Cancer treatment personalization method

Abstract

The present disclosure provides, inter alia, methods of personalizing the administration of PCS6422 in combination with capecitabine, methods of personalizing cancer therapy, and methods of determining the frequency of administration of (i) PCS6422 with capecitabine or (ii) capecitabine in a subject.

Description

Cross-references to related applications

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 513,514, filed July 13, 2023, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0002] The following description of the technical background of the present invention is provided only to help understand the technical technology of the present invention, and is not intended to be an admission of prior art describing or constituting the technical technology of the present invention.

[0003] Fluoropyrimidine antimetabolites are important anticancer agents, and 5-fluorouracil (5-FU) is the most commonly used drug in this class. Capecitabine (XELODA®) is a commonly used oral fluoropyrimidine and a prodrug of 5-FU, which is converted through 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.

[0004] Previous clinical trials examining the toxicity profile of capecitabine compared to 5-FU have shown a dose-dependent improvement in side effects compared to 5-FU / leucovorin (LV), including reduced stomatitis, diarrhea, nausea, and neutropenic sepsis. Despite this potential improvement in side effects, capecitabine treatment significantly increases the 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 metabolizes over 80% of administered 5-FU.

[0005] DPD levels can be highly variable within individual subjects (e.g., due to circadian rhythm patterns and tissue-specific variations) and between different subjects. Such variability has been shown to contribute at least in part to the variability in pharmacokinetics (PK), toxicity, and clinical response observed in 5-FU clinical studies. While DPD activity in most subjects falls within a normal distribution, a small percentage (approximately <5%) exhibit significantly below-normal DPD activity (e.g., due to inactivating mutations in one or both genes encoding DPD), which can lead to life-threatening or fatal toxicity when administered standard doses of 5-FU or capecitabine. Therefore, inhibiting 5-FU catabolicity by inactivating DPD could provide an alternative approach to prolonging systemic exposure to 5-FU, increasing exposure to the active metabolite, reducing exposure to the toxic metabolite, and / or improving efficacy. Summary of the Invention

[0006] This disclosure provides, in particular, a personalized approach to treating cancer in subjects in need, and a method for determining the frequency of administration of (i) PCS6422 and capecitabine or (ii) capecitabine in subjects, and a method for treating cancer, including determining whether the treatment regimen should be adjusted based on a treatment index.

[0007] In one aspect, this disclosure provides a method for determining the frequency of administration of PCS6422 and capecitabine to a subject, comprising: (i) administering at least one effective dose of PCS6422 to the subject; (ii) administering at least one therapeutically effective dose of capecitabine to the subject about 12 to about 24 hours after the administration of the at least one effective dose of PCS6422, wherein α-fluoro-β-alanine (FBAL) and 5-fluorouracil (5-FU) are measured in a blood sample obtained from the subject; and (iii) determining one or more of the following (i) The measured 5-FU, the measured FBAL, and / or the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio); and (iv) after the withdrawal period, repeat steps (i) and (ii) when 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.

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

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

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

[0011] In some embodiments, the blood sample obtained from the subject is obtained approximately 12 to approximately 24 hours after the subject is given a therapeutically effective amount of capecitabine.

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

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

[0014] In one aspect, this disclosure provides a method for determining the frequency of capecitabine administration to a subject, comprising: (i) administering at least one effective dose of PCS6422 to the subject; (ii) administering at least one therapeutically effective dose of capecitabine to the subject about 12 to about 24 hours after the administration of the at least one effective dose of PCS6422, wherein α-fluoro-β-alanine (FBAL) and / or 5-fluorouracil (5-FU) in a blood sample obtained from the subject are measured; (iii) determining one or more of the following: the measured 5-FU, the measured FBAL, or the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio); and (iv) stopping the administration of an additional therapeutically effective dose of capecitabine to the subject when 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, or the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold.

[0015] In some embodiments, a withdrawal period is defined as the period after the administration of additional therapeutically effective doses of capecitabine to the subject is stopped.

[0016] In some embodiments, steps (i) and (ii) are repeated after the drug withdrawal period.

[0017] In one aspect, this disclosure provides a method of treating cancer in a subject of need, comprising: (i) administering at least one dose of an effective amount of PCS6422 to the subject; (ii) administering at least one dose of a therapeutically effective amount of capecitabine to the subject about 12 to about 24 hours after the administration of at least one dose of the effective amount of PCS6422; (iii) measuring metabolites in a blood sample obtained from the subject, the metabolites comprising one or more of α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), deoxyfluorouridine (5'-DFUR), and 5-fluorouracil (5-FU); and (iv) determining whether the treatment regimen should be adjusted based on a treatment index comprising the metabolite measurements determined in step (iii). Detailed Implementation

[0018] PCS6422 is an irreversible and potent inactivator of dihydropyrimidine dehydrogenase (DPD). Small amounts of PCS6422 inactivate DPD and prevent it from catabolizing 5-FU (including 5-FU produced from the 5-FU prodrug capecitabine). DPD enzyme activity subsequently arises if not all existing DPD enzymes are inhibited and / or when active DPD reappears in the subject over time (e.g., as a result of the synthesis of newly formed DPD enzymes). PCS6422 shifts the 5-FU elimination pathway from metabolism to renal excretion by inhibiting DPD-induced 5-FU catabolism, thereby extending the half-life from 10 to 20 minutes to several hours. PCS6422 also prevents the formation of 5-FU catabolites (e.g., FBAL), which appear to cause side effects such as hand-foot syndrome, cardiotoxicity, and neurotoxicity, and potentially antagonizes the antitumor activity of 5-FU. However, identifying appropriate dosing and / or treatment regimens of PCS6422 with capecitabine to realize the full potential of combination therapy remains a challenge.

[0019] To advance technologies related to PCS6422 and capecitabine dosing, treatment regimens, and / or treatment, it is important to identify personalized treatment regimens and / or methods for personalizing such regimens, which at least partially result in variability in DPD content and variability in DPD reformation 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 cancer treatment, and a method for determining the frequency of administration of (i) PCS6422 with capecitabine or (ii) capecitabine in a subject. Such personalized methods, described in more detail herein, can improve the safety and / or efficacy of capecitabine regimens.

[0021] It should be understood that certain scopes, modes, embodiments, variations and features of the methods of the present invention are described below in varying degrees of detail in order to provide a full understanding of the technical implementation of the present invention.

[0022] This disclosure is not limited to the specific embodiments described in this application, which are merely intended to illustrate corresponding aspects of this disclosure. Not all various embodiments of this disclosure will be described herein. It will be apparent to those skilled in the art that many modifications and alterations can be made to this disclosure without departing from its spirit and scope. Functionally equivalent methods and apparatuses other than those listed herein will be readily apparent to those skilled in the art from the foregoing description. Such modifications and alterations are intended to fall within the scope of the appended claims. This disclosure is limited only by the terminology of the appended claims and the full scope of the equivalents granted thereto.

[0023] It should be understood that this disclosure is not limited to specific uses, methods, reagents, compounds, compositions, or biological systems, and these can certainly be modified. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be restrictive.

[0024] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains. The following references provide general definitions of many terms used in this disclosure to one of ordinary skill in the art. Unless otherwise stated, as used herein, the following terms have the meanings assigned to them hereinafter. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit this disclosure.

[0025] Unless the context clearly specifies otherwise, as used herein, the singular forms “a,” “an,” and “the” include both single and multiple references. For example, the term “a cell” includes a single cell as well as multiple cells, including mixtures thereof.

[0026] As used herein, the term "administration" of a drug or composition to a subject includes any route by which said drug or composition is introduced or delivered to the subject to perform its intended function. Administration can be performed via any suitable route, including but not limited to oral administration, intravenous administration, and other suitable routes described herein. Administration can include self-administration and administration by another person.

[0027] As used herein, the term “adverse event” or “AE” refers to any adverse medical event that occurs in a subject receiving one or more medications. Thus, an adverse event can be any unfavorable and / or unexpected symptom (e.g., an abnormal laboratory finding), symptom, and / or condition that is temporally related to the administration of the medication, whether or not it is considered to be related to the use of the medication.

[0028] As used herein, the term "pharmaceutical" refers to an entity (e.g., lipids, metals, nucleic acids, polypeptides, polysaccharides, small molecules, etc., or complexes, combinations, mixtures, or systems thereof [e.g., cells, tissues, organisms]), or a phenomenon (e.g., heat, electric current or electric field, magnetic force or magnetic field, etc.). Where appropriate, as will be understood by one of ordinary skill in the art from the context, the term may be used to refer to an entity that is or comprises a cell or organism, or a portion thereof, extract, or component (e.g., nucleic acids). Or, or additionally, as will be clear from the context, the term may be used to refer to a natural product because it is found in and / or obtained from nature. In some cases, further as will be understood from the context, the term may be used to refer to one or more artificial entities because they are designed, engineered, and / or produced through artificial means and / or are not found in nature. For example, pharmaceuticals may be used in isolated or pure forms; pharmaceuticals may be used in crude forms.

[0029] As used in this article, the terms “approximately” or “about” mean plus or minus 10% and a specified number. For example, “about 10” should be understood as “10” versus “9-11”.

[0030] As used herein, the term "combination therapy" refers to a situation where two or more different pharmaceutical agents are administered in an overlapping or identical regimen, resulting in simultaneous exposure of the subject to both agents. When used in combination therapy, the two or more different agents may be administered simultaneously or separately. This combination administration can include simultaneous administration of two or more agents in the same dosage form, simultaneous administration in a single dosage form, and separate administration. That is, two or more agents may be mixed together in the same dosage form and administered simultaneously. Alternatively, two or more agents may be administered simultaneously, wherein the agents are present in a separate formulation. In another alternative, one or more additional agents may be administered immediately after the first agent is administered. In separate administration regimens, two or more agents may be administered, for example, at intervals of minutes, hours, or days.

[0031] As used herein, “comprising” should be interpreted as specifying the presence of a feature, integer, step, or component as mentioned, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Furthermore, the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and are interchangeable. Additionally, the term “comprising” is intended to include instances and aspects covered by the terms “substantially constitutes” and “consistent with.” Similarly, the term “substantially constitutes” is intended to include instances covered by the term “consistent with.”

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

[0033] As used herein, the term "diagnostic information" or "information for diagnosis" is any information applicable to determining whether a patient has a disease or condition and / or applicable to classifying said disease or condition into a phenotypic category or any category whose significance relates to the prognosis of the disease or condition, or any information regarding the possible response of said disease or condition to treatment (general treatment or any specific treatment). Similarly, diagnosis refers to providing any type of diagnostic information, including but not limited to whether a subject is likely to have a disease or condition (e.g., cancer), the state, stage, or characteristics of the disease or condition exhibited by the subject, information relating to the nature or classification of the tumor, information relating to prognosis, and / or information applicable to the selection of appropriate therapy. The selection of therapy may include options for a specific treatment (e.g., chemotherapy) agent or other treatment modality, such as surgery, radiation, etc.; options regarding whether to discontinue or deliver therapy; options regarding dosing regimens (e.g., the frequency or level of a single or multiple doses of a specific therapeutic agent or combination of agents), etc.

