Classifications

• • 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
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• • 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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • 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
  • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present disclosure relates to a pharmaceutical composition for coadministration including a phthalazinone derivative used for prevention or treatment of cancer. More particularly, the present disclosure relates to a pharmaceutical composition for co-administration including a phthalazinone derivative and an anticancer drug.
• the present disclosure also relates to a pharmaceutical composition for co- administration including a phthalazinone derivative used for prevention or treatment of cancer, and irinotecan and/or oxaliplatin.
• the present disclosure also relates to a method of treating cancer in a patient, the method including administering a phthalazinone derivative used for prevention or treatment of cancer in combination with irinotecan and/or oxaliplatin.
• PARP belongs to a family of enzymes involved in DNA repair and consists of 18 components. Enzymes belonging thereto are located in the cell nucleus, and are key enzymes in the DNA repair mechanism of human cells when damage occurs to single-stranded DNA of cancer cell.
• PARP inhibitors induce and increase DNA damage in cells through a homologous recombination repair process.
• HRD homologous recombination deficiency
• PARP inhibitors block the action of PARP in order to accumulate DNA damage in cancer cells and induce apoptosis.
• PARP inhibitors are Olaparib (AZD-2281), Rucaparib (AG-014699), Niraparib (MK-4827), Talazoparib (BMN-673), Veliparib (ATB-888), Fluzoparib (SHR- 3162), Pamiparib (BGN-290), Senaparib (IMP -4297), Stenoparib (2X-121), AZD-5305, and the like.
• Olaparib is a strong inhibitor of human PARP, and inhibits in vitro proliferation of specific tumor cell lines and in vivo proliferation of tumors using a monotherapy or a combination therapy with established chemotherapy (Cancers 2020, 12(2), 334; doi: 10.3390/cancersl2020334).
• Olaparib when used as a therapeutic agent, cancer cells that have acquired resistance to Olaparib in vivo appear, thereby reducing therapeutic effect. Accordingly, the development of new therapeutic agents that can effectively treat cancer having resistance to certain PARP inhibitors, such as Olaparib, is urgently required.
• a monotherapy using a particular PARP inhibitor alone has shown excellent efficacy and safety profile in clinical practice, but major limitations thereof are the need for HRD and rapid emergence of resistance. Many tumors that initially respond to a therapy using PARP inhibitors eventually relapse by restoring homologous recombination activity or through compensatory mutations that stimulate the activity of alternative repair pathways. Therefore, use of a particular PARP inhibitor is limited to specific tumor types, and cannot be used in any cancer treatment.
• US Patent No. 9,682,973 which is incorporated herein by reference in its entirety, discloses a PARP inhibitor compound represented by Formula 1, which is a phthalazinone derivative having anticancer activity, or a pharmaceutically acceptable salt thereof.
• the hydrochloride salt form of the compound represented by Formula 1 is one of the promising therapeutic drug candidates as anticancer drugs.
• An object of the present disclosure is to provide a pharmaceutical composition for co-administration, including a phthalazinone derivative as a poly(ADP -ribose) polymerase (PARP) inhibitor having excellent activity, and at least one anticancer drug.
• a phthalazinone derivative as a poly(ADP -ribose) polymerase (PARP) inhibitor having excellent activity
• PARP poly(ADP -ribose) polymerase
• An object of the present disclosure is to provide a pharmaceutical composition for co-administration, including a compound represented by Formula 1, which is a phthalazinone derivative, or a pharmaceutically acceptable salt thereof.
• An object of the present disclosure is to provide a kit including, as a concomitant agent for simultaneous, separate, or sequential use in cancer treatment, a phthalazinone derivative as a PARP inhibitor having excellent activity, and at least one anticancer drug capable of co-administration.
• An object of the present disclosure is to provide a method of treating cancer, the method including co-administering a PARP inhibitor and at least one anticancer drug simultaneously or sequentially for the treatment of cancer.
• the method is not limited to those related to homologous recombination deficiency (HRD).
• HRD homologous recombination deficiency
• the present disclosure provides a synergistic therapeutic effect on tumors by providing co-administration of the compound represented by Formula 1 or the pharmaceutically acceptable salt thereof and an anticancer drug.
• An aspect of the present disclosure provides a pharmaceutical composition for coadministration, including, as active ingredients, (i) a compound represented by Formula 1 ⁇ 4- [3-(3-[(cyclopropylamino)methyl]azetidine-l-carbonyl)-4-fluorobenzyl]phthalazine-l(2H)- on ⁇ or a pharmaceutically acceptable salt thereof, and (ii) at least one anticancer drug:
• compositions for co-administration to prevent or treat cancer wherein the combination comprises: (i) a first pharmaceutical composition comprising, as an active ingredient, a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof;
• a second pharmaceutical composition comprising, as an active ingredient, at least one anticancer drug.
• the compound represented by Formula 1 may be a type of phthalazinone derivative.
• the term “compound represented by Formula 1” may be also simply referred to as “compound of Formula 1” or “compound of the present disclosure”.
• the term “salt of the compound represented by Formula 1” may be also referred to as “salt of the compound of Formula 1” or “salt compound of Formula 1”.
• the compound represented by Formula 1 when the compound represented by Formula 1 is present in the form of hydrochloride, the compound may be referred to as “hydrochloride of the compound of Formula 1" or “hydrochloride compound of Formula 1".
• Such a salt form may include inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, etc ), organic carboxylic acid (acetic acid, haloacetic acid such as trifluoroacetic acid, propionic acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, salicylic acid, etc.), sugar acid (glucuronic acid, galacturonic acid, gluconic acid, ascorbic acid, etc.), acidic polysaccharide (hyaluronic acid, chondroitin sulfate, argininic acid, etc.), sulfonic acid such as chondroitin sulfate, organic sulfonic acid including sugar ester (methane sulfonic acid, p-toluene sulfonic acid, etc.), and the like.
• the salt form of the compound represented by Formula 1 may be hydrochloride.
• the pharmaceutically acceptable salt may be prepared by any suitable method in the art by preparing the compound represented by Formula 1 in the form of a free base.
• the free base may be prepared by treating a free base with inorganic acid (e.g., hydrochloric acid, bromic acid, sulfuric acid, nitric acid, methane sulfonic acid, phosphoric acid, etc.), organic acid (e g., acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pymvic acid, oxalic acid, glycolic acid, salicylic acid, etc.), pyranosidyl acid (e.g., glucuronic acid, galacturonic acid, etc.), alpha hydroxyl acid (e.g., citric acid, tartaric acid, etc.), amino acid (e g., aspartic acid, glutamic acid, etc.), aromatic acid (e
• inorganic acid e.
