Patent Description:
Triptolide, a diterpene isolated from a Chinese medicinal herb, has potent antitumor, immunosuppressive, and anti-inflammatory properties. However, its clinical potential is greatly hampered by limited aqueous solubility and oral bioavailability, and multi-organ toxicity. The prodrug Minnelide™ (<NUM>-O-phosphonooxymethyltriptolide disodium salt) is a prodrug that is rapidly converted to triptolide when exposed to phosphatases in the bloodstream. Minnelide prodrug has greater aqueous solubility and less organ toxicity than triptolide. Triptolide has been shown to inhibit tumor cell proliferation and induce apoptosis in vitro and in animal models of cancer, including human mammary tumors (<NPL>), cholangio-carcinoma cells (<NPL>), xenografts of several different tumor types, including melanoma, breast cancer, bladder cancer, gastric carcinoma (<NPL>), pancreatic tumors (<NPL>) and neuroblastoma (<NPL>). The greater aqueous solubility of minnelide prodrug compared to triptolide is beneficial for controlling the dosage and safety of the drug.

The antitumor effect of triptolide is the result of inhibition of heat shock protein (HSP)<NUM> expression in tumor cells and induction of apoptosis. While the mechanism of action of triptolide inhibition of HSP70 expression has not been fully elucidated, it has been shown to induce caspase activation (<NPL>; <NPL>; <NPL>; <NPL>).

In gastric cancer, triptolide has been shown to inhibit cell growth and induce apoptosis by stimulating the expression of p53 and p21 (waf1/cip1) (<NPL>). Triptolide was also shown to be effective in inhibiting colony formation as well as tumor regression in animal models (<NPL>). Other studies have also shown that triptolide inhibits NF-kB in gastric cancer thereby inducing cell death (<NPL>). Minnelide prodrug, the water-soluble prodrug of triptolide, inhibits Sp1 to decrease HSP70 and induce cell death in gastric cancer cell lines MKN28 and MKN45 (<NPL>). Sp1 is a transcription factor that regulates a number of pro-survival pathways like HSF1. Inhibition of Sp1 transcriptional ability downregulates HSF1 activity thereby decreasing HSP70 and inducing cell death (<NPL>).

Minnelide prodrug, when "activated" by concurrent incubation with alkaline phosphatase, was determined to be as potent as triptolide with respect to decreasing viability of pancreatic tumor cell lines in vitro. "Activated" minnelide prodrug also reduced the proliferation of ovarian carcinoma cells in vitro in a concentration-dependent manner (<NUM>-<NUM>). Daily intraperitoneal administration of minnelide prodrug at a dose of both <NUM>/kg as well as <NUM>/kg resulted in markedly decreased tumor weights and volumes in subcutaneous gastric cancer models using cell lines MKN45, MKN28I-N-<NUM>.

Combination therapy is a therapeutic intervention in which more than one therapy is administered to a patient. Examples of combination therapy include treatment regimens that involve administering several separate pills, each containing a particular drug, or single pills that contain several drugs. For example, immunotherapy plus chemotherapy. One example is to treat breast or pancreatic cancer with a mix of immunotherapy and chemotherapy drugs such as cisplatin and taxol. A combination of <NUM>/kg minnelide prodrug with <NUM>/kg irinotecan was found to be more effective in regressing subcutaneous NCO-N-<NUM> tumors compared to either drug alone in mouse model of gastric cancer.

Taken together, the results of the minnelide prodrug pharmacology program demonstrate that minnelide prodrug has potent antitumor activity against pancreatic, gastric and ovarian tumor cells in vitro (when "activated" with alkaline phosphatase to release triptolide) and markedly improved animal survival and significantly reduced tumor volumes and weights when administered by the oral or IP route either alone or in combination with various "standard of care" agents in models of pancreatic and ovarian cancer. These results support the rationale for evaluation of minnelide prodrug in cancer patients as an individual agent or in combination with other therapies.

As clinical development of minnelide prodrug was initiated using an intravenous drug product, IND-enabling toxicology 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 minnelide prodrug to patients with advanced solid tumors. To support the clinical development of a new solid oral dosage form of minnelide prodrug (capsules), exploratory and definitive toxicity studies were conducted with minnelide prodrug in solution via oral gavage in dogs. Taken together, the results of the intravenous and oral toxicity studies conducted with minnelide prodrug indicate that the target organ profile of minnelide prodrug is consistent in both species (rats and dogs) when administered by either route of administration (intravenous or oral). In each definitive toxicity study conducted with minnelide prodrug, adverse, largely irreversible histopathological effects were noted in reproductive tract tissues of both males and females. Additional effects on primary and/or secondary lymphoid tissues were noted in some studies. No adverse histopathological effects were noted on the gastrointestinal tract of dogs administered minnelide prodrug via oral gavage for up to <NUM> consecutive days.

While oral minnelide prodrug is easier to administer than intravenous formulations, it continues to have toxicities at high doses (thus, a dose limiting toxicity (DLT)) and side effects at high dose levels. Accordingly, there is a need for safer ways to administer minnelide prodrug and a need for other drug combination therapies with minnelide prodrug that enhance the effectiveness of the combination therapy, while limiting the toxicity of individual drugs used in the therapy. Furthermore, despite the availability of known antitumor agents, there continues to be a need for novel treatment regimens that are more effective and better tolerated by patients.

JEEYUN LEE: "Phase I study of Minnelide and paclitaxel combination chemotherapy in refractory gastric cancer (GC). ", <NPL>, discloses a phase <NUM> trial aimed at determining the maximum tolerated dose (MTD) of minnelide as a monotherapy and in combination with paclitaxel for patients with refractory gastric cancer (GC). Minnelide is administered once per day on days <NUM> to <NUM> of the <NUM>-day treatment cycle.