[0034] As used herein, the terms "dosing regimen" or "treatment regimen" refer to a set of unit doses administered independently to a subject, typically at intervals. A specified therapeutic agent may have a recommended dosing regimen, which may involve one or more doses. A dosing regimen may consist of multiple doses, each spaced at intervals from the others. These intervals may be of equal or different durations. A dosing regimen may consist of multiple doses and at least two distinct time intervals separating the individual doses. A dosing regimen may be relevant to the desired treatment outcome when administered to a subject and / or a subject population. "Dosing regimen" or "treatment regimen" may also refer to a method for partially or completely reducing, improving, alleviating, suppressing, preventing, delaying the onset, reducing severity, and / or decreasing the incidence of one or more symptoms or features of a specific disease, condition, and / or symptom (e.g., cancer). It may include a therapy or series of therapies designed to achieve a specific efficacy (e.g., reducing or eliminating a harmful symptom or disease, such as cancer). A therapy may include the simultaneous, sequential, or at-different times administration of one or more compounds (e.g., therapeutic agents) in the same or different amounts for the same or different durations.

[0035] As used herein, the term "durable clinical benefit" (DCB) has the meaning known in the art and refers to a clinical benefit that persists over a relevant time period. In some embodiments, this clinical benefit is or includes an extension of progression-free survival, an extension of overall survival, a reduction in overall tumor burden, a reduction in symptoms associated with tumor growth (e.g., pain, organ failure, bleeding, musculoskeletal injury, and other associated sequelae of metastatic cancer, and combinations thereof). In some embodiments, the relevant time period is at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, or longer. In some specific embodiments, the relevant time period is 6 months.

[0036] As used herein, the term "therapeutic effective amount" refers to the quantity of a drug or composition sufficient to achieve a beneficial or desired clinical outcome after treatment. In the context of therapeutic application, the amount of therapeutic agent administered to the subject may depend on the type and severity of the disease or symptom, as well as the subject's characteristics, such as general health status, age, sex, weight, and / or tolerance to the drug. It may also depend on the extent, severity, and type of the disease. A person skilled in the art will be able to determine the appropriate dosage based on these and other factors. Therapeutic effective amounts may be administered to the subject in one or more doses. In the context of treatment, a therapeutic effective amount is the quantity sufficient to alleviate, improve, stabilize, reverse, or slow the progression of the disease, or otherwise reduce the pathological outcomes of the disease. Therapeutic effective amounts are generally determined by a physician on a case-by-case basis and within the skill level of a person skilled in the art.

[0037] As used herein, the term "favorable response" refers to 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 improvements in the pathophysiology of the disease. Symptom relief occurs when the magnitude (e.g., intensity, severity, etc.) and / or frequency of one or more symptoms of a specific disease, condition, or symptom decreases. For clarity, a delay in the onset of a specific symptom is considered a form of symptom frequency reduction. Many cancer patients with small tumors are asymptomatic. It is not intended that the techniques of this disclosure be limited to cases in which symptoms are eliminated. This disclosure specifically covers treatments that result in a reduction (and thereby "improvement") of one or more symptoms, but not complete elimination. A favorable response can be identified when a specific treatment regimen shows statistically significant efficacy when applied to a relevant population or individual subjects. A specific treatment regimen can be identified as having a favorable response when its application is related to the desired effect.

[0038] As used herein, the terms “improvement,” “increase,” or “relief,” or grammatically similar comparative terms, indicate a numerical value relative to a similar reference measurement. For example, in some embodiments, the assessment value achieved by the agent of interest relative to an assessment value obtained with a similar reference agent may be “improved.” Or, additionally, in some embodiments, the assessment value achieved by the object or system of interest relative to the assessment value obtained with the same object or system under different conditions (e.g., objects treated with different regimens of PCS6422 and capecitabine) or similar different objects (e.g., objects or systems different from the object or system of interest, possessing one or more indicators of the specific disease, symptom, or condition of interest, or previously exposed to a condition or vector) may be “improved.” Comparative terms may refer to statistically relevant differences (e.g., prevalence and / or magnitudes sufficient to achieve statistical significance). Those skilled in the art will appreciate, or will be able to readily determine, in specified circumstances the degree and / or prevalence of differences necessary to achieve such statistical significance or sufficient to achieve such statistical significance.

[0039] As used herein, the term "long-term benefit" refers to a desired clinical outcome, such as a clinical outcome observed after administration of a specific treatment or therapy of interest (e.g., combination therapy), lasting for a clinically relevant period. For example, a long-term benefit of cancer treatment may be or include (i) evidence of disease (e.g., after radiographic evaluation) and / or (ii) disease stabilization or reduction in disease volume. A clinically relevant period may be, for example, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year, or at least 5 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 structural unit (DNA base) to a large segment of a chromosome. Mutations can include, for example, missense mutations, frameshift mutations, replication, insertion, nonsense mutations, deletions, and duplications. A missense mutation can be a change of a single DNA base pair, in which, in the protein produced by the gene, one amino acid replaces another. A nonsense mutation can also be a change of a single DNA base pair. However, the altered DNA sequence prematurely signals the cell to stop building the protein, rather than replacing one amino acid with another. Insertion can change the number of DNA bases in a gene by adding a segment of DNA. Deletion can change the number of DNA bases by removing a segment of DNA. In some embodiments, small deletions can remove one or several base pairs within a gene, while larger deletions can remove the entire gene or several adjacent genes. Replication can consist of an aberrant replication of a segment of DNA once or multiple times. Frameshift mutations can occur when the addition or loss of DNA bases alters the reading frames of a gene. A reading frame consists of groups of 3 bases, each encoding one amino acid. Frameshift mutations can cause the grouping of these bases to shift and alter the coding of amino acids. In some embodiments, insertions, deletions, and replications can all be frameshift mutations. Repeat amplification is another type of mutation. In some embodiments, nucleotide repeats are short DNA sequences that are repeated consecutively multiple times. 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, repeat amplification is a mutation that increases the number of repetitions of a short DNA sequence.

[0041] As used in this article, the term "objective response" refers to a reduction in the size of the cancerous mass as defined. A cancerous mass can be a tumor. A confirmed objective response is a response that is demonstrated to be present for a period of time after treatment.

[0042] As used herein, the term "objective response rate" (ORR) has the meaning understood in the field and refers to the proportion of patients whose tumor size shrinks by a predefined amount within the shortest possible time period. Response duration is typically measured from the initial response time until a recorded tumor progression. ORR can refer to, for example, the sum of a partial response and a complete response.

[0043] As used in this article, the term "personalization" refers to adapting a specific treatment regimen to the needs and / or special circumstances of a particular individual and / or a specific individual (e.g., the pharmacokinetic parameters of one or more specific agents in a particular individual).

[0044] As used herein, the term "progression-free survival" refers to the length of time a subject survives with a disease (e.g., cancer) without the disease worsening during and after treatment. Measuring progression-free survival can be used to assess how well a therapy (e.g., combination therapy) works.

[0045] As used herein, the terms “reduction” or “reduction” mean a negative change of at least about 5%, including but not limited to negative changes of about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or about 100%.

[0046] As used herein, the term "response" refers to a change in a subject's condition resulting from treatment (e.g., combination therapy), or a change associated with treatment (e.g., combination therapy). A response may be or includes a beneficial response. A beneficial response may include symptom stabilization (e.g., prevention or delay of exacerbation, which is expected or commonly observed in the absence of treatment), symptom and / or one or more symptoms associated with the symptom (e.g., reduced frequency and / or intensity), and / or improved prognosis. "Response" may refer to the response of an organism (e.g., a subject, such as a human), organ, cell, and / or clinical response.

[0047] As used herein, a "reference" entity, system, quantity, condition set, etc., is an entity, system, quantity, condition set, etc., compared to the test entity, system, quantity, condition set, etc., as described herein. For example, a reference "treatment protocol" could be a control treatment protocol, such as a treatment protocol not disclosed herein. References or controls can be tested and / or determined simultaneously with the test or determination of interest. References or controls can optionally be historical references or controls implemented in tangible media. Generally, as those skilled in the art will understand, references or controls are determined or characterized under conditions or environments similar to the conditions or environments under evaluation. Those skilled in the art will understand when sufficient similarity exists to demonstrate dependence on a specific possible reference or control and / or comparison with it.

[0048] As used herein, the term "sample" generally refers to a biological sample obtained from or derived from a source of interest (e.g., an object and / or a subject in need). The source of interest can be, for example, an organism, such as an animal or a human. A biological sample can be or contains biological tissue or body fluids. A biological sample can be or contains bone marrow; blood; blood cells; ascites; tissue or fine-needle section samples; body fluids containing cells; free-floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid; peritoneal fluid; pleural fluid; feces; plasma; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washing or lavage solutions, such as catheter lavage or bronchoalveolar lavage fluid; extracts; scrapings; bone marrow specimens; tissue section specimens; surgical specimens; feces, other body fluids, secretions and / or excretions; and / or cells derived therefrom, etc. A biological sample can be or contains cells obtained from an individual. A sample can be a "primary sample" obtained directly from the source of interest by any appropriate means. For example, primary biological samples can be obtained by methods selected from the group consisting of: slicing (e.g., fine-needle aspiration or tissue sectioning), surgery, collection of bodily fluids (e.g., blood, lymph, feces, etc.). In some embodiments, as will be understood from the context, the term "sample" refers to a "secondary sample," such as a preparation obtained by processing a primary sample (e.g., by removing one or more components of the primary sample and / or by adding one or more agents to the primary sample). This "secondary sample" may contain nucleic acids or proteins, for example, obtained by extraction from the sample or by performing techniques such as mRNA amplification or reverse transcription, separation and / or purification of certain components on the primary sample.

[0049] As used herein, the terms “object,” “person,” or “patient” are used interchangeably and refer to an individual organism, vertebrate, or mammal, and may include humans, non-human primates, rodents, etc. (e.g., who will be the recipient of a specific therapy). In a preferred embodiment, the person, patient, or object is a human.

[0050] As used herein, the term "treatment cycle" refers to a period of treatment followed by a period of withdrawal (e.g., a withdrawal period). A treatment cycle may include more than one withdrawal period. Treatment cycles can be repeated (e.g., based on a regular schedule or a variable schedule). For example, one week of treatment followed by one week of withdrawal (e.g., a one-week withdrawal period) can be considered a treatment cycle.