• the compound represented by Formula 1 of the present disclosure or the pharmaceutically acceptable salt thereof may be easily obtained by, for example, the method disclosed in US 9,682,973 or in accordance with the method.
• the anticancer drug as used in the present disclosure may refer to all drugs used to kill cancer cells.
• the anticancer drug in the second pharmaceutical composition is selected from the group consisting of a chemotherapy drug, a targeted therapy drug, an immunotherapy drug, and a hormone therapy drug.
• the type of anticancer drug that can be used in the composition of the present invention is not particularly limited.
• the anticancer drug may be selected under the general principles considered when selecting the anticancer drug, such as the type of cancer cell, the absorption rate of the anticancer drug (treatment period and the route of administration of the anticancer drug), the location of the tumor, and the size of the tumor.
• the anti cancer drug available in the present disclosure may be (i) chemotherapy drugs, such as alkylating agent, antimetabolites, antitumor antibiotics, Topoisomerase inhibitor, Mitotic inhibitors or other chemotherapy; (ii) targeted therapy drugs, such as angiogenesis inhibitor, monoclonal antibody, proteasome inhibitor, signal transduction inhibitor or new class; (iii) immunotherapy drugs, such as checkpoint inhibitor, chimeric antigen receptor(CAR) T-cell therapy or cytokine; or (iv) hormone therapy drugs, such as aromatase inhibitor, selective estrogen receptor modulators, Estrogen receptor antagonist, luteinizing horm one-releasing hormone agonist, anti-androgen or CYP17 inhibitor; but is not limited thereto.
• chemotherapy drugs such as alkylating agent, antimetabolites, antitumor antibiotics, Topoisomerase inhibitor, Mitotic inhibitors or other chemotherapy
• targeted therapy drugs such as angiogenesis inhibitor, monoclonal antibody, proteasome inhibitor, signal transduction inhibitor or new class
• the chemotherapy drug is selected from the group consisting of an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a Topoisomerase inhibitor and a Mitotic inhibitor.
• the targeted therapy drug is selected from the group consisting of an angiogenesis inhibitor, a monoclonal antibody, a proteasome inhibitor and a signal transduction inhibitor.
• the immunotherapy drug is selected from the group consisting of a checkpoint inhibitor, a chimeric antigen receptor(CAR) T-cell therapy and a cytokine.
• the hormone therapy drug is selected from the group consisting of an aromatase inhibitor, a selective estrogen receptor modulators, an Estrogen receptor antagonist, a luteinizing hormone-rel easing hormone agonist, an anti-androgen and a CYP17 inhibitor.
• the anticancer drug available in the present disclosure may be preferably an anticancer drug belonging to the platinum class among DNA alkylating agents, or an anticancer drug belonging to the Topoisomerase inhibitor class.
• the anticancer drug belonging to the platinum class among DNA alkylating agents may be selected from Altretamine, Carboplatin, Cisplatin, Cyclophosphamide, dacarbazine, Ifosfamide, Oxaliplatin, Temozolomide, and preferably Oxaliplatin, but is not limited thereto.
• the anticancer drug belonging to the Topoisomerase inhibitor class may be selected from Irinotecan, Irinotecan liposomal, Topotecan, Etoposide, Teniposide, and preferably Irinotecan, but is not limited thereto.
• the anticancer drug is selected from irinotecan and oxaliplatin. In certain embodiments, the anticancer drug is irinotecan. In some embodiments, the anticancer drug is oxaliplatin.
• the pharmaceutical composition of the present disclosure may be administered in a form in which the compound represented by Formula 1 or the pharmaceutically acceptable salt thereof is mixed with the at least one anticancer drug, or in a form in which the compound represented by Formula 1 and the at least one anticancer drug are each formulated and administered simultaneously or sequentially.
• the pharmaceutical compositions for co-admini strati on are administered in which the first pharmaceutical composition and the second pharmaceutical composition are in a form of a mixture.
• the first pharmaceutical composition and the second pharmaceutical composition are each comprised in the form of a separate dosage form.
• the pharmaceutical compositions for co-admini strati on are administered in which the first pharmaceutical composition and the second pharmaceutical composition are each formulated and administered simultaneously or sequentially.
• the pharmaceutical composition of the present disclosure may be in a form for simultaneous administration of two drugs that include a mixture form in which the compound represented by Formula 1 or the pharmaceutically acceptable salt thereof is mixed with the anticancer drug are mixed.
• the pharmaceutical composition of the present disclosure may be in a form in which the compound represented by Formula 1 or the pharmaceutically acceptable salt thereof and the anticancer drug are each formulated and administered simultaneously or sequentially. In the case of sequential administration, the order may be interchanged. According to an embodiment of the present disclosure, it is confirmed that, when the hydrochloride of the compound represented by Formula 1 is co-administered with the anticancer drug, anti-proliferative effects are exhibited in a concentration-dependent manner with respect to cancer cell lines (see FIGs. 1 and 2).
• “sequentially” is used to mean that the active agents or compositions (e.g., pharmaceutical compositions) are not administered concurrently, but one after the other.
• administration “sequentially” may permit one agent/composition (e.g., pharmaceutical composition) to be administered within 5 minutes, 10 minutes or a matter of hours after the other provided the circulatory half-life of the first administered agent is such that they are both concurrently present in therapeutically effective amounts.
• the time delay between administrations of the components will vary depending on the exact nature of the components, the interaction there between, and their respective half-lives.
• “separately” is used herein to mean that the gap between administering one agent/composition (e g., pharmaceutical composition) and the other is significant i.e. the first administered agent may no longer be present in the bloodstream in a therapeutically effective amount when the second agent is administered.
• the pharmaceutical composition of the present disclosure may be used for prevention or treatment of cancer.
• cancer refers to cancer consisting of a mass caused by abnormal cell growth in various solid organs, such as bladder, breast, intestine, kidney, lung, liver, brain, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid gland, prostate, and skin.
