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WO2024086735A1 - Procédés d'utilisation d'un dérivé de (thiazolyl)benzènesulfonamide - Google Patents

Procédés d'utilisation d'un dérivé de (thiazolyl)benzènesulfonamide Download PDF

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Publication number
WO2024086735A1
WO2024086735A1 PCT/US2023/077327 US2023077327W WO2024086735A1 WO 2024086735 A1 WO2024086735 A1 WO 2024086735A1 US 2023077327 W US2023077327 W US 2023077327W WO 2024086735 A1 WO2024086735 A1 WO 2024086735A1
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Prior art keywords
compound
administered
capecitabine
day
gemcitabine
Prior art date
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PCT/US2023/077327
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English (en)
Inventor
Matthew Alan Belmonte
William D. Bradley
John Paul Secrist
Judson Englert
Markus Renschler
Thomas O'shea
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Cyteir Therapeutics Inc
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Cyteir Therapeutics Inc
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Publication of WO2024086735A1 publication Critical patent/WO2024086735A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid

Definitions

  • MCTs Monocarboxylate transporters
  • Monocarboxylates mediate influx and efflux of monocarboxylates such as lactate, pyruvate, ketone bodies (acetoacetate and beta- hydroxybutyrate) across cell membranes.
  • Monocarboxylates play a central role in cellular metabolism and metabolic communications among tissues.
  • MCT family contains 14 members (e.g., MCT1, MCT2, MCT3, and MCT4 perform the function of transporting lactate, pyruvate, and ketone bodies).
  • Cancer cells often utilize glycolysis rather than, or in addition to, oxidative phosphorylation to generate energy by metabolizing glucose into lactate, and are thus referred to as glycolytic tumors.
  • FIG.1 depicts patient enrollment and disposition.
  • FIGs.2A Compound A+capecitabine
  • 2B Compound A+gemcitabine
  • FIGs.3A and 3B depict the Compound A pharmacokinetic profiles across combination dose levels.
  • FIG.3A depicts the Compound A plasma PK profiles in combination with capecitabine on C2D1.
  • FIG.3B depicts Compound A plasma PK profiles in combination with gemcitabine on C1D22. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181
  • FIG.4 depicts a Swimmer’s plot of duration of treatment and response when using the combination of Compound A and capecitabine.
  • FIG.5 depicts a waterfall plot of best percentage change in tumor size when using the combination of Compound A and capecitabine.
  • FIG.6 depicts PR in ovarian cancer treated with Compound A (300 mg) and capecitabine.
  • FIG.7 depicts a Swimmer’s plot of duration of treatment and response when using the combination of Compound A and gemcitabine.
  • FIG.8 depicts a waterfall plot of best percentage change in tumor size when using the combination of Compound A and gemcitabine.
  • FIG.9 depicts enhanced cytotoxic effect of Compound A when used in combination with metformin.
  • FIG.10 depicts the additional synthetic lethal hits generated from SU8686 Compound A sensitivity CRISPR screen.
  • FIG.11 depicts the gene sets enriched from hits in SU8686 screen.
  • FIG.12 depicts Compound A combination data with 5-FU or gemcitabine.
  • FIG.13 depicts Compound A combination data with 5-FU or gemcitabine in 24 cell line panel.
  • FIG.14A depicts the % viable (Bliss Model Predicted Additive) in vitro synergy between Compound A and 5-FU in Panc 04.03 pancreatic cancer cell line.
  • FIG.14B depicts the % viable (Experimental) in vitro synergy between Compound A and 5-FU in Panc 04.03 pancreatic cancer cell line.
  • FIG.14C depicts the Synergy Score of the in vitro synergy between Compound A and 5-FU.
  • FIG.14D depicts that Compound A synergizes with 5-fluorouracil in Panc0403 pancreatic cancer cell model.
  • FIG.15 depicts the combination benefit of Compound A and capecitabine in pancreatic model in terms of tumor growth.
  • FIG.16 depicts the combination benefit of Compound A and capecitabine in pancreatic model in terms of body weight.
  • FIG.17 depicts treatment-emergent adverse events occurring in ⁇ 10 % of patients by relatedness. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181
  • FIG.18 depicts Compound A pharmacokinetic profiles across combination dose levels.
  • FIG.19 depicts waterfall plot of best percentage change in target lesion size.
  • FIG.20 depicts sum of target lesion sizes by RECIST.
  • FIG.21 depicts Kaplan-Meier Estimate of progression-free survival (days).
  • FIG.22 depicts Swimmer’s Plot of duration of treatment and response.
  • FIG.23 depicts confirmed PR in ovarian cancer with Compound A (400 mg) + capecitabine in patient 230, a 72-year-old platinum refractory female with high grade serous ovarian cancer previously treated with carboplatin/paclitaxel, niraparib, carboplatin/liposomal doxorubicin, gemcitabine, and experimental therapy.
  • FIG.24 depicts confirmed PR in ovarian cancer with Compound A (300 mg) + capecitabine in patient 184, a 67-year-old platinum refractory female with high grade serous ovarian cancer previously treated with 11 lines of therapy, including carboplatin, paclitaxel, gemcitabine, bevacizumab, topotecan, liposomal doxorubicin, pembrolizumab, and cyclophosphamide.
  • Compound A (Compound A), or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, for the treatment and/or prevention of a disease or disorder with implicated MCT activity.
  • the present disclosure relates to using Compound A, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent selected from 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 capecitabine, gemcitabine, metformin, IACS-010759 and fluorouracil (5-FU), for the treatment and/or prevention of a disease or disorder with implicated MCT activity.
  • a second therapeutic agent selected from 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 capecitabine, gemcitabine, metformin, IACS-010759 and fluorouracil (5-FU)
  • the present disclosure also relates to a method of treating and/or preventing a disease or disorder with implicated MCT activity, comprising administering Compound A, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and 5-FU.
  • the present disclosure further relates to use of Compound A, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and 5-FU, for the preparation of a medicament for the treatment and/or prevention of a disease or disorder with implicated MCT activity.
  • a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and 5-FU for use in treating and/or preventing a disease or disorder with implicated MCT activity.
  • the present disclosure relates to using Compound A or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and 5-FU, for the treatment and/or prevention of cancer.
  • a method of treating and/or preventing cancer comprising administering Compound A, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and 5-FU.
  • the present disclosure further relates to use of Compound A, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and 5-FU, for the preparation of a medicament for the treatment and/or prevention of cancer.
  • a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and 5-FU for use in treating and/or preventing cancer.
  • the present disclosure relates to using Compound A or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent selected from 292800319 v3 Docket No.
  • the present disclosure also relates to a method of treating and/or preventing solid tumors, comprising administering Compound A, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and 5-FU.
  • the present disclosure further relates to use of Compound A, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and 5-FU, for the preparation of a medicament for the treatment and/or prevention of solid tumors.
  • a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and 5-FU
  • the present disclosure further relates to Compound A, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and 5-FU, for use in treating and/or preventing solid tumors.
  • the second therapeutic agent is an inhibitor of oxidative phosphorylation.
  • the second therapeutic agent is capecitabine, 5-FU or gemcitabine. [046] In some embodiments, the second therapeutic agent is capecitabine or 5-FU. [047] In some embodiments, the second therapeutic agent is capecitabine or gemcitabine. [048] In some embodiments, the second therapeutic agent is capecitabine. [049] In some embodiments, the second therapeutic agent is gemcitabine. [050] In some embodiments, the second therapeutic agent is metformin. [051] In some embodiments, the second therapeutic agent is IACS-010759. [052] In some embodiments, the second therapeutic agent is 5-FU. [053] In some embodiments, the cancer is a solid tumor.
  • the solid tumor is ovarian cancer or pancreatic cancer.
  • pharmaceutically acceptable salt refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically-acceptable salts are well 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1–19.
  • the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs.
  • the subject is a mammal.
  • the mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.
  • the subject can also be a bird or fowl.
  • the subject is a human.
  • the term “subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease.
  • a subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein.
  • a subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein.
  • a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large).
  • a subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment.
  • the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.
  • the term “treating”, “treatment”, or “treat” describes the management and care of a subject for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” can also include treatment of a cell in vitro or an animal model.
  • the term “preventing,” “prevention”, “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
  • the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 excipient” as used in the specification and claims includes both one and more than one such excipient.
  • the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof
  • the dosage will also depend on the route of administration.
  • routes including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [064] As used herein, the term “second therapeutic agent” or “second agent” is capecitabine, gemcitabine, metformin, IACS-010759 and/or 5-FU.
  • a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment.
  • a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches.
  • the dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects.
  • the state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.
  • a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least 292800319 v3 Docket No.
  • CYTH-023/001WO 335739-2181 one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements.
  • the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from anyone or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified.
  • “at least one of A and B” can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • Combination of Compound A with a Second Therapeutic Agent are combinations comprising Compound A and a second therapeutic agent selected from capecitabine and gemcitabine.