[0051] As used herein, the term “treatment index” refers to a number of factors that determine a treatment regimen and may be used in combination with indicators of the overall effectiveness of the agent (e.g., PCS644, capecitabine) and / or indicators of whether the treatment regimen and / or treatment duration should be adjusted (e.g., the number of times an additional dose of the agent to be administered is modified relative to the planned number of additional doses; the extension or shortening of the withdrawal period relative to the planned duration). Treatment indices may take into account factors that determine a treatment regimen, such as, but not limited to, disease type and / or severity, diagnostic information, the subject’s response to the agent, and / or the pharmacokinetic analysis (or “metabolite measurements”) described herein.

[0052] As used herein, in the context of molecules such as nucleic acids or peptides, the term "variant" refers to a molecule that exhibits significant structural similarity to a reference molecule but differs structurally from it, for example, in the presence or absence or abundance of one or more chemical motifs compared to the reference molecule. A variant may also differ functionally from its reference molecule. Generally, whether a particular molecule is properly considered a "variant" of a reference molecule is based on the degree of its structural similarity to the reference molecule. As those skilled in the art will appreciate, any biological or chemical reference molecule possesses certain characteristic structural elements. By definition, a variant is a unique molecule that shares one or more of these characteristic structural elements with a reference molecule but differs from it in at least one respect. To cite just a few examples, a peptide may have a characteristic sequence element comprising multiple amino acids that occupy designated positions relative to each other in linear or three-dimensional space and / or contribute to a specific structural motif and / or biological function; a nucleic acid may have a characteristic sequence element comprising multiple nucleotide residues that occupy 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 due to one or more differences in the amino acid or nucleotide sequence and / or one or more differences in the chemical portion (e.g., carbohydrate, lipid, phosphate ester groups) that is a covalent component of the polypeptide or nucleic acid (e.g., linked to the polypeptide or nucleic acid backbone). The variant polypeptide or nucleic acid may show at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 99% overall sequence identity with the reference polypeptide or nucleic acid. Compared to the reference, the 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 substituted residue. Typically, relative to the reference, the variant polypeptide or nucleic acid contains very few (e.g., fewer than about 5, about 4, about 3, about 2, or about 1) substituted, inserted, or deleted functional residues (i.e., residues involved in specific biological activities).

[0053] therapy This disclosure provides, in particular, a personalized method for treating cancer in a subject in need, comprising: (i) administering at least one effective dose of PCS6422 to the subject; (ii) administering at least one therapeutically effective dose of capecitabine to the subject approximately 12 to approximately 36 hours (e.g., approximately 12 to approximately 24 hours) after administration of at least one effective dose of PCS6422; and (iii) optionally repeating steps (i) and (ii) after a withdrawal period.

[0054] In another aspect, this disclosure provides a method for treating cancer in a subject in need, comprising: (i) administering at least one effective dose of PCS6422 to the subject; and (ii) administering at least one therapeutically effective dose of capecitabine to the subject approximately 12 to approximately 36 hours (e.g., approximately 12 to approximately 24 hours) after the administration of at least one effective dose of PCS6422, wherein one or more of the following are measured in a blood sample obtained from the subject: α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), deoxyfluorouridine (5'-DFUR), capecitabine, and 5-fluorouracil (5-FU). Such methods for treating cancer may further comprise determining whether a treatment regimen should be adjusted based on a treatment index, said treatment index comprising measurements of one or more of the following: FBAL, 5-DFCR, 5'-DFUR, capecitabine, and 5-FU. Adjusting a treatment regimen may include, for example, modifying the number of additional doses of the therapeutic agent to be administered relative to the planned number of additional doses; extending or shortening the withdrawal period relative to the planned duration; and changing the number of treatment cycles to be administered relative to the planned number of treatment cycles.

[0055] In another aspect, this disclosure provides a method for treating cancer in a subject in need, comprising: (i) administering at least one effective dose of PCS6422 to the subject; and (ii) administering at least one therapeutically effective dose of capecitabine to the subject about 12 to about 36 hours (e.g., about 12 to about 24 hours) after the administration of at least one effective dose of PCS6422; (iii) measuring metabolites in a blood sample obtained from the subject, the metabolites comprising one or more of α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), deoxyfluorouridine (5'-DFUR), and 5-fluorouracil (5-FU); and (iv) determining whether the treatment regimen should be adjusted based on a treatment index comprising the metabolite measurements determined in step (iii). In some embodiments, measuring metabolites in step (iii) comprises measuring one or more of FBAL and 5-FU. In some embodiments, such methods further comprise determining an FBAL:5-FU ratio. As described elsewhere in this article, these metabolite measurements are also referred to as "pharmacokinetics analysis".

[0056] In another aspect, this disclosure provides a method for determining the frequency of administration of PCS6422 and capecitabine to a subject, comprising: (i) administering at least one effective dose of PCS6422 to the subject; (ii) administering at least one therapeutically effective dose of capecitabine to the subject approximately 12 to approximately 36 hours (e.g., approximately 12 to approximately 24 hours) after the administration of the at least one effective dose of PCS6422, wherein α-fluoro-β-alanine (FBAL) and 5-fluorouracil (5-FU) are measured in a blood sample obtained from the subject; and (iii) determining the following... One or more of the following: the measured 5-FU, the measured FBAL, and / or the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio); and (iv) after the withdrawal period, repeat steps (i) and (ii) when 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.

[0057] In another aspect, this disclosure provides a method for determining the frequency of capecitabine administration in a subject, comprising: (i) administering at least one effective dose of PCS6422 to the subject; and (ii) administering at least one therapeutically effective dose of capecitabine to the subject approximately 12 to approximately 36 hours (e.g., approximately 12 to approximately 24 hours) after the administration of the at least one effective dose of PCS6422, wherein α-fluoro-β-alanine (FBAL) and / or 5-fluorouracil (5-) are measured in a blood sample obtained from the subject. (iii) Determine one or more of the following: the measured 5-FU, the measured FBAL, or the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio); and (iv) when 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, or the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, stop administering an additional dose of therapeutically effective capecitabine to the subject.

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

[0059] The method disclosed herein may include administering an additional dose of an effective amount of PCS6422. In some embodiments, an effective amount of PCS6422 is administered 2, 3, 4, 5, or 6 times. In some embodiments, an effective amount of PCS6422 is administered 2 times. In some embodiments, an effective amount of PCS6422 is administered 3 times. In some embodiments, an effective amount of PCS6422 is administered 4 times. In some embodiments, an effective amount of PCS6422 is administered 5 times. In some embodiments, an effective amount of PCS6422 is administered 6 times.

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

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

[0062] The method of this disclosure may include administering an additional therapeutically effective dose of capecitabine to the subject approximately 12 to 36 hours (e.g., approximately 12 to 24 hours) after the previous dose of a therapeutically effective dose of capecitabine has been administered. In some embodiments, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 doses of a therapeutically effective dose of capecitabine are administered. In some embodiments, 2 doses of a therapeutically effective dose of capecitabine are administered. In some embodiments, 3 doses of a therapeutically effective dose of capecitabine are administered. In some embodiments, 4 doses of a therapeutically effective dose of capecitabine are administered. In some embodiments, 5 doses of a therapeutically effective dose of capecitabine are administered. In some embodiments, 6 doses of a therapeutically effective dose of capecitabine are administered. In some embodiments, 7 doses of a therapeutically effective dose of capecitabine are administered. In some embodiments, 8 doses of a therapeutically effective dose of capecitabine are administered. In some embodiments, 9 doses of a therapeutically effective dose of capecitabine are administered. In some embodiments, 10 doses of a therapeutically effective dose of capecitabine are administered. In some embodiments, 11 therapeutically effective doses of capecitabine are administered. In some embodiments, 12 therapeutically effective doses of capecitabine are administered. In some embodiments, 13 therapeutically effective doses of capecitabine are administered. In some embodiments, 14 therapeutically effective doses of capecitabine are administered. In some embodiments, 15 therapeutically effective doses of capecitabine are administered. In some embodiments, 16 therapeutically effective doses of capecitabine are administered.

[0063] In some embodiments, the method of this disclosure may include stopping the administration of an additional therapeutically effective dose of capecitabine to the subject when 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, or the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold. In some embodiments, stopping the administration of an additional therapeutically effective dose of capecitabine to the subject is followed by a withdrawal period (e.g., as described herein). In some such embodiments, steps (i) and (ii) are repeated after the withdrawal period.

[0064] In some embodiments, the methods of this disclosure may include adjusting the treatment regimen based on a treatment index, which includes the metabolite measurements (“pharmacokinetic analysis”) described herein. Adjusting the treatment regimen may include, for example, modifying the number of additional doses of the therapeutic agent to be administered relative to the planned number of additional doses; extending or shortening the withdrawal period relative to the planned duration; and changing the number of treatment cycles to be administered relative to the planned number of treatment cycles.

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

[0066] In some embodiments, the method of this disclosure includes administering at least one dose of a therapeutically effective amount of capecitabine to the subject on any one day or each day of days 2-8 of a treatment cycle, wherein days 3-7 of the treatment cycle include at least one discontinuation period.

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

[0068] The method disclosed herein may involve administering a therapeutically effective dose of capecitabine in multiple doses.

[0069] withdrawal period The methods and / or treatment cycles disclosed herein may include one or more withdrawal periods (e.g., after administering at least one therapeutically effective dose of capecitabine to the subject and / or the subject in need). A withdrawal period refers to a time during which no dose of PCS6422 or capecitabine is administered to the subject and / or the subject in need (e.g., a subject with cancer). Alternatively or additionally, a withdrawal period may refer to a time period in which the subject and / or the subject in need (e.g., a subject with cancer) is determined, by pharmacokinetic analysis as described herein, to have no or undetectable amounts of PCS6422 and / or capecitabine in blood samples obtained from the subject.

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

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

[0072] In some embodiments, the withdrawal period occurs on day 3 of the treatment cycle. In some embodiments, the withdrawal period occurs on day 4 of the treatment cycle. In some embodiments, the withdrawal period occurs on day 5 of the treatment cycle. In some embodiments, the withdrawal period occurs on day 6 of the treatment cycle. In some embodiments, the withdrawal period occurs on day 7 of the treatment cycle. In some embodiments, the withdrawal period occurs on days 3-7 of the treatment cycle. In some embodiments, the withdrawal period occurs on days 4-7 of the treatment cycle. In some embodiments, the withdrawal period occurs on days 3-5 of the treatment cycle. In some embodiments, the withdrawal period occurs on days 4-5 of the treatment cycle. In some embodiments, the withdrawal period occurs on days 5-7 of the treatment cycle. In some embodiments, the withdrawal period occurs on days 5-14 of the treatment cycle. In some embodiments, the withdrawal period occurs on days 7-14 of the treatment cycle. In some embodiments, the withdrawal period occurs on days 9-14 of the treatment cycle. In some embodiments, the withdrawal period occurs on days 16-21 of the treatment cycle.