• Cancer that can be prevented or treated by the pharmaceutical composition of the present disclosure may include breast cancer, ovarian cancer, uterine endometrial cancer, small cell lung cancer, neuroendocrine tumor, biliary tract cancer, cholangiocarcinoma, uroepithelial cancer, bladder cancer, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, colorectal cancer, thyroid cancer, hematologic cancer, cancers with homologous recombinant deficiency among aforementioned cancer types, and the like, and may preferably include gastric cancer.
• gastric cancer refers to cancer occurring in the stomach, and includes adenocarcinoma occurring in glandular cells of the mucous membrane of the stomach walls and other diseases including lymphomas occurring in the lymphatic system and gastrointestinal stromal tumor occurring in the interstitial tissue.
• prevention refers to any action that inhibits or delays the occurrence, spread, and recurrence of cancer by administration of the pharmaceutical composition of the present disclosure
• treatment refers to any action that improves or beneficially changes symptoms of a subject with suspected or developed cancer by administration of the pharmaceutical composition of the present disclosure.
• the term "administration" refers to providing a predetermined substance to a patient by any suitable method, and regarding the administration route, the pharmaceutical composition of the present disclosure may be administered by any general route as long as it can reach a target tissue.
• the administration may include oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, or intrarectal administration, but is not limited thereto.
• the pharmaceutical composition of the present disclosure may be administered by any device capable of transporting an active ingredient to a target cell.
• each may be formulated for use in a form of powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, and the like, according to a conventional method.
• the pharmaceutical composition of the present disclosure may be used in a form of an external preparation, a suppository, or an external preparation for skin (ointment, lotion, spray, patch, cream, powder, suspending agent, gel, gel form, etc ).
• the first pharmaceutical composition is to be administered once daily. In some embodiments, the first pharmaceutical composition is in an oral dosage form. In some embodiments, the first pharmaceutical composition is a tablet. In some embodiments, the first pharmaceutical composition is to be administered at a dose from about 1 mg to about 50 mg. In some embodiments, the first pharmaceutical composition is to be administered at a dose of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg per administration. In some embodiments, the first pharmaceutical composition is to be dosed at about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 120 mg, or about 160 mg per administration.
• Preferable parenteral administration methods and preparations of the pharmaceutical composition of the present disclosure include intravenous injections, subcutaneous injections, intradermal injections, muscular injections, drip injections, and the like.
• the injections may be prepared by using an aqueous solvent, such physiological saline solution and Ringer's solution, and a non-aqueous solvent, such as plant oil, high fatty acid ester (e.g., ethyl oleate, etc.), alcohol (e.g., ethanol, benzylalcohol, propyleneglycol, glycerin, etc.).
• the injections may include a pharmaceutical carrier, such as a stabilizer (e.g., ascorbic acid, sodium bisulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.) for preventing deterioration, an emulsifier, a buffer for adjusting pH, and a preservative (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzylalcohol, etc.) for inhibiting the growth of microorganisms.
• a pharmaceutical carrier such as a stabilizer (e.g., ascorbic acid, sodium bisulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.) for preventing deterioration, an emulsifier, a buffer for adjusting pH, and a preservative (e.g., phenylmercuric nitrate, thimerosal,
• the second pharmaceutical composition is in an injection dosage form. In some embodiments, the second pharmaceutical composition is administered once daily. In some embodiments, the second pharmaceutical composition is to be administered intravenously. In some embodiments, the second pharmaceutical composition is to be administered continuously.
• the pharmaceutical composition of the present disclosure may further include a pharmaceutically acceptable carrier.
• pharmaceutically acceptable refers to exhibiting non-toxic characteristics to cells or humans exposed to the composition.
• any material known in the art may be used without limitation, such as a buffer, a preservative, a painless agent, a solubilizer, an isotonic agent, a stabilizer, a base agent, an excipient, a lubricant, and the like.
• excipient refers to a pharmaceutically acceptable inactive ingredient used in the manufacture of pharmaceutical preparations.
• the excipient may include, for example, a diluent, a binder, a disintegrant, a super-intense disintegrant, a glidant, a pH adjuster, a lubricant, a filler, a stabilizer, an antioxidant, a film- coating agent, and the like, but is not limited thereto.
• the excipient used in the present disclosure may be appropriately selected by referring to the document known in the art, for example, [Handbook of Pharmaceutical Excipients, Sixth edition, Pharmaceutical Press] which is incorporated herein by reference.
• lactose for use as a carrier, an excipient, and a diluent that can be included in the pharmaceutical composition of the present disclosure, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil may be used.
• a commonly used diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and the like, may be used for preparation.
• Examples of solid preparations for oral administration are a tablet, a pill, a powder, a granule, a capsule, and the like. Such solid preparations may be prepared by mixing the compound represented by Formula 1 with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, or gelatin. In addition, other than a simple excipient, a lubricant such as magnesium stearate or the like may be used.
• Examples of liquid preparations for oral administration are a suspending agent, an oral liquid, an emulsion, a syrup, and the like. In addition to water and liquid paraffin, which are simple diluents commonly used, various excipients such as a wetting agent, a sweetening agent, a fragrance, a preservative, and the like may be included.
• Preparations for parenteral administration may include a sterile solution, a nonaqueous solvent, a suspending agent, an emulsion, a freeze-dried agent, a suppository, and the like.
• a nonaqueous solvent and a suspending agent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable ester such as ethyl oleate may be used.
• a base agent for suppository witepsol, macrogol, tween 61, cacao butter, laurinum, glycerogelatin, or the like may be used.
• the pharmaceutical composition of the present disclosure in mammals including humans, may be used alone or in combination with other active ingredients included in the pharmaceutical composition or with a kit, a product, or a concomitant agent, thereby preventing, removing, or reducing harmful effects of cancer.
• the term "pharmaceutically effective amount” refers to an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the level of “therapeutically effective amount” may be determined by factors, which includes a patient's health condition, a cancer type, severity, drug activity, drug sensitivity, an administration method, an administration time, an administration route and an excretion rate, a period of treatment, combination or drugs simultaneously used, and other factors well known in the medical field. It is understood that a dose administered in the present disclosure may be lower for each compound in the composition relative to "therapeutically effective amount” defined for each compound used alone or in combination with treatments other than the combined therapy described above.
• the pharmaceutical composition, the kit, the product, and the concomitant agent of the present disclosure may reduce tumor development, reduce tumor burden, cause tumor regression in a mammalian host, and/or prevent occurrence of metastasis or cancer.
• the pharmaceutical composition of the present disclosure may be administered in a therapeutically effective amount.
