Individualized cancer treatment methods

Abstract

This disclosure provides, in particular, a personalized method for administering PCS6422 in combination with capecitabine, a personalized method for treating cancer, and a method for determining the frequency of administration of (i) PCS6422 and capecitabine or (ii) capecitabine in a subject.

Description

Background Art

[0001] Cross - reference to related applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 513,514, filed on July 13, 2023, the entire content of which is incorporated herein by reference.

[0002] The following description of the background of the technology is provided merely as an aid in understanding the technology and is not admitted to describe or constitute the prior art of the technology.

[0003] Fluoropyrimidine antimetabolites are important cancer therapeutics, and 5 - fluorouracil (5 - FU) is the most commonly used drug in this class. Capecitabine (Xeloda®) is a commonly used oral fluoropyrimidine, a prodrug of 5 - FU, which is converted through three enzymatic steps. First, capecitabine is converted by carboxylesterase to 5'-deoxy - 5 - fluorocytidine (5'-DFCR), then 5'-DFCR is converted by cytidine deaminase to 5'-deoxy - 5 - fluorouridine (5'-DFUR), and finally 5'-DFUR is converted by thymidine phosphorylase to 5 - FU.

[0004] In previous clinical trials examining the toxicity profile of capecitabine compared to 5 - FU, a dose - dependent improvement in the side - effect profile, including a reduction in stomatitis, diarrhea, nausea, and neutropenic sepsis, has been suggested compared to 5 - FU / leucovorin (LV). Treatment with capecitabine, although the side - effect profile may be improved, has a relatively high incidence of hyperbilirubinemia and hand - foot syndrome (HFS), and is rapidly degraded to α - fluoro - β - alanine (FBAL) by dihydropyrimidine dehydrogenase (DPD), an enzyme that can catabolize more than 80% of the administered 5 - FU.

[0005] DPD levels can exhibit high variability both within individual subjects (e.g., due to circadian rhythms or tissue-specific variations) and between subjects. Such variability has been shown, at least in part, to contribute to the variability in pharmacokinetics (PK), toxicity, and clinical responses observed in clinical trials of 5-FU. While most individuals have DPD activity within a normal distribution, a small percentage of the population (less than approximately 5%) have significantly below-normal distribution DPD activity (e.g., due to inactivating mutations in one or two genes encoding DPD). Therefore, administering standard doses of 5-FU or capecitabine to these patients can lead to life-threatening or fatal toxicity. Thus, inactivating DPD and inhibiting 5-FU catabolism can provide an alternative approach to prolong systemic exposure to 5-FU, increase exposure to active metabolites, reduce exposure to toxic metabolites, and / or improve potency. [Overview of the project]

[0006] This disclosure provides, in particular, an individualized method for treating cancer in subjects requiring cancer treatment, and a method for treating cancer that includes (i) determining the frequency of administration of PCS6422 and capecitabine or (ii) capecitabine to subjects, and determining whether or not to adjust the treatment regimen based on a treatment index.

[0007] In one embodiment, the present disclosure is a method for determining the frequency of administration of PCS6422 and capecitabine to a subject, comprising: (i) administering to the subject at least one effective dose of PCS6422; (ii) administering to the subject at least one therapeutically effective dose of capecitabine about 12 to 24 hours after the administration of at least one effective dose of PCS6422, wherein a blood sample taken from the subject is measured for α-fluoro-β-alanine (FBAL) and 5-fluorouracil (5-FU); and (iii) the measured 5-FU, measured FB The present invention provides a method comprising: determining one or more of the ratios of measured FBAL to AL and / or measured 5-FU (FBAL:5-FU ratio); and repeating steps (i) and (ii) if, after a drug-free period, at least one of the following conditions is met: measured 5-FU was below a certain 5-FU threshold, measured FBAL was greater than or equal to a certain FBAL threshold, the determined FBAL:5-FU ratio was greater than or equal to a certain FBAL:5-FU ratio threshold, measured 5-FU was zero, or measured FBAL was zero.

[0008] In some embodiments, a therapeutically effective dose of capecitabine is administered to the subject approximately 12 hours after an effective dose of PCS6422 has been administered.

[0009] In some embodiments, a therapeutically effective dose of capecitabine is administered to the subject approximately 24 hours after an effective dose of PCS6422 has been administered.

[0010] In some embodiments, a therapeutically effective dose of capecitabine is administered to the subject both approximately 12 hours and approximately 24 hours after administration of an effective dose of PCS6422.

[0011] In some embodiments, blood samples were collected from subjects approximately 12 to 24 hours after administration of a therapeutically effective dose of capecitabine.

[0012] In some embodiments, FBAL and 5-FU were measured daily from the first day of capecitabine treatment.

[0013] In some embodiments, steps (i) and (ii) are repeated 1 to 7 days, 8 days, or 14 days after step (ii).

[0014] In one embodiment, the present disclosure is a method for determining the frequency of administration of capecitabine to a subject, comprising: (i) administering to the subject at least one effective dose of PCS6422; and (ii) administering to the subject at least one therapeutically effective dose of capecitabine about 12 to 24 hours after the administration of at least one effective dose of PCS6422, wherein a blood sample taken from the subject is measured for α-fluoro-β-alanine (FBAL) and / or 5-fluorouracil (5-FU). The present invention provides a method comprising: (iii) determining one or more of the measured 5-FU, measured FBAL, or the ratio of measured FBAL to measured 5-FU (FBAL:5-FU ratio); and (iv) discontinuing the administration of an additional therapeutically effective dose of capecitabine to the subject if the measured 5-FU is below a certain 5-FU threshold, the measured FBAL is above a certain FBAL threshold, or the determined FBAL:5-FU ratio is above a certain FBAL:5-FU ratio threshold.

[0015] In some embodiments, a drug-free period is provided after discontinuing the administration of additional therapeutically effective doses of capecitabine to the subject.

[0016] In some embodiments, steps (i) and (ii) are repeated after a drug-free period.

[0017] In one embodiment, the Disclosure provides a method for treating cancer in a subject requiring cancer treatment, comprising: (i) administering to the subject at least one effective dose of PCS6422; (ii) administering to the subject at least one therapeutically effective dose of capecitabine about 12 to 24 hours after the administration of at least one effective dose of PCS6422; (iii) measuring metabolites in a blood sample taken from the subject, including one or more of α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), doxifluridine (5'-DFUR), and 5-fluorouracil (5-FU); and (iv) determining whether it is necessary to adjust the treatment regime based on a treatment index including the metabolite measurements determined in step (iii). [Modes for carrying out the invention]

[0018] PCS6422 is a potent and irreversible inactivator of dihydropyrimidine dehydrogenase (DPD). Small amounts of PCS6422 can inactivate DPD and render it unable to catabolize 5-FU, including 5-FU produced from the 5-FU prodrug capecitabine. If all existing DPD enzymes are not inhibited, and / or if active DPD reappears in the subject over time, for example as a result of de novo synthesis of the DPD enzyme, then subsequent DPD enzyme activity will occur. By inhibiting the catabolism of 5-FU by DPD, PCS6422 shifts the 5-FU elimination pathway from metabolism to renal excretion, extending the half-life from 10-20 minutes to several hours. PCS6422 also prevents the formation of 5-FU catabolites such as FBAL, which can antagonize the antitumor activity of 5-FU and cause side effects such as hand-foot syndrome, cardiotoxicity, and neurotoxicity. However, identifying the appropriate dosage and / or treatment regimen to maximize the potential of PCS6422 and capecitabine combination therapy remains a challenge.

[0019] To advance the dosage, treatment regimens, and / or treatment techniques of PCS6422 and capecitabine, it is important to determine individualized treatment regimens and / or methods for individualizing such regimens, taking at least partially into account the variability of DPD levels and the variability of de novo DPD formation, both within and between individual subjects.

[0020] This disclosure provides, in particular, a personalized method for administering PCS6422 in combination with capecitabine, a personalized method for treating cancer, and a method for determining the frequency of administration of (i) PCS6422 and capecitabine or (ii) capecitabine in a subject. As will be described in more detail herein, such personalized methods can improve the safety and / or efficacy of capecitabine regimens.

[0021] To provide a substantial understanding of this technology, please note that certain aspects, modes, embodiments, variations, and features of this method are described below at varying levels of detail.

[0022] This disclosure is not intended to be limited in terms of any particular embodiment described in this application, but rather as a single example of individual aspects of this disclosure. Not all of the various embodiments of this disclosure are described herein. As will be apparent to those skilled in the art, many modifications and variations of this disclosure can be made without departing from its spirit and scope. In addition to those enumerated herein, functionally equivalent methods and apparatus within the scope of this disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. This disclosure is limited only by the terms of the appended claims, together with the entire scope of equivalents for which such claims are entitled.

[0023] This disclosure is not limited to any particular use, method, reagent, compound, composition, or biological system, and it should be understood that these are, of course, subject to change. It should also be understood that the terms used herein are intended solely to describe specific embodiments and are not intended to be limiting.

[0024] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings generally understood by those skilled in the art in which this disclosure pertains. The following references provide general definitions of many of the terms used herein. Where used herein, the following terms have the meanings attributed to them unless otherwise specified. The terms used herein are for the sole purpose of describing specific embodiments and are not intended to limit this disclosure.

[0025] As used herein, the singular forms "a," "an," and "the" include singular and plural references unless otherwise clearly indicated by the context. For example, the term "a cell" includes not only a single cell but also multiple cells and mixtures thereof.

[0026] As used herein, the term “administration” of a drug or composition to a subject includes any route by which the drug or composition is introduced or delivered to the subject in order to perform its intended function. Administration may be carried out by any preferred route, including, but not limited to, oral administration, intravenous administration, and other preferred routes described herein. Administration may include self-administration and administration by another person.

[0027] As used herein, "adverse event" or "AE" refers to any undesirable medical event that occurs in a subject to whom a drug(s) has been administered. Thus, an adverse event is an undesirable and / or unintended sign (e.g., abnormal clinical laboratory finding), symptom, and / or condition that is temporally related to the administration of a drug(s), whether or not it is considered related to the use of the drug(s).

[0028] As used herein, the term "drug" refers to an entity (e.g., lipid, metal, nucleic acid, polypeptide, polysaccharide, small molecule, etc., or a complex, combination, mixture, or system thereof ([e.g., cell, tissue, organism]), or a phenomenon (e.g., heat, electric current or field, magnetic force or field, etc.). In appropriate contexts, as will be apparent to those skilled in the art from the context, this term can be used to refer to a cell or organism, or a part, extract, or component thereof (e.g., nucleic acid), or an entity that includes them. Alternatively, or in addition, as the context makes clear, this term can be used to refer to a natural product in that it is found in nature and / or obtained from nature. In some cases, again as will be apparent from the context, this term can be used to refer to one or more entities that are artificial in that they are designed, engineered, and / or produced through the actions of man and / or not found in nature. For example, a drug can be utilized in isolated form or in pure form, or a drug can be utilized in crude form.

[0029] As used herein, the term "about" or "approximately" means not only the specified number but also plus or minus 10%. For example, "about 10" needs to be understood as both "10" and "9 - 11".

[0030] As used herein, “combination therapy” refers to a situation in which two or more different drugs are administered in overlapping or identical regimens, and the subject is simultaneously exposed to both drugs. In combination therapy, two or more different drugs may be administered simultaneously or separately. This combination administration may include simultaneous administration of two or more drugs in the same dosage form, simultaneous administration of drugs in different dosage forms, and separate administrations. That is, two or more drugs may be combined into the same dosage form and administered simultaneously. Alternatively, two or more drugs may be administered simultaneously, in which case the drugs are contained in separate formulations. Another option is to administer one or more additional drugs immediately after the administration of the first drug. In separate dosing protocols, two or more drugs may be administered, for example, at intervals of a few minutes, a few hours, or a few days.

[0031] As used herein, “comprising” is to be interpreted as identifying the presence of a feature, element, step, or component described as being referred to, but not as excluding the presence or addition of one or more features, elements, steps, or components, or groups thereof. Furthermore, each of the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” may be used interchangeably in their open, non-restrictive senses. In addition, the term “comprising” is intended to include examples and aspects that are encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples that are encompassed by the term “consisting.”

[0032] As used herein, the term “effective dose” refers to a sufficient amount of a drug or composition to obtain the desired biological outcome (e.g., the desired degree of inhibition of DPD).

[0033] As used herein, “diagnostic information” or “information used for diagnosis” means any information useful for determining whether a patient has a disease or condition, and / or classifying such disease or condition into a phenotypic category or any category that is significant in terms of the prognosis of the disease or condition, or the likelihood of response to treatment (general treatment or any specific treatment) of the disease or condition. Similarly, diagnosis means providing any kind of diagnostic information, including, but not limited to, whether a subject is likely to have a disease or condition (such as cancer), the state, stage, or characteristics of the disease or condition present in the subject, information relating to the nature or classification of a tumor, information relating to prognosis, and / or information useful for selecting appropriate treatment. Treatment selection may include the selection of a specific therapeutic agent (e.g., a chemotherapy agent) or other therapeutic means such as surgery or radiation, the choice of whether to withhold or perform treatment, and the choice of administration regimen (e.g., the frequency or level of one or more doses of a specific therapeutic agent or combination of therapeutic agents).