[0073] The withdrawal period disclosed herein can be a segmented withdrawal period within a specified treatment cycle (e.g., dividing the number of withdrawal days within a specified treatment cycle into the total number of days throughout the entire treatment cycle). For example, and without limitation, PCS6422 may be administered on day 1, followed by a therapeutically effective dose of capecitabine on each of days 2 and 3, and then a withdrawal period for days 4-5. Next, a second effective dose of PCS6422 may be administered on day 6, followed by a therapeutically effective dose of capecitabine on each of days 7-8, and then the remaining withdrawal period for days 9-14 of the treatment cycle. In some embodiments, the withdrawal period occurs on days 4-7, 11-14, and 18-28 of the treatment cycle.

[0074] The withdrawal period disclosed herein may be a variable withdrawal period (e.g., the duration of the withdrawal period in the first treatment cycle differs from that in the second treatment cycle). For example, and without limitation, the first treatment cycle may include a 3-day withdrawal period (e.g., days 3, 4, and 5 of the first treatment cycle), and the subsequent second treatment cycle may include a 5-day withdrawal period (e.g., days 3, 4, 5, 6, and 7 of the second treatment cycle). The withdrawal period may be adjusted from treatment cycle to treatment cycle for several reasons, including, for example, the observation of adverse side effects in the subject and / or the determination of 5-FU measurements, FBAL measurements, and / or the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio) in blood samples obtained from the subject and / or the subject in need (e.g., as described elsewhere herein).

[0075] PCS6422 PCS6422 (chemical name 5-ethynyl-1H-pyrimidine-2,4-dione, formerly known as eniluracil, 5-ethynyluracil, 776C85, and ADH300004) is an irreversible and potent inactivator of DPD. Without being bound by any theory, it should be understood that PCS6422 changes the 5-FU elimination pathway from metabolism to renal excretion and extends the 5-FU elimination half-life from 10-20 minutes to several hours. PCS6422 also inhibits the formation of 5-FU catabolites such as FBAL, which are known to cause neurotoxicity and potentially antagonize the antitumor activity of 5-FU. FBAL has also been shown to reduce the antitumor activity of 5-FU in laboratory animals. Additionally, because DPD exists in variable amounts (e.g., for a given object and between objects), the highly variable nonlinear pharmacokinetics (PK) of 5-FU can exhibit enhanced predictability and / or linearity when PCS6422 inactivates DPD in cancer patients. PCS6422 is typically administered orally. In some embodiments, PCS6422 is administered orally. In some embodiments, PCS6422 is administered intravenously.

[0076] PCS6422 may be administered in an effective amount according to this disclosure. In some embodiments, the effective amount of PCS6422 is the maximum tolerated dose. In some embodiments, the effective amount 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 about 30 mg to about 50 mg. In some embodiments, the effective amount 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 amount of PCS6422 is about 10 mg. In some embodiments, the effective amount of PCS6422 is about 20 mg. In some embodiments, the effective amount of PCS6422 is about 30 mg. In some embodiments, the effective amount of PCS6422 is about 40 mg. In some embodiments, the effective amount of PCS6422 is about 50 mg. In some embodiments, the effective amount of PCS6422 is about 60 mg.

[0077] An effective amount of PCS6422 may be administered in fractionated doses (e.g., as part of a full dose) according to the methods of this disclosure. In some embodiments, an effective amount of PCS6422 in fractionated doses (e.g., half a dose) is administered in the morning, followed by the remaining fractionated dose (e.g., half a dose) in the evening. In some embodiments, an effective amount of PCS6422 in fractionated doses is administered at 0:00 on day 1 of the treatment cycle, followed by the remaining fractionated dose approximately between 8 and 16 hours of day 1 of the treatment cycle. In some embodiments, an effective amount of PCS6422 of 40 mg is administered in fractionated doses of 20 mg twice daily.

[0078] Capecitabine Capecitabine (Xeloda®) is a commonly used oral fluoropyrimidine and a 5-FU prodrug, which is converted through 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 usually administered orally. In some embodiments, capecitabine is administered orally. In some embodiments, capecitabine is administered intravenously.

[0079] Capecitabine may be administered in a therapeutically effective dose according to 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 therapeutically effective dose of capecitabine is about 25 mg. In some embodiments, a therapeutically effective dose of capecitabine is about 50 mg. In some embodiments, a therapeutically effective dose of capecitabine is about 75 mg. In some embodiments, a therapeutically effective dose of capecitabine is about 150 mg. In some embodiments, a therapeutically effective dose of capecitabine is about 225 mg. In some embodiments, a therapeutically effective dose of capecitabine is about 300 mg. In some embodiments, a therapeutically effective dose of capecitabine is about 450 mg.

[0080] A therapeutically effective dose of capecitabine may be administered in fractionated doses (e.g., as part of a full dose) according to the methods of this disclosure. In some embodiments, a fractionated dose (e.g., half a dose) of the therapeutically effective dose of capecitabine is administered in the morning, followed by the remaining fractionated dose (e.g., half a dose) in the evening. For example, a therapeutically effective dose of capecitabine may be about 450 mg and may be administered in fractionated doses of 225 mg twice daily.

[0081] Pharmacokinetic analysis Pharmacokinetic analysis can be used to evaluate capecitabine and its metabolites (e.g., the personalized methods described herein). Without wishing to be bound by any theory, pharmacokinetic analysis of one or more of the measured 5-FU, the measured FBAL, and / or the measured FBAL to measured 5-FU ratio (FBAL:5-FU ratio) can indicate when sufficient DPD is formed (e.g., by resynthesis) to significantly reduce 5-FU performance and / or efficacy (e.g., to a level similar to that of capecitabine when administered alone), thus determining the appropriate time to administer an additional dose of an effective amount of PCS6422 and / or a therapeutically effective amount of capecitabine (e.g., including additional treatment cycles) and / or indicating whether the subject and / or the subject in need (e.g., a subject with cancer) has undetectable amounts of PCS6422 and / or capecitabine in a blood sample obtained from said subject. Alternatively, and without wishing to be bound by any theory, pharmacokinetic analysis of one or more of the measured 5-FU, the measured FBAL, or the FBAL:5-FU ratio can indicate the time at which only a small amount of the additional capecitabine administered will be metabolized into 5-FU (e.g., due to the presence of excess drug in the subject and / or the recipient, such as due to DPD inhibition by PCS6422) and could potentially cause adverse events (e.g., due to capecitabine catabolic substances), thus indicating when to discontinue the administration of an additional therapeutically effective dose of capecitabine to the subject and / or the recipient. Therefore, such analysis can be used to personalize (i) the frequency of PCS6422 and capecitabine or (ii) the frequency of capecitabine in the treatment regimen and / or treatment cycle for a specific subject and / or the recipient. Therefore, in some embodiments, the treatment cycle or treatment regimen of this disclosure may be repeated when 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. However, in some embodiments, the treatment cycle or treatment regimen of this disclosure includes stopping the administration of an additional dose of therapeutically effective capecitabine to the subject when 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, or the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold.

[0082] The pharmacokinetic analysis of this disclosure can be used in combination with other factors that determine treatment regimens to adjust the treatment regimens and / or treatment durations of this disclosure (e.g., to personalize such approaches). These other factors determining treatment regimens may include, for example, disease type and / or severity and the subject's response to the therapeutic agent. The combination of these factors with the pharmacokinetic analysis of this disclosure (e.g., "metabolite measurements") can be evaluated (e.g., by healthcare professionals) to determine treatment indices that can be used as a basis for adjusting the treatment regimens (e.g., treatment durations) of this disclosure.

[0083] A variety of analytical methods are available and known to those skilled in the art and can be used to measure the concentration of one or more of the following: α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), deoxyfluorouridine (5'-DFUR), capecitabine, and 5-fluorouracil (5-FU). For example, and without limitation, the following methods may be used for measurement: chromatographic methods (see, for example, Wang Z et al., J Anal Methods Chem. Jan 3, 2019; 2019:9371790; Radovanovic M et al., J Chromatogr B Analyt Technol Biomed Life Sci. Jan 1, 2022; 1188:123075; Chen J et al., Bioanalysis. Dec 2010; 2(12):2011-7; Knikman JE et al., Biomed Chromatogr. Jan 2020; 34(1):e4732; Knikman, JE et al., available at SSRN ID No. 4193341) and / or enzyme-linked immunosorbent assay (ELISA) (see, for example, Blaschke M et al., Journal of Cancer Therapy, Vol. 3, No. 1, 2012, pp. 28-36).

[0084] The methods disclosed herein may include measuring one or more of the following in a blood sample obtained from a subject: α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), deoxyfluorouridine (5'-DFUR), capecitabine, and 5-fluorouracil (5-FU). In some embodiments, α-fluoro-β-alanine (FBAL) and 5-fluorouracil (5-FU) are measured in a blood sample obtained from a subject. In some embodiments, the method includes determining one or more of the following: 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 aspect, this disclosure provides a method of treating a subject with cancer, comprising: (i) administering at least one dose of an effective amount of PCS6422 to the subject; and (ii) administering at least one dose of a therapeutically effective amount of capecitabine to the subject about 12 to about 24 hours after the administration of at least one dose of an effective amount of PCS6422, wherein one or more of the following are measured in a blood sample obtained from the subject: α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), deoxyfluorouridine (5'-DFUR), capecitabine, and 5-fluorouracil (5-FU).

[0086] In another aspect, this disclosure provides a method of treating cancer in a subject in need, comprising: (i) administering at least one effective dose of PCS6422 to the subject; and (ii) administering at least one therapeutically effective dose of capecitabine to the subject about 12 to about 36 hours (e.g., about 12 to about 24 hours) after the administration of at least one effective dose of PCS6422; (iii) measuring metabolites in a blood sample obtained from the subject, the metabolites comprising one or more of α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), deoxyfluorouridine (5'-DFUR), and 5-fluorouracil (5-FU); and (iv) determining whether the treatment regimen should be adjusted based on a treatment index comprising the metabolite measurements determined in step (iii).

[0087] In another aspect, this disclosure provides a method for determining the frequency of administration of PCS6422 and capecitabine to a subject, comprising: (i) administering at least one effective dose of PCS6422 to the subject; (ii) administering at least one therapeutically effective dose of capecitabine to the subject approximately 12 to approximately 36 hours (e.g., approximately 12 to approximately 24 hours) after the administration of the at least one effective dose of PCS6422, wherein α-fluoro-β-alanine (FBAL) and 5-fluorouracil (5-FU) are measured in a blood sample obtained from the subject; and (iii) determining the following... One or more of the following: the measured 5-FU, the measured FBAL, and / or the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio); and (iv) after the withdrawal period, repeat steps (i) and (ii) when 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.

