WO2018147275A1 - 腫瘍治療用医薬組成物 - Google Patents

腫瘍治療用医薬組成物 Download PDF

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WO2018147275A1
WO2018147275A1 PCT/JP2018/004007 JP2018004007W WO2018147275A1 WO 2018147275 A1 WO2018147275 A1 WO 2018147275A1 JP 2018004007 W JP2018004007 W JP 2018004007W WO 2018147275 A1 WO2018147275 A1 WO 2018147275A1
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tumor
lenvatinib
pharmaceutical composition
combination
administered
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French (fr)
Japanese (ja)
Inventor
小澤　陽一
優作 堀
一彦 山田
洋 神山
正尋 松木
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Eisai R&D Management Co Ltd
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Eisai R&D Management Co Ltd
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Priority to CA3044658A priority Critical patent/CA3044658A1/en
Priority to ES18751614T priority patent/ES2971448T3/es
Priority to KR1020197016853A priority patent/KR102539920B1/ko
Priority to JP2018567437A priority patent/JP6581320B2/ja
Priority to MX2019006504A priority patent/MX380144B/es
Priority to EP18751614.1A priority patent/EP3581183B1/en
Priority to US16/465,277 priority patent/US12303505B2/en
Priority to BR112019014127-8A priority patent/BR112019014127A2/pt
Priority to CN201880005026.1A priority patent/CN110072528B/zh
Application filed by Eisai R&D Management Co Ltd filed Critical Eisai R&D Management Co Ltd
Priority to RU2019120680A priority patent/RU2750539C2/ru
Priority to AU2018219637A priority patent/AU2018219637B2/en
Publication of WO2018147275A1 publication Critical patent/WO2018147275A1/ja
Priority to IL267159A priority patent/IL267159B/en
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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
    • A61K31/435—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
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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 invention relates to lenvatinib and (6S, 9aS) -N-benzyl-8-( ⁇ 6- [3- (4-ethylpiperazin-1-yl) azetidin-1-yl] pyridin-2-yl ⁇ methyl)- 6- (2-Fluoro-4-hydroxybenzyl) -4,7-dioxo-2- (prop-2-en-1-yl) hexahydro-2H-pyrazino [2,1-c] [1,2,4
  • the present invention relates to a pharmaceutical composition for tumor treatment used for a combination therapy of triazine-1 (6H) -carboxamide.
  • Lenvatinib has an angiogenesis inhibitory action (Patent Document 1), vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, Rearranged During Transfection (RET), An oral tyrosine kinase inhibitor that targets KIT and platelet-derived growth factor receptor (PDGFR) ⁇ (Patent Documents 2-5), thyroid cancer, lung cancer, melanoma, endometrial cancer, renal cell cancer, nerve It is known as a therapeutic agent for various tumors such as glioma, hepatocellular carcinoma and ovarian cancer.
  • the compound name for lenvatinib is 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide.
  • tumor therapeutic agents are often not effective for all patients when used alone. So far, attempts have been made to improve the treatment rate by using a plurality of tumor therapeutic agents in combination to enhance the antitumor effect and reduce the side effects (Patent Documents 7-9).
  • the present invention provides the following [1] to [33].
  • a pharmaceutical composition comprising hexahydro-2H-pyrazino [2,1-c] [1,2,4] triazine-1 (6H) -carboxamide.
  • lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate.
  • the present invention relates to lenvatinib and (6S, 9aS) -N-benzyl-8-( ⁇ 6- [3- (4-ethylpiperazin-1-yl) azetidin-1-yl] pyridin-2-yl ⁇ methyl)- 6- (2-Fluoro-4-hydroxybenzyl) -4,7-dioxo-2- (prop-2-en-1-yl) hexahydro-2H-pyrazino [2,1-c] [1,2,4
  • a pharmaceutical composition for treating tumors is provided for use in a combination therapy of triazine-1 (6H) -carboxamide. Such a pharmaceutical composition for treating tumor exhibits an unexpected antitumor effect on a patient in need thereof.