[0034] As used herein, the terms “dosage regimen” or “treatment regimen” refer to a series of unit doses administered to a subject individually, typically divided into periods of time. A given therapeutic agent may have a recommended dosage regimen, which may include one or more doses. A dosage regimen may include multiple doses, each dose spaced at intervals of a certain period. Such intervals may be the same length or of different lengths. A dosage regimen may include multiple doses and at least two different periods separating the individual doses. A dosage regimen may be correlated with a desired therapeutic outcome when administered to a subject and / or to a population of subjects. The terms “dosage regimen” or “treatment regimen” may also refer to any method used to partially or completely alleviate, improve, mitigate, inhibit, prevent, delay the onset, reduce the severity, and / or reduce the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition (e.g., cancer). The term may also include treatments or series of treatments designed to achieve a specific effect, e.g., reduction or elimination of an adverse condition or disease such as cancer. Treatment may involve administering one or more compounds (e.g., therapeutic agents) simultaneously, sequentially, or at different times, for the same or different durations.

[0035] As used herein, the term “Sustained Clinical Benefit” (DCB) has the meaning understood in the art and refers to a clinical benefit that lasts for a relevant period. In some embodiments, such clinical benefit is or includes a reduction in symptoms caused by tumor growth, such as a reduction in tumor size, an increase in progression-free survival, an increase in overall survival, a reduction in total tumor burden, pain, organ failure, bleeding, skeletal damage, and other associated sequelae of metastatic cancer, as well as combinations thereof. In some embodiments, the relevant period is at least one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, or longer. In some specific embodiments, the relevant period is six months.

[0036] As used herein, the term “therapeutic dose” refers to the amount of a drug or composition sufficient to achieve a beneficial or desired clinical effect at the time of treatment. In the context of therapeutic use, the amount of therapeutic agent administered to a subject may depend on the type and severity of the disease or condition, as well as individual characteristics such as general health, age, sex, weight, and / or tolerance to the drug. It may also depend on the degree, severity, and type of the disease. A person skilled in the art will be able to determine an appropriate dose according to these and other factors. A therapeutic dose may be administered to a subject in one or more doses. From a therapeutic standpoint, a therapeutic dose is an amount sufficient to alleviate, improve, stabilize, reverse, or delay the progression of the disease, or to otherwise reduce the pathological outcomes of the disease. The therapeutic dose is generally determined on a case-by-case basis by a physician and is within the scope of the skill of a person skilled in the art.

[0037] As used herein, “good response” means a reduction in the frequency and / or intensity of one or more symptoms, such as a reduction in tumor burden, complete or partial remission, and / or other improvement of the pathophysiology of the disease. A symptom is reduced if the magnitude (intensity, severity, etc.) and / or frequency of one or more symptoms of a particular disease, disorder, or condition is reduced. For clarification, a delay in the onset of a particular symptom is considered a form of reducing the frequency of that symptom. Many cancer patients with small tumors are asymptomatic. The techniques of this disclosure are not intended to be limited only to cases where symptoms are completely eliminated. This disclosure particularly envisions treatments in which one or more symptoms are reduced (i.e., thereby “improved” the condition in question), even if not completely eliminated. A good response can be established when a particular treatment regimen demonstrates a statistically significant effect when administered to the entire population or individual subjects in question. A particular treatment regimen can be determined to demonstrate a good response if its administration correlates with the desired effect in question.

[0038] As used herein, “improved,” “increased,” or “reduced,” or grammatically equivalent comparative terms, indicate values ​​relative to comparable reference measures. For example, in some embodiments, an evaluation value obtained with the drug of interest may be “improved” compared to a value obtained with an equivalent reference drug. Alternatively, or in addition, in some embodiments, an evaluation value obtained in a subject or system of interest may be “improved” compared to an evaluation value obtained in the same subject or system under different conditions (e.g., a subject treated with different treatment regimens of PCS6422 and capecitabine), or compared to an evaluation value obtained in a different but comparable subject (e.g., a comparable subject or system different from the subject or system of interest in terms of the presence or absence of one or more indicators of a particular disease, disorder, or condition of interest, or in terms of conditions or prior exposure to the drug). Comparative terms may refer to statistically relevant differences (e.g., those of sufficient prevalence and / or magnitude to achieve a statistical relevance). A person skilled in the art will be able to recognize or easily determine, in a given context, the degree of difference and / or prevalence necessary or sufficient to achieve such statistical significance.

[0039] As used herein, the term “long-term benefit” refers to a desirable clinical outcome observed and maintained over a clinically relevant period after a particular treatment or therapy of interest (e.g., combination therapy) has been administered. For example, the long-term benefit of cancer treatment may include, or may include, (i) no evidence of disease (e.g., in radiographic evaluation) and / or (ii) stable or reduced disease load. A clinically relevant period may be, for example, at least one month, at least two months, at least three months, at least six months, at least one year, or at least five years.

[0040] As used herein, the term “mutation” refers to a permanent change in the DNA sequence that makes up a gene. Mutations can range in size from a single DNA component (DNA base) to a large region of a chromosome. Examples of mutations include missense mutations, frameshift mutations, duplications, insertions, nonsense mutations, deletions, and extensions of repetitive sequences. A missense mutation can result in a change of one base pair in DNA, causing an amino acid in the protein produced by the gene to be replaced by another amino acid. A nonsense mutation can also result in a change of one base pair in DNA. However, the altered DNA sequence signals the cell to stop protein synthesis prematurely, rather than substituting one amino acid for another. Insertions can change the number of DNA bases in a gene by adding a DNA fragment. Deletions can change the number of DNA bases by removing a DNA fragment. In some embodiments, small deletions can remove one or several base pairs in a gene. Larger deletions can remove an entire gene or several adjacent genes. Duplication can consist of a DNA fragment that has been abnormally copied one or more times. Frameshift mutations can occur when the reading frame of a gene is altered by the addition or deletion of DNA bases. A reading frame consists of groups of three bases, each encoding one amino acid. Frameshift mutations can shift the grouping of these bases, thereby changing the encoding of amino acids. In some embodiments, insertions, deletions, and duplications can all be considered frameshift mutations. Repetitive sequence extension is a type of mutation. In some embodiments, a nucleotide repeat is a short DNA sequence that is repeated many times in a row. For example, a trinucleotide repeat consists of a 3-base pair sequence, and a tetranucleotide repeat consists of a 4-base pair sequence. In some embodiments, repetitive sequence extension is a mutation that increases the number of times a short DNA sequence is repeated.

[0041] As used herein, the term "objective response" refers to a reduction in the size of a cancerous tumor by a predetermined amount. A cancerous tumor can be a tumor. A confirmed objective response may be a response observed after a certain period following treatment.

[0042] As used herein, “objective response rate” (ORR) has the meaning understood in the art, referring to the proportion of patients who have a predefined amount of tumor size reduction over a minimum period of time. Duration of response is typically measured as the time from the first response until tumor progression is observed. ORR may include, for example, the sum of partial responses and complete responses.

[0043] As used herein, the term “personalized” refers to a specific treatment regimen adapted to a particular subject and / or the needs and / or specific circumstances of a particular subject requiring treatment (e.g., the pharmacokinetic parameters of a particular drug(s) in a particular subject).

[0044] As used herein, the term “progression-free survival” refers to the length of time during and after treatment for a disease (e.g., cancer) in which a subject survives with the disease without disease progression. Progression-free survival can be used to measure and evaluate the effectiveness of a treatment (e.g., combination therapy).

[0045] As used herein, the terms “reduce” or “decrease” mean modifying by at least about 5%, including but not limited to changing by about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or about 100%.

[0046] As used herein, the term “response” refers to an alteration of a condition in question that results from or correlates with a treatment (e.g., combination therapy). A response may be a beneficial response or include beneficial responses. Beneficial responses may include stabilization of the condition (e.g., prevention or delay of an exacerbation that would be expected or typically observed if no treatment is given), improvement of one or more symptoms of the condition or symptoms associated with the condition (e.g., reduction in frequency and / or intensity), and / or improvement in prognosis. “Response” may refer to an organism (e.g., a human subject), organ, cell, and / or clinical response.

[0047] Where used herein, “reference” entities, systems, quantities, sets of conditions, etc., are those compared to the entities, systems, quantities, sets of conditions, etc., of the test as described herein. For example, a “reference” treatment regimen may be a control treatment regimen, e.g., a treatment regimen not disclosed herein. A reference or control may be tested and / or determined concurrently with the test or determination of interest. A reference or control may be a historical reference or control and may optionally be embodied in a tangible medium. Typically, as will be understood by those skilled in the art, a reference or control is determined or characterized under conditions or circumstances equivalent to those being measured and evaluated. Those skilled in the art will understand when sufficient similarity exists to justify reliance on and / or comparison to a particular possible reference or control.

[0048] As used herein, the term “sample” typically refers to a biological sample taken from or derived from a source of interest (e.g., a subject and / or subject requiring treatment). The source of interest may be, for example, an animal or a human. A biological sample may be or contain biological tissue or fluid. A biological sample may be, or contain, bone marrow, blood; blood cells; ascites; tissue or fine-needle biopsy specimens; cell-containing fluids; free suspended nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; plasma; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as mammary duct lavage or bronchoalveolar lavage; aspirates; scrapes; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other bodily fluids, secretions, and / or excretions; and / or cells derived therefrom. A biological sample may be or may include cells taken from an individual. The sample may be a “primary sample” obtained directly from a source of interest by any suitable means. For example, a primary biological sample may be obtained by a method selected from the group consisting of biopsy (e.g., fine-needle aspiration or tissue biopsy), surgery, or collection of bodily fluids (e.g., blood, lymph, feces, etc.). In some embodiments, as will be apparent from the context, the term “sample” refers to a “secondary sample,” for example, a preparation obtained by processing a primary sample (e.g., by removing one or more components and / or by adding one or more agents). Such a “secondary sample” may include nucleic acids or proteins extracted from the sample or obtained by subjecting the primary sample to techniques such as mRNA amplification or reverse transcription, isolation and / or purification of certain components.

[0049] As used herein, the terms “subject,” “individual,” or “patient” are interchangeable and refer to individual organisms, vertebrates, or mammals, which may include humans, non-human primates, rodents, etc. (e.g., recipients of a particular treatment). In a preferred embodiment, the individual, patient, or subject is human.

[0050] As used herein, the term “treatment cycle” refers to a treatment period followed by a rest period (e.g., a drug-free period). A treatment cycle may include multiple rest periods. A treatment cycle may be repeated (e.g., on a regular or variable schedule). For example, one treatment cycle may consist of one week of treatment followed by one week of rest (e.g., a one-week drug-free period).

[0051] As used herein, the term “treatment index” refers to a set of treatment regimen determinants that can be used in combination as an indicator of the overall effectiveness of a drug (e.g., PCS644, capecitabine) and / or as an indicator of whether a treatment regimen and / or treatment cycle should be adjusted (e.g., changing the number of additional doses of the treatment drug to be administered relative to the planned number of additional doses, or lengthening or shortening the drug-free period relative to the planned period). Treatment index may take into account, for example, but is not limited to, the type and / or severity of the disease, diagnostic information, the subject’s response to the treatment drug, and / or pharmacokinetic analyses (or “metabolite measurements”) as described herein.

[0052] As used herein, in the context of molecules (e.g., nucleic acids, polypeptides), the term “variant” refers to a molecule that exhibits significant structural identity with a reference molecule but is structurally different from the reference molecule, for example, in the presence or absence of one or more chemical moieties, or at that level, compared to the reference entity. A variant may also be functionally different from its reference molecule. Generally, whether a particular molecule is appropriately considered a “variant” of a reference molecule depends on the degree of its structural identity with the reference molecule. As will be understood by those skilled in the art, any biological or chemical reference molecule has certain characteristic structural elements. A variant is, by definition, a distinct molecule that shares one or more such characteristic structural elements but is different from the reference molecule in at least one aspect. To give some examples, a polypeptide may have characteristic sequence elements consisting of a plurality of amino acids that have designated positions relative to each other in linear or three-dimensional space and / or contribute to a particular structural motif and / or biological function, and a nucleic acid may have characteristic sequence elements consisting of a plurality of nucleotide residues that have designated positions relative to each other in linear or three-dimensional space. For example, a variant polypeptide or nucleic acid may differ from a reference polypeptide or nucleic acid as a result of one or more differences in the amino acid or nucleotide sequence, and / or one or more differences in the chemical moieties (e.g., carbohydrates, lipids, phosphate groups) that are covalent components of the polypeptide or nucleic acid (e.g., those attached to the polypeptide or nucleic acid backbone). A variant polypeptide or nucleic acid may exhibit overall sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 99% with respect to the reference polypeptide or nucleic acid. A variant polypeptide or nucleic acid may contain about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 substitution residue compared to the reference.In many cases, variant polypeptides or nucleic acids contain a very small number (e.g., about 5, 4, 3, 2, or less than 1) of substituted, inserted, or deleted functional residues (i.e., residues involved in specific biological activity) relative to a reference.

[0053] treatment The disclosure provides, in particular, an individualized method for treating cancer in subjects requiring cancer treatment, comprising: (i) administering to the subject at least one effective dose of PCS6422; (ii) administering to the subject at least one therapeutically effective dose of capecitabine about 12 to 36 hours (e.g., about 12 to 24 hours) after the administration of at least one effective dose of PCS6422; and (iii) optionally repeating steps (i) and (ii) after a drug-free period.

[0054] In another embodiment, the Disclosure provides a method for treating cancer in a subject in need of cancer treatment, comprising: (i) administering to the subject at least one effective dose of PCS6422; and (ii) administering to the subject at least one therapeutically effective dose of capecitabine about 12 to about 36 hours after the administration of at least one effective dose of PCS6422 (e.g., about 12 to about 24 hours later), wherein a blood sample taken from the subject is measured for one or more of α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), doxifluridine (5'-DFUR), capecitabine, and 5-fluorouracil (5-FU). Such a method for treating cancer may further include determining whether the treatment regime should be adjusted based on a treatment index including one or more measurements of FBAL, 5-DFCR, 5'-DFUR, capecitabine, and 5-FU. Adjustments to the treatment regimen may include, for example, modifying the number of additional doses of the drug relative to the planned number of additional doses, extending or shortening the drug-free period relative to the planned period, or changing the number of treatment cycles performed relative to the planned number of treatment cycles.