[0088] In another aspect, this disclosure provides a method for determining the frequency of capecitabine administration in a subject, comprising: (i) administering at least one effective dose of PCS6422 to the subject; and (ii) administering at least one therapeutically effective dose of capecitabine to the subject approximately 12 to approximately 36 hours (e.g., approximately 12 to approximately 24 hours) after the administration of the at least one effective dose of PCS6422, wherein α-fluoro-β-alanine (FBAL) and / or 5-fluorouracil (5-) are measured in a blood sample obtained from the subject. (iii) Determine one or more of the following: the measured 5-FU, the measured FBAL, or the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio); and (iv) when 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, or the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, stop administering an additional dose of therapeutically effective capecitabine to the subject.

[0089] In some embodiments, the method of this disclosure may include stopping the administration of an additional therapeutically effective dose of capecitabine to the subject when 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, or the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold. In some embodiments, stopping the administration of an additional therapeutically effective dose of capecitabine to the subject is followed by a withdrawal period (e.g., as described herein). In some embodiments, after the withdrawal period, steps (i) and (ii) are repeated (e.g., when the measured 5-FU is zero and / or the measured FBAL is zero).

[0090] In some embodiments, from about 1 day to about 29 days after step (ii) of the method described herein, steps (i) and (ii) may be repeated if 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.

[0091] In some embodiments, approximately 1 to approximately 29 days after step (ii) of the method described herein, steps (i) and (ii) may be repeated when the therapeutic index of the metabolite measurements included in (iii) indicates, among other factors described herein for determining the treatment regimen, that 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.

[0092] In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 29 days after step (ii) of the method described herein, when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 22 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 15 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 12 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 10 days after step (ii) when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 8 days after step (ii) when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 6 days after step (ii) when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 4 days after step (ii) when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold. In some embodiments, approximately 1 to 2 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 1 day after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 2 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 3 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated.In some embodiments, approximately 4 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 5 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 6 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 7 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 8 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 10 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 12 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 14 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 15 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 21 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 22 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 28 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 29 days after step (ii), when the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, steps (i) and (ii) are repeated.

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

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

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

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

[0097] In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 29 days after step (ii) of the method described herein, when the determined 5-FU measurement is less than a certain 5-FU threshold. In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 22 days after step (ii) of the method described herein, when the determined 5-FU measurement is less than a certain 5-FU threshold. In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 15 days after step (ii) of the method described herein, when the determined 5-FU measurement is less than a certain 5-FU threshold. In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 12 days after step (ii), when the determined 5-FU measurement is less than a certain 5-FU threshold. In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 10 days after step (ii), when the determined 5-FU measurement is less than a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 8 days after step (ii) when the determined 5-FU measurement value is less than a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 6 days after step (ii) when the determined 5-FU measurement value is less than a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 4 days after step (ii) when the determined 5-FU measurement value is less than a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 2 days after step (ii) when the determined 5-FU measurement value is less than a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 day after step (ii) when the determined 5-FU measurement value is less than a certain 5-FU threshold. In some embodiments, steps (i) and (ii) are repeated approximately 2 days after step (ii) when the determined 5-FU measurement value is less than a certain 5-FU threshold. In some embodiments, approximately 3 days after step (ii), when the determined 5-FU measurement value is less than a certain 5-FU threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 4 days after step (ii), when the determined 5-FU measurement value is less than a certain 5-FU threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 5 days after step (ii), when the determined 5-FU measurement value is less than a certain 5-FU threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 6 days after step (ii), when the determined 5-FU measurement value is less than a certain 5-FU threshold, steps (i) and (ii) are repeated.In some embodiments, approximately 7 days after step (ii), when the determined 5-FU measurement value is less than a certain 5-FU threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 8 days after step (ii), when the determined 5-FU measurement value is less than a certain 5-FU threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 10 days after step (ii), when the determined 5-FU measurement value is less than a certain 5-FU threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 12 days after step (ii), when the determined 5-FU measurement value is less than a certain 5-FU threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 14 days after step (ii), when the determined 5-FU measurement value is less than a certain 5-FU threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 15 days after step (ii), when the determined 5-FU measurement value is less than a certain 5-FU threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 21 days after step (ii), steps (i) and (ii) are repeated when the determined 5-FU measurement is less than a certain 5-FU threshold. In some embodiments, approximately 22 days after step (ii), steps (i) and (ii) are repeated when the determined 5-FU measurement is less than a certain 5-FU threshold. In some embodiments, approximately 28 days after step (ii), steps (i) and (ii) are repeated when the determined 5-FU measurement is less than a certain 5-FU threshold. In some embodiments, approximately 29 days after step (ii), steps (i) and (ii) are repeated when the determined 5-FU measurement is less than a certain 5-FU threshold.

[0098] In some embodiments, steps (i) and (ii) are not repeated when the determined 5-FU measurement is greater than or equal to a certain 5-FU threshold.

[0099] In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 29 days after step (ii) of the method described herein, when the determined 5-FU measurement is zero. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 22 days after step (ii), when the determined 5-FU measurement is zero. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 15 days after step (ii), when the determined 5-FU measurement is zero. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 12 days after step (ii), when the determined 5-FU measurement is zero. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 10 days after step (ii), when the determined 5-FU measurement is zero. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 8 days after step (ii), when the determined 5-FU measurement is zero. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 6 days after step (ii) when the determined 5-FU measurement value is zero. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 4 days after step (ii) when the determined 5-FU measurement value is zero. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 2 days after step (ii) when the determined 5-FU measurement value is zero. In some embodiments, steps (i) and (ii) are repeated approximately 1 day after step (ii) when the determined 5-FU measurement value is zero. In some embodiments, steps (i) and (ii) are repeated approximately 2 days after step (ii) when the determined 5-FU measurement value is zero. In some embodiments, steps (i) and (ii) are repeated approximately 3 days after step (ii) when the determined 5-FU measurement value is zero. In some embodiments, approximately 4 days after step (ii), when the determined 5-FU measurement value is zero, steps (i) and (ii) are repeated. In some embodiments, approximately 5 days after step (ii), when the determined 5-FU measurement value is zero, steps (i) and (ii) are repeated. In some embodiments, approximately 6 days after step (ii), when the determined 5-FU measurement value is zero, steps (i) and (ii) are repeated. In some embodiments, approximately 7 days after step (ii), when the determined 5-FU measurement value is zero, steps (i) and (ii) are repeated. In some embodiments, approximately 8 days after step (ii), when the determined 5-FU measurement value is zero, steps (i) and (ii) are repeated.In some embodiments, approximately 10 days after step (ii), when the determined 5-FU measurement is zero, steps (i) and (ii) are repeated. In some embodiments, approximately 12 days after step (ii), when the determined 5-FU measurement is zero, steps (i) and (ii) are repeated. In some embodiments, approximately 14 days after step (ii), when the determined 5-FU measurement is zero, steps (i) and (ii) are repeated. In some embodiments, approximately 15 days after step (ii), when the determined 5-FU measurement is zero, steps (i) and (ii) are repeated. In some embodiments, approximately 21 days after step (ii), when the determined 5-FU measurement is zero, steps (i) and (ii) are repeated. In some embodiments, approximately 22 days after step (ii), when the determined 5-FU measurement is zero, steps (i) and (ii) are repeated. In some embodiments, steps (i) and (ii) are repeated approximately 28 days after step (ii) when the determined 5-FU measurement is zero. In some embodiments, steps (i) and (ii) are repeated approximately 29 days after step (ii) when the determined 5-FU measurement is zero.

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

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

[0102] In some embodiments, after step (ii) of the method described herein, when the determined 5-FU measurement is greater than or equal to a certain 5-FU threshold, an additional dose of therapeutically effective capecitabine is administered to the subject.

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

[0104] In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 29 days after step (ii) of the methods described herein, when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 22 days after step (ii) of the methods described herein, when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 15 days after step (ii) of the methods described herein, when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 12 days after step (ii), when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, steps (i) and (ii) may be repeated approximately 1 to 10 days after step (ii), when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 8 days after step (ii) when the determined FBAL measurement value is greater than or equal to a certain FBAL threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 6 days after step (ii) when the determined FBAL measurement value is greater than or equal to a certain FBAL threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 4 days after step (ii) when the determined FBAL measurement value is greater than or equal to a certain FBAL threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 to 2 days after step (ii) when the determined FBAL measurement value is greater than or equal to a certain FBAL threshold. In some embodiments, steps (i) and (ii) are repeated approximately 1 day after step (ii) when the determined FBAL measurement value is greater than or equal to a certain FBAL threshold. In some embodiments, steps (i) and (ii) are repeated approximately 2 days after step (ii) when the determined FBAL measurement value is greater than or equal to a certain FBAL threshold. In some embodiments, approximately 3 days after step (ii), when the determined FBAL measurement value is greater than or equal to a certain FBAL threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 4 days after step (ii), when the determined FBAL measurement value is greater than or equal to a certain FBAL threshold, steps (i) and (ii) are repeated. In some embodiments, approximately 5 days after step (ii), when the determined FBAL measurement value is greater than or equal to a certain FBAL threshold, steps (i) and (ii) are repeated.In some embodiments, approximately 6 days after step (ii), steps (i) and (ii) are repeated when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, approximately 7 days after step (ii), steps (i) and (ii) are repeated when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, approximately 8 days after step (ii), steps (i) and (ii) are repeated when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, approximately 10 days after step (ii), steps (i) and (ii) are repeated when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, approximately 12 days after step (ii), steps (i) and (ii) are repeated when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, approximately 14 days after step (ii), steps (i) and (ii) are repeated when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, approximately 15 days after step (ii), steps (i) and (ii) are repeated when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, approximately 21 days after step (ii), steps (i) and (ii) are repeated when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, approximately 22 days after step (ii), steps (i) and (ii) are repeated when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, approximately 28 days after step (ii), steps (i) and (ii) are repeated when the determined FBAL measurement is greater than or equal to a certain FBAL threshold. In some embodiments, approximately 29 days after step (ii), steps (i) and (ii) are repeated when the determined FBAL measurement is greater than or equal to a certain FBAL threshold.

[0105] In some embodiments, steps (i) and (ii) are not repeated when the determined FBAL measurement value is less than a certain FBAL threshold.

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

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

[0108] In some embodiments, after step (ii) of the method described herein, when the determined FBAL measurement is greater than or equal to a certain FBAL threshold, the administration of an additional dose of therapeutically effective capecitabine to the subject is stopped.