Any subject-matter falling outside the scope of the claims is provided for information purposes, only. The references to methods of treatment in this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy.

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 markedly improved animal survival and significantly reduced tumor volumes and weights when administered daily in models of pancreatic and ovarian cancer. <CHM>
<CHM>.

Gastric cancer is the most prevalent cancer in South Korea and worldwide. Minnelide prodrug has shown effectiveness in various cancers, including gastric cancer, in several pre-clinical models and in human trials in the United States. Minnelide prodrug in combination with paclitaxel has shown significant antitumor activity in pre-clinical models of pancreatic cancers and in ongoing US clinical trial in pancreatic and breast cancers. Herein, we have evaluated efficacy of minnelide prodrug in combination with paclitaxel in a subcutaneous mouse model of gastric cancer and in a human clinical trial. The results indicate that minnelide prodrug and paclitaxel alone or in combination have no significant toxic effects when properly dosed, and treating mice with a combination of low doses of minnelide prodrug and paclitaxel results in a significant decrease in tumor burden as compared to minnelide prodrug or paclitaxel alone. Further analysis of the tumors showed that the combination therapy was not only successful in reducing tumor growth, but also promotes tumor shrinkage in the animal models used in the study. The study therefore demonstrates that a combination of minnelide prodrug and paclitaxel, properly dosed, is an effective therapy for gastric cancer.

Accordingly, this disclosure provides a method for treating gastric cancer in a cancer patient, the method comprising administering to the cancer patient during a <NUM> day cycle a therapeutically effective combination of:.

wherein the <NUM>-day cycle is repeated one or more times, and the combination effectively treats the gastric cancer.

The medicament can include a pharmaceutically acceptable diluent, excipient, or carrier.

The following drawings form part of the specification and are included to further demonstrate certain embodiments or various aspects of the invention. In some instances, embodiments of the 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 a certain specific example, or a certain aspect of the invention.

Only regimen C forms part of the present invention. Regimens A and B are reference examples.

The results of the current studies indicate that combination therapy of low dose minnelide prodrug and paclitaxel (standard of care dose of the drug) was unexpectedly synergistic in reducing the tumor growth as compared to the single agent in the mouse model of gastric cancer (<FIG>). Further analysis of the tumors showed that the combination therapy was not only successful in reducing tumor growth but also promotes tumor shrinkage in the animal models used in the study. Therefore, these studies show that a combination of minnelide prodrug and paclitaxel is an effective therapy for cancers, particularly gastric cancer.

Additional information and data supporting the invention can be found in <CIT>) and <CIT>).

The following definitions are included to provide a clear and consistent understanding of the specification and claims. As used herein, the recited terms have the following meanings. All other terms and phrases used in this specification have their ordinary meanings as one of skill in the art would understand. Such ordinary meanings may be obtained by reference to technical dictionaries, such as <NPL>.

References in the specification to "one embodiment", "an embodiment", etc., indicate that the embodiment described may include a particular aspect, feature, structure, moiety, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, moiety, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, moiety, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to affect or connect such aspect, feature, structure, moiety, or characteristic with other embodiments, whether or not explicitly described.

The singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds, so that a compound X includes a plurality of compounds X. As such, this statement is intended to serve as antecedent basis for the use of exclusive terminology, such as "solely," "only," and the like, in connection with any element described herein, and/or the recitation of claim elements or use of "negative" limitations.

The term "and/or" means any one of the items, any combination of the items, or all of the items with which this term is associated. The phrases "one or more" and "at least one" are readily understood by one of skill in the art, particularly when read in context of its usage. For example, the phrase can mean one, two, three, four, five, six, ten, <NUM>, or any upper limit approximately <NUM>, <NUM>, or <NUM> times higher than a recited lower limit. For example, one or more substituents on a phenyl ring refers to one to five, or one to four, for example if the phenyl ring is disubstituted.

As will be understood by the skilled artisan, all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term "about. " These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability resulting from the standard deviations 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.

The terms "about" and "approximately" are used interchangeably. Both terms can refer to a variation of ± <NUM>%, ± <NUM>%, ± <NUM>%, or ± <NUM>% of the value specified. For example, "about <NUM>" percent can in some embodiments carry a variation from <NUM> to <NUM> percent, or as otherwise defined by a particular claim. For integer ranges, the term "about" can include one or two integers greater than and/or less than a recited integer at each end of the range. Unless indicated otherwise herein, the terms "about" and "approximately" are intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, composition, or embodiment. The terms "about" and "approximately" can also modify the endpoints of a recited range as discussed above in this paragraph.

As will be understood by one 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 sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. It is therefore understood that each unit between two particular units are also disclosed. For example, if <NUM> to <NUM> is disclosed, then <NUM>, <NUM>, <NUM>, and <NUM> are also disclosed, individually, and as part of a range. A recited range (e.g., weight percentages or carbon groups) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art, all language such as "up to", "at least", "greater than", "less than", "more than", "or more", and the like, include the number recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio. Accordingly, specific values recited for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents.

This disclosure provides ranges, limits, and deviations to variables such as volume, mass, percentages, ratios, etc. It is understood by an ordinary person skilled in the art that a range, such as "number1" to "number2", implies a continuous range of numbers that includes the whole numbers and fractional numbers. For example, <NUM> to <NUM> means <NUM>, <NUM>, <NUM>, <NUM>, <NUM>,. <NUM>, <NUM>. It also means <NUM>, <NUM>, <NUM>. , <NUM>, <NUM>, <NUM>, and also means <NUM>, <NUM>, <NUM>, and so on. If the variable disclosed is a number less than "number10", it implies a continuous range that includes whole numbers and fractional numbers less than number10, as discussed above. Similarly, if the variable disclosed is a number greater than "number10", it implies a continuous range that includes whole numbers and fractional numbers greater than number10. These ranges can be modified by the term "about", whose meaning has been described above.