• a daily dose of the compound represented by Formula 1 of the present disclosure may be about 1 mg to about 400 mg, preferably, about 2 mg to about 240 mg, more preferably, about 5 mg to about 160 mg, and even more preferably, about 5 mg to about 120 mg.
• a daily dose of irinotecan which is the anticancer drug of the present disclosure may be about 10 mg/m2 to about 350 mg/m2, preferably, about 25 mg/m2 to about 100 mg/m2, and more preferably, about 25 mg/m2 to about 75 mg/m2.
• the anticancer drug e.g., irinotecan
• the anticancer drug is to be intravenously dosed at about 30 mg/m2 to about 120 mg/m2.
• the anticancer drug (e.g., irinotecan) is to be dosed at about 50 mg/m2, about 75 mg/m2, or about 100 mg/m2. In some embodiments, the anticancer drug (e.g., irinotecan) is to be intravenously dosed at about 125 mg/m2, 180 mg/m2, or about 350 mg/m2. In some embodiments, the second pharmaceutical composition is to be intravenously dosed at about 30 mg/m2 to about 120 mg/m2. In some embodiments, the second pharmaceutical composition is to be dosed at about 50 mg/m2, about 75 mg/m2, or about 100 mg/m2. However, due to the nature of cancer which is a target disease of the pharmaceutical composition of the present disclosure, a dose of each ingredient may vary greatly depending on the conditions described above, and is not limited to the embodiments above.
• the term “about” or “approximately” refers to a ⁇ 10% variation from the recited quantitative value (and includes the recited quantitative value itself) unless otherwise indicated or inferred from the context.
• a dose of about 100 mg/m2 indicates a dose range of 100 ⁇ 10% mg/m2, i.e., from 90 mg/m2 to 110 mg/m2, inclusive.
• a suitable administration cycle of (i) the compound represented by Formula 1 or the pharmaceutically acceptable salt thereof and (ii) the anticancer drug may be determined according to the dose.
• the compound represented by Formula 1 or the pharmaceutically acceptable salt thereof may be administered once a day to once a week, and preferably, once a day
• the anticancer drug may be administered once a day to once a week, and preferably, once a week.
• one cycle of administration of the pharmaceutical composition for co-administration of the present disclosure may be 14 days to 21 days, but is not limited thereto.
• the compound represented by Formula 1 or the pharmaceutically acceptable salt may be orally administered once a day or administered by injection once a day, and (ii) on the 1st day or from the 2nd day to the 6th day, the anticancer drug may be administered by injection once a day.
• the compound represented by Formula 1 or the pharmaceutically acceptable salt may be orally administered once a day or administered by injection once a day, and (ii) on the 1st day, or from the 2nd day to the 6th day, the anticancer drug may be administered by injection once a day.
• the first pharmaceutical composition is to be dosed as a cycle, wherein the cycle comprises administering the first pharmaceutical composition for about 14 days or about 21 days.
• the first pharmaceutical composition is administered to a subject in need thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.
• the second pharmaceutical composition is to be dosed as a cycle, wherein the cycle comprises administering the second pharmaceutical composition for about 14 days or about 21 days.
• the second pharmaceutical composition is to be dosed as a cycle, wherein the cycle is repeated at least once.
• the second pharmaceutical composition is administered to a subject in need thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.
• the first pharmaceutical composition in one cycle, is to be administered from the 1st day to the 7th day, from the 1st day to the 5th day, or from 2nd day to the 6th day; and the second pharmaceutical composition is to be administered on the 1st day, or from 2nd to 6th day, wherein the first pharmaceutical composition is to be administered once daily, the second pharmaceutical composition is to be administered once daily, and the one cycle has a duration of 14 days or 21 days.
• the first pharmaceutical composition containing 40 mg, 20 mg, or 10 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof is to be administered once daily, and the second pharmaceutical composition is to be administered once daily at a intravenously dose of 100 mg/m2.
• the pharmaceutical composition for co-administration of the present disclosure may be administered as an individual therapeutic agent, may be administered again in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered once or multiple times. In consideration of all of the factors described above, it is important to administer an amount capable of obtaining the maximum effect with a minimum amount without side effects.
• the term “kit”, “product”, or “concomitant agent” specifically defines “kit of components” in the sense that the compound represented by Formula 1 as defined above may be administered independently or used in combination with a unique amount of a fixed combination different from a combined anticancer drug, and that is, may be administered at the same time or at different times.
• Components of the component kit may be then administered, for example, at the same time or in chronological order, i.e., at different times. In other words, any component of the component kit may be administered at the same time or at different time intervals.
• a ratio of the total amounts of the compound represented by Formula 1 and the concomitant anticancer drug administered in the concomitant preparations may vary.
• the combined anticancer drug may be administered by the same or different route.
• the first pharmaceutical composition is present in a single dosage form and the second pharmaceutical composition is present in a separate dosage form.
• the first pharmaceutical composition is to be administered simultaneously, separately, or sequentially.
• treatment refers to curative, symptomatic, and prophylactic treatment.
• the pharmaceutical composition, the kit, the product, and the concomitant agent of the present disclosure may be used in humans with cancer or tumor at an early stage or latter stages of cancer progression.
• the pharmaceutical composition, the kit, the product, and the concomitant agent of the present disclosure may not necessarily treat a patient with cancer, but may improve a patient's condition by delaying or slowing the progression or preventing further progression of the disease.
• the cancer treatment may refer to: (a) as a method of treating cancer, the method including administering the pharmaceutical composition of the present disclosure to a target in need of such treatment; (b) use of the pharmaceutical composition of the present disclosure for treatment of cancer; (c) use of the pharmaceutical composition of the present disclosure for preparation of a pharmaceutical for treatment of cancer; and/or (d) the pharmaceutical composition of the present disclosure for use in treatment of cancer.
• Another aspect of the present disclosure provides a method of preventing or treating cancer, the method including administering the pharmaceutical composition for coadministration to a subject in need thereof, wherein the pharmaceutical composition includes (i) the compound represented by Formula 1 or the pharmaceutically acceptable salt thereof and (ii) at least one anticancer drug.
• the present disclosure provides a method of treating cancer in a subject in need thereof, wherein the method comprises administering to the subject (i) a first pharmaceutical composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof;
• a second pharmaceutical composition comprising an anticancer drug.
• the cancer is gastric cancer.
• the cancer is advanced gastric cancer.