[0055] In another embodiment, the Disclosure provides a method for treating cancer in a subject requiring cancer treatment, comprising: (i) administering to the subject at least one effective dose of PCS6422; (ii) administering to the subject at least one therapeutically effective dose of capecitabine about 12 to about 36 hours after the administration of at least one effective dose of PCS6422 (e.g., about 12 to about 24 hours); (iii) measuring metabolites in a blood sample taken from the subject, including one or more of α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), doxifluridine (5'-DFUR), and 5-fluorouracil (5-FU); and (iv) determining whether the treatment regime needs to be adjusted based on a treatment index including the metabolite measurements determined in step (iii). In some embodiments, the measurement of metabolites in step (iii) includes measuring one or more of FBAL and 5-FU. In some embodiments, such methods further include determining the FBAL:5-FU ratio. Such measurement of metabolites is also referred to as “pharmacokinetic analysis,” as described elsewhere in this specification.

[0056] In another embodiment, the Disclosure provides a method for determining the frequency of administration of PCS6422 and capecitabine to a subject, comprising: (i) administering to the subject at least one effective dose of PCS6422; (ii) administering to the subject at least one therapeutically effective dose of capecitabine about 12 to about 36 hours after the administration of at least one effective dose of PCS6422 (e.g., about 12 to about 24 hours later), wherein a blood sample taken from the subject is measured for α-fluoro-β-alanine (FBAL) and 5-fluorouracil (5-FU); and (iii) measuring the measured 5-FU, The present invention provides a method comprising: determining one or more of the defined FBAL and / or the ratio of measured FBAL to measured 5-FU (FBAL:5-FU ratio); and repeating steps (i) and (ii) if, after a drug-free period, at least one of the following conditions is met: measured 5-FU was below a certain 5-FU threshold, measured FBAL was greater than or equal to a certain FBAL threshold, the determined FBAL:5-FU ratio was greater than or equal to a certain FBAL:5-FU ratio threshold, measured 5-FU was zero, or measured FBAL was zero.

[0057] In yet another embodiment, the Disclosure provides a method for determining the frequency of administration of capecitabine to a subject, comprising: (i) administering to the subject at least one effective dose of PCS6422; and (ii) administering to the subject at least one therapeutically effective dose of capecitabine about 12 to about 36 hours after the administration of at least one effective dose of PCS6422 (e.g., about 12 to about 24 hours later), wherein a blood sample taken from the subject is measured for α-fluoro-β-alanine (FBAL) and / or 5-fluorouracil (5-FU). The present invention provides a method comprising: (iii) administering; determining one or more of the measured 5-FU, measured FBAL, or the ratio of measured FBAL to measured 5-FU (FBAL:5-FU ratio); and (iv) discontinuing the administration of an additional therapeutically effective dose of capecitabine to the subject if the measured 5-FU is below a certain 5-FU threshold, the measured FBAL is above a certain FBAL threshold, or the determined FBAL:5-FU ratio is above a certain FBAL:5-FU ratio threshold.

[0058] In some embodiments, a therapeutically effective dose of capecitabine is administered to the subject approximately 12 hours after administration of an effective dose of PCS6422. In some embodiments, a therapeutically effective dose of capecitabine is administered to the subject approximately 12 to 36 hours after administration of an effective dose of PCS6422. In some embodiments, a therapeutically effective dose of capecitabine is administered to the subject approximately 12 to 24 hours after administration of an effective dose of PCS6422. In some embodiments, a therapeutically effective dose of capecitabine is administered to the subject both approximately 12 and 36 hours after administration of an effective dose of PCS6422. In some embodiments, a therapeutically effective dose of capecitabine is administered to the subject both approximately 12 and 24 hours after administration of an effective dose of PCS6422.

[0059] The method of this disclosure may include administering an additional effective dose of PCS6422. In some embodiments, an effective dose of PCS6422 is administered two, three, four, five, or six times. In some embodiments, an effective dose of PCS6422 is administered twice. In some embodiments, an effective dose of PCS6422 is administered three times. In some embodiments, an effective dose of PCS6422 is administered four times. In some embodiments, an effective dose of PCS6422 is administered five times. In some embodiments, an effective dose of PCS6422 is administered six times.

[0060] In some embodiments, the method of the present disclosure includes administering at least one dose of an effective dose of PCS6422 to the target on day 1 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of an effective dose of PCS6422 to the target on days 1 and 5 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of an effective dose of PCS6422 to the target on days 1 and 6 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of an effective dose of PCS6422 to the target on days 1 and 8 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of an effective dose of PCS6422 to the target on days 1, 8, and 15 of the treatment cycle.

[0061] The method disclosed herein may include administering an effective dose of PCS6422 as a single divided dose.

[0062] The method of this disclosure may include administering an additional therapeutically effective dose of capecitabine to a subject approximately 12 to 36 hours (e.g., approximately 12 to 24 hours) after the previous dose of a therapeutically effective dose of capecitabine. In some embodiments, a therapeutically effective dose of capecitabine is administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 times. In some embodiments, a therapeutically effective dose of capecitabine is administered twice. In some embodiments, a therapeutically effective dose of capecitabine is administered three times. In some embodiments, a therapeutically effective dose of capecitabine is administered four times. In some embodiments, a therapeutically effective dose of capecitabine is administered five times. In some embodiments, a therapeutically effective dose of capecitabine is administered six times. In some embodiments, a therapeutically effective dose of capecitabine is administered seven times. In some embodiments, a therapeutically effective dose of capecitabine is administered eight times. In some embodiments, a therapeutically effective dose of capecitabine is administered nine times. In some embodiments, a therapeutically effective dose of capecitabine is administered ten times. In some embodiments, a therapeutically effective dose of capecitabine is administered eleven times. In some embodiments, a therapeutically effective dose of capecitabine is administered twelve times. In some embodiments, a therapeutically effective dose of capecitabine is administered thirteen times. In some embodiments, a therapeutically effective dose of capecitabine is administered fourteen times. In some embodiments, a therapeutically effective dose of capecitabine is administered fifteen times. In some embodiments, a therapeutically effective dose of capecitabine is administered sixteen times.

[0063] In some embodiments, the method of the present disclosure may include discontinuing the administration of an additional therapeutically effective dose of capecitabine to a subject if the measured 5-FU is below a certain 5-FU threshold, the measured FBAL is above a certain FBAL threshold, or the determined FBAL:5-FU ratio is above a certain FBAL:5-FU ratio threshold. In some such embodiments, a drug-free period (e.g., as described herein) is provided after discontinuing the administration of an additional therapeutically effective dose of capecitabine to a subject. In some such embodiments, steps (i) and (ii) are repeated after the drug-free period.

[0064] In some embodiments, the methods of the present disclosure may include adjusting a treatment regimen based on a treatment index including metabolite measurements described herein ("pharmacokinetic analysis"). Adjustments to a treatment regimen may include, for example, modifying the number of additional doses of the drug relative to the planned number of additional doses, extending or shortening the drug-free period relative to the planned period, or changing the number of treatment cycles performed relative to the planned number of treatment cycles.

[0065] In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to each of the following days of the treatment cycle: days 2-3, days 2-4, days 2-5, days 2-6, days 2-7, days 2-8, days 2-10, days 2-12, day 15, days 3-4, days 3-5, days 3-6, days 3-7, days 3-8, days 4-5, days 4-6, days 4-7, days 4-8, days 5-6, days 5-7, days 5-8, days 6-7, days 6-8, or days 7-8, or any combination thereof. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to each of the following days of the treatment cycle: days 2-3, days 2-3, days 2-4, days 2-5, days 2-6, days 2-7, days 5-8, days 6-7, days 6-8, or days 7-8, or any combination thereof. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each day from day 2 to day 4 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each day from day 2 to day 5 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each day from day 2 to day 6 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each day from day 2 to day 7 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each day from day 2 to day 8 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each day from day 2 to day 10 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on each of the 2nd through 12th days of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on each of the 2nd through 15th days of the treatment cycle.In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each of the 3rd to 4th days of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each of the 3rd to 5th days of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each of the 3rd to 6th days of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each of the 3rd to 7th days of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each of the 3rd to 8th days of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each of the 4th to 5th days of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each day from day 4 to day 6 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each day from day 4 to day 7 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each day from day 4 to day 8 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each day from day 5 to day 6 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each day from day 5 to day 7 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one dose of a therapeutically effective dose of capecitabine to the target on each day from day 5 to day 8 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on each of the 6th and 7th days of the treatment cycle.In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on each of the 6th to 8th days of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on each of the 7th to 8th days of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on each of the 2nd to 3rd, 9th to 10th, and 16th to 17th days of the treatment cycle.

[0066] In some embodiments, the method of the present disclosure comprises administering at least one therapeutically effective dose of capecitabine to the target on any or each of days 2 through 8 of the treatment cycle, with at least one drug-free period included within days 3 through 7 of the treatment cycle.

[0067] In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 2 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 3 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 4 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 5 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 6 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 7 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 8 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 9 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 10 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 11 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 12 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 13 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 14 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 15 of the treatment cycle.In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 16 of the treatment cycle. In some embodiments, the method of the present disclosure includes administering at least one therapeutically effective dose of capecitabine to the target on day 17 of the treatment cycle.

[0068] The method disclosed herein may include administering a single therapeutically effective dose of capecitabine in divided doses.

[0069] Drug-free period The methods and / or treatment cycles of this disclosure may include one or more drug-free periods (for example, after administering at least one therapeutically effective dose of capecitabine to the subject and / or subject requiring treatment). A drug-free period means a period during which the subject and / or subject requiring treatment (e.g., a subject with cancer) receives no administration of either PCS6422 or capecitabine. Alternatively, or in addition, a drug-free period may mean a period during which the subject and / or subject requiring treatment (e.g., a subject with cancer) is determined to have no or no detectable amount of PCS6422 and / or capecitabine in a blood sample taken from the subject, using pharmacokinetic analysis as described herein.

[0070] In some embodiments, the drug-free period is approximately 1 to 28 days, approximately 1 to 26 days, approximately 1 to 24 days, approximately 1 to 22 days, approximately 1 to 21 days, approximately 1 to 15 days, approximately 1 to 14 days, approximately 1 to 12 days, approximately 1 to 10 days, approximately 1 to 8 days, approximately 1 to 6 days, approximately 1 to 4 days, approximately 1 to 3 days, or approximately 1 to 2 days. In some embodiments, the drug-free period is approximately 1 to 2 days. In some embodiments, the drug-free period is approximately 1 to 3 days. In some embodiments, the drug-free period is approximately 1 to 4 days. In some embodiments, the drug-free period is approximately 1 to 5 days. In some embodiments, the drug-free period is approximately 1 to 6 days. In some embodiments, the drug-free period is approximately 1 to 7 days. In some embodiments, the drug-free period is approximately 1 to 8 days. In some embodiments, the drug-free period is approximately 1 to 10 days. In some embodiments, the drug-free period is approximately 1 to 12 days. In some embodiments, the drug-free period is approximately 1 to 14 days. In some embodiments, the drug-free period is approximately 1 to 15 days. In some embodiments, the drug-free period is approximately 1 to 21 days. In some embodiments, the drug-free period is approximately 1 to 22 days. In some embodiments, the drug-free period is approximately 1 to 24 days. In some embodiments, the drug-free period is approximately 1 to 26 days. In some embodiments, the drug-free period is approximately 1 to 28 days.

[0071] In some embodiments, the drug-free period may be approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 21 days, 22 days, 24 days, 26 days, or 28 days. In some embodiments, the drug-free period is approximately 1 day. In some embodiments, the drug-free period is approximately 2 days. In some embodiments, the drug-free period is approximately 3 days. In some embodiments, the drug-free period is approximately 4 days. In some embodiments, the drug-free period is approximately 5 days. In some embodiments, the drug-free period is approximately 6 days. In some embodiments, the drug-free period is approximately 7 days. In some embodiments, the drug-free period is approximately 8 days. In some embodiments, the drug-free period is approximately 10 days. In some embodiments, the drug-free period is approximately 12 days. In some embodiments, the drug-free period is approximately 14 days. In some embodiments, the drug-free period is approximately 15 days. In some embodiments, the drug-free period is approximately 21 days. In some embodiments, the drug-free period is approximately 22 days. In some embodiments, the drug-free period is approximately 24 days. In some embodiments, the drug-free period is approximately 26 days. In some embodiments, the drug-free period is approximately 28 days.

[0072] In some embodiments, the drug-free period is provided on the third day of the treatment cycle. In some embodiments, the drug-free period is provided on the fourth day of the treatment cycle. In some embodiments, the drug-free period is provided on the fifth day of the treatment cycle. In some embodiments, the drug-free period is provided on the sixth day of the treatment cycle. In some embodiments, the drug-free period is provided on the seventh day of the treatment cycle. In some embodiments, the drug-free period is provided from the third to the seventh day of the treatment cycle. In some embodiments, the drug-free period is provided from the fourth to the seventh day of the treatment cycle. In some embodiments, the drug-free period is provided from the third to the fifth day of the treatment cycle. In some embodiments, the drug-free period is provided from the fourth to the fifth day of the treatment cycle. In some embodiments, the drug-free period is provided from the fifth to the seventh day of the treatment cycle. In some embodiments, the drug-free period is provided from the fifth to the fourteenth day of the treatment cycle. In some embodiments, the drug-free period is provided from the seventh to the fourteenth day of the treatment cycle. In some embodiments, the drug-free period is provided from the ninth to the fourteenth day of the treatment cycle. In some embodiments, the drug-free period is set between days 16 and 21 of the treatment cycle.