The recitation of a), b), c),. or i), ii), iii), or the like in a list of components or steps do not confer any particular order unless explicitly stated.

One skilled in the art will also readily recognize that where members are grouped together in a common manner, such as in a Markush group, the invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the invention encompasses not only the main group, but also the main group absent one or more of the group members. The invention therefore envisages the explicit exclusion of any one or more of members of a recited group. Accordingly, provisos may apply to any of the disclosed categories or embodiments whereby any one or more of the recited elements, species, or embodiments, may be excluded from such categories or embodiments, for example, for use in an explicit negative limitation.

The term "contacting" refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e.g., in a solution, in a reaction mixture, in vitro, or in vivo.

An "effective amount" refers to an amount effective to treat a disease, disorder, and/or condition, or to bring about a recited effect. For example, an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art. The term "effective amount" is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host. Thus, an "effective amount" generally means an amount that provides the desired effect.

Alternatively, the terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of an agent or a composition or combination of compositions being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be 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 uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study. The dose could be administered in one or more administrations. However, the precise determination of what would be considered an effective dose may be based on factors individual to each patient, including, but not limited to, the patient's age, size, type or extent of disease, stage of the disease, route of administration of the compositions, the type or extent of supplemental therapy used, ongoing disease process and type of treatment desired (e.g., aggressive vs. conventional treatment).

The terms "treating", "treat" and "treatment" include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and/or (iv) diminishing symptoms associated with the disease, pathologic or medical condition. Thus, the terms "treat", "treatment", and "treating" can extend to prophylaxis and can include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated. As such, the term "treatment" can include medical, therapeutic, and/or prophylactic administration, as appropriate.

As used herein, "subject" or "patient" means an individual having symptoms of, or 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 a mouse model as described herein. Likewise, the patient may include either adults or juveniles (e.g., children). Moreover, patient may mean any living organism, preferably a mammal (e.g., human or non-human) that may benefit from the administration of compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. 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.

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

The compound and compositions described herein may be administered with additional compositions to prolong stability and activity of the compositions, or in combination with other therapeutic drugs.

The terms "inhibit", "inhibiting", and "inhibition" refer to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, or group of cells. The inhibition can be greater than about <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, or <NUM>%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting.

The term "substantially" as used herein, is a broad term and is used in its ordinary sense, including, without limitation, being largely but not necessarily wholly that which is specified. For example, the term could refer to a numerical value that may not be <NUM>% the full numerical value. The full numerical value may be less by about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>%.

Wherever the term "comprising" is used herein, options are contemplated wherein the terms "consisting of" or "consisting essentially of" are used instead. 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 aspect element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the aspect. In each instance herein any of the terms "comprising", "consisting essentially of" and "consisting of" may be replaced with either of the other two terms. The disclosure illustratively described herein may be suitably practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.

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.

The term "serious adverse event" refers to death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse, etc..

The term "regimen" refers to a course of medical treatment over a period of time. The regimen described herein includes one or more sub-regimens, such as a first regimen, a second regime, and so on, that make up the entire regimen of medical treatment. The period of time for treatment may be one or more days, one or more weeks, one or more months, etc., wherein the period of time may be repeated in a cyclic fashion one or more times. For example, a period of time may be <NUM> days, defining the length of a cycle that may be repeated. A regimen may be a <NUM> day cycle where a compound A is administered on specific days of the cycle, defining a first regimen, and where compound B is administered on other specific days of the cycle that define a second regimen, which in total defines the entire regimen.

The minnelide prodrug (MINNELIDE, or Minnelide™ prodrug) is also known as <NUM>-O-phosphonooxymethyltriptolide disodium salt, the IUPAC chemical name for which is: disodium;[(<NUM>S,<NUM>S,<NUM>S,<NUM>S,<NUM>S,<NUM>R,<NUM>R,<NUM>S,<NUM>S)-<NUM>-methyl-<NUM>-oxo-<NUM>-propan-<NUM>-yl-<NUM>,<NUM>,<NUM>,<NUM>-tetraoxaheptacyclo[<NUM>. <NUM><NUM>,<NUM>. <NUM><NUM>,<NUM>. <NUM><NUM>,<NUM>. <NUM><NUM>,<NUM>. <NUM><NUM>,<NUM>]icos-<NUM>(<NUM>)-en-<NUM>-yl]oxymethyl phosphate. The neutral compound and pharmaceutically acceptable salt forms thereof are referred to herein as the minnelide prodrug or compound <NUM>.

This disclosure provides a method for treating cancer in a cancer patient, the method comprising administering to a gastric cancer patient during a <NUM> day cycle a therapeutically effective combination of:.

wherein the <NUM>-day cycle is repeated one or more times and the combination effectively treats the cancer.

In various embodiments, the cancer patient is administered about <NUM> to about <NUM> of minnelide prodrug according to the first regimen. In various embodiments, according to the first regimen, the cancer patient is administered a milligram amount of minnelide prodrug that is about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or about <NUM>.

In various embodiments, the cancer patient is administered about <NUM>/m<NUM> to about <NUM>/m<NUM> of paclitaxel according to the second regimen. In various embodiments, according to the second regimen, the cancer patient is administered a milligram of paclitaxel that is about <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, <NUM>/m<NUM>, or about <NUM>/m<NUM>.