• the anticancer drug is selected from irinotecan and oxaliplatin.
• the anticancer drug is irinotecan.
• the anticancer drug is oxaliplatin.
• the pharmaceutically acceptable salt is hydrochloride.
• Another aspect of the present disclosure provides a use of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a first medicament and use of an anticancer drug for the manufacture of a second medicament, wherein the first medicament and the second medicament are for preventing or treating a cancer in a subject in need thereof.
• the cancer is gastric cancer.
• the cancer is advanced gastric cancer.
• the anticancer drug is selected from irinotecan and oxaliplatin.
• the anticancer drug is irinotecan.
• the anticancer drug is oxaliplatin.
• the pharmaceutically acceptable salt is hydrochloride.
• Yet another aspect of the present disclosure provides a use of a first pharmaceutical composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a first medicament and use of a second pharmaceutical composition comprising an anticancer drug for the manufacture of a second medicament, wherein the first medicament and the second medicament are for preventing or treating a cancer in a subject in need thereof.
• the cancer is gastric cancer.
• the cancer is advanced gastric cancer.
• the anticancer drug is selected from irinotecan and oxaliplatin.
• the anticancer drug is irinotecan.
• the anticancer drug is oxaliplatin.
• the pharmaceutically acceptable salt is hydrochloride.
• the anticancer drug is selected from the group consisting of a chemotherapy drug, a targeted therapy drug, a immunotherapy drug, and a hormone therapy drug.
• the chemotherapy drug is selected from the group consisting of an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a Topoisomerase inhibitor and a Mitotic inhibitor.
• the targeted therapy drug is selected from the group consisting of an angiogenesis inhibitor, a monoclonal antibody, a proteasome inhibitor and a signal transduction inhibitor.
• the immunotherapy drug is selected from the group consisting of a checkpoint inhibitor, a chimeric antigen receptor(CAR) T-cell therapy and a cytokine.
• the hormone therapy drug is selected from the group consisting of an aromatase inhibitor, a selective estrogen receptor modulators, an Estrogen receptor antagonist, a luteinizing hormone-releasing hormone agonist, an anti-androgen and a CYP17 inhibitor.
• the anticancer drug is selected from irinotecan and oxaliplatin.
• the anticancer drug is irinotecan.
• the anticancer drug is oxaliplatin.
• the pharmaceutically acceptable salt is hydrochloride.
• the method or use comprises administering the first pharmaceutical composition and the second pharmaceutical composition in a form of a mixture. In some embodiments, the method or use comprises administering the first pharmaceutical composition and the second pharmaceutical composition in separate formulations, wherein the first pharmaceutical composition and second pharmaceutical composition are administered simultaneously or sequentially.
• the method or use comprises administering the first pharmaceutical composition and the second pharmaceutical composition each in the form of a separate dosage form. In some embodiments, the method or use comprises administering the first pharmaceutical composition in an oral dosage form, and the second pharmaceutical composition in an injection dosage form. In some embodiments, the method or use comprises administering the first pharmaceutical composition in a tablet, and the second pharmaceutical composition intravenously.
• the method or use comprises administering the first pharmaceutical composition and the second pharmaceutical composition each once daily. In some embodiments, the method or use comprises administering the first pharmaceutical composition is to be dosed at about 1 mg to about 180 mg. In some embodiments, the method or use comprises administering the first pharmaceutical composition is to be dosed at about 5 mg to about 170 mg. In some embodiments, the method or use comprises administering the first pharmaceutical composition is to be dosed at about 10 mg to about 160 mg. In some embodiments, the method or use comprises administering the first pharmaceutical composition at a dose of about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 120 mg, or about 160 mg per administration.
• the first pharmaceutical composition comprises about 1 mg to about 50 mg of the compound represented by Formula I. In some embodiments, the first pharmaceutical composition comprises about 5 mg to about 40 mg of the compound represented by Formula I. In some embodiments, the first pharmaceutical composition comprises about 5 mg, about 10 mg, about 20 mg, or about 40 mg of the compound represented by Formula I. In some embodiments, the first pharmaceutical composition is administered to a subject in need thereof with at least 8 ounces of water.
• the method or use comprises administering the second pharmaceutical composition is to be intravenously dosed at about 30 mg/m2 to about 120 mg/m2. In some embodiments, the method or use comprises administering the second pharmaceutical composition is to be intravenously dosed at about 50 mg/m2, about 75 mg/m2, or about 100 mg/m2. In some embodiments, the method or use comprises administering the first pharmaceutical composition and the second pharmaceutical composition in one cycle, wherein the one cycle has a duration of about 14 or 21 days. In some embodiments, the cycle is repeated at least once. In some embodiments, the second pharmaceutical composition comprises an anticancer drug (e.g., irinotecan) at a concentration of about 20 mg/mL.
• an anticancer drug e.g., irinotecan
• the second pharmaceutical composition comprises 5% dextrose or 0.9% sodium chloride.
• the anticancer drug e.g., irinotecan
• the anticancer drug is administered for about 90 minutes. In some embodiments, the anticancer drug (e.g., irinotecan) is administered for more than about 90 minutes.
• the method or use comprises administering the first pharmaceutical composition at a dosage of about 40 mg, and intravenously administering the second pharmaceutical composition at a dosage of about 50 mg/m2. In some embodiments, the method or use comprises administering the first pharmaceutical composition at a dosage of about 40 mg, and intravenously administering the second pharmaceutical composition at a dosage of about 75 mg/m2. In some embodiments, the method or use comprises administering the first pharmaceutical composition at a dosage of about 10 mg, and intravenously administering the second pharmaceutical composition at a dosage of about 100 mg/m2. In some embodiments, the method or use comprises administering the first pharmaceutical composition at a dosage of about 20 mg, and intravenously administering the second pharmaceutical composition at a dosage of about 100 mg/m2.
• the method or use comprises administering the first pharmaceutical composition at a dosage of about 40 mg, and intravenously administering the second pharmaceutical composition at a dosage of about 100 mg/m2. In some embodiments, the method or use comprises administering the first pharmaceutical composition at a dosage of about 80 mg, and intravenously administering the second pharmaceutical composition at a dosage of about 100 mg/m2. In some embodiments, the method or use comprises administering the first pharmaceutical composition at a dosage of about 120 mg, and intravenously administering the second pharmaceutical composition at a dosage of about 100 mg/m2.