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

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

[0111] Blood samples obtained from the subject using the methods according to this disclosure can be obtained at a single time point or multiple time points during the treatment cycle. In some embodiments, blood samples obtained from the subject can be obtained in the morning (e.g., before a therapeutically effective dose of capecitabine is administered to the subject). In some embodiments, blood samples obtained from the subject can be obtained in the evening (e.g., before a fractionated therapeutically effective dose of capecitabine is administered to the subject and / or approximately 12 hours after a therapeutically effective dose of capecitabine is administered in the morning). In some embodiments, blood samples obtained from the subject can be obtained approximately 24 hours after an effective dose of PCS6422 is administered.

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

[0113] In some embodiments, starting on the first day of capecitabine treatment (e.g., before administration of the initial dose of capecitabine), one or more of FBAL, 5'-DFCR, 5'-DFUR, capecitabine, and 5-FU are measured daily. In some embodiments, starting on the first day of capecitabine treatment (e.g., before administration of the initial dose of capecitabine), FBAL and 5-FU are measured daily. In some embodiments, at each time point at which blood samples are obtained from the subject, one or more of FBAL, 5'-DFCR, 5'-DFUR, capecitabine, and 5-FU are measured.

[0114] target group According to the techniques described herein, the object and / or desired object includes, but is not limited to, humans and non-human vertebrates. In some embodiments, according to the techniques disclosed herein, the object and / or desired object includes, for example, mammals. Mammals include, for example, but not limited to, domestic pets (e.g., dogs, cats, rabbits, hamsters), livestock and / or agricultural animals (e.g., dairy cows, pigs, sheep, goats, chickens, or other poultry), horses, monkeys, laboratory animals (e.g., mice, rats, rabbits), etc. In a preferred embodiment, according to the methods described herein, the object and / or desired object is a human.

[0115] The object and / or desired object of this disclosure may be an adult (e.g., an adult). In some embodiments, the object and / or desired object is a human object over 18 years of age. In some embodiments, the object and / or desired object is a human object over 21 years of age. In some embodiments, the object and / or desired object is a human object over 45 years of age. In some embodiments, the object and / or desired object is a human object over 65 years of age. In some embodiments, the object and / or desired object is a human object 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 object and / or desired object is a human object 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 object and / or the object of need of this disclosure may be a non-adult (e.g., a human child, a human adolescent). In some embodiments, the object and / or the object of need is a human object under the age of 18. In some embodiments, the object and / or the object of need is a human object under the age of 12. In some embodiments, the object and / or the object of need is a human object under the age of 5.

[0117] In some aspects, the methods described herein can be used and / or implemented on any subject who has (e.g., has been diagnosed with) cancer (e.g., cancer that can and / or may benefit from the methods described herein). A subject with a tumor (e.g., a solid tumor) is a subject with detectable tumor cells. This disclosure is particularly contemplated for the use of any of the methods described herein to treat a subject with cancer and / or to determine (i) the frequency of administration of PCS6422 and capecitabine or (ii) capecitabine to a subject (e.g., a subject in need).

[0118] In some respects, the methods disclosed herein can be used on subjects with cancer and / or subjects in need of cancer treatment. Subjects with cancer and / or subjects in need of cancer treatment have detectable cancer cells. Examples of cancers treatable according to the techniques of this disclosure in some embodiments include, but are not limited to, adrenocortical carcinoma, astrocytoma, basal cell carcinoma, breast cancer, carcinoid tumor, cardiac cancer, cholangiocarcinoma, chordoma, chronic myeloproliferative neoplasm, craniopharyngioma, ductal carcinoma in situ of the breast, ependymoma, intraocular melanoma, gastrointestinal tumors (e.g., gastrointestinal carcinoid tumors, colorectal tumors, gastrointestinal stromal tumors (GIST)), trophoblastic disease of pregnancy, 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, and myeloid leukemia), lymphoma (e.g., Burkitt lymphoma (non-Hodgkin lymphoma)), cutaneous T-cell lymphoma, Hodgkin lymphoma, mycosis fungoides, and Sezary syndrome). (Syndrome), AIDS-related lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, melanoma, Merkel cell carcinoma, mesothelioma, myeloma (e.g., multiple myeloma), myelodysplastic syndrome, pancreatic tumors, papilloma, paraganglioma, pheochromocytoma, pleural pulmonary blastoma, retinoblastoma, sarcoma (e.g., Ewing sarcoma, Kaposi's sarcoma) Sarcoma, osteosarcoma, rhabdomyosarcoma, uterine sarcoma, angiosarcoma, Wilms' tumor, and / or adrenocortical cancer, anal cancer, appendix cancer, bile duct cancer, bladder cancer, bone cancer, brain cancer, breast cancer, bronchial cancer, central nervous system cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, fallopian tube cancer, gallbladder cancer, gastrointestinal cancer, germ cell cancer, head and neck cancer, heart cancer, bowel cancer, kidney cancer (e.g., Wilms' tumor), laryngeal cancer, liver cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), oral cancer, nasal cavity cancer, oral cavity cancer, ovarian cancer, pancreatic cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, laryngeal cancer, thyroid cancer, penile cancer, pharyngeal cancer, peritoneal cancer, pituitary cancer, prostate cancer, rectal cancer, salivary gland cancer, ureteral cancer, urethral cancer, uterine cancer, vaginal cancer, or vulvar cancer. In some embodiments, the subject and / or the subject in need suffers from colorectal cancer (e.g., metastatic colorectal cancer). In some embodiments, the subject and / or the subject in need suffers from gastrointestinal cancer (e.g., metastatic gastrointestinal cancer). In some embodiments, the subject and / or the subject in need suffers from breast cancer (e.g., metastatic breast cancer).In some embodiments, the object and / or the object in need suffers from pancreatic cancer (e.g., metastatic pancreatic cancer).

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

[0120] The cancers disclosed herein may be advanced (e.g., metastatic, stage 3, stage 4). Advanced cancers may be considered and / or determined (e.g., considered and / or determined by a layperson) to be unlikely to be cured and / or controlled by therapeutic interventions. The cancers disclosed herein may be refractory (e.g., cancers that do not respond to treatment).

[0121] The tests used to diagnose cancers intended for treatment using the methods described herein are known in the field and familiar to the average medical practitioner. These laboratory tests include, but are not limited to, microscopic analysis, culture-dependent tests (e.g., cultures), and nucleic acid detection tests. These tests include wet mount, stain-enhanced microscopy, immunomicroscopy (e.g., FISH), hybridization microscopy, particle bonding, enzyme-linked immunosorbent assay (ELISA), urine screening tests, DNA probe hybridization, serological tests, etc. Medical practitioners typically obtain a complete medical history and perform a full physical examination in addition to conducting the laboratory tests listed above.

[0122] In some aspects, the subject and / or the subject in need has previously undergone one or more other cancer therapies (e.g., chemotherapy, radiation therapy, or surgical tumor removal). In some embodiments, the subject and / or the subject in need has previously undergone one or more other cancer therapies (e.g., chemotherapy, radiation therapy, or surgical tumor removal), and the subject's cancer has recurred. In some embodiments, the subject and / or the subject in need has previously undergone one or more other cancer therapies (e.g., chemotherapy, radiation therapy, or stem cell transplantation), and the subject has developed resistance to one or more other cancer therapies. In some embodiments, the subject and / or the subject in need is in remission (e.g., the cancer is in partial or complete remission). In some embodiments, the subject and / or the subject in need is difficult to treat with one or more other cancer therapies (e.g., chemotherapy, radiation therapy, or stem cell transplantation).

[0123] In other embodiments, this document contemplates treating subjects at risk of developing cancer, which may (or could) benefit from any treatment regimen described herein according to the methods and uses of this disclosure. Subjects at risk of developing cancer are those with a higher than normal probability of developing cancer. These subjects include, for example, subjects with genetic abnormalities that have been shown to be associated with a higher probability of developing cancer, subjects with a familial predisposition to cancer, subjects exposed to carcinogenic agents (i.e., carcinogens) (e.g., tobacco, asbestos, or other chemical toxins), and subjects who have previously been treated for cancer and are in significant remission. This disclosure contemplates the application of PCS6422 and capecitabine, or compositions comprising them, as described herein, to subjects at risk of developing cancer.

[0124] Encoding dihydropyrimidine dehydrogenase (DPD) DPYD Gene variants can produce enzymes with reduced or absent DPD enzyme activity. Without being bound by any theory, it should be understood that these enzymes possess non-functionality. DPYD At least one copy of the variant of the object cannot metabolize fluorouracil (e.g., 5-FU) at a normal rate. Therefore, these objects have an increased risk of potentially life-threatening fluorouracil toxicity, such as bone marrow suppression, gastrointestinal toxicity, and, in rare cases, neurotoxicity. Therefore, according to the techniques of this disclosure, the object and / or desired object may include an object having at least partial DPD enzyme activity (e.g., DPYD Normal metabolizers DPYD (Moderate metabolizer). DPYD Normal metabolizers possess fully functional DPD enzyme activity. Compared to the general population, DPYD Moderate metabolizers may have reduced DPD enzyme activity of approximately 30% to approximately 70%. In some embodiments, according to the techniques of this disclosure, the object and / or the desired object is... DPYD Normal metabolizers. In some embodiments, according to the techniques of this disclosure, the object and / or the desired object is... DPYD Moderate metabolizer.

[0125] In some embodiments, according to the technology of this disclosure, the object and / or the desired object exhibits at least about 1% normal DPD enzyme activity, at least about 5% normal DPD enzyme activity, at least about 10% normal DPD enzyme activity, at least about 20% normal DPD enzyme activity, at least about 30% normal DPD enzyme activity, at least about 40% normal DPD enzyme activity, at least about 50% normal DPD enzyme activity, at least about 60% normal DPD enzyme activity, at least about 70% normal DPD enzyme activity, at least about 80% normal DPD enzyme activity, at least about 90% normal DPD enzyme activity, or at least about 95% normal DPD enzyme activity. In some embodiments, according to the technology of this disclosure, the object and / or the desired object exhibits approximately 100% normal DPD enzyme activity, approximately 95% normal DPD enzyme activity, approximately 90% normal DPD enzyme activity, approximately 85% normal DPD enzyme activity, approximately 80% normal DPD enzyme activity, approximately 75% normal DPD enzyme activity, approximately 70% normal DPD enzyme activity, approximately 60% normal DPD enzyme activity, approximately 50% normal DPD enzyme activity, approximately 40% normal DPD enzyme activity, approximately 30% normal DPD enzyme activity, approximately 20% normal DPD enzyme activity, approximately 10% normal DPD enzyme activity, approximately 5% normal DPD enzyme activity, or approximately 1% normal DPD enzyme activity.