[0073] The drug-free period described herein may be a divided drug-free period within a given treatment cycle (for example, the total number of days of the drug-free period in a given treatment cycle may be divided throughout the course of the treatment cycle). For example, but not limited to, PCS6422 may be administered on day 1, a therapeutically effective dose of capecitabine may be administered on days 2 and 3, respectively, followed by a drug-free period on days 4 and 5. Then, a second dose of an effective dose of PCS6422 may be administered on day 6, a therapeutically effective dose of capecitabine may be administered on days 7 and 8, followed by the remaining portion of the drug-free period of the treatment cycle on days 9 to 14. In some embodiments, the drug-free period may be provided on days 4 to 7, days 11 to 14, and days 18 to 28 of the treatment cycle.

[0074] The drug-free intervals in this disclosure may be variable (for example, the drug-free interval of the first treatment cycle may be of a different length than the drug-free interval of the second treatment cycle). For example, but not limited to, the first treatment cycle may include a 3-day drug-free interval (e.g., days 3, 4, and 5 of the first treatment cycle), and the subsequent second treatment cycle may include a 5-day drug-free interval (e.g., days 3, 4, 5, 6, and 7 of the second treatment cycle). Drug-free intervals may be adjusted from one treatment cycle to the next for several reasons (e.g., as described elsewhere in this specification), including, for example, observation of adverse events in the subject and / or determined measurements of 5-FU, measured FBAL, and / or the ratio of measured FBAL to measured 5-FU (FBAL:5-FU ratio) in blood samples taken from the subject and / or subjects requiring treatment.

[0075] PCS6422 PCS6422 (chemical name 5-ethinyl-1H-pyrimidine-2,4-dione, formerly known as enyluracil, 5-ethinyluracil, 776C85, and ADH300004) is a potent and irreversible inactivator of DPD. While we do not wish to be bound by any one theory, PCS6422 is understood to redirect the 5-FU elimination pathway from metabolism to renal excretion, increasing the elimination half-life of 5-FU from 10-20 minutes to several hours. PCS6422 also prevents the formation of 5-FU catabolites such as FBAL, which are understood to cause neurotoxicity and potentially antagonize the antitumor activity of 5-FU. FBAL has also been demonstrated to reduce the antitumor activity of 5-FU in experimental animals. Furthermore, because DPD exists in fluctuating levels (e.g., within and between subjects), inactivation of DPD by PCS6422 in cancer patients can lead to improved predictability and / or linearity of the highly variable and nonlinear pharmacokinetics (PK) of 5-FU. PCS6422 is generally administered orally. In some embodiments, PCS6422 is administered orally. In some embodiments, PCS6422 is administered intravenously.

[0076] PCS6422 can be administered in an effective dose in accordance with this disclosure. In some embodiments, the effective dose of PCS6422 is the maximum tolerated dose. In some embodiments, the effective dose of PCS6422 is about 10 mg to about 60 mg, about 15 mg to about 60 mg, about 20 mg to about 60 mg, about 25 mg to about 50 mg, or 30 mg to about 50 mg. In some embodiments, the effective dose of PCS6422 is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg. In some embodiments, the effective dose of PCS6422 is about 10 mg. In some embodiments, the effective dose of PCS6422 is about 20 mg. In some embodiments, the effective dose of PCS6422 is about 30 mg. In some embodiments, the effective dose of PCS6422 is about 40 mg. In some embodiments, the effective dose of PCS6422 is approximately 50 mg. In some embodiments, the effective dose of PCS6422 is approximately 60 mg.

[0077] The effective dose of PCS6422 may be administered in divided doses (e.g., as part of a total dose) according to the methods of this disclosure. In some embodiments, a divided dose of the effective dose of PCS6422 (e.g., half a dose) is administered in the morning, and the remaining portion of the divided dose (e.g., half a dose) is administered in the evening. In some embodiments, a divided dose of the effective dose of PCS6422 is administered at time 0 on day 1 of the treatment cycle, and the remaining portion of the divided dose is administered at approximately 8 to 16 hours on day 1 of the treatment cycle. In some embodiments, the effective dose of PCS6422 is 40 mg, and is administered in divided doses of 20 mg twice daily.

[0078] Capecitabine Capecitabine (Xeloda®) is a commonly used oral fluoropyrimidine, a prodrug of 5-FU, which is converted via three enzymatic steps. First, capecitabine is converted to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase, then 5'-DFCR is converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase, and finally 5'-DFUR is converted to 5-FU by thymidine phosphorylase. Capecitabine is generally administered orally. In some embodiments, capecitabine is administered orally. In some embodiments, capecitabine is administered intravenously.

[0079] Capecitabine can be administered in a therapeutically effective dose in accordance with this disclosure. In some embodiments, the therapeutically effective dose of capecitabine is the maximum tolerated dose. In some embodiments, the therapeutically effective dose of capecitabine is about 25 mg to about 450 mg, about 25 mg to about 300 mg, about 25 mg to about 225 mg, about 25 mg to about 150 mg, about 25 mg to about 75 mg, about 50 mg to about 450 mg, about 50 mg to about 300 mg, about 50 mg to about 225 mg, about 50 mg to about 150 mg, about 75 mg to about 450 mg, about 75 mg to about 300 mg, about 75 mg to about 225 mg, or about 75 mg to about 150 mg. In some embodiments, the therapeutically effective dose of capecitabine is about 25 mg, about 50 mg, about 75 mg, about 150 mg, about 225 mg, about 300 mg, or about 450 mg. In some embodiments, the therapeutic effective dose of capecitabine is approximately 25 mg. In some embodiments, the therapeutic effective dose of capecitabine is approximately 50 mg. In some embodiments, the therapeutic effective dose of capecitabine is approximately 75 mg. In some embodiments, the therapeutic effective dose of capecitabine is approximately 150 mg. In some embodiments, the therapeutic effective dose of capecitabine is approximately 225 mg. In some embodiments, the therapeutic effective dose of capecitabine is approximately 300 mg. In some embodiments, the therapeutic effective dose of capecitabine is approximately 450 mg.

[0080] The therapeutically effective dose of capecitabine may be administered in divided doses (e.g., as part of a total dose) according to the methods of this disclosure. In some embodiments, a divided dose of the therapeutically effective dose of capecitabine (e.g., half) is administered in the morning, and the remaining portion of the divided dose (e.g., half) is administered in the evening. For example, the therapeutically effective dose of capecitabine may be about 450 mg, which can be administered in two divided doses of 225 mg each day.

[0081] Pharmacokinetic analysis Pharmacokinetic analyses can be used to evaluate capecitabine and its metabolites (for example, to personalize the methods described herein). While we do not wish to be bound by any one theory, one or more pharmacokinetic analyses of measured 5-FU, measured FBAL, and / or the ratio of measured FBAL to measured 5-FU (FBAL:5-FU ratio) may indicate when a sufficient amount of DPD has been formed (e.g., by de novo synthesis) to significantly reduce the potency and / or efficacy of 5-FU (e.g., to a level comparable to that of capecitabine administered alone). This would indicate the appropriate timing for additional administration of an effective dose of PCS6422 and / or a therapeutically effective dose of capecitabine (e.g., including an additional treatment cycle), and / or whether a subject and / or a subject requiring treatment (e.g., a subject with cancer) contains no PCS6422 and / or capecitabine, or only undetectable amounts, in blood samples taken from said subject. Alternatively, while we do not wish to be bound by any one theory, one or more pharmacokinetic analyses of measured 5-FU, measured FBAL, or FBAL:5-FU ratio may indicate when the additional dose of capecitabine is metabolized to only a low amount of 5-FU (e.g., due to the presence of excess drug in the subject and / or subject requiring treatment, e.g., due to inhibition of DPD by PCS6422), which may rather contribute to adverse events (e.g., due to catabolism of capecitabine), and therefore inform when to discontinue additional doses of therapeutically effective capecitabine to the subject and / or subject requiring treatment. Thus, such analyses can be used to individualize the frequency of (i) PCS6422 and capecitabine or (ii) capecitabine in treatment regimens and / or treatment cycles for specific subjects and / or subjects requiring treatment.Therefore, in some embodiments, a treatment cycle of the treatment regimen of the present disclosure can be repeated if at least one of the following conditions is met: the measured 5-FU is below a certain 5-FU threshold, the measured FBAL is above a certain FBAL threshold, the determined FBAL:5-FU ratio is above a certain FBAL:5-FU ratio threshold, the measured 5-FU is zero, or the measured FBAL is zero. On the other hand, in some embodiments, a treatment cycle of the treatment regimen of the present disclosure includes discontinuing the administration of an additional therapeutically effective dose of capecitabine to the subject if the measured 5-FU is below a certain 5-FU threshold, the measured FBAL is above a certain FBAL threshold, or the determined FBAL:5-FU ratio is above a certain FBAL:5-FU ratio threshold.

[0082] The pharmacokinetic analyses of this disclosure may be used in combination with other therapeutic regimen determinants to adjust the therapeutic regimens and / or therapeutic cycles of this disclosure (e.g., to individualize such methods). Such other therapeutic regimen determinants may include, for example, disease type and / or severity, subject response to therapeutic agents, etc. Such factors, combined with the pharmacokinetic analyses of this disclosure (e.g., “measurements of metabolites”), may be evaluated (e.g., by a healthcare professional) to determine therapeutic indices that can be used as a basis for adjusting the therapeutic regimens (e.g., therapeutic cycles) of this disclosure.

[0083] Several analytical methods are available, known to those skilled in the art, and usable to measure the concentration of one or more of the following: α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), doxifluridine (5'-DFUR), capecitabine, and 5-fluorouracil (5-FU). For example, but not limited to, measurements may be performed using chromatography (see, for example, Wang Z et al., J Anal Methods Chem. 2019 Jan 3;2019:9371790, Radovanovic M et al., J Chromatogr B Analyt Technol Biomed Life Sci. 2022 Jan 1;1188:123075, Chen J et al., Bioanalysis. 2010 Dec;2(12):2011-7, Knikman JE et al., Biomed Chromatogr. 2020 Jan;34(1):e4732, Knikman, JE et al. (available under SSRN ID No. 4193341)) and / or using enzyme-linked immunosorbent assay (ELISA) (see, for example, Blaschke M et al., Journal of Cancer Therapy, Vol. 3) (See No. 1, 2012, pp. 28-36.) This can be done.

[0084] The methods of the present disclosure may include measuring a blood sample taken from a subject for one or more of the following: α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), doxifluridine (5'-DFUR), capecitabine, and 5-fluorouracil (5-FU). In some embodiments, a blood sample taken from a subject was measured for α-fluoro-β-alanine (FBAL) and 5-fluorouracil (5-FU). In some embodiments, the method includes determining one or more of the measured 5-FU, the measured FBAL, and / or the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio). In some embodiments, the method includes determining the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio).

[0085] In one embodiment, the Disclosure provides a method for treating cancer in a subject in need of cancer treatment, comprising: (i) administering to the subject at least one effective dose of PCS6422; and (ii) administering to the subject at least one therapeutically effective dose of capecitabine about 12 to about 24 hours after administering at least one effective dose of PCS6422, wherein a blood sample taken from the subject is measured for one or more of the following: α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), doxifluridine (5'-DFUR), capecitabine, and 5-fluorouracil (5-FU).

[0086] In another embodiment, the Disclosure provides a method for treating cancer in a subject in need of cancer treatment, comprising: (i) administering to the subject at least one effective dose of PCS6422; (ii) administering to the subject at least one therapeutically effective dose of capecitabine about 12 to about 36 hours after the administration of at least one effective dose of PCS6422 (e.g., about 12 to about 24 hours); (iii) measuring metabolites in a blood sample taken from the subject, including one or more of α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), doxifluridine (5'-DFUR), and 5-fluorouracil (5-FU); and (iv) determining whether it is necessary to adjust the treatment regime based on a treatment index including the metabolite measurements determined in step (iii).

[0087] In another embodiment, the Disclosure provides a method for determining the frequency of administration of PCS6422 and capecitabine to a subject, comprising: (i) administering to the subject at least one effective dose of PCS6422; (ii) administering to the subject at least one therapeutically effective dose of capecitabine about 12 to about 36 hours after the administration of at least one effective dose of PCS6422 (e.g., about 12 to about 24 hours later), wherein a blood sample taken from the subject is measured for α-fluoro-β-alanine (FBAL) and 5-fluorouracil (5-FU); and (iii) measuring the measured 5-FU, The present invention provides a method comprising: determining one or more of the defined FBAL and / or the ratio of measured FBAL to measured 5-FU (FBAL:5-FU ratio); and repeating steps (i) and (ii) if, after a drug-free period, at least one of the following conditions is met: measured 5-FU was below a certain 5-FU threshold, measured FBAL was greater than or equal to a certain FBAL threshold, the determined FBAL:5-FU ratio was greater than or equal to a certain FBAL:5-FU ratio threshold, measured 5-FU was zero, or measured FBAL was zero.

