the study drug due to treatment-emergent adverse events (TEAEs). All cases were considered grade 3, and two of these TEAEs were considered possibly related to the use of the 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 the study drug.

[0073] Overall, 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.

[0074] A total of 32 patients had at least one AE considered related to the study drug. Short-lasting grade 3 and 4 neutropenic adverse events were observed at all dose levels and were determined to be drug-related. Neutropenia resolved during the treatment-free period of several days. Neutropenic 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 possibly related to the drug included nausea, vomiting, diarrhea, constipation, anorexia, stomatitis, cerebellar toxicity, embolism, and dyspnea of ​​any grade and occurred in ≤3% of patients.

[0075] Oral Minnelide. A Phase 1, multicenter, open-label, dose-escalation safety pharmacokinetic and pharmacodynamic study of Minnelide™ capsules administered alone or in combination with protein-bound paclitaxel in patients with advanced solid tumors.

[0076] A total of 51 patients were enrolled and dosed in the Phase 1 study, of which 44 were evaluable for safety (34 in the monotherapy regimen and 16 in the combination regimen). Twenty-nine patients completed treatment in the monotherapy regimen, with six dose escalations occurring. One DLT was observed in the monotherapy regimen, which occurred in the 1.25 mg cohort. This patient did not fully complete cycle 1 dosing and later died of grade 5-associated sepsis. As a result of this DLT, out of an abundance of caution, three additional patients were enrolled in the 1.0 mg cohort.

[0077] A total of 45 SAEs occurred in 25 patients, 8 of which were found to be related to the investigational drug (IP): one each of grade 5 sepsis, grade 4 sepsis, grade 3 nausea, grade 3 polymicrobial bacteremia, grade 3 refractory nausea, grade 3 hypokalemia, and grade 2 enterocolitis in patients receiving monotherapy; and one each of grade 5 sepsis and grade 2 esophagitis in patients receiving combination therapy.

[0078] A total of 17 patients were enrolled in the combination therapy regimen. Two DLTs occurred: Minnelide 0.25 mg and protein-bound paclitaxel 125 mg / m 2 and one study at a dose level of 0.25 mg Minnelide and 100 mg / m protein-bound paclitaxel. 2One event was observed at the dose level of 100 mg / m. One patient did not fully complete cycle 1 dosing and was hospitalized with unrelated influenza A. This patient also presented with a grade 4 decrease in lymphocytes that may have been related to IP. A total of two SAEs occurred in this patient, neither of which was determined to be related to IP. Because this patient was the first patient on a combination regimen receiving protein-bound paclitaxel with Minnelide, enrollment in this combination regimen was withheld until further dose escalation parameters were implemented. A second DLT: a grade 5 event of sepsis occurred at the dose level of Minnelide 0.25 mg and protein-bound paclitaxel 100 mg / m. 2 This occurred in the first patient in the cohort. Five additional patients received Minnelide 0.25 mg and protein-bound paclitaxel 100 mg / m 2 No DLTs were observed in the cohort.

[0079] Summary of Adverse Events. Overall, the most commonly reported AEs (incidence >10%), regardless of causality, included: anemia (18%), neutropenia (30%), leukopenia (12%), abdominal distension (12%), abdominal pain (30%), constipation (24%), vomiting (18%), gastroesophageal reflux disease (12%), nausea (24%), lower extremity edema (24%), pyrexia (24%), fatigue (18%), chills (12%), local swelling (18%), pain (12%), dehydration (18%), back pain (12%), dizziness (12%), dyspnea (12%), pleural effusion (12%), dermatitis (12%), and neutrophil count decreased (13%).

[0080] Study design. In an open-label Phase 1b study, Minnelide was administered once daily on days 1-5, 8-12, and 15-19 in combination with nab-paclitaxel (Abraxane) and gemcitabine, administered intravenously on days 1, 8, and 15, once weekly for 3 weeks, according to Table 1 in the Examples. This study was conducted in patients who had disease progression during first-line FOLFIRINOX and had not previously been treated with nab-paclitaxel (Abraxane) and gemcitabine, or nab-paclitaxel or gemcitabine alone or in any other combination. The total number of treatment cycles administered was determined according to the patient's drug tolerability. Approximately 36 patients were enrolled in this study. Approximately 18 patients were enrolled at the MTD dose.

[0081] Dose-Limiting Toxicity. Dose-limiting toxicities (DLTs) were assessed during treatment cycle 1. Toxicity was assessed and recorded according to the NCI CTCAE guidelines (briefly defined above). No dose reductions were allowed during cycle 1. DLTs included: Grade 4 neutropenia lasting ≥5 days, Grade 4 neutropenia with growth factor use, or Grade 3 or 4 neutropenia with 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 >72 hours despite maximal therapy constitutes 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 investigational drug, including:

[0082] Inclusion criteria for study eligibility. Patients must meet the inclusion criteria listed below: • Signed, written, IRB-approved informed consent. Patients diagnosed with histologically confirmed metastatic adenocarcinoma of the pancreas and concomitant adenocarcinoma and adenosquamous carcinoma will be allowed, but patients with pure adenosquamous carcinoma will be excluded. Tumor progression after standard / approved chemotherapy or in the absence of approved treatment. ●The patient had disease progression on FOLFIRINOX as first-line treatment. No prior treatment with nab-paclitaxel (Abraxane) plus gemcitabine or nab-paclitaxel or gemcitabine alone or in any other combination. Patients who have received any killed vaccine, including influenza, pneumococcal, or COVID-19, prior to or scheduled to receive it during the study are permitted, but not those receiving any live vaccine, such as shingles. • One or more metastatic tumors measurable by computed tomography (CT) scan according to Response Evaluation Criteria in Solid Tumors (RECIST) V1.1, excluding the primary pancreatic lesion. Karnofsky Performance Score: 70% (Able to care for self, but unable to continue normal activities or perform active work). • Life expectancy of at least 3 months. ●Age ≥ 19 years old. ●Negative pregnancy test (for women). 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 (ALP) of ≤2.5 × ULN (≤5 × ULN is acceptable if liver metastases are present). · Albumin ≥ 3.0 g / dL. Acceptable renal function: ≥ 60 mL / min / 1.73 m in patients with serum creatinine within the normal range or creatinine levels above normalized normal values 2Calculated creatinine clearance. Acceptable hematological status: · Baseline absolute neutrophil count (ANC) of ≥ 2000 cells / mm3. ≥100,000 (plt / mm 3 ) platelet count. · Hemoglobin ≥ 9g / dL. ●Urine test: No clinically significant abnormalities. Acceptable coagulation conditions: · Prothrombin time (PT) of ≤1.5 times the normalized ULN. · Partial thromboplastin time (PTT) ≤ 1.5 times the normalized ULN. · ≤ 1.5 × normalized international normalized ratio (INR) of ULN. Men and women of childbearing potential must use effective contraception during this study. From the last dose, effective contraception should be maintained as follows: Men: 100 days after the last dose of Minnelide. Women of childbearing potential: 6 months after the last dose of Minnelide. For women, agree to use two physician-approved methods of contraception (oral, injectable, or implantable hormonal contraceptives; tubal ligation; intrauterine device; barrier contraception using spermicide; or a vasectomized partner) during the study IP; and for 3 months after the last dose of IP. • A negative serum pregnancy test (β-hCG) result at screening. For men, even if they have successfully undergone a vasectomy, they must either practice true abstinence or agree to use condoms during sexual contact with pregnant or potentially pregnant women while they are involved in the study, during any treatment interruptions, and for 6 months after IP discontinuation.

[0083] Minnelide administration was discontinued. Decreases in blood counts are usually observed within the first 5 to 7 days of starting Minnelide treatment and resolve within 4 to 8 days of stopping Minnelide treatment.

[0084] CBC with differential was performed on days 1, 8, 15, and 22, and more frequently if clinically indicated. ANC levels <1000mm 3 (Grade 3 or more severe) or platelet count <100,000 cells / mm 3 If ANC levels were ≥ 1500 mmHg, the patient was admitted to the hospital for close monitoring. 3 or platelet cell count ≥ 100,000 cells / mm 3 It didn't resume until

[0085] The following examples are intended to illustrate the above invention and should not be construed as narrowing its scope. Those skilled in the art will readily recognize that the examples suggest many other ways in which the invention can be practiced. It should be understood that numerous variations and modifications may be made while remaining within the scope of the invention.

[0086] Example Example 1. Treatment regimen. Minnelide was administered orally once daily on days 1-5, 8-12, and 15-19. Nab-paclitaxel (Abraxane) plus gemcitabine was administered IV on days 1, 8, and 15 once weekly for 3 weeks according to the dose escalation schedule in Table 1. One cycle corresponds to 28 days. Patients were administered Minnelide™ capsules in the fasting state.

[0087] Three patients were treated at dose level 1. If no patients experienced CTCAE version 5.0 grade 3 or higher toxicity after a minimum of 3 weeks of treatment, dose escalation proceeded to dose level 2.

[0088] If a DLT was observed in 1 of 3 patients at any dose level, up to 3 additional patients were enrolled and treated at that dose level. If 2 patients had a DLT at that dose level, the dose was halved. If 1 of 6 patients had a DLT, this dose was increased to the second dose level. If 2 or more of up to 6 patients had a DLT at the second dose level, the previous dose (dose level 1) was declared the maximum tolerated dose (MTD). If 1 or fewer of 6 patients had a DLT, dose level 2 was declared the MTD.

[0089] [Table 1]

[0090] Example 2. Disease assessment. Target Lesions. Response criteria for target lesions are shown in Table 2. All measurable lesions, up to two per organ, for a total of five lesions representing all involved organs, were identified, recorded, and measured at baseline. Target lesions were selected based on their size (lesion with the longest diameter), which represented all involved organs, and which demonstrated suitability for reproducible repeated measurements. When clinically assessed, all measurements were recorded using calipers.

[0091] The sum of the diameters (longest diameter for non-nodal lesions and short axis for nodal lesions) for all target lesions was calculated and reported as the baseline sum diameter, which was used as a reference to further characterize any objective tumor regression in the measurable dimension of disease. When lymph nodes were included in the sum, only the short axis contributed.