In some embodiments, the cancer patient is administered about <NUM> of minnelide according to the first regimen and about <NUM>/m<NUM> of paclitaxel according to the second regimen.

In various embodiments, minnelide prodrug is administered orally or intravenously, preferably orally. In various embodiments, paclitaxel is administered intravenously or orally, preferably intravenously.

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 a cancer patient suffering from or further suffering from gastric cancer and one or more of pancreatic cancer, ovarian cancer, liver cancer, lung cancer, breast cancer, bladder cancer, and skin cancer.

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 juvenile female human or a juvenile male human.

In various embodiments, the combination effectively treats the cancer without causing a complete blood count of the cancer patient to lower by more than <NUM> %, <NUM> %, <NUM> %, <NUM> %, or <NUM> % from baseline. In various embodiments, the combination effectively treats the cancer without causing a platelet count or an absolute neutrophil count in the cancer patient to lower by more than <NUM> %, <NUM> %, <NUM> %, <NUM> %, or <NUM> % from baseline.

In some embodiments, the cancer patient has tumors that continued to progress after receiving paclitaxel chemotherapy, and in various embodiments described herein, the tumors of the cancer patient are reduced in diameter by <NUM>% or greater after two, three, four, or five or more <NUM>-day cycles.

In some embodiments, the methods described herein are used to treat a cancer that has become refractory, or to treat a cancer that is resistant or non-responsive to other methods of cancer treatment. In various embodiments, the cancer is gastric cancer, for example, advanced gastric cancer (AGC).

In one specific embodiment, the invention provides a method for treating advanced gastric cancer in a cancer patient that has tumors that continued to progress after receiving paclitaxel chemotherapy, the method comprising administering to a cancer patient diagnosed with advanced gastric cancer during a <NUM> day cycle a therapeutically effective combination of:.

wherein the <NUM>-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 the gastric cancer without causing a complete blood count of the cancer patient to lower by more than <NUM> % from baseline, and the combination effectively treats the gastric cancer without causing a platelet count or an absolute neutrophil count in the cancer patient to lower by more than <NUM> % from baseline.

The severity of each Adverse Event (AE) follows guidelines from the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), which are summarized as follows.

Grade <NUM>: An AE that is transient or mild discomfort, not interfering with the patient's daily activity performance or functioning; medical intervention/therapy may be required.

Grade <NUM>: An AE of sufficient severity as to possibly make the patient moderately uncomfortable; possibly influencing the patient's daily activity performance or functioning; generally, not impairing the patient's ability to continue in the study; and/or possibly needing therapeutic intervention.

Grade <NUM>: An AE event generally causing severe discomfort, significantly influencing the patient's daily activity performance or functioning, generally requiring alteration or cessation of study drug administration, and/or generally requiring therapeutic intervention with hospitalization possible.

Grade <NUM>: An AE that is considered to be life threatening, resulting in significant disability or incapacity, and/or representing the worst possible occurrence of that event with hospitalization probable.

Intravenous Minnelide Prodrug. Phase <NUM>, Multi-Center, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of minnelide prodrug given intravenously daily for <NUM> days followed by <NUM> days off schedule in patients with Advanced Gastrointestinal Tumors. A second dosing schedule of minnelide prodrug given intravenously QD for <NUM> days with <NUM> days off for three weeks followed by a <NUM>-day rest period was also explored during this study.

A total of <NUM> patients enrolled in the Phase <NUM> study, however <NUM> patients were not dosed with study drug. The remaining <NUM> patients were dosed in the study. The primary reason for the discontinuation of treatment was disease progression. There were <NUM> deaths in the study, but these occurred after the study drug had ended and were within the <NUM>-day follow-up period. The deaths that occurred during the study were found to be not related to the study drug and were found to be related to progression of the patient's disease (pancreatic/gastric cancer). One patient who died from respiratory failure, and this was also found to be not related to use of the study drug.

There were <NUM> patients who discontinued the study drug due to a treatment emergent adverse events (TEAEs). All instances were considered Grade <NUM>, and two of these TEAEs were considered as likely related to use of the study drug. These two cases were also considered DLTs. A total of <NUM> Serious Adverse Events occurred in <NUM> patients and six were found to be related to the study drug.

The most commonly reported TEAE (> <NUM>%) 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.

A total of <NUM> patients had at least <NUM> adverse event (AE) that was considered related to the study drug. Adverse events of neutropenia grade <NUM> and <NUM> of short durations have been observed at all dose levels and were determined to be drug related. The neutropenia resolved within a couple of days of not receiving treatment. Neutropenic fever and neutropenic infection were observed in three patients and determined to be drug related. Anemia and thrombocytopenia Grade <NUM> and <NUM> were observed in <NUM>% of the patients and determined to be drug related. Other side effects of any grade that were possibly related to the drug included nausea, vomiting, diarrhea, constipation, anorexia, stomatitis, cerebellar toxicity, embolism and dyspnea, which occurred in ≤ <NUM>% of the patients.

Oral Minnelide Prodrug. A Phase <NUM>, Multi-Center, 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 <NUM> patients were enrolled and dosed in the Phase <NUM> study, <NUM> in the monotherapy regimen, and <NUM> in the combination regimen. The primary reason for discontinuation of treatment has been disease progression. There were <NUM> deaths in the study, <NUM> of which were assessed as not related to minnelide prodrug and were after discontinuation of the study drug. One patient on the <NUM> monotherapy regimen passed away from G5 related sepsis. One patient on the combination regimen at <NUM> of minnelide prodrug passed away from G5 sepsis, which after investigation and review of pharmacokinetic data, was found to be unrelated to minnelide prodrug.