  • pharmaceutical combinations comprising Compound A and a second therapeutic agent selected from capecitabine and gemcitabine.
  • Compound A and the second therapeutic agent selected from capecitabine and gemcitabine are co-administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially.
  • the co-administration of Compound A and the second therapeutic agent selected from capecitabine and gemcitabine increases the bioavailability of Compound A.
  • the co-administration of Compound A and the second therapeutic agent selected from capecitabine and gemcitabine increases the C max of Compound A. In some embodiments, the co-administration of Compound A and the second therapeutic agent selected from capecitabine and gemcitabine increases the AUC of Compound A. In some embodiments, the co-administration of Compound A and the second therapeutic agent selected from capecitabine and gemcitabine increases the T1/2 of Compound A.
  • Compositions or therapies disclosed herein may be administered individually to a patient or may be administered in combination (e.g. simultaneously, sequentially or separately). In some embodiments, Compound A is administered in advance of the second 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 therapeutic agent.
  • Compound A is administered in advance of the second therapeutic agent and the second therapeutic agent is capecitabine. In some embodiments, Compound A is administered in advance of the second therapeutic agent and the second therapeutic agent is gemcitabine. In some embodiments, the second therapeutic agent selected from capecitabine and gemcitabine is administered before Compound A. In some embodiments, the second therapeutic agent selected from capecitabine and gemcitabine is capecitabine and is administered in advance of Compound A. In some embodiments, the second therapeutic agent is gemcitabine and is administered in advance of Compound A.
  • Compound A and the second therapeutic agent selected from capecitabine and gemcitabine are administered in temporal proximity (e.g., Compound A and the second therapeutic agent selected from capecitabine and gemcitabine can be initially administered simultaneously).
  • the present disclosure provides a method of treating or preventing cancer comprising administering Compound A and a second therapeutic agent selected from capecitabine and gemcitabine in temporal proximity.
  • “temporal proximity” means that administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that the therapeutic effect of the one therapeutic agent overlaps with the therapeutic effect of the another therapeutic agent. In some embodiments, the therapeutic effect of the one therapeutic agent completely overlaps with the therapeutic effect of the other therapeutic agent.
  • “temporal proximity” means that administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that there is a synergistic effect between the one therapeutic agent and the another therapeutic agent. “Temporal proximity” may vary according to various factors, including but not limited to, the age, gender, weight, genetic background, medical condition, disease history, and treatment history of the subject to which the therapeutic agents are to be administered; the disease or condition to be treated or ameliorated; the therapeutic outcome to be achieved; the dosage, dosing frequency, and dosing duration of the therapeutic agents; the pharmacokinetics and pharmacodynamics of the therapeutic agents; and the route(s) through which the therapeutic agents are administered.
  • “temporal proximity” means within 15 minutes, within 30 minutes, within an hour, within two hours, within four hours, within six hours, within eight hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 within a week, within 2 weeks, within 3 weeks, within 4 weeks, with 6 weeks, or within 8 weeks.
  • multiple administration of one therapeutic agent can occur in temporal proximity to a single administration of another therapeutic agent.
  • temporal proximity may change during a treatment cycle or within a dosing regimen.
  • Combination therapy is intended to embrace administration of the therapeutic agents disclosed herein in a sequential or simultaneous manner, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents concurrently, or in a substantially simultaneous manner. Simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed or variable ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be affected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection.
  • the sequence in which the therapeutic agents are administered can vary.
  • Therapeutic agents may also be administered in alternation.
  • the disclosure provides a synergistic combination of Compound A and the second therapeutic agent, wherein Compound A and the second therapeutic agent selected from capecitabine and gemcitabine come into contact with each other in the human body (e.g., only in the human body).
  • the disclosure provides a method of preparing a combination therapy by bringing Compound A and the second therapeutic agent selected from capecitabine and gemcitabine into contact with each other at a locus.
  • the method of preparing a combination therapy by bringing Compound A and the second therapeutic agent selected from capecitabine and gemcitabine into contact with each other at a locus occurs in the human body (e.g., only in the human body). 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [084]
  • Compound A and the second therapeutic agent selected from capecitabine and gemcitabine are co-administration concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially.
  • Compound A and the second therapeutic agent selected from capecitabine and gemcitabine are co-administered in separate dosage forms. In some embodiments, Compound A and the second therapeutic agent selected from capecitabine and gemcitabine are co-administered in combined dosage forms. [086] In some embodiments, the co-administration of Compound A and the second therapeutic agent selected from capecitabine and gemcitabine increases the bioavailability of Compound A. In some embodiments, the co-administration of Compound A and the second therapeutic agent selected from capecitabine and gemcitabine increases the Cmax of Compound A.
  • the co-administration of Compound A and the second therapeutic agent selected from capecitabine and gemcitabine increases the AUC of Compound A. In some embodiments, the co-administration of Compound A and the second therapeutic agent selected from capecitabine and gemcitabine increases the T1/2 of Compound A.
  • Dosing and Treatment Regimens [087] In some embodiments, described herein is a method of treating and/or preventing a disease or disorder with implicated MCT activity, a cancer, or a solid tumor, the method comprising administering a therapeutically effective dose of Compound A, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective dose of a second therapeutic agent selected from capecitabine and gemcitabine to a subject in need thereof.
  • described herein is a use of Compound A, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent selected from capecitabine and gemcitabine, for the preparation of a medicament for the treatment and/or prevention of a disease or disorder with implicated MCT activity, a cancer, or a solid tumor in a subject in need thereof.
  • a second therapeutic agent selected from capecitabine and gemcitabine for use in treating and/or preventing a disease or disorder with implicated MCT activity, a cancer, or a solid tumor in a subject in need thereof.
  • a combination composition e.g., a composition comprising a combination of Compound A, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent selected from capecitabine and gemcitabine
  • a combination composition for use in treating and/or preventing a disease or disorder with implicated MCT activity, a cancer, or a solid tumor in a subject in need thereof.
  • a combination composition e.g., a composition comprising a combination of Compound A, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent selected from capecitabine and gemcitabine
  • a combination composition for the treatment and/or prevention of a disease or disorder with implicated MCT activity, a cancer, or a solid tumor in a subject in need thereof.
  • a combination composition e.g., a composition comprising a combination of Compound A, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent selected from capecitabine and gemcitabine
  • a second therapeutic agent selected from capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg to about 800 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg to about 700 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg to about 600 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg to about 500 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg to about 400 mg. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0100] In some embodiments, the amount of Compound A that is administered in combination with a second therapeutic agent (e.g., capecitabine and gemcitabine) (e.g., human dosage) ranges from about 100 mg to about 300 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg to about 200 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg to about 800 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg to about 700 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg to about 600 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg to about 500 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • human dosage ranges from about 200 mg to about 400 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg to about 300 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 300 mg to about 800 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 300 mg to about 700 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 300 mg to about 600 mg. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0111] In some embodiments, the amount of Compound A that is administered in combination with a second therapeutic agent (e.g., capecitabine and gemcitabine) (e.g., human dosage) ranges from about 300 mg to about 500 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 300 mg to about 400 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 400 mg to about 800 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 400 mg to about 700 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 400 mg to about 600 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 400 mg to about 500 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 500 mg to about 800 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 500 mg to about 700 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 500 mg to about 600 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 600 mg to about 800 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 600 mg to about 700 mg. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0122] In some embodiments, the amount of Compound A that is administered in combination with a second therapeutic agent (e.g., capecitabine and gemcitabine) (e.g., human dosage) ranges from about 700 mg to about 800 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 100 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 200 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 300 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 400 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 500 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 600 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 700 mg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 800 mg. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 1000 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg/day to about 1000 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 150 mg/day to about 1000 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg/day to about 1000 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 250 mg/day to about 1000 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 300 mg/day to about 1000 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 350 mg/day to about 1000 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 400 mg/day to about 1000 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 450 mg/day to about 1000 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 500 mg/day to about 1000 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 550 mg/day to about 1000 mg/day. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 600 mg/day to about 1000 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 700 mg/day to about 1000 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 800 mg/day to about 1000 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 900 mg/day to about 1000 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 900 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg/day to about 900 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 150 mg/day to about 900 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg/day to about 900 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 250 mg/day to about 900 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 300 mg/day to about 900 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 350 mg/day to about 900 mg/day. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0154] In some embodiments, the amount of Compound A that is administered in combination with a second therapeutic agent (e.g., capecitabine and gemcitabine) (e.g., human dosage) ranges from about 400 mg/day to about 900 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 450 mg/day to about 900 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 500 mg/day to about 900 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 550 mg/day to about 900 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 600 mg/day to about 900 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 700 mg/day to about 900 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 800 mg/day to about 900 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 800 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg/day to about 800 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 150 mg/day to about 800 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg/day to about 800 mg/day. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 250 mg/day to about 800 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 300 mg/day to about 800 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 350 mg/day to about 800 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 400 mg/day to about 800 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 450 mg/day to about 800 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 500 mg/day to about 800 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 550 mg/day to about 800 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 600 mg/day to about 800 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 700 mg/day to about 800 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 700 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg/day to about 700 mg/day. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0176] In some embodiments, the amount of Compound A that is administered in combination with a second therapeutic agent (e.g., capecitabine and gemcitabine) (e.g., human dosage) ranges from about 150 mg/day to about 700 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg/day to about 700 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 250 mg/day to about 700 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 300 mg/day to about 700 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 350 mg/day to about 700 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 400 mg/day to about 700 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 450 mg/day to about 700 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 500 mg/day to about 700 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 550 mg/day to about 700 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 600 mg/day to about 700 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 600 mg/day. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg/day to about 600 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 150 mg/day to about 600 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg/day to about 600 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 250 mg/day to about 600 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 300 mg/day to about 600 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 350 mg/day to about 600 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 400 mg/day to about 600 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 450 mg/day to about 600 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 500 mg/day to about 600 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 550 mg/day to about 600 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 500 mg/day. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0198] In some embodiments, the amount of Compound A that is administered in combination with a second therapeutic agent (e.g., capecitabine and gemcitabine) (e.g., human dosage) ranges from about 100 mg/day to about 500 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 150 mg/day to about 500 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg/day to about 500 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 250 mg/day to about 500 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 300 mg/day to about 500 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 350 mg/day to about 500 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 400 mg/day to about 500 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 450 mg/day to about 500 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 450 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg/day to about 450 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 150 mg/day to about 450 mg/day. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg/day to about 450 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 250 mg/day to about 450 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 300 mg/day to about 450 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 350 mg/day to about 450 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 400 mg/day to about 450 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 400 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg/day to about 400 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 150 mg/day to about 400 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg/day to about 400 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 250 mg/day to about 400 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 300 mg/day to about 400 mg/day. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0220] In some embodiments, the amount of Compound A that is administered in combination with a second therapeutic agent (e.g., capecitabine and gemcitabine) (e.g., human dosage) ranges from about 350 mg/day to about 400 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 350 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg/day to about 350 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 150 mg/day to about 350 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg/day to about 350 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 250 mg/day to about 350 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 300 mg/day to about 350 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 300 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg/day to about 300 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 150 mg/day to about 300 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg/day to about 300 mg/day. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 250 mg/day to about 300 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 250 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg/day to about 250 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 150 mg/day to about 250 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 200 mg/day to about 250 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 200 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg/day to about 200 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 150 mg/day to about 200 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 150 mg/day.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 100 mg/day to about 150 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 50 mg/day to about 100 mg/day. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 50 mg/day, about 60 mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, about 100 mg/day, about 110 mg/day, about 120 mg/day, about 130 mg/day, about 140 mg/day, about 150 mg/day, about 160 mg/day, about 170 mg/day, about 180 mg/day, about 190 mg/day, about 200 mg/day, about 210 mg/day, about 220 mg/day, about 230 mg/day, about 240 mg/day, about 250 mg/day, about 260 mg/day, about 270 mg/day, about 280 mg/day, about 290 mg/day, about 300 mg/day, about 310 mg/day, about 320 mg/day, about 330 mg/day, about 340 mg