[0092] [Table 2]

[0093] While specific embodiments have been described above with reference to embodiments and examples of the present disclosure, such embodiments are merely illustrative and do not limit the scope of the present invention. Modifications and variations can be made by those skilled in the art without departing from the invention in its broader aspects, as defined in the following claims.

[0094] 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 may be made while remaining within the spirit and scope of the invention.

Claims

1. A composition for use in a method for treating pancreatic cancer in cancer patients, The composition comprises minneride or triptolide, nab-paclitaxel, and / or gemcitabine. The above method involves the cancer patient being subjected to the above method during a 28-day cycle. a) Minneride or triptolide, approximately 0.15 mg to approximately 2.0 mg, administered once daily on days 1-5, 8-12, and 15-19 of the cycle; b) Nab-paclitaxel approximately 40 mg / m² according to a second regimen administered once daily on days 1, 8, and 15 of the cycle. ２ ~Approx. 125mg / m ２ ; and c) Gemcitabine approximately 600 ± 25% mg / m² according to the second regimen of the period described above. ２ ~Approx. 1000mg / m ２ The step includes administering a therapeutically effective combination of the following: The aforementioned cycle is repeated once or more times, and the aforementioned combination effectively treats the pancreatic cancer. composition.

2. The composition according to claim 1, wherein the cancer patient is administered about 0.25 mg to about 1.00 mg of minneride or triptolide in accordance with the first regimen.

3. To the aforementioned cancer patients, approximately 0.25 mg of minneride or triptolide according to the first regimen, and approximately 75 mg / m² of nab-paclitaxel according to the second regimen. ２ and gemcitabine approximately 600 mg / m² ２ The composition according to claim 1, wherein the agent is administered.

4. To the aforementioned cancer patients, approximately 0.25 mg of minneride or triptolide according to the first regimen, and approximately 100 mg / m² of nab-paclitaxel according to the second regimen. ２ and gemcitabine approximately 800 mg / m² ２ The composition according to claim 1, wherein the agent is administered.

5. The cancer patient is administered with about 0.25 mg of minnelide or triptolide according to the first regimen, and about 125 mg / m of nab-paclitaxel and about 1000 mg / m of gemcitabine respectively according to the second regimen. ２ ２ The composition according to claim 1, wherein the administration is carried out.

6. To the aforementioned cancer patients, approximately 0.50 mg of minneride or triptolide according to the first regimen, and approximately 125 mg / m² of nab-paclitaxel according to the second regimen. ２ and gemcitabine approximately 1000 mg / m² ２ The composition according to claim 1, wherein the agent is administered.

7. To the aforementioned cancer patients, approximately 0.75 mg of minneride or triptolide according to the first regimen, and approximately 125 mg / m² of nab-paclitaxel according to the second regimen. ２ and gemcitabine approximately 1000 mg / m² ２ The composition according to claim 1, wherein the agent is administered.

8. To the aforementioned cancer patients, approximately 1.00 mg of minneride or triptolide according to the first regimen, and approximately 125 mg / m² of nab-paclitaxel according to the second regimen. ２ and gemcitabine approximately 1000 mg / m² ２ The composition according to claim 1, wherein the agent is administered.

9. The composition according to claim 1, wherein the cancer patient is administered about 0.50 mg of minneride or triptolide according to the first regimen, and about 80 mg / m² of nab-paclitaxel and about 800 mg / m² of gemcitabine, respectively, according to the second regimen.

10. The composition according to claim 1, wherein the cancer patient is administered about 0.50 mg of minneride or triptolide according to the first regimen, and about 100 mg / m² of nab-paclitaxel and about 800 mg / m² of gemcitabine, respectively, according to the second regimen.

11. The composition according to claim 1, wherein the cancer patient is administered about 0.50 mg of minneride or triptolide according to the first regimen, and about 125 mg / m² of nab-paclitaxel and about 800 mg / m² of gemcitabine, respectively, according to the second regimen.

12. The composition according to any one of claims 1 to 11, wherein minneride or triptolide is administered orally.

13. The composition according to any one of claims 1 to 11, wherein nab-paclitaxel is administered intravenously simultaneously with or consecutively with gemcitabine.

14. The composition according to any one of claims 1 to 11, wherein the subject is further suffering from gastric cancer, ovarian cancer, breast cancer, bladder cancer, skin cancer, or a combination thereof, and the method effectively treats the subject suffering from the cancer.

15. The composition according to any one of claims 1 to 11, wherein the subject suffering from cancer is a human.

16. The composition according to any one of claims 1 to 11, wherein the combination effectively treats pancreatic cancer without causing a decrease of 25% or more in the total blood count of the cancer patient from baseline.

17. The composition according to any one of claims 1 to 11, wherein the combination effectively treats pancreatic cancer without reducing the platelet count or absolute neutrophil count in the cancer patient by 25% or more from baseline.

18. The composition according to any one of claims 1 to 11, wherein the pancreatic cancer is metastatic adenocarcinoma of the pancreas.

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