• the method or use comprises administering the first pharmaceutical composition at a dosage of about 40 mg once daily, and intravenously administering the second pharmaceutical composition at a dosage of about 50 mg/m2 once daily. In some embodiments, the method or use comprises administering the first pharmaceutical composition at a dosage of about 40 mg once daily, and intravenously administering the second pharmaceutical composition at a dosage of about 75 mg/m2 once daily. In some embodiments, the method or use comprises administering the first pharmaceutical composition at a dosage of about 10 mg once daily, and intravenously administering the second pharmaceutical composition at a dosage of about 100 mg/m2 once daily.
• the method or use comprises administering the first pharmaceutical composition at a dosage of about 20 mg once daily, and intravenously administering the second pharmaceutical composition at a dosage of about 100 mg/m2 once daily. In some embodiments, the method or use comprises administering the first pharmaceutical composition at a dosage of about 40 mg once daily, and intravenously administering the second pharmaceutical composition at a dosage of about 100 mg/m2 once daily. In some embodiments, the method or use comprises administering the first pharmaceutical composition at a dosage of about 80 mg once daily, and intravenously administering the second pharmaceutical composition at a dosage of about 100 mg/m2 once daily. In some embodiments, the method or use comprises administering the first pharmaceutical composition at a dosage of about 120 mg once daily, and intravenously administering the second pharmaceutical composition at a dosage of about 100 mg/m2 once daily.
• the present disclosure provides a method of treating cancer, wherein the method comprises administering to a subject in need thereof (i) a first pharmaceutical composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof;
• a second pharmaceutical composition comprising irinotecan.
• the cancer is gastric cancer. In some embodiments, the cancer is advanced gastric cancer.
• the present disclosure provides a method of treating cancer, wherein the method comprises administering to a subject in need thereof (i) a first pharmaceutical composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof;
• a second pharmaceutical composition comprising oxaliplatin.
• the cancer is gastric cancer. In some embodiments, the cancer is advanced gastric cancer.
• the term "subject" refers to all animals including humans that have developed or can develop cancer, and the cancer may be effectively prevented or treated by administering the pharmaceutical composition of the present disclosure to a subject.
• the pharmaceutical composition of the present disclosure may be administered in combination of the existing therapeutic agent.
• the pharmaceutical composition of the present disclosure may be used in combination with other therapies known for the treatment of diseases.
• Other therapies may include chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem-cell replacement therapy, other biological therapies, immunotherapy, and the like, but are not limited thereto.
• therapeutic efficacy of the combination of the pharmaceutical compositions of the disclosure can be determined by various endpoints.
• the therapeutic efficacy of the treatment is determined by assessing improvement based on the objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), time to response (TTR), best overall response (BOR), time to progression (TTP), or overall survival (OS) as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST).
• ORR objective response rate
• PFS progression-free survival
• DCR disease control rate
• DOR duration of response
• TTR time to response
• BOR best overall response
• TTP time to progression
• OS overall survival
• therapeutic efficacy of the combination of the pharmaceutical compositions of the disclosure can be determined by a reduction in tumor volume.
• the therapeutic efficacy of the combination can be determined by a reduction in volume growth of the tumor after administration of the combination when compared with that of the anticancer drug alone.
• the therapeutic efficacy of the combination can also be determined by the inhibitory effect on the proliferation of tumor cells.
• the therapeutic efficacy of the combination can be determined by the inhibitory effect on the proliferation of tumor cells after administration of the combination when compared with that of the anticancer drug alone.
• a compound represented by Formula 1 of the present disclosure or a pharmaceutically acceptable salt thereof shows a synergistic complementary effect when co-administered with a known anticancer drug, as compared with administration of an anticancer drug alone, thereby exhibiting excellent anticancer activity.
• an anticancer drug specifically irinotecan or oxaliplatin
• the same or better anticancer effect can be obtained even at a lower dose than the previously known anticancer drug, and excellent effects can be even obtained in cancers that have been limited by the existing treatments.
• effects of reducing dose-dependent side effects may be obtained.
• the pharmaceutical composition for co-administration of the present disclosure is remarkably useful as an anticancer drug by exhibiting considerably synergistic effects in prevention or treatment of cancer, especially even solid cancer such as gastric cancer, by specially combining the compound represented by Formula 1 or the pharmaceutically acceptable salt thereof (first active ingredient) and the anticancer drug (second active ingredient).
• FIG. 1 is a graph showing cell viability compared in a case where hydrochloride of a compound represented by Formula 1 is co-administered with irinotecan with a case where irinotecan is administered alone.
• FIG. 2 is a graph showing cell viability compared in a case where hydrochloride of a compound represented by Formula 1 is co-administered with oxaliplatin with a case where oxaliplatin is administered alone.
• FIG. 3 is a graph showing effects on tumor volume compared in a case where hydrochloride of the compound of Formula 1 is administered alone with a case where hydrochloride of the compound of Formula 1 is co-administered with irinotecan, in a subcutaneous MKN45 human gastric cancer xenograft model (mean ⁇ SEM).
• Hydrochloride of a compound represented by Formula 1 (M.W. 442.92, hereinafter, referred to as 'hydrochloride compound of Formula 1') was obtained from Ildong Pharmaceutical.
• Irinotecan hydrochloride (M.W. 623.14) was obtained from Sigma Aldrich.
• cell lines five human-derived gastric cancer cell lines (i.e., AGC, SNU-668, SNU-216, SNU-484, and SNU-638) were used.
• the source of the cell lines is the Korean Cell Line Bank (KCLB).
• KCLB Korean Cell Line Bank
• a complete growth medium consisting of 90 % RPMI1640 and 10 % heat-inactivated fetal bovine serum was used.
• Frozen cells were thawed in a water bath at 37 °C, suspended in a culture medium, and then centrifuged at 1,200 rpm for 2 minutes. The precipitated cells were suspended in a culture medium, spread on a culture dish, and cultured at 37 °C in 5 % CO2. Reflecting the growth rate of each cell, the cells were cultured periodically at intervals of 3 days to 5 days.
• the cells were treated with trypsine and allowed for a reaction in an incubator at 37 °C in 5 % CO2.
• the cells collected after the completion of the reaction were suspended in a culture medium, and centrifuged at 1,200 rpm for 3 minutes.