Four patients discontinued the study drug due to a treatment-emergent adverse event (TEAE). Two instances were considered Grade <NUM>, one was Grade <NUM>, one was Grade <NUM>. One of the TEAEs was considered likely related to use of the study drug, the other three possibly related (two Grade <NUM> sepsis, one Grade <NUM> hypokalemia, one Grade <NUM> neutrophil count decrease). Three SAE cases were considered dose limiting toxicities (DLTs). These events included: two events of sepsis and one case of influenza A pneumonia. A total of <NUM> Serious Adverse Events occurred in <NUM> patients and <NUM> were found to be related to the study drug.

Adverse Events classified according to responses noted with Minnelide Prodrug <NUM> plus either protein bound paclitaxel <NUM>/m<NUM> or <NUM>/m<NUM> dose. The most commonly reported TEAE (> <NUM>%) regardless of causality included: Anemia, Abdominal Pain, Constipation, Vomiting, Diarrhea, Nausea, Fatigue, Hypokalemia, and Hypoalbuminaemia. Twenty-seven patients had at least <NUM> AE that was considered related to the study drug. The Grade <NUM> to Grade <NUM> TEAEs reported for minnelide prodrug <NUM> plus either protein bound paclitaxel <NUM>/m<NUM> or <NUM>/m<NUM> dose were as follows:.

The objective of the dose escalation was to define the safety and toxicity characteristics (e.g., the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT)) of Minnelide™ Capsules as monotherapy in advanced gastric cancer (Regimen A) and in combination with paclitaxel in gastric cancers (Regimen B and C).

Regimen A (monotherapy). Minnelide™ Capsules were given as a single agent orally once daily x <NUM> days followed by a <NUM>-day rest period. One cycle was <NUM> days. Minnelide™ Capsules were given with the patient in a fasting state.

Regimen B (combination). Minnelide™ Capsules were given orally once daily x <NUM> days in combination with paclitaxel given intravenously on days <NUM>, <NUM> and <NUM>. One cycle was <NUM> days. Minnelide™ Capsules were given with the patient in a fasting state.

Regimen C (combination). Minnelide™ Capsules was given orally once daily on days <NUM> to <NUM>, <NUM> to <NUM> and <NUM> to <NUM> in combination with paclitaxel given intravenously on days <NUM>, <NUM> and <NUM>. One cycle was <NUM> days. Minnelide™ Capsules were given with the patient in a fasting state.

Dose-Limiting Toxicity. Dose-limiting toxicities (DLT) were evaluated during Cycle <NUM> of treatment. Toxicities were graded and documented according to the NCI CTCAE guidelines (described above). Dose reductions were not allowed during Cycle <NUM>. DLTs include adverse events that are considered to be related to the study drug, including:.

Patients meeting study participation eligibility signed IRB-approved informed consent and met the following inclusion criteria.

A drop in blood counts is usually seen within the first <NUM>-<NUM> days of the start of minnelide prodrug and resolved in <NUM>-<NUM> days of withholding the drug.

CBC with differential was done on days <NUM>, <NUM>, <NUM>, <NUM> and more frequently as clinically indicated. Patient were hospitalized for close monitoring when the ANC level was <<NUM><NUM> (grade <NUM> or higher) or platelet was < <NUM>,<NUM> cells/mm<NUM> at any time. Minnelide™ Capsules would not resume until the ANC level was ≥<NUM><NUM> or platelet was ≥<NUM>,<NUM> cells/mm<NUM>.

The following Examples are intended to illustrate the above invention and should not be construed as to narrow its scope.

Minnelide™ Capsules were given as a single agent orally once daily x <NUM> days followed by a <NUM>-day rest period. Dose escalation for Regimen A was followed according to Table <NUM>. At each dose level the first patient was treated. If the patient did not develop CTCAE V4. <NUM> Grade <NUM> or greater toxicity after one week of treatment, a second patient and a third patient could receive the same dose of Minnelide™ Capsules (capsules containing minnelide prodrug). If the second and third patients do not experience CTCAE V4. <NUM> Grade <NUM> or greater toxicity after a minimum of three weeks of treatment, dose escalation will proceed to dose level <NUM>.

If a DLT is observed in <NUM> out of <NUM> patients at the first dose level, up to an additional <NUM> patients will be enrolled and treated at that dose level. If two patients at this dose level have DLTs, dosing will be decreased to ½ of dose level <NUM>. If <NUM> of <NUM> patients has a DLT, the dose will be increased to the second dose level. If <NUM> or more of the up to <NUM> patients at the second dose level have DLTs, the preceding dose (dose level <NUM>) will be declared the MTD. If <NUM> or less of <NUM> patients has a DLT, the dose level <NUM> will be declared the MTD.

Minnelide™ Capsules were given orally once daily x <NUM> days in combination with paclitaxel given intravenously on days <NUM>, <NUM> and <NUM>. Once dose level <NUM> in Regimen A (monotherapy) had been cleared, dose escalation in Regimen B (combination) was begun following Table <NUM>. At each dose level the first patient was treated. If the patient did not develop CTCAE V4. <NUM> Grade <NUM> or greater toxicity after one week of treatment, a second patient and a third patient could receive the same dose of Minnelide™ Capsules and paclitaxel. Paclitaxel is given at <NUM>/m<NUM> as a starting dose and increased to <NUM>/m<NUM> if no DLTs were noted in <NUM> patients and would remain at <NUM>/m<NUM>, and dose levels for the escalation of the minnelide prodrug would proceed as outlined in Table <NUM>. Escalation would proceed according to the parameters described for Regimen A.