[0088] In yet another embodiment, the Disclosure provides a method for determining the frequency of administration of capecitabine to a subject, comprising: (i) administering to the subject at least one effective dose of PCS6422; and (ii) administering to the subject at least one therapeutically effective dose of capecitabine about 12 to about 36 hours after the administration of at least one effective dose of PCS6422 (e.g., about 12 to about 24 hours later), wherein a blood sample taken from the subject is measured for α-fluoro-β-alanine (FBAL) and / or 5-fluorouracil (5-FU). The present invention provides a method comprising: (iii) administering; determining one or more of the measured 5-FU, measured FBAL, or the ratio of measured FBAL to measured 5-FU (FBAL:5-FU ratio); and (iv) discontinuing the administration of an additional therapeutically effective dose of capecitabine to the subject if the measured 5-FU is below a certain 5-FU threshold, the measured FBAL is above a certain FBAL threshold, or the determined FBAL:5-FU ratio is above a certain FBAL:5-FU ratio threshold.

[0089] In some embodiments, the method of the present disclosure may include discontinuing the administration of an additional therapeutically effective dose of capecitabine to a subject if the measured 5-FU is below a certain 5-FU threshold, the measured FBAL is above a certain FBAL threshold, or the determined FBAL:5-FU ratio is above a certain FBAL:5-FU ratio threshold. In some such embodiments, a drug-free period (e.g., as described herein) is provided after discontinuing the administration of an additional therapeutically effective dose of capecitabine to a subject. In some embodiments, steps (i) and (ii) are repeated after the drug-free period (e.g., if the measured 5-FU is zero and / or the measured FBAL is zero).

[0090] In some embodiments, steps (i) and (ii) can be repeated if, about 1 to 29 days after step (ii) of the method described herein, at least one of the following conditions is met: the measured 5-FU was below a certain 5-FU threshold, the measured FBAL was above a certain FBAL threshold, the determined FBAL:5-FU ratio was above a certain FBAL:5-FU ratio threshold, the measured 5-FU was zero, or the measured FBAL was zero.

[0091] In some embodiments, steps (i) and (ii) can be repeated if, about 1 to 29 days after step (ii) of the method described herein, the therapeutic index, including the metabolite measurement of step (iii), indicates that, among the other therapeutic regimen determinants described herein, the measured 5-FU was below a certain 5-FU threshold, the measured FBAL was above a certain FBAL threshold, the determined FBAL:5-FU ratio was above a certain FBAL:5-FU ratio threshold, the measured 5-FU was zero, or the measured FBAL was zero.

[0092] In some embodiments, steps (i) and (ii) can be repeated if the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold about 1 to 29 days after step (ii) of the method described herein. In some embodiments, steps (i) and (ii) are repeated if the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold about 1 to 22 days after step (ii). In some embodiments, steps (i) and (ii) are repeated if the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold about 1 to 15 days after step (ii). In some embodiments, steps (i) and (ii) are repeated if the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold about 1 to 12 days after step (ii). In some embodiments, if the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold approximately 1 to 10 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold approximately 1 to 8 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold approximately 1 to 6 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold approximately 1 to 4 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold approximately 1 to 2 days after step (ii), steps (i) and (ii) are repeated.In some embodiments, if the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold approximately one day after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold approximately two days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold approximately three days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold approximately four days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold approximately five days after step (ii), steps (i) and (ii) are repeated. In some embodiments, steps (i) and (ii) are repeated if, approximately 6 days after step (ii), the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 7 days after step (ii), the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 8 days after step (ii), the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 10 days after step (ii), the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 12 days after step (ii), the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold.In some embodiments, steps (i) and (ii) are repeated if, approximately 14 days after step (ii), the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 15 days after step (ii), the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 21 days after step (ii), the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 22 days after step (ii), the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 28 days after step (ii), the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 29 days after step (ii), the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold.

[0093] In some embodiments, steps (i) and (ii) are not repeated if the determined FBAL:5-FU ratio is below a certain FBAL:5-FU ratio threshold.

[0094] In some embodiments, if, after step (ii) of the method described herein, the determined FBAL:5-FU ratio is greater than or equal to a specific FBAL:5-FU ratio threshold, the administration of an additional therapeutically effective dose of capecitabine to the subject is discontinued.

[0095] In some embodiments, if, after step (ii) of the method described herein, the determined FBAL:5-FU ratio is below a certain FBAL:5-FU ratio threshold, the administration of an additional therapeutically effective dose of capecitabine to the subject is continued.

[0096] A particular FBAL:5-FU ratio threshold can be determined as approximately 2 to approximately 15, approximately 4 to approximately 15, approximately 6 to approximately 15, approximately 2 to approximately 12, approximately 4 to approximately 12, approximately 6 to approximately 12, approximately 2 to approximately 10, approximately 4 to approximately 10, or approximately 6 to approximately 10. In some embodiments, a particular FBAL:5-FU ratio threshold can be determined as approximately 5, approximately 5.5, approximately 6, approximately 6.5, approximately 7, approximately 7.5, approximately 8, approximately 8.5, approximately 9, approximately 9.5, approximately 10, approximately 10.5, approximately 11, approximately 11.5, approximately 12, approximately 12.5, approximately 13, approximately 13.5, approximately 14, approximately 14.5, or approximately 15. In some embodiments, a particular FBAL:5-FU ratio threshold can be determined as approximately 5. In some embodiments, a particular FBAL:5-FU ratio threshold can be determined as approximately 5.5. In some embodiments, a particular FBAL:5-FU ratio threshold can be determined as approximately 6. In some embodiments, a particular FBAL:5-FU ratio threshold can be determined as approximately 6.5. In some embodiments, a particular FBAL:5-FU ratio threshold can be determined as approximately 7. In some embodiments, a particular FBAL:5-FU ratio threshold can be determined as approximately 7.5. In some embodiments, a particular FBAL:5-FU ratio threshold can be determined as approximately 8. In some embodiments, a particular FBAL:5-FU ratio threshold can be determined as approximately 8.5. In some embodiments, a particular FBAL:5-FU ratio threshold can be determined as approximately 9. In some embodiments, a particular FBAL:5-FU ratio threshold can be determined as approximately 9.5. In some embodiments, a particular FBAL:5-FU ratio threshold can be determined as approximately 10.

[0097] In some embodiments, steps (i) and (ii) can be repeated if, about 1 to 29 days after step (ii) of the method described herein, the 5-FU determined by measurement is below a certain 5-FU threshold. In some embodiments, steps (i) and (ii) can be repeated if, about 1 to 22 days after step (ii) of the method described herein, the 5-FU determined by measurement is below a certain 5-FU threshold. In some embodiments, steps (i) and (ii) can be repeated if, about 1 to 15 days after step (ii) of the method described herein, the 5-FU determined by measurement is below a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated if, about 1 to 12 days after step (ii), the 5-FU determined by measurement is below a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 1 to 10 days after step (ii), the 5-FU determined by measurement is below a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 1 to 8 days after step (ii), the 5-FU determined by measurement is below a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 1 to 6 days after step (ii), the 5-FU determined by measurement is below a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 1 to 4 days after step (ii), the 5-FU determined by measurement is below a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 1 to 2 days after step (ii), the 5-FU determined by measurement is below a certain 5-FU threshold. In some embodiments, if, about one day after step (ii), the 5-FU determined by measurement is below a certain 5-FU threshold, steps (i) and (ii) are repeated.In some embodiments, if the 5-FU determined by measurement is below a certain 5-FU threshold approximately two days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is below a certain 5-FU threshold approximately three days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is below a certain 5-FU threshold approximately four days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is below a certain 5-FU threshold approximately five days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is below a certain 5-FU threshold approximately six days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is below a certain 5-FU threshold approximately 7 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is below a certain 5-FU threshold approximately 8 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is below a certain 5-FU threshold approximately 10 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is below a certain 5-FU threshold approximately 12 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is below a certain 5-FU threshold approximately 14 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, steps (i) and (ii) are repeated if, approximately 15 days after step (ii), the 5-FU determined by measurement is below a certain 5-FU threshold.In some embodiments, steps (i) and (ii) are repeated if, approximately 21 days after step (ii), the 5-FU determined by measurement is below a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 22 days after step (ii), the 5-FU determined by measurement is below a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 28 days after step (ii), the 5-FU determined by measurement is below a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 29 days after step (ii), the 5-FU determined by measurement is below a certain 5-FU threshold.

[0098] In some embodiments, if the 5-FU determined by measurement is above a certain 5-FU threshold, steps (i) and (ii) are not repeated.

[0099] In some embodiments, if the 5-FU determined by measurement is zero about 1 day to about 29 days after step (ii) of the method described herein, steps (i) and (ii) may be repeated. In some embodiments, if the 5-FU determined by measurement is zero about 1 day to about 22 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero about 1 day to about 15 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero about 1 day to about 12 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero about 1 day to about 10 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 1 to 8 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 1 to 6 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 1 to 4 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 1 to 2 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 1 day after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 2 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately three days after step (ii), steps (i) and (ii) are repeated.In some embodiments, if the 5-FU determined by measurement is zero approximately 4 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 5 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 6 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 7 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 8 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 10 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 12 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 14 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 15 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 21 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 22 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FU determined by measurement is zero approximately 28 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, steps (i) and (ii) are repeated if, approximately 29 days after step (ii), the 5-FU determined by measurement is zero.

[0100] In some embodiments, if the 5-FU determined by measurement is greater than zero, steps (i) and (ii) are not repeated.

[0101] In some embodiments, if, after step (ii) of the method described herein, the administration of an additional therapeutically effective dose of capecitabine to the subject is discontinued if the 5-FU determined by measurement is below a certain 5-FU threshold.

[0102] In some embodiments, if, after step (ii) of the method described herein, the 5-FU determined by measurement is above a certain 5-FU threshold, the administration of an additional therapeutically effective dose of capecitabine to the subject is continued.

[0103] A particular 5-FU threshold can be determined as approximately 0 ng / mL to 5 ng / mL, approximately 0 ng / mL to 4 ng / mL, approximately 0 ng / mL to 3 ng / mL, approximately 1 ng / mL to 5 ng / mL, approximately 1 to 4 ng / mL, approximately 1 ng / mL to 3 ng / mL, approximately 1.5 ng / mL to 5 ng / mL, approximately 1.5 ng / mL to 4 ng / mL, or approximately 1.5 ng / mL to 3 ng / mL. In some embodiments, a particular 5-FU threshold can be determined as approximately 0.5 ng / mL, approximately 1 ng / mL, approximately 1.5 ng / mL, approximately 2 ng / mL, approximately 2.5 ng / mL, approximately 3 ng / mL, approximately 3.5 ng / mL, approximately 4 ng / mL, approximately 4.5 ng / mL, or approximately 5 ng / mL. In some embodiments, a particular 5-FU threshold can be determined as approximately 0 ng / mL. In some embodiments, a particular 5-FU threshold can be determined as approximately 0.5 ng / mL. In some embodiments, a particular 5-FU threshold can be determined as approximately 1 ng / mL. In some embodiments, a particular 5-FU threshold can be determined as approximately 2 ng / mL. In some embodiments, a particular 5-FU threshold can be determined as approximately 3 ng / mL. In some embodiments, a particular 5-FU threshold can be determined as approximately 4 ng / mL. In some embodiments, a particular 5-FU threshold can be determined as approximately 5 ng / mL.

[0104] In some embodiments, steps (i) and (ii) can be repeated if the FBAL determined by measurement is above a certain FBAL threshold approximately 1 to 29 days after step (ii) of the method described herein. In some embodiments, steps (i) and (ii) can be repeated if the FBAL determined by measurement is above a certain FBAL threshold approximately 1 to 22 days after step (ii) of the method described herein. In some embodiments, steps (i) and (ii) can be repeated if the FBAL determined by measurement is above a certain FBAL threshold approximately 1 to 15 days after step (ii) of the method described herein. In some embodiments, steps (i) and (ii) are repeated if the FBAL determined by measurement is above a certain FBAL threshold approximately 1 to 12 days after step (ii). In some embodiments, steps (i) and (ii) are repeated if the FBAL determined by measurement is above a certain FBAL threshold approximately 1 to 10 days after step (ii). In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately 1 to 8 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately 1 to 6 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately 1 to 4 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately 1 to 2 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately 1 day after step (ii), steps (i) and (ii) are repeated.In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately two days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately three days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately four days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately five days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately six days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately seven days after step (ii), steps (i) and (ii) are repeated. In some embodiments, steps (i) and (ii) are repeated if, approximately 8 days after step (ii), the FBAL determined by measurement is greater than or equal to a specific FBAL threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 10 days after step (ii), the FBAL determined by measurement is greater than or equal to a specific FBAL threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 12 days after step (ii), the 5-FBAL determined by measurement is greater than or equal to a specific FBAL threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 14 days after step (ii), the FBAL determined by measurement is greater than or equal to a specific FBAL threshold. In some embodiments, steps (i) and (ii) are repeated if, approximately 15 days after step (ii), the FBAL determined by measurement is greater than or equal to a specific FBAL threshold.In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately 21 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately 22 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately 28 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is above a certain FBAL threshold approximately 29 days after step (ii), steps (i) and (ii) are repeated.

[0105] In some embodiments, steps (i) and (ii) are not repeated if the FBAL determined by measurement is below a certain FBAL threshold.