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 50 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 60 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 70 mg/day. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 80 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 90 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 100 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 110 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 120 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 130 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 140 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 150 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 160 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 170 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 180 mg/day. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 190 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 200 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 210 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 220 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 230 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 240 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 250 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 260 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 270 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 280 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 290 mg/day. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 300 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 310 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 320 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 330 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 340 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 350 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 360 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 370 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 380 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 390 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 400 mg/day. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 410 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 420 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 430 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 440 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 450 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 460 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 470 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 480 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 490 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 500 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 510 mg/day. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 520 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 530 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 540 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 550 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 560 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 570 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 580 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 610 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 620 mg/day. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 630 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 640 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 650 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 660 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 670 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 680 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 690 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 700 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 710 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 720 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 730 mg/day. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 740 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 750 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 760 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 770 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 780 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 790 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 800 mg/day.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 1 mg/kg to about 50 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 10 mg/kg to about 40 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 10 mg/kg to about 30 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 10 mg/kg to about 20 mg/kg. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 20 mg/kg to about 50 mg/kg.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 20 mg/kg to about 40 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 20 mg/kg to about 30 mg/kg.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 30 mg/kg to about 50 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 30 mg/kg to about 40 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent ranges from about 40 mg/kg to about 50 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 1 mg/kg, about 5 mg/kg, about 9.8 mg/kg, about 10 mg/kg, about 15 mg/kg, about 16.3 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, or about 50 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • human dosage is about 1 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 5 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 9.8 mg/kg. 292800319 v3 Docket No.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 10 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 15 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 16.3 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 20 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 25 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 30 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 35 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent e.g., capecitabine and gemcitabine
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 40 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 45 mg/kg.
  • the amount of Compound A that is administered in combination with a second therapeutic agent is about 50 mg/kg.
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 4000 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 3000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 2500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 2000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 900 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 800 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 700 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 600 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 500 mg/m 2 . 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0355] In some embodiments, the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A (e.g., human dosage) ranges from about 100 mg/m 2 to about 400 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 300 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 200 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 4500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 3000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 2500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 2000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 1000 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 900 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 800 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 700 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 600 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 400 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 300 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 4500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 3000 mg/m 2 . 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0377] In some embodiments, the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A (e.g., human dosage) ranges from about 300 mg/m 2 to about 2500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 2000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 900 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 800 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 700 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 600 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 400 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 4500 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 3000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 2500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 2000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 900 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 800 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 700 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 600 mg/m 2 . 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0399] In some embodiments, the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A (e.g., human dosage) ranges from about 400 mg/m 2 to about 500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 4500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 3000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 2500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 2000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 900 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 800 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 700 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 600 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 4500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 3000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 2500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 2000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 900 mg/m 2 . 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0421] In some embodiments, the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A (e.g., human dosage) ranges from about 600 mg/m 2 to about 800 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 700 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 4500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 3000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 2500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 2000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 900 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 800 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 4500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 3000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 2500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 2000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 900 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 900 mg/m 2 to about 4500 mg/m 2 . 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0443] In some embodiments, the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A (e.g., human dosage) ranges from about 900 mg/m 2 to about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 900 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 900 mg/m 2 to about 3000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 900 mg/m 2 to about 2500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 900 mg/m 2 to about 2000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 900 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 900 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 1000 mg/m 2 to about 4500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 1000 mg/m 2 to about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 1000 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 1000 mg/m 2 to about 3000 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 1000 mg/m 2 to about 2500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 1000 mg/m 2 to about 2000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 1000 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 1500 mg/m 2 to about 4500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 1500 mg/m 2 to about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 1500 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 1500 mg/m 2 to about 3000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 1500 mg/m 2 to about 2500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 1500 mg/m 2 to about 2000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 2000 mg/m 2 to about 4500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 2000 mg/m 2 to about 4000 mg/m 2 . 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0465] In some embodiments, the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A (e.g., human dosage) ranges from about 2000 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 2000 mg/m 2 to about 3000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 2000 mg/m 2 to about 2500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 2500 mg/m 2 to about 4500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 2500 mg/m 2 to about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 2500 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 2500 mg/m 2 to about 3000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 3000 mg/m 2 to about 4500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 3000 mg/m 2 to about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 3000 mg/m 2 to about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 3500 mg/m 2 to about 4500 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 3500 mg/m 2 to about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A ranges from about 4000 mg/m 2 to about 4500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 100 mg/m 2 , about 120 mg/m 2 , about 140 mg/m 2 , about 160 mg/m 2 , about 180 mg/m 2 , about 200 mg/m 2 , about 220 mg/m 2 , about 240 mg/m 2 , about 260 mg/m 2 , about 280 mg/m 2 , about 300 mg/m 2 , about 320 mg/m 2 , about 340 mg/m 2 , about 360 mg/m 2 , about 380 mg/m 2 , about 400 mg/m 2 , about 420 mg/m 2 , about 440 mg/m 2 , about 460 mg/m 2 , about 480 mg/m 2 , about 500 mg/m 2 , about 520 mg/m 2 , about 540 mg/m 2 , about 560 mg/m 2 , about
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 100 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 200 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 400 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 600 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 700 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 800 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 900 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 1000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 1100 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 1200 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 1300 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 1400 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 1500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 1600 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 1700 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 1800 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 1900 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 2000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 2100 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 2200 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 2300 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 2400 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 2500 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 2600 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 2700 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 2800 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 2900 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 3000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 3100 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 3200 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 3300 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 3400 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 3500 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 3600 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 3700 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 3800 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 3900 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 4000 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 4100 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 4200 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 4300 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 4400 mg/m 2 .