Minnelide™ Capsules were given orally once daily on days <NUM> to <NUM>, <NUM> to <NUM> and <NUM> to <NUM> in combination with paclitaxel given intravenously on days <NUM>, <NUM> and <NUM>. Dose escalation in Regimen C (combination) would begin following Table <NUM>. At each dose level the first patient was treated. If the patient did not develop CTCAE V4. <NUM> Grade <NUM> or greater toxicity after one week of treatment, a second patient and a third patient would receive the same dose of Minnelide™ Capsules and paclitaxel. Paclitaxel was given at <NUM>/m<NUM> if no DLTs were noted in <NUM> patients and would remain at <NUM>/m<NUM>, and dose levels for the escalation of the minnelide prodrug would proceed as outlined in Table <NUM>. Adjustments to the paclitaxel would be considered in Cycle <NUM> and beyond after a safety evaluation.

Target Lesions. Response criteria for target lesions are shown in Table <NUM>. All measurable lesions up to a maximum of two lesions per organ and five lesions in total, representative of all involved organs, were identified as target lesions and recorded and measured at baseline. Target lesions were selected on the basis of their size (lesions with the longest diameter) and were representative of all involved organs, as well as their suitability for reproducible repeated measurements. All measurements were recorded using calipers if clinically assessed.

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

This study, evaluating the safety and preliminary antitumor activity of minnelide prodrug was administered alone or with paclitaxel in patients with advanced gastric cancer (AGC) (NCT <NUM>).

Study design. This was an open-label, nonrandomized, phase <NUM> study conducted at Samsung Medical Center (SMC) in Korea. The study consisted of three regimens: Monotherapy with minnelide prodrug (Regimen A) and Combination therapy (minnelide prodrug plus paclitaxel), which was further divided into Regimen B and C.

Adult (≥<NUM> years of age) Korean patients with histologically confirmed advanced-unresectable or metastatic gastric or gastro-esophageal junction adenocarcinoma, who had failed initial standard therapy or for whom no standard treatment was available, were eligible to participate in the study, regardless of HER2 status. Study treatment was discontinued if the patient experienced radiological progressive disease (PD) per Response Evaluation Criteria in Solid Tumors version <NUM> (RECIST v1. <NUM>) as assessed by the investigator, clinical progression as assessed by the investigator, or developed unacceptable toxicity.

Treatments. In Regimen A, <NUM>-<NUM> patients were treated at escalating doses of minnelide prodrug alone to determine the maximum tolerated dose (MTD). Minnelide prodrug was administered per oral (PO) once daily for 21days followed by a <NUM>-day rest period, starting at <NUM>, and escalating to <NUM>, and <NUM>. One cycle was equal to <NUM> days and minnelide prodrug was given with the patient in a fasting state. In Regimen B, the same dosing scheme was used for minnelide prodrug <NUM> PO in combination with paclitaxel intravenously on days <NUM>, <NUM> and <NUM> (Q4W), starting at <NUM>/m<NUM>, and escalating to <NUM>/m<NUM>. In Regimen C, patients were treated with paclitaxel <NUM>/m<NUM> given intravenously on days <NUM>, <NUM> and <NUM> (Q4W) in combination with minnelide prodrug PO once daily on days <NUM> to <NUM>, <NUM> to <NUM> and <NUM> to <NUM>, starting at <NUM>, escalating to <NUM>, <NUM>, and <NUM>. Dose-limiting toxicities (DLTs) were assessed during cycle <NUM>. Treatment continued until disease progression, death, unacceptable toxicity, or patient or investigator decision to discontinue.

In this phase <NUM> study, the primary objective was to determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT) of minnelide prodrug when given alone or in combination with paclitaxel and to establish recommended phase <NUM> dose (RP2D) of single-agent minnelide prodrug and in combination with paclitaxel every <NUM> weeks. Secondary objectives were to assess any 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). Disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS) analysis were performed.

Assessment. Adverse events were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version <NUM>. Tumor assessments were performed after cycles <NUM>, <NUM>, <NUM>, and <NUM>, and every <NUM> cycles thereafter, or as indicated. Response was determined by investigators using RECIST criteria, version <NUM>. The objective response rate (ORR) was determined in patients with measurable disease at baseline and defined as complete response or partial response, confirmed by repeat assessment after <NUM> or more weeks. The disease control rate (DCR) was defined as the proportion of patients achieving complete response, partial response, or stable disease.

Statistical methods. Safety analyses were performed for the safety-evaluable population, which comprised all patients who received any study drug. Safety was assessed through DLTs and AEs. Patients with missing baseline or no response assessments were classified as non-responders. ORR and DCR were reported with exact <NUM>% confidence intervals (CIs). PFS, OS, and DOR were estimated using the Kaplan-Meier method with <NUM>% CIs. Safety data were summarized descriptively. Data are presented separately for Regimen A (minnelide prodrug monotherapy), and Regimen B and C (minnelide prodrug plus paclitaxel). Data analysis was performed on December <NUM>, <NUM>, using Statistical Package for the Social Sciences for Windows (version <NUM>; IBM Corp. Armonk, NY, USA).

Between November <NUM>, <NUM>, and October <NUM>, <NUM>, <NUM> patients were screened and <NUM> patients (median age, <NUM> [range, <NUM>-<NUM>]) met eligibility criteria and <NUM> were treated in Regimen A, <NUM> in Regimen B and <NUM> in Regimen C (<FIG> and Table <NUM>). Study exclusions (n = <NUM>) were due to failing to meet inclusion criteria (n = <NUM>) or declining to participate in the study (n = <NUM>). All <NUM> enrolled patients were included in data analysis (<FIG>). Baseline demographics and characteristics are summarized in Table <NUM>.