[0106] In some embodiments, if the FBAL determined by measurement is zero about 1 to 29 days after step (ii) of the method described herein, steps (i) and (ii) can be repeated. In some embodiments, if the FBAL determined by measurement is zero about 1 to 22 days after step (ii) of the method described herein, steps (i) and (ii) can be repeated. In some embodiments, if the FBAL determined by measurement is zero about 1 to 15 days after step (ii) of the method described herein, steps (i) and (ii) can be repeated. In some embodiments, if the FBAL determined by measurement is zero about 1 to 12 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero about 1 to 10 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 1 to 8 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 1 to 6 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 1 to 4 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 1 to 2 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 1 day after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 2 days after step (ii), steps (i) and (ii) are repeated.In some embodiments, if the FBAL determined by measurement is zero approximately 3 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 4 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 5 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 6 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 7 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 8 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 10 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the 5-FBAL determined by measurement is zero approximately 12 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 14 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 15 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 21 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, if the FBAL determined by measurement is zero approximately 22 days after step (ii), steps (i) and (ii) are repeated. In some embodiments, steps (i) and (ii) are repeated if, approximately 28 days after step (ii), the FBAL determined by measurement is zero.In some embodiments, steps (i) and (ii) are repeated if, approximately 29 days after step (ii), the FBAL determined by measurement is zero.

[0107] In some embodiments, if the FBAL determined by measurement is greater than zero, steps (i) and (ii) are not repeated.

[0108] In some embodiments, if, after step (ii) of the method described herein, the FBAL determined by measurement is above a certain FBAL threshold, the administration of an additional therapeutically effective dose of capecitabine to the subject is discontinued.

[0109] In some embodiments, if, after step (ii) of the method described herein, the FBAL determined by measurement is below a certain FBAL threshold, the administration of an additional therapeutically effective dose of capecitabine to the subject is continued.

[0110] A particular FBAL threshold can be determined as approximately 5 ng / mL to approximately 50 ng / mL, approximately 10 ng / mL to approximately 50 ng / mL, approximately 15 ng / mL to approximately 50 ng / mL, approximately 5 ng / mL to approximately 40 ng / mL, approximately 10 ng / mL to approximately 40 ng / mL, or approximately 15 ng / mL to approximately 40 ng / mL, approximately 5 ng / mL to approximately 30 ng / mL, approximately 10 ng / mL to approximately 30 ng / mL, or approximately 15 ng / mL to approximately 30 ng / mL. In some embodiments, a particular FBAL threshold can be determined as approximately 5 ng / mL, approximately 10 ng / mL, approximately 15 ng / mL, approximately 20 ng / mL, approximately 25 ng / mL, approximately 30 ng / mL, approximately 35 ng / mL, approximately 40 ng / mL, approximately 45 ng / mL, or approximately 50 ng / mL. In some embodiments, a particular FBAL threshold can be determined as approximately 5 ng / mL. In some embodiments, a particular FBAL threshold can be determined as approximately 10 ng / mL. In some embodiments, a particular FBAL threshold can be determined as approximately 15 ng / mL. In some embodiments, a particular FBAL threshold can be determined as approximately 20 ng / mL. In some embodiments, a particular FBAL threshold can be determined as approximately 25 ng / mL. In some embodiments, a particular FBAL threshold can be determined as approximately 30 ng / mL. In some embodiments, a particular FBAL threshold can be determined as approximately 35 ng / mL. In some embodiments, a particular FBAL threshold can be determined as approximately 40 ng / mL. In some embodiments, a particular FBAL threshold can be determined as approximately 45 ng / mL. In some embodiments, a particular FBAL threshold can be determined as approximately 50 ng / mL. In some embodiments, a particular FBAL threshold can be determined as approximately 0 ng / mL.

[0111] Blood samples taken from a subject for use in accordance with the methods of this disclosure may be taken at one or more points in time during the course of a treatment cycle. In some embodiments, blood samples taken from a subject may be taken in the morning (for example, before administering a single dose of a therapeutically effective dose of capecitabine to the subject). In some embodiments, blood samples taken from a subject may be taken in the evening (for example, before administering a divided dose of a therapeutically effective dose of capecitabine to the subject and / or about 12 hours after administering a therapeutically effective dose of capecitabine in the morning). In some embodiments, blood samples taken from a subject may be taken about 24 hours after administration of an effective dose of PCS6422.

[0112] Blood samples taken from subjects are collected approximately 12 to 24 hours after administering a therapeutically effective dose of capecitabine to the subject (for example, before additional administration of capecitabine, e.g., C min) can be collected. In some embodiments, blood samples collected from subjects were collected daily after at least one administration of a therapeutically effective dose of capecitabine. In some embodiments, blood samples collected from subjects were obtained on each day from day 2 to 29 of the treatment cycle. In some embodiments, blood samples collected from subjects were obtained on each day from day 2 to 28 of the treatment cycle. In some embodiments, blood samples collected from subjects were obtained on each day from day 2 to 22 of the treatment cycle. In some embodiments, blood samples collected from subjects were obtained on each day from day 2 to 21 of the treatment cycle. In some embodiments, blood samples collected from subjects were obtained on each day from day 2 to 15 of the treatment cycle. In some embodiments, blood samples collected from subjects were obtained on each day from day 2 to 14 of the treatment cycle. In some embodiments, blood samples collected from subjects were obtained on each day from day 2 to 10 of the treatment cycle. In some embodiments, blood samples collected from subjects were obtained on each day from day 2 to 9 of the treatment cycle. In some embodiments, blood samples collected from subjects were obtained on each day from day 2 to 8 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 2 to day 7 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 2 to day 6 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 2 to day 5 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 2 to day 4 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 2 to day 3 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 3 to day 10 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 3 to day 9 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 3 to day 8 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 3 to day 7 of the treatment cycle.In some embodiments, blood samples were obtained from subjects on each day from day 3 to day 6 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 3 to day 5 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 3 to day 4 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 4 to day 10 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 4 to day 9 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 4 to day 8 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 4 to day 7 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 4 to day 6 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 4 to day 5 of the treatment cycle. In some embodiments, blood samples were obtained from subjects on each day from day 2 to day 4 and day 6 to day 14 of the treatment cycle. In some embodiments, blood samples taken from subjects were obtained on days 2–7, 9–14, and 16–28 of the treatment cycle.

[0113] In some embodiments, one or more of FBAL, 5'-DFCR, 5'-DFUR, capecitabine, and 5-FU were measured daily from the first day of capecitabine treatment (e.g., before the first dose of capecitabine). In some embodiments, FBAL and 5-FU were measured daily from the first day of capecitabine treatment (e.g., before the first dose of capecitabine). In some embodiments, one or more of FBAL, 5'-DFCR, 5'-DFUR, capecitabine, and 5-FU were measured at each point in time when a blood sample was taken from the subject.

[0114] Target group Subjects requiring treatment and / or subject to the techniques described herein include, but are not limited to, humans and non-human vertebrates. In some embodiments, subjects requiring treatment and / or subject to the techniques disclosed herein include, for example, mammals. Examples of mammals include, but are not limited to, domestic pets (e.g., dogs, cats, rabbits, hamsters), livestock and / or farm animals (e.g., cattle, pigs, sheep, goats, chickens or other poultry), horses, monkeys, and laboratory animals (e.g., mice, rats, rabbits). In a preferred embodiment, the subject requiring treatment and / or subject to the methods described herein is a human.

[0115] The subjects of this disclosure and / or subjects requiring treatment may be adults (e.g., adult humans). In some embodiments, the subjects and / or subjects requiring treatment are human subjects aged 18 years or older. In some embodiments, the subjects and / or subjects requiring treatment are human subjects aged 21 years or older. In some embodiments, the subjects and / or subjects requiring treatment are human subjects aged 45 years or older. In some embodiments, the subjects and / or subjects requiring treatment are human subjects aged 65 years or older. In some embodiments, the subjects and / or subjects requiring treatment are human subjects under 45 years of age (or between 18 and 45 years of age, or between 21 and 45 years of age). In some embodiments, the subjects and / or subjects requiring treatment are human subjects under 65 years of age (or between 18 and 65 years of age, between 21 and 65 years of age, or between 45 and 65 years of age).

[0116] The subjects of this disclosure and / or subjects requiring treatment may be non-adults (e.g., children, adolescents). In some embodiments, the subjects and / or subjects requiring treatment are human subjects under 18 years of age. In some embodiments, the subjects and / or subjects requiring treatment are human subjects under 12 years of age. In some embodiments, the subjects and / or subjects requiring treatment are human subjects under 5 years of age.

[0117] In some embodiments, the methods described herein may be used and / or implemented in any subject having cancer (e.g., diagnosed with cancer) (e.g., cancer that may and / or is likely to benefit from the methods described herein). Subjects having tumors (e.g., solid tumors) are subjects having detectable tumor cells. This disclosure intends, among other things, to use any of the methods described herein to treat cancer in subjects in need of treatment and / or to determine the frequency of administration of (i) PCS6422 and capecitabine or (ii) capecitabine to subjects (e.g., subjects in need of treatment).

[0118] In some embodiments, the methods of this disclosure can be used on subjects who have cancer and / or require treatment. Subjects who have cancer and / or require treatment have detectable cancer cells. Examples of cancers that can be treated in some embodiments according to the technology of this disclosure include, without limitation, adrenocortical carcinoma, astrocytoma, basal cell carcinoma, breast cancer, carcinoid, cardiac cancer, cholangiocarcinoma, chordoma, chronic myeloproliferative neoplasm, craniopharyngioma, ductal carcinoma in situ (DCIS), ependymoma, intraocular melanoma, gastrointestinal tumors (e.g., gastrointestinal carcinoid tumors, colorectal tumors, gastrointestinal stromal tumors (GIST)), gestational trophoblastic disease, glioma, histiocytosis, leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), hairy cell leukemia, myeloid leukemia, myeloid leukemia), lymphoma (e.g., Burkitt lymphoma (non-Hodgkin lymphoma), cutaneous T-cell lymphoma, Hodgkin lymphoma) (e.g., kin lymphoma, mycosis fungoides, Sézary syndrome, AIDS-associated lymphoma, follicular lymphoma, diffuse large B-cell lymphoma), melanoma, Merkel cell carcinoma, malignant mesothelioma, myeloma (e.g., multiple myeloma), myelodysplastic syndrome, pancreatic tumors, papillomatosis, paraganglioma, pheochromocytoma, pleuroblastoma, retinoblastoma, sarcoma (e.g., Ewing's sarcoma, Kaposi's sarcoma, osteosarcoma, rhabdomyosarcoma, etc.) Examples of cancers include cysarcoma (angiosarcoma), Wilms' tumor, and / or cancers of the adrenal cortex, anus, appendix, bile duct, bladder, bone, brain, breast, bronchi, central nervous system, cervix, colon, large intestine, endometrium, esophagus, eye, fallopian tube, gallbladder, digestive tract, germ cells, head and neck, heart, intestines, kidneys (e.g., Wilms' tumor), larynx, liver, lungs (e.g., non-small cell lung cancer, small cell lung cancer), mouth, nasal cavity, oral cavity, ovaries, pancreas, rectum, skin, stomach, testes, throat, thyroid gland, penis, pharynx, peritoneum, pituitary gland, prostate, rectum, salivary glands, ureters, urethra, uterus, vagina, or vulva. In some embodiments, the subject and / or subject requiring treatment has colorectal cancer (e.g., metastatic colorectal cancer). In some embodiments, the subject and / or subject requiring treatment has gastrointestinal cancer (e.g., metastatic gastrointestinal cancer).In some embodiments, the subject and / or subject requiring treatment has breast cancer (e.g., metastatic breast cancer). In some embodiments, the subject and / or subject requiring treatment has pancreatic cancer (e.g., metastatic pancreatic cancer).

[0119] The cancers described herein may include one or more tumors, such as solid tumors. Examples of solid tumors include, but are not limited to, tumors of the bladder, breast, central nervous system, cervix, colon, large intestine, esophagus, endometrium, gastrointestinal tract, head and neck, liver, lung, ovary, pancreas, skin, stomach, uterus, and / or upper respiratory tract.

[0120] The cancers described herein may be advanced-stage cancers (e.g., metastatic cancer, stage 3 cancer, stage 4 cancer). Advanced cancers may be considered and / or judged (e.g., by a typical physician) to be unlikely to be cured and / or controlled by therapeutic intervention. The cancers described herein may be refractory (e.g., cancer that does not respond to treatment).

[0121] The tests for diagnosing cancers treated by the methods described herein are known in the art and will be familiar to a typical physician. These clinical tests include, but are not limited to, microscopic analysis, culture-dependent tests (e.g., cultures), and nucleic acid detection tests. These include wet specimens, stain-enhanced microscopy, immunomicroscopy (e.g., FISH), hybridization microscopy, particle agglutination, enzyme-linked immunosorbent assay (ELISA), urine screening tests, DNA probe hybridization, and serological tests. In general, in addition to the clinical tests described above, a physician will take a detailed medical history and perform a complete physical examination.

[0122] In some embodiments, the subject and / or subject requiring treatment has previously received one or more other cancer treatments (e.g., chemotherapy, radiotherapy, or surgical tumor resection). In certain embodiments, the subject and / or subject requiring treatment has previously received one or more other cancer treatments (e.g., chemotherapy, radiotherapy, or surgical tumor resection) and the subject's cancer has recurred. In certain embodiments, the subject and / or subject requiring treatment has previously received one or more other cancer treatments (e.g., chemotherapy, radiotherapy, or stem cell transplantation) and the subject has developed resistance to one or more other cancer treatments. In certain embodiments, the subject and / or subject requiring treatment is in remission (e.g., partial or complete remission of cancer). In certain embodiments, the subject and / or subject requiring treatment is refractory to one or more other cancer treatments (e.g., chemotherapy, radiotherapy, or stem cell transplantation).