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

[0127] In some embodiments, according to the techniques of this disclosure, the subject and / or the desired subject is not a subject lacking DPD enzyme activity (also referred to herein as "DPD deficiency" (e.g., 0% DPD enzyme activity, or DPD enzyme activity below the limit of quantitation)). In some embodiments, according to the techniques of this disclosure, the subject and / or the desired subject is a subject lacking DPD enzyme activity (DPD-deficient).

[0128] A variety of methods for assessing DPD enzyme activity are available and known to those skilled in the art, and these methods can be used to determine whether a subject and / or a desired subject is... DPYD Normal metabolizers DPYDModerate metabolizers or DPD-deficient individuals. For example, and without limitation, reversed-phase high-performance liquid chromatography combined with electrospray tandem mass spectrometry can be used to assess DPD enzyme activity in peripheral blood mononuclear cells (PBMCs) by measuring the concentrations of uracil and thymine (endogenous substrates of DPD). See, for example, Henricks LM et al., Int J Cancer. 2018 Jan 15;142(2):424-430.

[0129] This can be based on a certain degree of DPD enzyme activity. DYPD The presence or absence of specific variants of the gene is used to determine the DPD enzyme activity of a specific object and / or desired object. This activity is readily available and known to those skilled in the art for identifying the object and / or desired object. DYPD Multiple methods for determining the presence or absence of specific gene variants, including, for example, Sanger sequencing and next-generation sequencing. Specifically... DYPD Examples of variants and their associated DPD enzyme activities are shown in Table 1.

[0130] Table 1: Selected DYPD Active state of the variant In some embodiments, according to the techniques of this disclosure, the subject and / or the desired subject is not a subject that has one or more of the following: significantly reduced renal function, current brain metastases, a history of prolonged QT > 480 ms with heart rate correction, prolonged QTc interval, ventricular tachycardia / fibrillation, or significant ventricular arrhythmia, or torsades de pointes ventricular tachycardia, or a history of ventricular ablation for arrhythmia, a history or presence of clinically significant abnormal 12-lead ECG results, congenital long QT syndrome or a family history of long QT syndrome, other significant heart disease (e.g., uncontrolled angina, myocardial ischemia or infarction within 6 months, congestive heart failure > Class II (according to the New York Heart Association)) or a history of myocarditis), electrolyte disturbances (e.g., uncorrected hypokalemia / hyperkalemia, hypomagnesemia or hypocalcemia), known hypersensitivity to either PCS6422 and / or capecitabine, and / or being pregnant or lactating.

[0131] Identification According to the techniques of this disclosure, one or more of the following can be evaluated in subjects and / or subjects in need: adverse events (e.g., any adverse medical event in subjects and / or subjects in need), durable clinical benefit, favorable response, long-term benefit, objective response, objective response rate, and / or progression-free survival. Relative to a suitable reference (e.g., subjects and / or subjects in need receiving a treatment regimen of PCS6422 and capecitabine not described herein; subjects and / or subjects in need receiving a treatment regimen of PCS6422 and capecitabine but not personalized as described herein), the techniques of this disclosure can provide one or more of the following: a reduction in adverse events and / or durable clinical benefit, favorable response, long-term benefit, objective response, objective response rate, and / or an increase in progression-free survival.

[0132] Examples of treatment plans The aforementioned duration and / or time range of drug administration, dosage, withdrawal period, and / or pharmacokinetic analysis are not limited to any specific combination, and any of the above embodiments can be used in any combination. The following treatment regimens describe specific examples of combinations of the foregoing embodiments.

[0133] In one embodiment, the treatment regimen of this disclosure includes administering an effective dose of PCS6422 once on day 1 of the treatment cycle, administering a therapeutically effective dose of capecitabine once on day 2 of the treatment cycle, and a withdrawal period on days 3 and 4 of the treatment cycle. In some embodiments, the treatment cycle is repeated (e.g., based on the results of the pharmacokinetic analysis described herein).

[0134] In one embodiment, the treatment regimen of this disclosure comprises a single 40 mg dose of PCS6422 administered on day 1 of the treatment cycle (i.e., in the morning), divided doses of capecitabine administered twice daily on days 2 through 6 of the treatment cycle, and a withdrawal period on days 7 through 14 of the treatment cycle. In some embodiments, the treatment cycle is repeated (e.g., based on the results of the pharmacokinetic analysis described herein).

[0135] In one embodiment, the treatment regimen of this disclosure comprises a single 40 mg dose of PCS6422 administered on day 1 of the treatment cycle (i.e., in the morning), 50 to 450 mg / day of capecitabine administered twice daily on days 2 and 3 of the treatment cycle, a break period on days 4 and 5 of the treatment cycle, a single 40 mg dose of PCS6422 administered on day 6 of the treatment cycle (i.e., in the morning), 50 to 450 mg / day of capecitabine administered twice daily on days 7 and 8 of the treatment cycle, and a break period on days 9 to 14 of the treatment cycle. In some embodiments, the treatment cycle is repeated (e.g., based on the results of the pharmacokinetic analysis described herein).

[0136] In one embodiment, the treatment regimen for the first treatment cycle of this disclosure includes a single dose of 40 mg of PCS6422 on day 1 of the treatment cycle (i.e., in the morning), divided doses of 50-450 mg / day of capecitabine twice daily on days 2 through 8 of the treatment cycle, and a withdrawal period on days 9 through 14 of the treatment cycle. On days 3 through 9 of the first treatment cycle, one or more of the following are measured from a blood sample obtained from the subject: α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), deoxyfluorouridine (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, the measured FBAL, and / or the FBAL:5-FU ratio, adjust the total number of capecitabine dosing days in the second treatment cycle until PCS6422 no longer has an impact on performance.

[0137] In one embodiment, the treatment regimen for the first treatment cycle of this disclosure includes a single dose of 40 mg of PCS6422 on day 1 of the treatment cycle (i.e., in the morning), divided doses of 50-450 mg / day of capecitabine twice daily on days 2 through 4 of the treatment cycle, and a withdrawal period on days 5 through 7 of the treatment cycle. On days 3 through 4 of the first treatment cycle, one or more of the following are measured from a blood sample obtained from the subject: α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), deoxyfluorouridine (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, the measured FBAL, and / or the FBAL:5-FU ratio, adjust the total number of capecitabine days in the second treatment cycle until PCS6422 has no further or minimal impact on performance, while maintaining at least 3 days without capecitabine administration (including the PCS6422 administration days in the second treatment cycle) and a total cycle of 7 days. In some embodiments, every third treatment cycle is replaced by a 7-day withdrawal period.

[0138] In one embodiment, the treatment regimen of this disclosure for a treatment cycle comprises administering a single 40 mg dose of PCS6422 on day 1 of the treatment cycle (i.e., in the morning), and twice daily divided doses of capecitabine of 50-450 mg / day on days 2 through 4 of the treatment cycle. On each day of days 2 through 4 of the first treatment cycle, one or more of the following are measured from a blood sample obtained from the subject: α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), deoxyfluorouridine (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, the measured FBAL, or the FBAL:5-FU ratio, additional twice daily divided doses of capecitabine of 50 to 450 mg / day are continued or discontinued. If the measured 5-FU, the measured FBAL, or the FBAL:5-FU ratio is less than a certain 5-FU threshold, greater than or equal to a certain FBAL threshold, or greater than or equal to a certain FBAL:5-FU ratio, then the administration of additional doses of capecitabine is stopped and a withdrawal period begins. In some embodiments, steps (i) and (ii) are repeated after the withdrawal period.

[0139] In one embodiment, the treatment regimen of this disclosure comprises a single 40 mg dose of PCS6422 administered on day 1 of the treatment cycle (i.e., in the morning), followed by divided doses of capecitabine (50-450 mg / day) administered twice daily on days 2 through 15 of the treatment cycle, provided that the measured 5-FU level from a blood sample obtained from the subject is greater than or equal to 2.0 ng / mL, the measured FBAL level is less than 15 ng / mL, or the FBAL:5-FU ratio is less than 7.5. When the measured 5-FU level from a blood sample obtained from the subject is less than 2.0 ng / mL, the FBAL level is greater than or equal to 15 ng / mL, or the FBAL:5-FU ratio is greater than or equal to 7.5, additional doses of therapeutically effective capecitabine are discontinued and a withdrawal period begins, lasting at least 2 to 14 days until the measured 5-FU level is greater than or equal to 2.0 ng / mL and the FBAL level is less than 15 ng / mL.

[0140] In one embodiment, the treatment regimen of this disclosure for a treatment cycle includes administering an effective dose of PCS6422 (e.g., as a single dose or fractionated dose) on day 1 of the treatment cycle, administering a therapeutically effective dose of capecitabine (e.g., as a single dose or fractionated dose) daily from day 2 to day 8 of the treatment cycle, and a break period from day 9 to day 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 that includes such pharmacokinetic analysis as described herein). In some embodiments, additional capecitabine administration is continued or discontinued based on the measured 5-FU, the measured FBAL and / or FBAL:5-FU ratio, or the treatment index.

[0141] In one embodiment, the treatment regimen of this disclosure for a treatment cycle includes administering an effective dose of PCS6422 (e.g., as a single dose or fractionated dose) on day 1 of the treatment cycle, administering a therapeutically effective dose of capecitabine (e.g., as a single dose or fractionated dose) on each day of days 2 through 4 of the treatment cycle, and a withdrawal period from days 5 to 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 that includes such pharmacokinetic analysis as described herein). In some embodiments, additional capecitabine administration is continued or discontinued based on the measured 5-FU, the measured FBAL and / or FBAL:5-FU ratio, or the treatment index.

[0142] In one embodiment, the treatment regimen of this disclosure for a treatment cycle includes administering an effective dose of PCS6422 (e.g., as a single dose or fractionated dose) on day 1 of the treatment cycle, administering a therapeutically effective dose of capecitabine (e.g., as a single dose or fractionated dose) on each day of days 2 to 3 of the treatment cycle, and a break period from day 4 to 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 that includes such pharmacokinetic analysis as described herein). In some embodiments, additional capecitabine administration is continued or discontinued based on the measured 5-FU, the measured FBAL and / or FBAL:5-FU ratio, or the treatment index.

[0143] In one embodiment, the treatment regimen of this disclosure for a treatment cycle includes administering an effective dose of PCS6422 (e.g., as a single dose or fractionated dose) on day 1 of the treatment cycle, administering a therapeutically effective dose of capecitabine (e.g., as a single dose or fractionated dose) on each day of days 2 through 4 of the treatment cycle, administering a second effective dose of PCS6422 (e.g., as a single dose or fractionated dose) on day 5 of the treatment cycle, administering a therapeutically effective dose of capecitabine (e.g., as a single dose or fractionated dose) on each day of days 6 through 8 of the treatment cycle, and a discontinuation period from days 9 to 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 that includes such pharmacokinetic analysis as described herein). In some embodiments, additional capecitabine administration is continued or discontinued based on the measured 5-FU, the measured FBAL and / or FBAL:5-FU ratio, or the treatment index.