The Regimen A comprised of <NUM> male and <NUM> female patients; all had an ECOG PS of <NUM> and had received median three prior cancer therapies (<NUM> [<NUM>%] had received prior immunotherapy). The Regimen B comprised of <NUM> male and <NUM> female patients and received median three prior cancer therapies (<NUM> [<NUM>%] had received prior immunotherapy). The Regimen C comprised of <NUM> male and <NUM> female patients and received median two prior therapies (range, <NUM>-<NUM>) and <NUM> (<NUM>%) had received prior immunotherapy. In total, six (<NUM>%) patients had HER2-positive tumors and <NUM> (<NUM>%) had PD-L1 (CPS ≥ <NUM>) expressed tumors (Table <NUM>). None of the patients had microsatellite instability-high tumors. In the combination treatment group, <NUM>% of patients in Regimen B and <NUM>% of patients in Regimen C were previously treated with paclitaxel.

At data cutoff date (December <NUM>, <NUM>), <NUM> patients (<NUM>%) had discontinued study treatment, and <NUM> patients were still undergoing treatment. The primary reason for discontinuation was progressive disease. Five patients (<NUM> in Regimen A, <NUM> in Regimen B, <NUM> in Regimen C) did not complete cycle <NUM> (<FIG>) and the number of evaluable subjects for safety and antitumor activity was <NUM> and <NUM>, respectively.

There were two dose-limiting toxicities (DLTs) in Minnelide Prodrug Monotherapy Regimen A (Dose level <NUM> minnelide prodrug <NUM>: Grade <NUM> abdominal pain). No DLTs occurred in minnelide prodrug plus paclitaxel combination treatment. The most common treatment-related AEs (TRAEs) were anorexia (<NUM>/<NUM>, <NUM>%), abdominal pain (<NUM>/<NUM>, <NUM>%), nausea (<NUM>/<NUM>, <NUM>%) and neutropenia (<NUM>/<NUM>, <NUM>%) (Table <NUM>). The majority of TRAEs were grade <NUM> or <NUM>. TRAEs above Grade <NUM> occurred in <NUM> patients (<NUM>%); neutropenia (<NUM>%) was most common followed by abdominal pain (<NUM>%). There were four Grade <NUM> AEs caused by gastric cancer progression.

Minnelide prodrug related adverse events (AEs) are summarized in Table <NUM>. The maximum tolerated dose (MTD) was minnelide prodrug <NUM> PO once daily for <NUM> days every <NUM> weeks as monotherapy. The most common minnelide prodrug-related treatment AEs experienced by patients were anorexia (<NUM>%), nausea (<NUM>%) and abdominal pain (<NUM>%) in Regimen A. In combination treatment Regimen (B&C), abdominal pain (<NUM>%) and neutropenia (<NUM>%) were most frequently occurred. Grade ≥<NUM> severity TRAEs were nausea (<NUM>%), vomiting (<NUM>%), abdominal pain (<NUM>%) and neutropenia (<NUM>%) in minnelide prodrug monotherapy group, whereas <NUM>% of patients experienced grade ≥<NUM> abdominal pain and <NUM>% of patients with grade ≥<NUM> neutropenia in combination treatment (Table <NUM>).

Antitumor activity. In Combination Regimen C, four patients (<NUM>%) showed Partial Response (PR) and six patients (<NUM>%) showed Stable Disease (SD) (<FIG>). Four patients experienced a stable disease (<NUM>%) in Regimen A and three patients (<NUM>%) in Regimen B. In Regimen A (Monotherapy) nine patients who completed at least <NUM> cycle of treatment with measurable lesions, the BOR was SD (<NUM>%) or PD (<NUM>%). DCR was <NUM>% (<NUM>% CI <NUM>-<NUM>) (<FIG>) (Table <NUM> and Table <NUM>).

In Regimen B, eight patients who completed at least <NUM> cycle of treatment with measurable lesions, the BOR was SD (<NUM>%) or PD (<NUM>%) (<FIG>). DCR was <NUM>% (<NUM>% CI <NUM>-<NUM>). In Regimen C, <NUM> patients who completed at least one cycle of treatment with measurable lesions, the BOR was PR (<NUM>%), SD (<NUM>%) or PD (<NUM>%). The ORR was <NUM>% (<NUM>% CI <NUM>-<NUM>) and DCR was <NUM>% (<NUM>% CI <NUM>-<NUM>) (Table <NUM>).

In Regimen B, two patients had SD ≥ <NUM> months (<FIG>). Among <NUM> patients showing SD in Regimen C, one patient received paclitaxel <NUM>/m<NUM> + Minnelide <NUM>/d had prolonged stable disease over 1year with reduction in tumor size (<FIG>). Two patients experienced prolonged PR (≥ <NUM> months). Four patients are still undergoing paclitaxel plus Minnelide treatment at time of submission.

The median PFS was <NUM> months (<NUM>% CI <NUM>-<NUM>) in Regimen A, <NUM> months (<NUM>% CI <NUM>-<NUM>) in Regimen B and <NUM> months (<NUM>% CI <NUM>-<NUM>) in Regimen C. The median OS was <NUM> months (<NUM>% CI <NUM>-<NUM>) in Regimen A, <NUM> months (<NUM>% CI <NUM>-<NUM>) in Regimen B and <NUM> months (<NUM>% CI <NUM>-<NUM>) in Regimen C (Table <NUM>).