  • the amount of the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU that is administered in combination with Compound A is about 4500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 1400 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 1300 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 1200 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 1100 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 900 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 800 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 700 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 600 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 100 mg/m 2 to about 300 mg/m 2 . 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0536] In some embodiments, the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) ranges from about 100 mg/m 2 to about 200 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 1400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 1300 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 1200 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 1100 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 900 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 800 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 700 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 600 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 200 mg/m 2 to about 300 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 1400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 1300 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 1200 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 1100 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 900 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 800 mg/m 2 . 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0558] In some embodiments, the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) ranges from about 300 mg/m 2 to about 700 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 600 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 300 mg/m 2 to about 400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 1400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 1300 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 1200 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 1100 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 900 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 800 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 700 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 600 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 400 mg/m 2 to about 500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 1400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 1300 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 1200 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 1100 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 900 mg/m 2 . 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0580] In some embodiments, the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) ranges from about 500 mg/m 2 to about 800 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 700 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 500 mg/m 2 to about 600 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 1400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 1300 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 1200 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 1100 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 900 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 800 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 600 mg/m 2 to about 700 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 1400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 1300 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 1200 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 1100 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 900 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 700 mg/m 2 to about 800 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 1400 mg/m 2 . 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0602] In some embodiments, the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) ranges from about 800 mg/m 2 to about 1300 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 1200 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 1100 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 1000 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 800 mg/m 2 to about 900 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 900 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 900 mg/m 2 to about 1400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 900 mg/m 2 to about 1300 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 900 mg/m 2 to about 1200 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 900 mg/m 2 to about 1100 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 900 mg/m 2 to about 1000 mg/m 2 . 292800319 v3 Docket No.
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 1000 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 1000 mg/m 2 to about 1400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 1000 mg/m 2 to about 1300 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 1000 mg/m 2 to about 1200 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 1000 mg/m 2 to about 1100 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 1100 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 1100 mg/m 2 to about 1400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 1100 mg/m 2 to about 1300 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 1100 mg/m 2 to about 1200 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 1200 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 1200 mg/m 2 to about 1300 mg/m 2 . 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0624] In some embodiments, the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) ranges from about 1200 mg/m 2 to about 1400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 1300 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A ranges from about 1300 mg/m 2 to about 1400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) ranges from about 1400 mg/m 2 to about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A is about 100 mg/m 2 , about 120 mg/m 2 , about 140 mg/m 2 , about 160 mg/m 2 , about 180 mg/m 2 , about 200 mg/m 2 , about 220 mg/m 2 , about 240 mg/m 2 , about 260 mg/m 2 , about 280 mg/m 2 , about 300 mg/m 2 , about 320 mg/m 2 , about 340 mg/m 2 , about 360 mg/m 2 , about 380 mg/m 2 , about 400 mg/m 2 , about 420 mg/m 2 , about 440 mg/m 2 , about 460 mg/m 2 , about 480 mg/m 2 , about 500 mg/m 2 , about 520 mg/m 2 , about 540 mg/m 2 , about 560 mg/m 2 .
  • the second therapeutic agent e.g., capecitabine
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A is about 500 mg/m 2 . 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0630] In some embodiments, the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) is about 600 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) is about 700 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) is about 800 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) is about 900 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) is about 1000 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) is about 1100 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) is about 1200 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) is about 1300 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) is about 1400 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) is about 1500 mg/m 2 .
  • the amount of the second therapeutic agent (e.g., capecitabine and gemcitabine) that is administered in combination with Compound A (e.g., human dosage) is about 50 mg/day, about 60 mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, 292800319 v3 Docket No.
  • CYTH-023/001WO 335739-2181 about 100 mg/day, about 110 mg/day, about 120 mg/day, about 130 mg/day, about 140 mg/day, about 150 mg/day, about 160 mg/day, about 170 mg/day, about 180 mg/day, about 190 mg/day, about 200 mg/day, about 210 mg/day, about 220 mg/day, about 230 mg/day, about 240 mg/day, about 250 mg/day, about 260 mg/day, about 270 mg/day, about 280 mg/day, about 290 mg/day, about 300 mg/day, about 310 mg/day, about 320 mg/day, about 330 mg/day, about 340 mg/day, about 350 mg/day, about 360 mg/day, about 370 mg/day, about 380 mg/day, about 390 mg/day, about 400 mg/day, about 410 mg/day, about 420 mg/day, about 430 mg/day, about 440 mg/day, about 450 mg/day, about 460
  • CYTH-023/001WO 335739-2181 mg/day about 1620 mg/day, about 1630 mg/day, about 1640 mg/day, about 1650 mg/day, about 1660 mg/day, about 1670 mg/day, about 1680 mg/day, about 1690 mg/day, about 1700 mg/day, about 1710 mg/day, about 1720 mg/day, about 1730 mg/day, about 1740 mg/day, about 1750 mg/day, about 1760 mg/day, about 1770 mg/day, about 1780 mg/day, about 1790 mg/day, about 1800 mg/day, about 1810 mg/day, about 1820 mg/day, about 1830 mg/day, about 1840 mg/day, about 1850 mg/day, about 1860 mg/day, about 1870 mg/day, about 1880 mg/day, about 1890 mg/day, about 1900 mg/day, about 1910 mg/day, about 1920 mg/day, about 1930 mg/day, about 1940 mg/day, about 1950 mg/day, about 1960 mg/day, about
  • Compound A and/or the second therapeutic agent are administered once daily, for example, at any of the dosage described herein.
  • Compound A and/or the second therapeutic agent e.g., capecitabine and gemcitabine
  • Compound A and/or the second therapeutic agent e.g., capecitabine and gemcitabine
  • Compound A and/or the second therapeutic agent are administered once daily, for example, at any of the dosage described herein, for three days per week.
  • Compound A and/or the second therapeutic agent are administered once daily, for example, at any of the dosage described herein, for four days per week.
  • Compound A and/or the second therapeutic agent are administered once daily, for example, at any of the dosage described herein, for five days per week.
  • Compound A and/or the second therapeutic agent are administered once daily, for example, at any of the dosage described herein, for six days per week.
  • Compound A and/or the second therapeutic agent are administered once daily, for example, at any of the dosage described herein, for seven days per week. 292800319 v3 Docket No.
  • Compound A and/or the second therapeutic agent are administered once daily, for example, at any of the dosage described herein, for two weeks.
  • Compound A and/or the second therapeutic agent are administered once daily, for example, at any of the dosage described herein, for three weeks.
  • Compound A and/or the second therapeutic agent are administered once daily, for example, at any of the dosage described herein, for four weeks.
  • Compound A is administered once daily and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily, for example, at any of the dosage described herein.
  • Compound A is administered once daily and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily, for example, at any of the dosage described herein, for one day per week.
  • Compound A is administered once daily and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily, for example, at any of the dosage described herein, for two days per week.
  • Compound A is administered once daily and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily, for example, at any of the dosage described herein, for three days per week.
  • Compound A is administered once daily and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily, for example, at any of the dosage described herein, for four days per week.
  • Compound A is administered once daily and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily, for example, at any of the dosage described herein, for five days per week.
  • Compound A is administered once daily and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily, for example, at any of the dosage described herein, for six days per week.
  • Compound A is administered once daily and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily, for example, at any of the dosage described herein, for seven days per week. 292800319 v3 Docket No.
  • Compound A is administered once daily and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily, for example, at any of the dosage described herein, for two weeks.
  • the second therapeutic agent e.g., capecitabine and gemcitabine
  • Compound A is administered once daily and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily, for example, at any of the dosage described herein, for three weeks.
  • Compound A is administered once daily and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily, for example, at any of the dosage described herein, for four weeks.
  • Compound A is administered once daily and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered on a 14 day on/7 day off schedule, for example, at any of the dosage described herein.
  • Compound A is administered orally once daily and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered orally on a 14 day on/7 day off schedule, for example, at any of the dosage described herein.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, once every other day.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, once every other day for four days.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, once every other day for 6 days.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, once every other day for two weeks.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, once every other day for three weeks.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, once every other day for four weeks. 292800319 v3 Docket No.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, without a dosing holiday.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, followed by a dosing holiday.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, for two weeks followed by a dosing holiday.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, for three weeks followed by a dosing holiday.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, for four weeks followed by a dosing holiday.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, followed by a 7-day dosing holiday.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, followed by a 14-day dosing holiday.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, followed by a 21-day dosing holiday.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, followed by a 28-day dosing holiday.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, followed by a 35-day dosing holiday.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, followed by a 42-day dosing holiday. 292800319 v3 Docket No.
  • Compound A and/or the second therapeutic agent are administered, for example, at any of the dosage described herein, followed by a 49-day dosing holiday.
  • Compound A and the second therapeutic agent are administered according to different dosing regimen.
  • Compound A is administered on consecutive days for a first period of time and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered on consecutive days for a second period of time. In some embodiments, the first period of time is different from the second period of time.
  • the first period of time is longer than the second period of time. In some embodiments, the first period of time is 21 days or 28 days, and the second period of time is 7 days or 14 days. In some embodiments, the first period of time and the second period of time start at the same time. In some embodiments, the first period of time and the second period of time start at different time. In some embodiments, the first period of time starts before the second period of time. In some embodiments, the first period of time starts after the second period of time.