[0144] In one embodiment, the treatment regimen of this disclosure for a treatment cycle includes administering an effective dose of PCS6422 (e.g., as a single dose or fractionated dose) on day 1 of the treatment cycle, administering a therapeutically effective dose of capecitabine (e.g., as a single dose or fractionated dose) each day from day 2 to day 8 of the treatment cycle, administering a second effective dose of PCS6422 (e.g., as a single dose or fractionated dose) on day 5 of the treatment cycle, and a discontinuation period from day 9 to day 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 that includes such pharmacokinetic analysis as described herein). In some embodiments, additional capecitabine administration is continued or discontinued based on the measured 5-FU, the measured FBAL and / or FBAL:5-FU ratio, or the treatment index.

[0145] In one embodiment, the treatment regimen of this disclosure for a treatment cycle includes administering an effective dose of PCS6422 (e.g., as a single dose or fractionated dose) on day 1 of the treatment cycle, administering a therapeutically effective dose of capecitabine (e.g., as a single dose or fractionated dose) daily from day 2 to day 15 of the treatment cycle, and a break period from day 16 to day 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 that includes such pharmacokinetic analysis as described herein). In some embodiments, additional capecitabine administration is continued or discontinued based on the measured 5-FU, the measured FBAL and / or FBAL:5-FU ratio, or the treatment index.

[0146] In one embodiment, the treatment regimen of the treatment cycle disclosed herein includes administering an effective dose of PCS6422 (e.g., as a single dose or fractionated dose) on day 1 of the treatment cycle, administering a therapeutically effective dose of capecitabine (e.g., as a single dose or fractionated dose) on each day of days 2 to 3 of the treatment cycle, a break period from day 4 to 7 of the treatment cycle, administering a second effective dose of PCS6422 (e.g., as a single dose or fractionated dose) on day 8 of the treatment cycle, administering a therapeutically effective dose of capecitabine (e.g., as a single dose or fractionated dose) on each day of days 9 to 10 of the treatment cycle, a break period from day 11 to 14 of the treatment cycle, administering a third effective dose of PCS6422 (e.g., as a single dose or fractionated dose) on day 15 of the treatment cycle, administering a therapeutically effective dose of capecitabine (e.g., as a single dose or fractionated dose) on each day of days 16 to 17 of the treatment cycle, and a break period from day 18 to 28 of the treatment cycle. In some embodiments, treatment cycles are repeated (e.g., based on the results of pharmacokinetic analysis or a treatment index that includes such pharmacokinetic analysis as described herein). In some embodiments, additional capecitabine administration is continued or discontinued based on the measured 5-FU, the measured FBAL and / or FBAL:5-FU ratio, or the treatment index.

[0147] Example Example 1: Groups 1 and 2A - PCS6422 and capecitabine 14-day cycle In a 14-day cycle, subjects with advanced, metastatic, or unresectable gastrointestinal (GI) tumors that were refractory to or intolerant of existing therapies were treated with PCS6422. On day 1, subjects were given 40 mg of PCS6422. Subsequently, on days 2 through 8, subjects were given 75 mg of capecitabine once daily (group 1) or twice daily (group 2A, morning and evening), followed by a 6-day withdrawal period (days 9 through 14).

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

[0149] Blood samples were drawn during screening and at the following times during Cycle 1 for analysis of DPD activity using uracil and dihydrouracil concentrations: Day 1, Day 2, Day 8, Day 9, and Day 10. Blood samples were also drawn on Day 1 of Cycle 2, prior to administration of PCS6422. If possible, all blood samples used for uracil and dihydrouracil concentration analysis were obtained before the subject's meal. The actual sampling times were recorded. The plasma concentrations of PCS6422, 5-acetyluracil, capecitabine, 5-FU, FBAL, 5'-DFCR and 5'-DFUR, uracil, and / or dihydrouracil were determined using validated analytical methods.

[0150] Exemplary PK results are shown in Table 1.1.

[0151] Table 1.1: Examples of 5-FU and FBAL analysis results for Group 1 (C1) and Group 2A (C2A). NA indicates inapplicable because no sample was obtained or analyzed.

[0152] Data from subjects receiving PCS6422 on day 1 (C1, C2A) on day 8 represented fully active DPD (e.g., DPD not inhibited by PCS6422). On day 2, not only was DPD inhibited, but DPD reformation was also observed. The lowest and highest 5-FU plasma concentrations (Cp) ranged from 8.1 ng / mL to 164 ng / mL (low Cp) and from 309 ng / mL to 466 ng / mL (high Cp) during the 0-9 hour period following capecitabine administration. High FBALCp on day 2 (0-9 hour following capecitabine administration) ranged from less than 15 ng / mL to 26 ng / mL, and low Cp on day 2 (0-9 hour following capecitabine administration) ranged from less than 15 ng / mL to 22.6 ng / mL.

[0153] Example 2: Groups 2B and 2D - PCS6422 and capecitabine 14-day cycle In a 14-day cycle, subjects with advanced, metastatic, or unresectable gastrointestinal (GI) tumors that are refractory to or intolerant of existing therapies were administered PCS6422 in combination with capecitabine. Subjects received 40 mg of PCS6422 on days 1 and 5 (group 2B) or on day 1 only (group 2D). This was followed by 75 mg of capecitabine twice daily (morning and evening) from days 2 to 8, followed by a 6-day withdrawal period (days 9 to 14).

[0154] On day 1 of cycle 1, blood samples were collected at 0 (before administration), 1, 2, 3, 5, 7, 9, and 24 hours for PK analysis of PCS6422 and its major metabolite 5-acetyluracil. Samples were collected 24 hours after administration, prior to capecitabine administration on day 2.

[0155] On day 1 of capecitabine treatment (cycle 1, day 2), blood samples were obtained at the following time points relative to the first dose of capecitabine administration (day 1) for pharmacokinetic analysis of capecitabine, 5-fluorouracil (5-FU), and the quantifiable major metabolites α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), and deoxyfluorouridine (5'-DFUR): 0 (before administration), 0.5, 1, 2, 3, 5, 7, and 9 hours. On day 8 of cycle 1, blood samples were obtained at the following time points relative to the morning dose of capecitabine administration: 0 (before administration / trough), 0.5, 1, 2, 3, 5, 7, and 9 hours.

[0156] Prior to administering the morning dose of capecitabine on days 3, 4, 5, 6, 7, and 9, other PK blood samples of capecitabine and its major metabolites were obtained. The plasma concentrations of PCS6422, 5-acetyluracil, capecitabine, 5-FU, FBAL, 5'-DFCR, and 5'-DFUR were determined using validated analytical methods.

[0157] Exemplary PK results are shown in Table 2.1.

[0158] Table 2.1: Results of 5-FU and FBAL analysis for group 2B (C2B) and group 2D (C2D). NA indicates inapplicable because no sample was obtained or analyzed.

[0159] Data from subjects receiving PCS6422 on day 1 (C2D) on day 8 represent fully active DPD (e.g., DPD not inhibited by PCS6422). On day 2, not only was DPD inhibited, but DPD reformation was also observed. During the 0 to 9 hours following capecitabine administration, the lowest and highest 5-FU plasma concentrations (Cp) ranged from 6.4 ng / mL to 283 ng / mL (low Cp) and from 197 ng / mL to 746 ng / mL (high Cp). At 24 hours following administration on the morning of day 2, the 5-FU Cp for patients with dose-limiting toxicities were 579 ng / mL and 653 ng / mL for patients 103 to 107 and 104 to 108, respectively, while for other patients, 5-FU levels were observed to be less than 2 ng / mL to 27.0 ng / mL. On day 2 (0 to 9 hours after capecitabine administration), high FBAL Cp ranged from less than 15 ng / mL to 33.1 ng / mL.

Claims

1. A method for determining the application frequency of PCS6422 and capecitabine in a subject, comprising: (i) Administer at least one dose of an effective amount of PCS6422 to the subject; (ii) Approximately 12 to approximately 24 hours after administration of the at least one effective dose of PCS6422, the subject is given at least one therapeutically effective dose of capecitabine. The measurements included α-fluoro-β-alanine (FBAL) and 5-fluorouracil (5-FU) in blood samples obtained from the subjects. (iii) Determine one or more of the following: the measured 5-FU, the measured FBAL, and / or the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio); and (iv) After the drug withdrawal period, steps (i) and (ii) are repeated when 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 of claim 1, wherein approximately 12 hours after the administration of the effective amount of PCS6422, the therapeutically effective amount of capecitabine is administered to the subject.

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

4. The method according to any one of claims 1 to 2, wherein the therapeutically effective amount of capecitabine is administered to the subject about 12 hours and about 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 obtained from the subject is obtained about 12 to about 24 hours after the therapeutically effective amount of capecitabine is administered to the subject.

6. The method according to any one of claims 1 to 5, wherein FBAL and 5-FU are measured daily starting on 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 on days 1 to 7, day 8 or day 14 following step (ii).

8. A method for determining the frequency of capecitabine administration in a subject, comprising: (i) Administer at least one dose of an effective amount of PCS6422 to the subject; (ii) About 12 to about 24 hours after administration of the at least one effective dose of PCS6422, the subject is given at least one therapeutically effective dose of capecitabine, wherein α-fluoro-β-alanine (FBAL) and / or 5-fluorouracil (5-FU) are measured in a blood sample obtained from the subject. (iii) Determine one or more of the following: the measured 5-FU, the measured FBAL, or the ratio of the measured FBAL to the measured 5-FU (FBAL:5-FU ratio); and (iv) When 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, or the determined FBAL:5-FU ratio is greater than or equal to a certain FBAL:5-FU ratio threshold, the administration of an additional dose of therapeutically effective capecitabine to the subject is stopped.

9. The method of claim 8, wherein a withdrawal period follows the cessation of administration of additional therapeutically effective doses of capecitabine to the subject.

10. The method of claim 9, wherein steps (i) and (ii) are repeated after the withdrawal period.

11. A method for treating cancer in a patient in need, comprising: (i) Administer at least one dose of an effective amount of PCS6422 to the subject; (ii) About 12 to about 24 hours after administration of the at least one effective dose of PCS6422, the subject is given at least one therapeutically effective dose of capecitabine; (iii) Measuring metabolites in a blood sample obtained from the subject, said metabolites comprising one or more of α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'-DFCR), deoxyfluorouridine (5'-DFUR), and 5-fluorouracil (5-FU); and (iv) Determine whether the treatment regimen should be adjusted based on a treatment index, which includes metabolite measurements determined in step (iii).

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