In Regimen B, the median PFS was <NUM> months (<NUM>% CI <NUM>-<NUM>) for patients who were previously treated with paclitaxel (n = <NUM>) and <NUM> months (<NUM>% CI NE-NE) for patients without previous exposure to paclitaxel (n = <NUM>) (p = <NUM>). The median OS was <NUM> months (<NUM>% CI <NUM>-<NUM>) for patients who were previously treated with paclitaxel (n = <NUM>) and <NUM> months (<NUM>% CI NE-NE) for patients without previous exposure to paclitaxel (n = <NUM>) (p = <NUM>).

In Regimen C, the median PFS and OS were <NUM> months (<NUM>% CI <NUM>-<NUM>) and <NUM> months (<NUM>% CI <NUM>-<NUM>) for patients who were previously treated with paclitaxel (n = <NUM>), respectively. Among the patients without previous exposure to paclitaxel (n = <NUM>), the median PFS and OS were <NUM> months (<NUM>% CI <NUM>-<NUM>) and <NUM> months (<NUM>% CI NE-NE) (p = <NUM> for PFS; p = <NUM> for OS. Among the patients without previous exposure to paclitaxel (n = <NUM>) in the last <NUM> cohorts of Regimen C, three had a confirmed ORR of <NUM>%, DCR of <NUM>%, and the median PFS was <NUM> months and the median OS was not reached.

Significantly, <FIG> illustrates the Regimen C synergy of minnelide prodrug when administered in combination with paclitaxel where <NUM> of <NUM> patients showed at least a <NUM>% reduction in tumor growth and nine had a reduction of tumor size, with five of those nine showing a significant reduction in tumor size (<NUM>-<NUM>%). This striking synergy is also shown in <FIG> (graphical results of a pre-clinical study in mice), which illustrates (a) the control subjects receiving a vehicle, and test mice receiving minnelide prodrug alone at (b) <NUM>/day and (c) <NUM>/day, and (d) paclitaxel alone in comparison to (e) <NUM>/day minnelide prodrug in combination with <NUM>/day paclitaxel and (f) <NUM>/day minnelide prodrug in combination with <NUM>/day paclitaxel.

This phase <NUM> study evaluated the safety and efficacy of oral minnelide prodrug monotherapy and minnelide prodrug plus paclitaxel combination therapy in Korean patients with locally advanced or metastatic gastric cancer who had previously received multiple lines of therapy. Two DLTs occurred at a dose of <NUM> of minnelide prodrug monotherapy, and minnelide prodrug <NUM> was confirmed as the MTD. No DLTs were observed in patients treated with minnelide prodrug plus paclitaxel and combination treatment was well tolerated.

Most treatment-related AEs with minnelide prodrug were anorexia, abdominal pain, neutropenia and nausea. Grade <NUM> or higher AEs with minnelide prodrug occurred in <NUM>% overall, followed by neutropenia (<NUM>%), abdominal pain (<NUM>%) and nausea (<NUM>%). No significant difference between previous gastrectomy and the occurrence of abdominal pain AE was observed. The overall TRAEs types and incidence rates were similar to minnelide prodrug-related AEs. The majority of TRAEs were grade <NUM> or <NUM> and the most common TRAEs were anorexia (<NUM>/<NUM>, <NUM>%), abdominal pain (<NUM>/<NUM>, <NUM>%), nausea (<NUM>/<NUM>, <NUM>%) and neutropenia (<NUM>/<NUM>, <NUM>%). Four grade <NUM> AEs caused by gastric cancer progression were reported (<NUM> in Regimen A, <NUM> in Regimen B).

Although objective responses were not observed with single-agent minnelide prodrug, some patients experienced tumor shrinkage who previously received at least two lines of chemotherapy. One patient who had previously failed four lines of therapy including immunotherapy showed a stable disease for <NUM> months.

The addition of paclitaxel with minnelide prodrug was shown to improve response rate and provide prolonged PFS and OS compared with minnelide prodrug alone. Especially in Regimen C, minnelide prodrug plus paclitaxel demonstrated promising antitumor activity with confirmed ORR of <NUM>%, DCR of <NUM>%; the median PFS was <NUM> months (<NUM>% CI <NUM>-<NUM>) and the median OS was <NUM> months (<NUM>% CI <NUM>-<NUM>). This is comparable to the median PFS of <NUM> months and OS of <NUM> months of paclitaxel plus ramucirumab, which is currently the most used second-line standard treatment for AGC.

Furthermore, minnelide prodrug in combination with paclitaxel (Regimen B and C) showed <NUM>% (<NUM>/<NUM>) of disease control rate among patients previously treated with paclitaxel (n = <NUM>). These findings indicate that administering minnelide prodrug in combination with paclitaxel can overcome resistance to paclitaxel and reverse sensitivity, as reported in a previous study (<NPL>)).

The results of this phase <NUM> study are limited by the poor prognosis of the study population, with many patients having received multiple prior chemotherapy.

Claim 1:
Minnelide and paclitaxel for use in a method for treating gastric cancer in a cancer patient, the method comprising administering to a gastric cancer patient during a <NUM> day cycle a therapeutically effective combination of:
a)<NUM> to <NUM> ± <NUM>% of minnelide according to a first regimen wherein a dose is given once per day on days <NUM> to <NUM>, <NUM> to <NUM>, and <NUM> to <NUM> of the cycle; and
b)<NUM>/m<NUM> to <NUM>/m<NUM> ± <NUM>% of paclitaxel according to a second regimen wherein a dose is given once per day on days <NUM>, <NUM>, and <NUM> of the cycle;
wherein the <NUM>-day cycle is repeated one or more times and the combination effectively treats the gastric cancer.