  • Compound A is administered at any of the dosage described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day) on consecutive days for 21 days, and the second therapeutic agent is capecitabine and is administered at any of the dosage described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ) daily on consecutive days for 14 days.
  • the 14-day period starts at the same time as the 21-day period.
  • Compound A is administered at any of the dosage described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day) on consecutive days for 21 days, and the second therapeutic agent is capecitabine and is administered at any of the dosage described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ) twice daily on consecutive days for 14 days.
  • the 14-day period starts at the same time as the 21-day period.
  • Compound A is orally administered at any of the dosage described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day) on consecutive days for 21 days, and the second therapeutic agent is capecitabine and is orally administered at any of the dosage 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ) twice daily on consecutive days for 14 days.
  • the dosage described herein e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day
  • the second therapeutic agent is capecitabine and is orally administered at any of the dosage 292800319 v3 Docket No.
  • the 14-day period starts at the same time as the 21-day period.
  • Compound A is administered at about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day on consecutive days for 21 days, and the second therapeutic agent is capecitabine and is administered at about 1000 mg/m 2 daily on consecutive days for 14 days.
  • the 14-day period starts at the same time as the 21-day period.
  • Compound A is administered at about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day on consecutive days for 21 days, and the second therapeutic agent is capecitabine and is administered at about 1000 mg/m 2 twice daily on consecutive days for 14 days. In some embodiments, the 14-day period starts at the same time as the 21-day period. [0690] In some embodiments, Compound A is orally administered at about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day on consecutive days for 21 days, and the second therapeutic agent is capecitabine and is orally administered at about 1000 mg/m 2 twice daily on consecutive days for 14 days.
  • the 14-day period starts at the same time as the 21-day period.
  • Compound A is administered at about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day on consecutive days for 21 days, and the second therapeutic agent is 5-FU and is administered at about 1000 mg/m 2 twice daily on consecutive days for 14 days.
  • the 14-day period starts at the same time as the 21-day period.
  • Compound A is administered on consecutive days for a first period of time and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered once weekly for a second period of time. In some embodiments, the first period of time is different from the second period of time.
  • the first period of time is longer than the second period of time. In some embodiments, the first period of time is 21 days or 28 days, and the second period of time is three weeks or four weeks. In some embodiments, the first period of time and the second period of time start at the same time. In some embodiments, the first period of time and the second period of time start at different time. In some embodiments, the first period of time starts before the second period of time. In some embodiments, the first period of time starts after the second period of time. 292800319 v3 Docket No.
  • Compound A is administered on consecutive days for a first period of time and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily for a second period of time.
  • the first period of time is different from the second period of time.
  • the first period of time is longer than the second period of time.
  • the first period of time is 21 days or 28 days, and the second period of time is two weeks, three weeks or four weeks.
  • the first period of time and the second period of time start at the same time. In some embodiments, the first period of time and the second period of time start at different time.
  • the first period of time starts before the second period of time. In some embodiments, the first period of time starts after the second period of time.
  • Compound A is administered at any of the dosage described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day) on consecutive days for 28 days, and the second therapeutic agent is capecitabine and is administered at any of the dosage described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ) once weekly on the first day of each week for three weeks.
  • the 3-week period starts at the same time as the 28-day period, i.e., Day 1 of the 3-week period is the Day 1 of the 28-day period.
  • Compound A is administered at about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day on consecutive days for 28 days, and the second therapeutic agent is capecitabine and is administered at about 1000 mg/m 2 once weekly on the first day of each week for three weeks.
  • the 3-week period starts at the same time as the 28-day period, i.e., Day 1 of the 3-week period is the Day 1 of the 28-day period.
  • Compound A is administered at any of the dosages described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day) on consecutive days for 21-days, and the second therapeutic agent is capecitabine and is administered at any of the dosages described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ) twice daily for two weeks every 21-days.
  • the second therapeutic agent is capecitabine and is administered at any of the dosages described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ) twice daily for two weeks every 21-days.
  • the 21-days period of Compound A starts at the same time as the 21-days period of the second therapeutic agent, i.e., Day 1 of 21-days period of Compound A and Day 1 of the 21-days period of the second therapeutic agent is the same. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0697]
  • Compound A is administered at about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day on consecutive days for 21 days, and the second therapeutic agent is capecitabine and is administered at about 1000 mg/m 2 twice daily for two weeks every 21-days.
  • the 21-days period of Compound A starts at the same time as the 21-days period of the second therapeutic agent, i.e., Day 1 of 21-days period of Compound A and Day 1 of the 21-days period of the second therapeutic agent is the same.
  • Compound A is administered at any of the dosage described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day) on consecutive days for 21 days, and the second therapeutic agent is gemcitabine and is administered at any of the dosage described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ) daily on consecutive days for 14 days.
  • the 14-day period starts at the same time as the 21-day period.
  • Compound A is administered at any of the dosage described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day) on consecutive days for 21 days, and the second therapeutic agent is gemcitabine and is administered at any of the dosage described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ) twice daily on consecutive days for 14 days.
  • the 14-day period starts at the same time as the 21-day period.
  • Compound A is administered at about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day on consecutive days for 21 days, and the second therapeutic agent is gemcitabine and is administered at about 1000 mg/m 2 daily on consecutive days for 14 days. In some embodiments, the 14-day period starts at the same time as the 21-day period.
  • Compound A is administered at about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day on consecutive days for 21 days, and the second therapeutic agent is gemcitabine and is administered at about 1000 mg/m 2 twice daily on consecutive days for 14 days. In some embodiments, the 14-day period starts at the same time as the 21-day period.
  • Compound A is administered at any of the dosage described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 about 500 mg/day, or about 600 mg/day) on consecutive days for 28 days, and the second therapeutic agent is gemcitabine and is administered at any of the dosage described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ) once weekly on the first day of each week for three weeks.
  • the dosage described herein e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 about 500 mg/day, or about 600 mg/day
  • the second therapeutic agent is gemcita
  • the 3-week period starts at the same time as the 28-day period, i.e., Day 1 of the 3-week period is the Day 1 of the 28-day period.
  • Compound A is administered at about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day on consecutive days for 28 days, and the second therapeutic agent is gemcitabine and is administered at about 1000 mg/m 2 once weekly on the first day of each week for three weeks.
  • the 3-week period starts at the same time as the 28-day period, i.e., Day 1 of the 3-week period is the Day 1 of the 28-day period.
  • Compound A is administered at any of the dosages described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day) on consecutive days for 21-days, and the second therapeutic agent is gemcitabine and is administered at any of the dosages described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ) twice daily for two weeks every 21-days.
  • the second therapeutic agent is gemcitabine and is administered at any of the dosages described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ) twice daily for two weeks every 21-days.
  • the 21-days period of Compound A starts at the same time as the 21-days period of the second therapeutic agent, i.e., Day 1 of 21-days period of Compound A and Day 1 of the 21-days period of the second therapeutic agent is the same.
  • Compound A is administered at about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day on consecutive days for 21 days, and the second therapeutic agent is gemcitabine and is administered at about 1000 mg/m 2 twice daily for two weeks every 21-days.
  • the 21-days period of Compound A starts at the same time as the 21-days period of the second therapeutic agent, i.e., Day 1 of 21-days period of Compound A and Day 1 of the 21-days period of the second therapeutic agent is the same.
  • Dosing Cycle [0706]
  • Compound A and/or the second therapeutic agent e.g., capecitabine and gemcitabine
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, or 49 days and wherein Compound A is administered daily.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, or 49 days and wherein the second therapeutic agent is administered daily.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days, wherein Compound A is administered once daily for 21 days and the second therapeutic agent is administered twice daily for two weeks every 21 days.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, or 49 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered weekly.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, or 49 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered at least once per dosing cycle.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, or 49 days and wherein Compound A is administered orally.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, or 49 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered orally.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, or 49 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered intravenously.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 7 days, 14 days, 21 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 days, 28 days, 35 days, 42 days, or 49 days and wherein Compound A and the second therapeutic agent are administered orally.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days, wherein Compound A is orally administered once daily for 21 days and the second therapeutic agent is orally administered twice daily for two weeks every 21 days.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 28 days.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days and wherein Compound A is administered daily.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days and wherein Compound A is administered once daily.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered daily for the first 14 days.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily for the first 14 days.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 28 days and wherein Compound A is administered daily.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 28 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered on Day 1, Day 8 and Day 15. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0724] In some embodiments, Compound A and/or the second therapeutic agent (e.g., capecitabine and gemcitabine) are administered with a dosing cycle of 21 days and wherein Compound A is orally administered daily.
  • the second therapeutic agent e.g., capecitabine and gemcitabine
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days and wherein Compound A is orally administered once daily.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is orally administered daily for the first 14 days.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is orally administered twice daily for the first 14 days.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 28 days and wherein Compound A is orally administered daily.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 28 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is orally administered on Day 1, Day 8 and Day 15.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days and wherein Compound A is administered daily at any of the dosage described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day).