[0123] In other embodiments, the subject herein contemplates treating subjects at risk of developing cancer who are likely to benefit (or are likely to benefit) from any treatment regimen described herein, in accordance with the treatment methods and uses described herein. Subjects at risk of developing cancer are those who have a higher-than-average probability of developing cancer. These subjects include, for example, those with genetic abnormalities shown to be associated with a higher risk of developing cancer, those with a familial predisposition to cancer, those exposed to cancer-causing factors (i.e., carcinogens) such as tobacco, asbestos, or other chemical toxic substances, and those who have previously received treatment for cancer and appear to be in apparent remission. The disclosure intends to administer PCS6422 and capecitabine, or compositions containing them, as described herein, to subjects at risk of developing cancer.

[0124] Genetic variants of the DPYD gene, which encodes dihydropyrimidine dehydrogenase (DPD), can result in enzymes with reduced or absent DPD enzyme activity. While we do not wish to be bound by any one theory, it is understood that subjects with at least one copy of a non-functional DPYD variant are unable to metabolize fluorouracil (e.g., 5-FU) at a normal rate. As a result, these subjects are at increased risk of potentially life-threatening fluorouracil toxicity, including myelosuppression, gastrointestinal toxicity, and rarely, neurotoxicity. Therefore, subjects following the techniques of this disclosure and / or those requiring treatment may include subjects with at least partial DPD enzyme activity (e.g., DPYD normal metabolizers, DPYD intermediate metabolizers). DPYD normal metabolizers have fully functional DPD enzyme activity. DPYD intermediate metabolizers may have DPD enzyme activity reduced by about 30% to about 70% compared to the normal population. In some embodiments, subjects following the techniques of this disclosure and / or those requiring treatment are DPYD normal metabolizers. In some embodiments, the subjects and / or subjects requiring treatment according to the technology of this disclosure are DPYD intermediate metabolizers.

[0125] In some embodiments, subjects and / or subjects requiring treatment according to the techniques of the present disclosure exhibit at least about 1% of normal DPD enzyme activity, at least about 5% of normal DPD enzyme activity, at least about 10% of normal DPD enzyme activity, at least about 20% of normal DPD enzyme activity, at least about 30% of normal DPD enzyme activity, at least about 40% of normal DPD enzyme activity, at least about 50% of normal DPD enzyme activity, at least about 60% of normal DPD enzyme activity, at least about 70% of normal DPD enzyme activity, at least about 80% of normal DPD enzyme activity, at least about 90% of normal DPD enzyme activity, and at least about 95% of normal DPD enzyme activity. In some embodiments, subjects and / or subjects requiring treatment according to the techniques of the present disclosure exhibit approximately 100% of normal DPD enzyme activity, approximately 95% of normal DPD enzyme activity, approximately 90% of normal DPD enzyme activity, approximately 85% of normal DPD enzyme activity, approximately 80% of normal DPD enzyme activity, approximately 75% of normal DPD enzyme activity, approximately 70% of normal DPD enzyme activity, approximately 60% of normal DPD activity, approximately 50% of normal DPD enzyme activity, approximately 40% of normal DPD enzyme activity, approximately 30% of normal DPD enzyme activity, approximately 20% of normal DPD enzyme activity, approximately 10% of normal DPD enzyme activity, approximately 5% of normal DPD enzyme activity, or approximately 1% of normal DPD enzyme activity.

[0126] For subjects exhibiting reduced DPD enzyme activity (e.g., DPYD intermediate metabolizers), the therapeutic effective dose of capecitabine can be reduced. In some embodiments, the therapeutic effective dose of capecitabine is reduced by at least about 50%, for example, by 60%, 70%, 80%, 90%, 95%, or more.

[0127] In some embodiments, subjects subject to the techniques of this disclosure and / or subjects requiring treatment are not subjects lacking DPD enzyme activity (e.g., DPD enzyme activity of 0% or below the limit of quantification), also referred to herein as “DPD deficiency.” In some embodiments, subjects subject to the techniques of this disclosure and / or subjects requiring treatment are subjects lacking DPD enzyme activity (DPD deficiency).

[0128] Several methods are available and known to those skilled in the art for measuring and evaluating DPD enzyme activity, and can be used to determine whether a subject and / or subject requiring treatment is a normal DPYD metabolizer, an intermediate DPYD metabolizer, or has DPD deficiency. For example, but not limited to, DPD enzyme activity can be measured and evaluated in peripheral blood mononuclear cells (PBMCs) by measuring the concentrations of uracil and thymine (endogenous substrates of DPD) using reversed-phase high-performance liquid chromatography and electrospray tandem mass spectrometry. See, for example, Henricks LM et al., Int J Cancer. 2018 Jan 15;142(2):424-430.

[0129] The DPD enzyme activity of a particular subject and / or subject requiring treatment may be determined based on the presence or absence of specific variants in the DYPD gene associated with a certain degree of DPD enzyme activity. Several methods for determining the presence or absence of specific variants in the DYPD gene of a subject and / or subject requiring treatment are readily available and known to those skilled in the art, including, for example, Sanger sequencing and next-generation sequencing. Examples of specific DYPD variants and their associated DPD enzyme activity are shown in Table 1. [Table 1]

[0130] In some embodiments, subjects subject to the techniques of this disclosure and / or those requiring treatment are not subject to one or more of the following: significantly impaired renal function, current brain metastases, prolongation of a heart rate-corrected QT interval greater than 480 milliseconds, a history of QTc prolongation, ventricular tachycardia / ventricular fibrillation, or a major ventricular arrhythmia, or a history of torsades de pointe or ventricular ablation for a ventricular arrhythmia, a history of or presence of a clinically significant 12-lead electrocardiogram abnormality, congenital long QT syndrome or a family history thereof, other major heart conditions (e.g., uncontrolled angina, myocardial ischemia or myocardial infarction within the last 6 months, congestive heart failure greater than class II according to the New York Heart Association (NYHA) classification, or a history of myocarditis), electrolyte abnormalities (e.g., uncorrected hypokalemia / hyperkalemia, hypomagnesemia, or hypocalcemia), known hypersensitivity to PCS6422 and / or capecitabine, and / or being pregnant or lactating.

[0131] Characterization Subjects and / or subjects requiring treatment who are subject to the technology of this disclosure may be evaluated for one or more of the following: adverse events (e.g., any undesirable medical events in subjects and / or subjects requiring treatment), sustained clinical benefit, favorable response, long-term benefit, objective response, objective response rate, and / or progression-free survival. The technology of this disclosure may provide one or more of the following compared to appropriate criteria (e.g., subjects and / or subjects requiring treatment who have been administered a PCS6422 and capecitabine treatment regimen not described herein, or subjects and / or subjects requiring treatment who have been administered a PCS6422 and capecitabine treatment regimen without the individualization described herein): reduced adverse events and / or sustained clinical benefit, favorable response, long-term benefit, objective response, objective response rate, and / or increased progression-free survival.

[0132] Examples of treatment regimens The above administration dates and / or administration periods, dosages, drug-free periods, and / or pharmacokinetic analyses are not limited to any particular combination, and any of the embodiments described above may be used in any combination. The following treatment regimens describe specific examples of the above embodiment combinations.

[0133] In one embodiment, the treatment regimen of the present disclosure includes administering a single effective dose of PCS6422 on day 1 of the treatment cycle, administering a single therapeutically effective dose of capecitabine on day 2 of the treatment cycle, and providing drug-free periods on days 3 and 4 of the treatment cycle. In some embodiments, the treatment cycle is repeated (for example, based on the results of pharmacokinetic analysis as described herein).

[0134] In one embodiment, the treatment regimen of the present disclosure includes administering a single dose of 40 mg of PCS6422 on day 1 of the treatment cycle (i.e., in the morning), administering capecitabine in divided doses of 50 to 450 mg per day on each of days 2 to 6 of the treatment cycle, and having a drug-free period from day 7 to 14 of the treatment cycle. In some embodiments, the treatment cycle is repeated (for example, based on the results of pharmacokinetic analysis as described herein).

[0135] In one embodiment, the treatment regimen of the present disclosure includes administering a single dose of 40 mg of PCS6422 on day 1 of the treatment cycle (i.e., in the morning), administering capecitabine in divided doses of 50-450 mg per day on each of days 2 and 3 of the treatment cycle, having a drug-free period on days 4 and 5 of the treatment cycle, administering a single dose of 40 mg of PCS6422 on day 6 of the treatment cycle (i.e., in the morning), administering capecitabine in divided doses of 50-450 mg per day on each of days 7 and 8 of the treatment cycle, and having a drug-free period on days 9 to 14 of the treatment cycle. In some embodiments, the treatment cycle is repeated (for example, based on the results of pharmacokinetic analyses described herein).

[0136] In one embodiment, the first treatment cycle regimen of the present disclosure includes administering PCS6422 as a single dose of 40 mg on day 1 of the treatment cycle (i.e., morning), administering capecitabine in divided doses of 50-450 mg per day on each of days 2-8 of the treatment cycle, and having a drug-free period on days 9-14 of the treatment cycle. On days 3-9 of the first treatment cycle, blood samples taken from subjects were measured for one or more of the following: α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), doxifluridine (5'-DFUR), capecitabine, and 5-fluorouracil (5-FU), and the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio) was determined. Based on one or more of the measured 5-FU, measured FBAL, and / or FBAL:5-FU ratio, the total number of capecitabine administration days is adjusted in the second treatment cycle to coincide with the point at which PCS6422 no longer has an effect on the potency.

[0137] In one embodiment, the first treatment cycle regimen of the present disclosure includes administering PCS6422 as a single dose of 40 mg on day 1 of the treatment cycle (i.e., morning), administering capecitabine in divided doses of 50-450 mg per day on each of days 2-4 of the treatment cycle, and having a drug-free period on days 5-7 of the treatment cycle. On days 3-4 of the first treatment cycle, blood samples taken from subjects are measured for one or more of the following: α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), doxifluridine (5'-DFUR), capecitabine, and 5-fluorouracil (5-FU), and the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio) is determined. Based on one or more of the measured 5-FU, measured FBAL, and / or FBAL:5-FU ratio, the total number of capecitabine administration days is adjusted in the second treatment cycle to coincide with the point in time when PCS6422 no longer has an effect on the potency, or has the least effect, while simultaneously ensuring at least three capecitabine-free days (including the PCS6422 administration days in the second treatment cycle) and making the entire treatment cycle seven days long. In some embodiments, every third treatment cycle is replaced by a seven-day rest period.

[0138] In one embodiment, a treatment regimen for a treatment cycle of the present disclosure includes administering PCS6422 as a single dose of 40 mg on day 1 of the treatment cycle (i.e., morning), and administering capecitabine in divided doses of 50 to 450 mg per day on each of days 2 to 4 of the treatment cycle. On each of days 2 to 4 of the treatment cycle, blood samples taken from subjects are measured for one or more of the following: α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), doxifluridine (5'-DFUR), capecitabine, and 5-fluorouracil (5-FU), and the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio) is determined. Based on the measured 5-FU, measured FBAL, or FBAL:5-FU ratio, an additional dose of capecitabine, 50-450 mg per day in divided doses twice daily, is continued or discontinued. If the measured 5-FU, measured FBAL, or FBAL:5-FU ratio is below a certain 5-FU threshold, above a certain FBAL threshold, or above a certain FBAL:5-FU ratio, respectively, the additional dose of capecitabine is discontinued and a drug-free period is established. In some embodiments, steps (i) and (ii) are repeated after the drug-free period.

[0139] In one embodiment, the treatment regimen for a treatment cycle of the present disclosure includes administering a single dose of 40 mg of PCS6422 on day 1 (i.e., morning) of the treatment cycle, provided that the measured 5-FU level in a blood sample taken from a subject is 2.0 ng / mL or higher, the measured FBAL level is less than 15 ng / mL, or the FBAL:5-FU ratio is less than 7.5, and administering capecitabine in divided doses of 50 to 450 mg per day on each day from days 2 to 15 of the treatment cycle. If the measured 5-FU level in a blood sample taken from a subject is less than 2.0 ng / mL, the FBAL level is 15 ng / mL or higher, or the FBAL:5-FU ratio is 7.5 or higher, the administration of the additional therapeutically effective dose of capecitabine is discontinued, and a drug-free period of 2 to 14 days is initiated until the measured level of 5-FU is at least 2.0 ng / mL or higher and the FBAL level is less than 15 ng / mL.

[0140] In one embodiment, a treatment regimen for a treatment cycle of the present disclosure includes administering an effective dose of PCS6422 on day 1 of the treatment cycle (e.g., as a single dose or in divided doses), administering a therapeutically effective dose of capecitabine on each of days 2 through 8 of the treatment cycle (e.g., as a single dose or in divided doses), and having a drug-free period on days 9 through 14 of the treatment cycle. In some embodiments, the treatment cycle is repeated (e.g., based on the results of pharmacokinetic analysis or a treatment index including pharmacokinetic analysis as described herein). In some embodiments, additional doses of capecitabine will be continued or discontinued based on measured 5-FU, measured FBAL and / or FBAL:5-FU ratio, or a treatment index.

[0141] In one embodiment, a treatment regimen for a treatment cycle of the present disclosure includes administering an effective dose of PCS6422 on day 1 of the treatment cycle (e.g., as a single dose or in divided doses), administering a therapeutically effective dose of capecitabine on each of days 2 through 4 of the treatment cycle (e.g., as a single dose or in divided doses), and having a drug-free period on days 5 through 14 of the treatment cycle. In some embodiments, the treatment cycle is repeated (e.g., based on the results of pharmacokinetic analysis or a treatment index including pharmacokinetic analysis as described herein). In some embodiments, additional doses of capecitabine will be continued or discontinued based on measured 5-FU, measured FBAL and / or FBAL:5-FU ratio, or a treatment index.