• the cell suspension was put into a hemocytometer to calculate the number of cells per unit volume. According to the conditions set for each cell line, the cell suspension was plated into a 96-well plate and then stabilized for 24 hours at 37 °C in 5 % CO2.
• the 10 mM stock solution containing irinotecan was serially diluted in DMSO at a ratio of 1/10 to prepare a 100X stock solution for each treatment concentration, and a 1000X stock solution containing 1 mM hydrochloride compound of Formula 1 was prepared, so as to prepare a stock solution with a final treatment concentration of 1 pM.
• each well contained 1.1 % DMSO.
• the stock solution of each concentration was added to a culture medium to have a 10X concentration, and then the cells were treated at a IX concentration.
• Each cell line was treated with irinotecan alone or in combination of hydrochloride compound of Formula 1 and irinotecan, each for 5 days. 1.4. MTT assay
• the absorbance was calculated as activity expressed in percent at each concentration of the drugs, as compared with a negative control group (100 %), which is the group including a solvent (DMSO) only.
• IC50 was calculated by nonlinear regression analysis in 3 or 4 parameter fits (GraphPad Prism version 7.04).
• FIG. 1 results thereof are shown in FIG. 1.
• the administration of irinotecan alone exhibited an effect of apoptosis
• the co-administration of irinotecan with the compound of Formula 1 resulted in a higher apoptosis rate. Accordingly, it was confirmed that the inhibitory effect on cancer growth obtained by such co-administration increased in a dose-dependent manner.
• the calculated IC50 values are shown in Table 1.
• Example 1 Referring to Table 1, the IC50 values of the five cell lines in Example 1 were found to be 1.3 times to 3.1 times lower than those in Comparative Example 1. Accordingly, it was confirmed that, in the experiment using the gastric cancer cell lines, the pharmaceutical composition of the present disclosure exhibited excellent inhibitory effect on the proliferation of tumor cells, compared to the administration of the anticancer drug alone.
• Hydrochloride of the compound represented by Formula 1 (M.W. 442.92, hereinafter, referred to as 'hydrochloride compound of Formula 1') was obtained from Ildong Pharmaceutical.
• Oxaliplatin (M.W. 397.29) was obtained from Sigma Aldrich.
• cell lines five human-derived gastric cancer cell lines (i.e., AGC, SNU-668, SNU-216, SNU-484, and SNU-638) were used.
• the source of the cell lines is the KCLB.
• a complete growth medium consisting of 90 % RPMI1640 and 10 % heat- inactivated fetal bovine serum was used.
• Frozen cells were thawed in a water bath at 37 °C, suspended in a culture medium, and then centrifuged at 1,200 rpm for 2 minutes. The precipitated cells were suspended in a culture medium, spread on a culture dish, and cultured at 37 °C in 5 % CO2. Reflecting the growth rate of each cell, the cells were cultured periodically at intervals of 3 days to 5 days. 2.3. Cell plating and drug treatment
• the cells were treated with trypsin and allowed for a reaction in an incubator at 37 °C in 5 % CO2.
• the cells collected after the completion of the reaction were suspended in a culture medium, and centrifuged at 1,200 rpm for 3 minutes.
• the cell suspension was put into a hemocytometer to calculate the number of cells per unit volume. According to the conditions set for each cell line, the cell suspension was plated into a 96-well plate and then stabilized for 24 hours at 37 °C in 5 % CO2.
• the 10 mM stock solution containing oxaliplatin was serially diluted in DMSO at a ratio of 1/10 to prepare a 100X stock solution for each treatment concentration, and a 1000X stock solution containing 1 mM hydrochloride compound of Formula 1 was prepared, so as to prepare a stock solution with a final treatment concentration of 1 pM.
• each well contained 1.1 % DMSO.
• the stock solution of each concentration was added to a culture medium to have a 10X concentration, and then the cells were treated at a IX concentration.
• Each cell line was treated with oxaliplatin alone or in combination of hydrochloride compound of Formula 1 and oxaliplatin, each for 5 days.
• the absorbance was calculated as activity expressed in percent at each concentration of each drug, as compared with a negative control group (100 %), which is the group including a solvent (DMSO) only.
• IC50 was calculated by nonlinear regression analysis in 3 or 4 parameter fits (GraphPad Prism 7.04).
• the IC50 values of the specific cell lines in Example 2 were found to be 2.7 times to 6.8 times lower than those in Comparative Example 2. Accordingly, it was confirmed that, in the experiment using the gastric cancer cell lines, the pharmaceutical composition of the present disclosure exhibited excellent inhibitory effect on the proliferation of tumor cells, compared to the administration of the anticancer drug alone.
• MKN45 tumor cells were cultured in RPMI1640 supplemented with 10 % fetal bovine serum at 37 °C in 5 % CO2. The cells were harvested before tumor transplantation was performed, and then counted using a cell counter.
• Randomization was performed when the average tumor size of the mouse reached about 150 mm 3 . A total of 40 mice were used for the test, and 10 mice per group were assigned to 4 groups as shown in Table 3 (Example 3 and Comparative Examples 3 to 5). Randomization was performed based on a "matched distribution" method (Study DirectorTM software, version 3.1.399.19). Here, the grouping date was marked as 0.
• Tumor volume was measured using a calipers twice a week after randomization, and was calculated according to the following formula:
• V (Length x Width x Width) / 2
• V(mm 3 ) refers to a volume of tumor
• L refers to a length of tumor (the longest size of tumor)
• W refers to a width of tumor (longest size of tumor perpendicular to L).
• administration was performed in a Laminar Flow Cabinet.
• Example 3 showed much less growth of tumor volume compared to Comparative Examples 4, 5. That is, it was confirmed that, in the experiment using mice, the pharmaceutical composition for co-administration of the present disclosure significantly reduced the volume growth of the tumor compared to the administration of the anticancer drug alone. 3.7. Inhibition of tumor growth
• Comparative Example 3 using the vehicle control group showed the average tumor size reaching 905.67 mm 3 on the 21st day
• Comparative Example 4 in which 2 mg/kg of the hydrochloride compound of Formula 1 was administered as QD showed the TGI value of 19.69 % on the 21 st day
• Comparative Example 5 in which 5 mg/kg of irinotecan was administered as QW showed the TGI value of 28.91 %.