  • the second therapeutic agent is capecitabine.
  • Compound A and/or the second therapeutic agent e.g., capecitabine and gemcitabine
  • Compound A is administered daily at any of the dosage described herein (e.g., about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day).
  • the second therapeutic agent is capecitabine.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days and wherein 292800319 v3 Docket No.
  • the second therapeutic agent e.g., capecitabine and gemcitabine
  • the second therapeutic agent is administered daily for the first 14 days at any of the dosage described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ).
  • the second therapeutic agent is capecitabine.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily for the first 14 days at any of the dosage described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ).
  • the second therapeutic agent is capecitabine.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered daily for the first 14 days at about 1000 mg/m 2 .
  • the second therapeutic agent is capecitabine.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily for the first 14 days at about 1000 mg/m 2 .
  • the second therapeutic agent is capecitabine.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days, wherein Compound A is administered daily at any of the dosage described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day), and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered daily for the first 14 days at any of the dosage described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ).
  • the second therapeutic agent is capecitabine.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days, wherein Compound A is administered once daily at any of the dosage described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day), and the second therapeutic agent (e.g., capecitabine and gemcitabine) is 292800319 v3 Docket No.
  • CYTH-023/001WO 335739-2181 administered twice daily for the first 14 days at any of the dosage described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ).
  • the second therapeutic agent is capecitabine.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days, wherein Compound A is administered daily at any of the dosage described herein (e.g., about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day), and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered daily for the first 14 days at about 1000 mg/m 2 .
  • the second therapeutic agent is capecitabine.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 21 days, wherein Compound A is administered once daily at any of the dosage described herein (e.g., about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day), and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered twice daily for the first 14 days at about 1000 mg/m 2 .
  • the second therapeutic agent is capecitabine.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 28 days and wherein Compound A is administered daily at any of the dosage described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day).
  • the second therapeutic agent is gemcitabine.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 28 days and wherein Compound A is administered daily at any of the dosage described herein (e.g., about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day).
  • the second therapeutic agent is gemcitabine.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 28 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered at any of the dosage described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ) on Day 1, Day 8 and Day 15.
  • the second therapeutic agent is gemcitabine. 292800319 v3 Docket No.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 28 days and wherein the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered at about 1000 mg/m 2 on Day 1, Day 8 and Day 15.
  • the second therapeutic agent is gemcitabine.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 28 days, wherein Compound A is administered daily at any of the dosage described herein (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day), and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered at any of the dosage described herein (e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2 ) on Day 1, Day 8 and Day 15.
  • the dosage described herein e.g., about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , or about 1200 mg/m 2
  • the second therapeutic agent is gemcitabine.
  • Compound A and/or the second therapeutic agent are administered with a dosing cycle of 28 days, wherein Compound A is administered daily at any of the dosage described herein (e.g., about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day), and the second therapeutic agent (e.g., capecitabine and gemcitabine) is administered at about 1000 mg/m 2 on Day 1, Day 8 and Day 15.
  • the second therapeutic agent is gemcitabine.
  • Compound A and/or the second therapeutic agent are administered as provided in Table A below.
  • Compound A and capecitabine are administered as provided in Table B below. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 Table B.
  • Compound A and/or the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU are administered, wherein Compound A is administered daily at any of the dosage described herein (e.g., about 300 mg/day, about 400 mg/day, about 500 mg/day, or about 600 mg/day), and wherein the second therapeutic agent selected from capecitabine, gemcitabine and 5-FU: (a) is administered at 400 mg/m 2 intravenous bolus on Day 1, followed by 2400 mg/m 2 to 3000 mg/m 2 intravenously as a continuous infusion over 46 hours every two weeks; (b) if administered in a bolus dosing regimen in combination with Compound A, is 500 mg/m 2 by intravenous bolus on Days 1, 8, 15, 22, 29, and 36 in 8-week cycles; (c) is administered as a component of a cyclophosphamide-based multidrug regimen, is 500 mg/m 2 or 600 mg/m 2 intravenously on Days 1
  • the frequency of dosing in each cycle and the length of each cycle will depend on the dose of fluorouracil and the specific regimen administered; or (e) is administered as an infusional regimen in combination with Compound A or as a component of a multidrug chemotherapy regimen, is 400 mg/m 2 intravenous bolus on Day 1, followed by 2400 mg/m 2 intravenously as a continuous infusion over 46 hours every two weeks.
  • Pharmaceutical Compositions [0749]
  • the combination disclosed therein comprises Compound A and a second therapeutic agent.
  • the combination disclosed therein comprises Compound A and capecitabine.
  • the combination disclosed therein comprises Compound A and gemcitabine.
  • the pharmaceutical composition of the present disclosure comprises Compound A, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, and a pharmaceutically acceptable carrier or diluent. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0751]
  • the pharmaceutical composition of the present disclosure comprises Compound A, or a pharmaceutically acceptable salt thereof, in combination with capecitabine, and a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition of the present disclosure comprises Compound A, or a pharmaceutically acceptable salt thereof, in combination with gemcitabine, and a pharmaceutically acceptable carrier or diluent.
  • “Pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject.
  • Non- limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • compositions of the present teachings optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose.
  • excipients such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.
  • the carriers, diluents and/or excipients are “acceptable” in the sense of being compatible with 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.
  • the term “dosage holiday”, also referred to as “drug holiday,” refers to a period of time wherein the subject is not administered or administered at a lower dosage of the therapeutic (i.e., Compound A, capecitabine or gemcitabine). The timing of a dosage holiday depends on the timing of the regular dosing regimen and the purpose for taking the dosage holiday (e.g., to regain drug sensitivity and/or to reduce unwanted side effects of continuous, long- term administration).
  • the dosage holiday may be a reduction in the dosage of the drug (e.g., to below the therapeutically effective amount for a certain interval of time).
  • administration of the dosage is stopped for a certain interval of time before administration is started again at the same or different dosing regimen (e.g., at a lower or higher dose and/or frequency of administration).
  • a dosage holiday of the disclosure may thus be selected from a wide range of time-periods and dosage regimens. Additional Aspects of Methods of Treatment [0756] Another embodiment is a method of treating and/or preventing a cancer by administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, or the corresponding pharmaceutical composition.
  • the cancer is solid cancer. In another aspect, the cancer is selected from the group consisting of lymphoma, leukemia, and a plasma cell neoplasm. In yet another aspect, the cancer selected from the group consisting of carcinoma and sarcoma. [0757] In some embodiments, the cancer to be treated is pancreatic cancer. [0758] In some embodiments, the cancer to be treated is ovarian cancer. [0759] In some embodiments, the cancer to be treated is platinum-resistant ovarian cancer. [0760] In some embodiments, the cancer to be treated is platinum-resistant advanced ovarian cancer. [0761] In some embodiments, the cancer to be treated is platinum refractory ovarian cancer.
  • the cancer to be treated is head and neck cancer.
  • the cancer to be treated is sarcoma.
  • the cancer to be treated is soft tissue sarcoma.
  • the cancer is breast cancer, colorectal cancer, recurrent squamous cell carcinoma of the head and neck cancer (HNSCC), non-small cell lung cancer (NSCLC), ovarian cancer, soft-tissue sarcoma, or pancreatic cancer. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0766]
  • the cancer is platinum-resistant ovarian cancer.
  • the cancer is platinum-resistant advanced ovarian cancer.
  • the cancer is platinum refractory ovarian cancer.
  • the pancreatic cancer is exocrine pancreatic cancer.
  • the exocrine pancreatic cancer is adenocarcinoma.
  • the exocrine pancreatic cancer is squamous cell carcinoma.
  • the exocrine pancreatic cancer is adenosquamous carcinoma.
  • the exocrine pancreatic cancer is colloid carcinoma.
  • the pancreatic cancer is neuroendocrine pancreatic cancer.
  • the neuroendocrine pancreatic cancer is a nonfunctioning neuroendocrine tumor. In some embodiments, the neuroendocrine pancreatic cancer is gastrinoma. In some embodiments, the neuroendocrine pancreatic cancer is insulinoma. In some embodiments, the neuroendocrine pancreatic cancer is glucagonoma. [0771] In some embodiments, the neuroendocrine pancreatic cancer is a VIPoma (i.e., an islet cell tumor which affects the vasoactive intestinal peptides). In some embodiments, the neuroendocrine pancreatic cancer is a somatostatinoma (i.e., an islet cell tumor which affects the somatostatin).
  • VIPoma i.e., an islet cell tumor which affects the vasoactive intestinal peptides
  • the neuroendocrine pancreatic cancer is a somatostatinoma (i.e., an islet cell tumor which affects the somatostatin).
  • the cancer is adenocarcinoma of the colon and rectum, adenocarcinoma of the breast, gastric adenocarcinoma, or pancreatic adenocarcinoma.
  • the pancreatic cancer is benign precancerous lesions.
  • the cancer to be treated is a lymphoma.