[0142] In one embodiment, a treatment regimen for a treatment cycle of the present disclosure includes administering an effective dose of PCS6422 on day 1 of the treatment cycle (e.g., as a single dose or in divided doses), administering a therapeutically effective dose of capecitabine on each of days 2 and 3 of the treatment cycle (e.g., as a single dose or in divided doses), and having a drug-free period on days 4 through 7 of the treatment cycle. In some embodiments, the treatment cycle is repeated (e.g., based on the results of pharmacokinetic analysis or a treatment index including pharmacokinetic analysis as described herein). In some embodiments, additional doses of capecitabine will be continued or discontinued based on measured 5-FU, measured FBAL and / or FBAL:5-FU ratio, or a treatment index.

[0143] In one embodiment, a treatment regimen for a treatment cycle of the present disclosure includes administering an effective dose of PCS6422 on day 1 of the treatment cycle (e.g., as a single dose or in divided doses), administering a therapeutically effective dose of capecitabine on each of days 2–4 of the treatment cycle (e.g., as a single dose or in divided doses), administering a second effective dose of PCS6422 on day 5 of the treatment cycle (e.g., as a single dose or in divided doses), administering a therapeutically effective dose of capecitabine on each of days 6–8 of the treatment cycle (e.g., as a single dose or in divided doses), and having a drug-free period on days 9–14 of the treatment cycle. In some embodiments, the treatment cycle is repeated (e.g., based on the results of pharmacokinetic analysis or a treatment index including pharmacokinetic analysis as described herein). In some embodiments, additional doses of capecitabine will be continued or discontinued based on measured 5-FU, measured FBAL and / or FBAL:5-FU ratio, or a treatment index.

[0144] In one embodiment, a treatment regimen for a treatment cycle of the present disclosure includes administering an effective dose of PCS6422 on day 1 of the treatment cycle (e.g., as a single dose or in divided doses), administering a therapeutically effective dose of capecitabine on each of days 2 through 8 of the treatment cycle (e.g., as a single dose or in divided doses), administering a second effective dose of PCS6422 on day 5 of the treatment cycle (e.g., as a single dose or in divided doses), and having a drug-free period on days 9 through 14 of the treatment cycle. In some embodiments, the treatment cycle is repeated (e.g., based on the results of pharmacokinetic analysis or a treatment index including pharmacokinetic analysis as described herein). In some embodiments, additional doses of capecitabine will be continued or discontinued based on measured 5-FU, measured FBAL and / or FBAL:5-FU ratio, or a treatment index.

[0145] In one embodiment, a treatment regimen for a treatment cycle of the present disclosure includes administering an effective dose of PCS6422 on day 1 of the treatment cycle (e.g., as a single dose or in divided doses), administering a therapeutically effective dose of capecitabine on each of days 2 through 15 of the treatment cycle (e.g., as a single dose or in divided doses), and having a drug-free period on days 16 through 21 of the treatment cycle. In some embodiments, the treatment cycle is repeated (e.g., based on the results of pharmacokinetic analysis or a treatment index including pharmacokinetic analysis as described herein). In some embodiments, additional doses of capecitabine will be continued or discontinued based on measured 5-FU, measured FBAL and / or FBAL:5-FU ratio, or a treatment index.

[0146] In one embodiment, a treatment regimen for a treatment cycle of the present disclosure involves administering an effective dose of PCS6422 on day 1 of the treatment cycle (e.g., as a single dose or in divided doses), administering a therapeutically effective dose of capecitabine on each of days 2 and 3 of the treatment cycle (e.g., as a single dose or in divided doses), having a drug-free period on days 4 to 7 of the treatment cycle, administering a second effective dose of PCS6422 on day 8 of the treatment cycle (e.g., as a single dose or in divided doses), and the treatment cycle The treatment includes administering a therapeutically effective dose of capecitabine on each day of days 9–10 (e.g., as a single dose or in divided doses), having a rest period on days 11–14 of the treatment cycle, administering a third effective dose of PCS6422 on day 15 of the treatment cycle (e.g., as a single dose or in divided doses), administering a therapeutically effective dose of capecitabine on each day of days 16–17 of the treatment cycle (e.g., as a single dose or in divided doses), and having a rest period on days 18–28 of the treatment cycle. In some embodiments, the treatment cycle is repeated (e.g., based on the results of pharmacokinetic analysis or a treatment index including pharmacokinetic analysis as described herein). In some embodiments, additional administration of capecitabine will be continued or discontinued based on measured 5-FU, measured FBAL and / or FBAL:5-FU ratio, or a treatment index. [Examples]

[0147] Example 1: Cohorts 1 and 2A: PCS6422 and capecitabine 14-day cycle Patients with advanced, metastatic, or unresectable gastrointestinal (GI) tumors that are refractory or intolerant to existing available treatments are administered PCS6422 and capecitabine in a 14-day cycle. Patients receive 40 mg of PCS6422 on day 1. Subsequently, from days 2 to 8, patients receive 75 mg of capecitabine once daily (Cohort 1) or twice daily (Cohort 2A, morning and evening), followed by a 6-day rest period (days 9-14).

[0148] Blood samples for pharmacokinetic (PK) analysis of PCS6422 and its major metabolite, 5-acetyluracil, are collected on day 1 of cycle 1 at 0 hours (pre-administration), and at 1, 2, 3, 5, 7, 9, and 24 hours after PCS6422 administration. On the first day of capecitabine treatment (cycle 1, day 2), blood samples for PK analysis of capecitabine, 5-fluorouracil (5-FU), and its quantifiable major metabolites, α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), and doxifluridine (5'-DFUR), are collected at 0 hours (pre-administration / trough), 0.5 hours, 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, and 9 hours, relative to the first dose of capecitabine (administration 1). On day 8 of cycle 1, blood samples are collected at 0 hours (pre-administration / trough), 0.5 hours, 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, 9 hours, 24 hours, 30 hours, and 48 hours after capecitabine administration (administration 7 of cycle 1), as relative time points to capecitabine administration. A capecitabine blood sample is also collected on day 1 of cycle 2, before the administration of PCS6422.

[0149] Additionally, blood samples will be collected at screening and at the following points during Cycle 1 for DPD activity analysis using uracil and dihydrouracil concentrations: Day 1, Day 2, Day 8, Day 9, and Day 10. Blood samples will also be collected on Day 1 of Cycle 2, before administration of PCS6422. All blood samples for uracil and dihydrouracil concentration analysis will be collected before the relevant meal, if possible. Actual collection times will be recorded. The concentrations of PCS6422, 5-acetyluracil, capecitabine, 5-FU, FBAL, 5'-DFCR, and 5'-DFUR, uracil, and / or dihydrouracil in plasma will be determined using validated analytical methods.

[0150] Table 1.1 shows an example of the PK results. [Table 2]

[0151] Fully active DPD (e.g., DPD not inhibited by PCS6422) is represented by data from day 8 in subjects administered PCS6422 on day 1 (C1, C2A). On day 2, DPD is inhibited, but de novo formation of DPD is also observed. The minimum and maximum plasma concentrations (Cp) of 5-FU 0-FU 0-9 hours after capecitabine administration ranged from 8.1 ng / mL to 164 ng / mL (low plasma concentration) and 309 ng / mL to 466 ng / mL (high plasma concentration). On day 2 (0-9 hours after capecitabine administration), the high plasma concentration of FBAL was <15 ng / mL to 26 ng / mL, and the low plasma concentration was <15 ng / mL to 22.6 ng / mL. Example 2: Cohort 2B and Cohort 2D: 14-day cycle administration of PCS6422 and capecitabine.

[0152] In subjects with advanced, metastatic, or unresectable gastrointestinal (GI) tumors that were refractory or intolerant to existing available treatments, the combination of PCS6422 and capecitabine was administered in 14-day cycles. 40 mg of PCS6422 was administered to subjects on both days 1 and 5 (Cohort 2B) or on day 1 only (Cohort 2D). Subsequently, 75 mg of capecitabine was administered twice daily (morning and evening) from days 2 to 8, followed by a 6-day rest period (days 9-14).

[0153] Blood samples for PK analysis of PCS6422 and its major metabolite, 5-acetyluracil, were collected on day 1 of cycle 1 at 0 hours (pre-administration), 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, 9 hours, and 24 hours. A sample collected 24 hours post-administration was taken before capecitabine administration on day 2.

[0154] On the first day of capecitabine treatment (cycles 1 and 2), blood samples for PK analysis of capecitabine, 5-fluorouracil (5-FU), and the major quantifiable metabolites α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), and doxifluridine (5'-DFUR) were collected at 0 hours (pre-administration), 0.5 hours, 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, and 9 hours, relative to the first dose of capecitabine (day 1). On day 8 of cycle 1, blood samples were collected at 0 hours (pre-administration / trough), 0.5 hours, 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, and 9 hours, relative to the morning dose of capecitabine.

[0155] Prior to the morning administration of capecitabine on days 3, 4, 5, 6, 7, and 9, additional PK blood samples of capecitabine and its major metabolites were collected. The concentrations of PCS6422, 5-acetyluracil, capecitabine, 5-FU, FBAL, 5'-DFCR, and 5'-DFUR in plasma were determined using validated analytical methods.

[0156] Table 2.1 shows an example of the PK results. [Table 3-1] [Table 3-2]

[0157] Fully active DPD (e.g., DPD not inhibited by PCS6422) is shown by the data on day 8 in subjects administered PCS6422 on day 1 (C2D). DPD was inhibited on day 2, but de novo formation of DPD was also observed. The minimum and maximum plasma concentrations (Cp) of 5-FU 0-9 hours after capecitabine administration ranged from 6.4 ng / mL to 283 ng / mL (low plasma concentration) and from 197 ng / mL to 746 ng / mL (high plasma concentration). In patients exhibiting dose-limiting toxicity, 5-FU plasma concentrations 24 hours after morning administration on day 2 were 579 ng / mL in patients 103-107 and 653 ng / mL in patients 104-108. In other patients, 5-FU was observed in the range of <2 ng / mL to 27.0 ng / mL. On day 2 (0-9 hours after capecitabine administration), the highest FBAL plasma concentrations ranged from less than 15 ng / mL to 33.1 ng / mL.

Claims

1. A method for determining the frequency of administration of PCS6422 and capecitabine to a subject, (i) administering at least one dose of an effective amount of PCS6422 to the subject, (ii) Approximately 12 to 24 hours after administering the effective amount of PCS6422, administer at least one dose of capecitabine to the subject, The blood sample collected from the subject was measured for α-fluoro-β-alanine (FBAL) and 5-fluorouracil (5-FU) before administration. (iii) Determining one or more of the measured 5-FU, the measured FBAL, and / or the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio), A method comprising: (iv) repeating steps (i) and (ii) if, after a drug-free period, at least one of the following conditions is met: the measured 5-FU is less than a certain 5-FU threshold, the measured FBAL is greater than or equal to a certain FBAL threshold, the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, the measured 5-FU is zero, or the measured FBAL is zero.

2. The method according to claim 1, wherein the therapeutically effective amount of capecitabine is administered to the subject approximately 12 hours after the administration of the effective amount of PCS6422.

3. The method according to any one of claims 1 to 2, wherein the therapeutically effective amount of capecitabine is administered to the subject approximately 24 hours after the administration of the effective amount of PCS6422.

4. The method according to any one of claims 1 to 2, wherein the therapeutically effective amount of capecitabine is administered to the subject both approximately 12 hours and approximately 24 hours after the administration of the effective amount of PCS6422.

5. The method according to any one of claims 1 to 4, wherein the blood sample taken from the subject is taken approximately 12 to 24 hours after administering the therapeutically effective amount of capecitabine to the subject.

6. The method according to any one of claims 1 to 5, wherein FBAL and 5-FU were measured daily from the first day of capecitabine treatment.

7. The method according to any one of claims 1 to 6, wherein steps (i) and (ii) are repeated 1 to 7 days, 8 days, or 14 days after step (ii).

8. A method for determining the frequency of capecitabine administration to a subject, (i) administering at least one dose of an effective amount of PCS6422 to the subject, (ii) Administering to the subject at least one dose of a therapeutically effective dose of capecitabine about 12 to 24 hours after administering the effective dose of PCS6422, wherein a blood sample taken from the subject is measured for α-fluoro-β-alanine (FBAL) and / or 5-fluorouracil (5-FU), (iii) Determine one or more of the measured 5-FU, the measured FBAL, or the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio), (iv) A method comprising discontinuing the administration of the additional therapeutically effective dose of capecitabine to the subject if the measured 5-FU is below a specific 5-FU threshold, the measured FBAL is above a specific FBAL threshold, or the determined FBAL:5-FU ratio is above a specific FBAL:5-FU ratio threshold.

9. The method according to claim 8, wherein a drug-free period is provided after discontinuing the administration of the additional therapeutically effective amount of capecitabine to the subject.

10. The method according to claim 9, wherein steps (i) and (ii) are repeated after the drug-free period.

11. A method of treating cancer in a person who requires cancer treatment, (i) administering at least one dose of an effective amount of PCS6422 to the subject, (ii) Approximately 12 to 24 hours after administering at least one dose of the effective amount of PCS6422, administer at least one dose of a therapeutically effective amount of capecitabine to the subject, (iii) Measuring metabolites in a blood sample taken from the subject, which include one or more of α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), doxyfluridine (5'-DFUR), and 5-fluorouracil (5-FU), A method comprising (iv) determining whether the treatment regime needs to be adjusted based on a treatment index including the measured value of the metabolite determined in step (iii).

Images