• In vivo TGI of 70 % or more may be regarded to be sensitive to treatment, in vivo TGI between 40 % and 70 % may be regarded to be partially responsive to a progressive disease, and in vivo TGI of 40 % or less may be regarded to be non-responsive (Cancer Res 2006; 66: (14). July 15, 2006, Chronic Administration of Valproic Acid Inhibits Prostate Cancer Cell Growth In vitro and In vivo).
• hydrochloride compound of Formula 1 of the present disclosure may be regarded to exhibit significant anti-tumor efficacy compared to the vehicle control group, the single preparation of the hydrochloride compound of Formula 1, and the single preparation of irinotecan.
• the primary objective of the present experiment is to evaluate the safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of the combination of the pharmaceutical compositions of the present disclosure for patients with advanced gastric cancer.
• MTD maximum tolerated dose
• R2D recommended phase 2 dose
• the secondary purpose of the present experiment is: to assess the efficacy of the combination of the pharmaceutical compositions of the present disclosure as defined by objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), time to response (TTR), best overall response (BOR), time to progression (TTP), and overall survival (OS) as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) vl.l; to evaluate pharmacokinetics (PK) of single ascending dose (SAD) of the compound of Formula 1 when given in combination with the compound of Formula 1 and irinotecan in patient with advanced gastric cancer; and to evaluate the population PK modeling of the compound of Formula 1 and irinotecan when given in combination with the compound of Formula 1 and irinotecan in patient with advanced gastric cancer.
• SAD single ascending dose
• Secondary endpoint of the experiment are related to safety and efficacy, wherein the safety endpoint refers to changes from the baseline in safety parameters including physical examination, vital signs and electrocardiogram (ECG), and clinical laboratory results including hematology, coagulation test, clinical chemistry, and urinalysis, and the efficacy endpoint refers to the number of patients with ORR, PFS, BOR, TTP, DCR, DOR, TTR, and OS as evaluated by RECIST vl .1.
• Exploratory endpoint of the experiment is to assess the correlation between the efficacy of the compound of Formula 1 and ATM levels (high or low) in patients with advanced gastric cancer.
• a dose finding includes a group of "compound of Formula 1 + irinotecan”.
• Administration cycle may be 14 days or 21 days in one cycle.
• **: The number of days of administration of the compound of Formula 1 may be 1 to 7 or 1 to 5 or 2 to 6.
• the number of days of administration of the irinotecan may be 1 or 2 to 6.
• the experimental population of the present disclosure includes patients with advanced gastric cancer, as defined by metastatic or recurrent/refractory advanced disease in third-line or fourth line treatment.
• the patients in the dose finding part must have evaluable disease.
• the patients in the dose expansion part must have measurable disease at baseline by imaging methods (computed tomography [CT] or magnetic resonance imaging [MRI]).
• a negative serum pregnancy test result within 4 weeks prior to the study drug administration is required for pre-menopausal women. Also, patients should have a negative urine pregnancy test result before study drug administration on Cycle 1 Day 1. Women with no childbearing potential because of surgical sterility or >1 year having passed after menopause can be included without a serum and/or urine pregnancy test.
• Effective contraception is defined as a method resulting in a low failure rate (i.e., ⁇ 1% per year) when used consistently and accurately (example: implant, injection, combined oral contraceptive, or intrauterine device).
• acceptable contraception can include complete abstinence if a patient’ s lifestyle is in line with it (periodic abstinence [example: calendar, ovulation, symptomatic, post ovulation method] and withdrawal are not acceptable contraception).
• the compound of Formula 1 was provided in 5mg, 10 mg, 20 mg, and 40 mg tablets.
• the compound of Formula 1 and irinotecan were provided as a sterile, pale yellow, clear, aqueous solution at a concentration of 20 mg/ml, intended for dilution with 5 % dextrose injection, United States Pharmacopoeia (USP), or a 0.9 % sodium chloride injection USP, before IV infusion.
• the preferred diluent is 5 % dextrose injection, USP.
• the compound of Formula 1 was administered as QD with at least 8 ounces (oz) (about 240 mL) of water. Irinotecan was administered through IV injection over 90 minutes after completion of all study procedures.
• Radiographic tumor assessment included all known or suspected disease sites per RECIST vl. l.
• the survival follow-up was performed for survival in all patients at least every 12 weeks after discontinuation of the study treatment. The survival monitoring continues until patient death or end of the study, whichever occurs first.
• ORR is defined as the proportion of patients confirmed with a partial response or complete response defined per RECIST vl.l. The analysis of ORR was performed in patients with measurable lesions at baseline. Patients with no adequate postbaseline tumor assessment at the time of the analysis of ORR are counted as non-responders. ORR ratios are provided for each treatment group, including the corresponding 95 % Wilson score CI.
• PFS is defined as the time from initiation of a study treatment to the date radiologically confirmed by determination of an investigator (per RECIST vl.l) for disease progression or to death from any cause, whichever comes first.
• DCR is defined as the proportion of patients achieving a BOR with a confirmed complete response (CR), confirmed PR or SD (minimum period of SD is 6 weeks).
• DOR is defined as the period from the date the objective response (confirmation of CR or PR) is first documented to the first documented date based on objective disease progression or death due to any cause, whichever comes first. Censoring rules are similar to PFS.
• TTR is defined as the period from the start date of a study treatment to the date the objective response (confirmation of CR or PR) is first documented. Censoring rules are similar to PFS.
• the confirmed BOR is defined as the best response evaluated during the period from the first administration of a test drug to progression/recurrence of disease or death.
• PR or CR responders in the final BOR assessment after satisfying the first response criteria at the tumor assessment the corresponding patients should be evaluated as PR or CR responders at the next consecutive assessment.
• the patients with measurable lesions at baseline and with available tumor assessment results are included in the BOR analysis, and patients with no tumor assessment after baseline are considered as non-responders.
• TTP is defined as the period from the first administration of an investigational drug to first disease progression. Patients with no disease progression at the study completion (including patients who died before disease progression) or patients who are out of follow-up due to dropout are censored at the last tumor assessment date.
• OS is defined as the period from the first administration of a study drug to death from any cause. Patients who are alive are censored on the date the patients are last known to be alive.
• Best Overall Response Best overall response (smallest measure) recorded from the start of the administration until the progress! on/rel apse of disease occurs
• Stable disease Neither for CR, PR, and PD, i.e., the state as it is [0152]
• Progressive disease (PD) At least 20 % increase in the sum of diameters, absolute increase of at least 5 mm in the sum of diameters, and appearance of one or more new lesions [0153]

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