  • Lymphomas which can be treated by the disclosed methods and combinations of the present application include Non-Hodgkin’s lymphoma; Burkitt’s lymphoma; small lymphocytic lymphoma; lymphoplasmacytic lymphoma; MALT lymphoma; follicular lymphoma; diffuse large B-cell lymphoma; and T-cell lymphoma.
  • Lymphoma is a malignancy in the lymphatic cells of the immune system (e.g. B cells, T cells, or natural killer (NK) cells). Lymphomas often originate in the lymph nodes and present as solid tumors. They can metastasize to other organs such as the brain, bone, or skin. Extranodal sites are often located in the abdomen.
  • Lymphomas are closely related to the lymphoid leukemia and in some cases a particular form of cancer is categorized as both a lymphoma and a leukemia.
  • Leukemias which can be treated by the disclosed methods and combinations of the present application include acute lymphoblastic leukemia (ALL); Burkitt’s leukemia; B-cell 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 leukemia; B-cell acute lymphoblastic leukemia; chronic lymphocytic leukemia (CLL); acute myelogenous leukemia (AML); chronic myelogenous leukemia (CML); and T-cell acute lymphoblastic leukemia (T-ALL).
  • ALL acute lymphoblastic leukemia
  • Burkitt’s leukemia B-cell 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 leukemia
  • B-cell acute lymphoblastic leukemia chronic lymphoc
  • the cancer to be treated is B-cell neoplasms, B-cell leukemia, B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Burkitt's leukemia, acute myelogenous leukemia and/or T-ALL.
  • B-cell leukemia B-cell leukemia
  • B-cell acute lymphoblastic leukemia chronic lymphocytic leukemia
  • chronic myelogenous leukemia chronic myelogenous leukemia
  • Burkitt's leukemia acute myelogenous leukemia and/or T-ALL.
  • the cancer to be treated is chronic lymphocytic leukemia (CLL) or chronic myelogenous leukemia (CML).
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • the cancer to be treated is a plasma cell neoplasm. Examples for plasma cell neoplasms include multiple myeloma; plasma cell myeloma; plasma cell leukemia and plasmacytoma.
  • Carcinomas which can be treated by the disclosed methods and combinations of the present application include colon cancer; liver cancer; gastric cancer; intestinal cancer; esophageal cancer; breast cancer; ovarian cancer (e.g. platinum-resistant ovarian cancer); head and neck cancer; lung cancer; and thyroid cancer.
  • Sarcomas which can be treated by the disclosed methods and combinations of the present application include soft tissue sarcoma and bone sarcoma.
  • Some cancers that can be treated by the disclosed methods and combinations of the present application include cancer of the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus.
  • the cancer may be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; sarcomas; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chrom
  • lymphoma follicular; mycosis fungoides; other specified non-Hodgkin’s lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.
  • administer refers to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like.
  • Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. [0783]
  • Compound A and the second therapeutic agent e.g., capecitabine and gemcitabine
  • co-administration can be co-administered with other therapeutic agents.
  • the terms “co-administration”, “administered in combination with”, and their grammatical equivalents are meant to encompass administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • the one or more compounds described herein will be co-administered with other agents.
  • These terms encompass administration of two or more agents to the subject so that both agents and/or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
  • the compounds described herein and the other agent(s) are administered in a single composition.
  • the compounds described herein and the other agent(s) are admixed in the composition.
  • the particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g., the subject, the disease, the disease state involved, the particular treatment).
  • Treatment can involve daily or 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years.
  • a person of ordinary skill in the art would immediately recognize appropriate and/or equivalent doses looking at dosages of approved compositions for treating solid cancer using the disclosed combination of Compound A and a second therapeutic agent (e.g., capecitabine and gemcitabine) for guidance.
  • a second therapeutic agent e.g., capecitabine and gemcitabine
  • the combination or the corresponding pharmaceutical composition taught herein can be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the combination of the present teachings may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.
  • the pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings.
  • the pharmaceutical composition is formulated for intravenous administration.
  • a combination of the present teachings may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • solutions of a combination of the present teachings can generally be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. [0789] Typically, for injectable use, sterile aqueous solutions or dispersion of, and sterile powders of, a combination described herein for the extemporaneous preparation of sterile injectable solutions or dispersions are appropriate. 292800319 v3 Docket No.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of Compound A: (Compound A), and an effective amount of a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and fluorouracil (5-FU).
  • a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and fluorouracil (5-FU) [0792] Exemplary Embodiment 2.
  • a method of treating cancer in a subject in need thereof wherein the method comprises administering to the subject a combination comprising an effective amount of Compound A: (Compound A), and an effective amount of a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and fluorouracil (5-FU).
  • a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising an effective amount of Compound A: 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 and a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS- 010759 and fluorouracil (5-FU).
  • a pharmaceutical composition comprising an effective amount of Compound A: 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 and a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS- 010759 and fluorouracil (5-FU).
  • Exemplary Embodiment 7 wherein the capecitabine is administered at a dosage of about 1,000 mg/m 2 orally twice daily.
  • Exemplary Embodiment 10 The method of any one of Exemplary Embodiments 1- 9, wherein the subject is administered with Compound A for a period of 21 days consecutively.
  • Exemplary Embodiment 11 The method of any one of Exemplary Embodiments 1- 10, wherein the subject is administered with capecitabine for a period of 14 days consecutively.
  • Exemplary Embodiment 12 The method of any one of Exemplary Embodiment 10- 11, wherein the subject is administered with capecitabine for the first 14 days of the 21-day period during which Compound A is administered.
  • Exemplary Embodiment 13 The method of any one of Exemplary Embodiment 13
  • Exemplary Embodiments 1- 6, wherein the second therapeutic agent is gemcitabine.
  • Exemplary Embodiment 14 The method of Exemplary Embodiment 13, wherein the gemcitabine is administered at a dosage of about 1,000 mg/m 2 intravenously. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181
  • Exemplary Embodiment 15 The method of any one of Exemplary Embodiments 1- 6 and 13-14, wherein the subject is administered with Compound A for a period of 28 days consecutively.
  • Exemplary Embodiment 16 The method of any one of Exemplary Embodiments 1- 6 and 13-15, wherein the subject is administered with gemcitabine once weekly for three weeks.
  • Exemplary Embodiment 17 The method of any one of Exemplary Embodiments 15-16, wherein the subject is administered with gemcitabine on the first day, the eighth day, and the fifteenth day of the 28-day period during which Compound A is administered.
  • Exemplary Embodiment 18 The method of any one of Exemplary Embodiments 1- 6, wherein the second therapeutic agent is 5-FU.
  • Exemplary Embodiment 19 The method of any one of Exemplary Embodiments 1- 6, wherein the second therapeutic agent is 5-FU.
  • Exemplary Embodiment 18 wherein the 5-FU is administered at a dosage of about 200 mg/m 2 , about 400 mg/m 2 , about 500 mg/m 2 , about 600 mg/m 2 , about 1000 mg/m 2 , about 2400 mg/m 2 , or about 3000 mg/m 2 , intravenously.
  • Exemplary Embodiment 20 The method of Exemplary Embodiment 18, wherein the 5-FU is administered in an infusional regimen at a dosage of about 400 mg/m 2 by intravenous bolus on Day 1, followed by at about 2400 mg/m 2 to about 3000 mg/m 2 continuous intravenous infusion over 46 hours every two weeks.
  • Exemplary Embodiment 21 Exemplary Embodiment 21.
  • Exemplary Embodiment 18 wherein the 5-FU is administered in a bolus dosing regimen at a dosage of about 500 mg/m 2 by intravenous bolus on Days 1, 8, 15, 22, 29, and 36 in 8-week cycles.
  • Exemplary Embodiment 22 The method of Exemplary Embodiment 18, wherein the 5-FU is administered at a dosage of about 500 mg/m 2 or about 600 mg/m 2 intravenously on Days 1 and 8 every 28 days for 6 cycles, optionally as a component of a cyclophosphamide-based multidrug regimen.
  • Exemplary Embodiment 23 Exemplary Embodiment 23.
  • Exemplary Embodiment 18 wherein the 5-FU is administered at a dosage of about 200 mg/m 2 to about 1000 mg/m 2 intravenously as a continuous infusion over 24 hours, optionally as a component of a platinum-containing multidrug chemotherapy regimen.
  • Exemplary Embodiment 24 The method of Exemplary Embodiment 18, wherein the 5-FU is administered in an infusional regimen at a dosage of about 400 mg/m 2 by intravenous bolus on Day 1, followed by at about 2400 mg/m 2 continuous intravenous 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 infusion over 46 hours every two weeks, optionally as a component of a multidrug chemotherapy regimen.
  • Exemplary Embodiment 25 A combination comprising Compound A, (Compound A), or a pharmaceutically acceptable salt thereof, and a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and fluorouracil (5-FU).
  • Exemplary Embodiment 26 A combination comprising Compound A, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent selected from capecitabine, wherein Compound A is administered at a dosage from about 100 mg to about 400 mg orally once daily and capecitabine is administered at a dosage of about 1,000 mg/m 2 orally once daily for 14 days consecutively, optionally for the first 14 days of a period of 21 days.
  • Exemplary Embodiment 27 Exemplary Embodiment 27.
  • a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent selected from capecitabine, wherein Compound A is administered at a dosage from about 100 mg to about 400 mg orally once daily and capecitabine is administered at a dosage of about 1,000 mg/m 2 orally once daily for 14 days consecutively, optionally for the first 14 days of a period of 21 days.
  • a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent selected from capecitabine, wherein Compound A is administered at a dosage from about 100 mg to about 400 mg orally once daily and capecitabine is administered at a dosage of about 1,000 mg/m 2 orally once daily for 14 days consecutively, optionally for the first 14 days of a period of 21 days.
  • Compound A is administered at a dosage from about 100 mg to about 400 mg orally once daily and capecitabine is administered at a dosage of about 1,000 mg/m 2 orally twice daily for 14 days consecutively, optionally for the first 14 days of a period of 21 days.
  • a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising Compound A, (Compound A), or a pharmaceutically acceptable salt thereof, and capecitabine, wherein Compound A is administered at a dosage from about 100 mg to about 400 mg orally once daily and capecitabine is administered at a dosage of about 1,000 mg/m 2 orally twice daily for 14 days consecutively, optionally for the first 14 days of a period of 21 days.
  • Exemplary Embodiment 30 The method of any one of Exemplary Embodiments 1- 24, 27 and 29, wherein the cancer is solid cancer.
  • Exemplary Embodiment 31 Exemplary Embodiment 31.
  • Exemplary Embodiments 1- 24, 27 and 29, wherein the cancer is lymphoma, leukemia, or a plasma cell neoplasm.
  • Exemplary Embodiment 32 The method of any one of Exemplary Embodiments 1- 24, 27 and 29, wherein the cancer is carcinoma or sarcoma.
  • Exemplary Embodiment 33 The method of any one of Exemplary Embodiments 1- 24, 27 and 29, wherein the cancer is colon cancer, liver cancer, gastric cancer, intestinal cancer, esophageal cancer, lung cancer, thyroid cancer, breast cancer, colorectal cancer, head and neck cancer, non-small cell lung cancer (NSCLC), ovarian cancer, soft-tissue sarcoma, or pancreatic cancer.
  • NSCLC non-small cell lung cancer
  • Exemplary Embodiment 34 The method of Exemplary Embodiment 33, wherein the cancer is pancreatic cancer.
  • Exemplary Embodiment 35 The method of Exemplary Embodiment 33, wherein the cancer is ovarian cancer. 292800319 v3 Docket No. CYTH-023/001WO 335739-2181
  • Exemplary Embodiment 36 The method of Exemplary Embodiment 35, wherein the ovarian cancer is platinum-resistant ovarian cancer.
  • Exemplary Embodiment 37 The method of Exemplary Embodiment 35, wherein the ovarian cancer is platinum-resistant advanced ovarian cancer.
  • Exemplary Embodiment 38 Exemplary Embodiment 38.
  • Exemplary Embodiment 39 A method of treating solid tumor in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of Compound A: (Compound A), and an effective amount of a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and fluorouracil (5-FU).
  • Compound A Compound A
  • a second therapeutic agent selected from capecitabine, gemcitabine, metformin, IACS-010759 and fluorouracil (5-FU).
  • Example 1 Phase 1 Results of Compound A in Combination with Capecitabine or Gemcitabine in Advanced Solid Tumors Study Objectives [0831] Primary objectives of the study were to determine the recommended Phase 2 dose (RP2D) and maximum-tolerated dose (MTD) of Compound A in combination with capecitabine and gemcitabine in solid tumors. The secondary objectives of the study were (a) to evaluate the safety and tolerability, (b) to determine the pharmacokinetic parameters and optimal dosing regimen for each combination, and (c) to characterize the preliminary anti- tumor activity for each combination.
  • R2D Phase 2 dose
  • MTD maximum-tolerated dose
  • FIG.6 depicts PR in ovarian cancer with Compound A (300 mg) and Capecitabine. Clinical Activity in Solid Tumors with Compound A and Gemcitabine 292800319 v3 Docket No. CYTH-023/001WO 335739-2181 [0851] The plot of the duration of treatment and response using the combination of Compound A and gemcitabine is provided in FIG.7 and the plot of best percentage change in tumor size is shown in FIG.8.
  • CYTH-023/001WO 335739-2181 Median Compound A dose compliance with continuous daily dosing was 99% (range 91– 100%). There were no treatment discontinuations or Compound A dose reductions for treatment related adverse events.7 patients (64%) experienced a treatment-related adverse event, all were Grade 1-2. There were no grade 3+ treatment related adverse events. The most common related adverse events (AEs) were fatigue reported in 5 patients (46%), and decreased appetite, diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome and vomiting, each reported in 2 patients (18%). Exposure of Compound A in combination with capecitabine exhibits dose proportional behavior and was similar between combination therapy and monotherapy.
  • Example 3 Compound A Induces Metabolic Rewiring [0857] Raji cells were treated with a titration of Compound A, metformin, or the combination of both drugs, cell viability was measured and data plotted using the NCI method (FIG.9). Metformin at concentrations known to inhibit oxidative phosphorylation (OXPHOS) had little effect on cell viability as a single agent, but when combined with Compound A profoundly enhanced cytotoxicity. Similar results were observed with other inhibitors of oxidative phosphorylation, such as IACS-010759.
  • OXPHOS oxidative phosphorylation
  • Both cell lines were transduced with an “all-in-one” whole genome lentiviral library containing viral particles enabling expression of both spCas9 and sgRNA’s targeting each gene in the genome.
  • Cells were selected for successful integration of the viral material with puromycin, and then split into separate treatments of DMSO or a cell line-specific GI20 dose of Compound A.
  • a third treatment group was utilized for the T47D cell line as well, and consisted of a GI80 dose of Compound A. Cells were passaged and expanded for at least 8 doublings of the DMSO control with an attempt at maintaining >300- fold library coverage.
  • a screen hit is defined as a gene that when genetically disrupted results in increased Compound A-mediated cell growth inhibition.
  • the most statistically significant hit in the SU8686 screen was TYMS, the gene that encodes for the thymidylate synthetase protein, which is one of the molecular targets of 5-fluorouracil (FIG.10).
  • TYMS was the 346 th highest scoring hit in the T47D screen performed in the presence of a GI20 dose of Compound A and was not considered statistically significant.
  • a panel of human pancreatic cancer and other cancer subtype cell lines were tested for sensitivity to Compound A as a single agent and in combination with 5-fluorouracil (5-FU) or gemcitabine in a cell viability assay (FIGs.12 and 13).
  • cell lines were plated in 96 well plates at their pre- determined optimal growth density for a 7-day viability assay.
  • mice were xenografted with the MiaPaca-2 human pancreatic cancer cell line. Once tumors were palpable and reached a pre-specified cohort median tumor volume of 150 cubic mm, mice were randomized into treatment groups and drug treatment initiated. Treatment groups were vehicle control, Compound A initially dosed once daily at 200 mg/kg orally, capecitabine dosed once daily at 400 mg/kg orally on a 14 day on/7 day off schedule, or the combination of both oral drug treatments.
  • TGI tumor growth inhibition
  • Treatment Compliance Median Compound A dose compliance with continuous daily dosing was 99% (range 94 – 100%). There were no treatment discontinuations or Compound A dose reductions for treatment related adverse events.

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Abstract

La présente demande concerne une méthode de traitement et/ou de prévention du cancer chez un sujet en ayant besoin, comprenant l'administration au sujet d'une combinaison comprenant le composé A; et un second agent thérapeutique choisi parmi la capécitabine, la gemcitabine, la metformine, l'IACS-010759 et le fluorouracile (5-FU), une composition ou une combinaison pharmaceutique les comprenant.
PCT/US2023/077327 2022-10-19 2023-10-19 Procédés d'utilisation d'un dérivé de (thiazolyl)benzènesulfonamide Ceased WO2024086735A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9198914B2 (en) * 2007-07-28 2015-12-01 The University Of Chicago Methods and compositions for modulating RAD51 and homologous recombination
US20200397760A1 (en) * 2019-06-21 2020-12-24 Cyteir Therapeutics, Inc. Methods of using rad51 inhibitors for treatment of pancreatic cancer
WO2021164746A1 (fr) * 2020-02-19 2021-08-26 江苏先声药业有限公司 Composé aryle substitué

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9198914B2 (en) * 2007-07-28 2015-12-01 The University Of Chicago Methods and compositions for modulating RAD51 and homologous recombination
US20200397760A1 (en) * 2019-06-21 2020-12-24 Cyteir Therapeutics, Inc. Methods of using rad51 inhibitors for treatment of pancreatic cancer
WO2021164746A1 (fr) * 2020-02-19 2021-08-26 江苏先声药业有限公司 Composé aryle substitué

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