  • FIG. 2 is a graph showing the antitumor effect of a combination of E7386 12.5 mg / kg and lenvatinib mesylate 10 mg / kg in a transgenic mouse (MMTV-Wnt-1) spontaneously transplanted breast cancer model. * And *** in the graph indicate that the combination of E7386 and lenvatinib mesylate statistically significantly inhibited tumor growth compared to the case where each was administered alone (*: p ⁇ 0.05, ***: p ⁇ 0.001; Repeated measurements ANOVA followed by Dunnett's type multiple comparison).
  • Lenvatinib means 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide, the structural formula of which is shown below.
  • Lenvatinib or a pharmaceutically acceptable salt thereof can be produced by the method described in Patent Document 1.
  • An example of a pharmaceutically acceptable salt of lenvatinib is lenvatinib mesylate.
  • Lenvatinib mesylate is also referred to as E7080 or Lenvima®.
  • “Pharmaceutically acceptable salt” is not limited to a specific type of salt, for example, a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, a salt with an organic base, an acidic Or a salt with a basic amino acid etc. are mention
  • Examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • Examples of salts with organic acids include acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (mesyl acid), ethanesulfonic acid, p-toluenesulfonic acid And salt.
  • Examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt.
  • Examples of the salt with an organic base include salts with diethylamine, diethanolamine, meglumine, N, N-dibenzylethylenediamine and the like.
  • Examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • Examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
  • the pharmaceutically acceptable salt of lenvatinib is, for example, a salt with an organic acid, and one aspect thereof is methanesulfonate (mesylate).
  • Triazine-1 (6H) -carboxamide may be crystalline or non-crystalline. When a crystalline polymorph exists, it may be a single substance or a mixture of any of those crystalline forms.
  • the dosage of lenvatinib or a pharmaceutically acceptable salt thereof depends on the severity of symptoms, the occurrence of side effects, patient age, sex, body weight, sensitivity difference, administration method, administration timing, administration interval, type of pharmaceutical preparation, etc. Depending on the situation, it can be appropriately selected.
  • the dose of lenvatinib or a pharmaceutically acceptable salt thereof is not particularly limited, but is usually 0.1 to 500 mg / day, 0.5 mg / day, orally administered to an adult (body weight 60 kg) or a child. To 300 mg, or 1 to 100 mg, or 0.1 to 500 mg / m 2 (body surface area, the same applies hereinafter), 0.5 to 300 mg / m 2 , or 1.0 to 100 mg / m 2 per day It is. This can usually be administered once a day or divided into 2-3 times. If the patient experiences excessive toxicity, a dose reduction is necessary. Dosage amount and regimen may be altered if one or more additional chemotherapeutic agents are used in addition to the combination therapy of the invention. The dosage regimen can be determined by the physician treating the particular patient.
  • the dose of triazine-1 (6H) -carboxamide can be set to the same dose or lower than that usually administered alone. Specific dosage, administration route, administration frequency, administration cycle and the like are appropriately determined in consideration of the age, sex, manifestation of symptoms or side effects of the patient.
  • the administration form of triazine-1 (6H) -carboxamide is not particularly limited, and at the time of administration, lenvatinib and (6S, 9aS) -N-benzyl-8-( ⁇ 6- [3- (4-ethylpiperazine-1- Yl) azetidin-1-yl] pyridin-2-yl ⁇ methyl) -6- (2-fluoro-4-hydroxybenzyl) -4,7-d
  • lenvatinib and (6S, 9aS) -N-benzyl-8-( ⁇ 6- [3- (4-ethylpiperazin-1-yl) azetidin-1-yl] pyridin-2-yl ⁇ methyl) -6- (2-Fluoro-4-hydroxybenzyl) -4,7-dioxo-2- (prop-2-en-1-yl) hexahydro-2H-pyrazino [2,1-c] [1,2,4] triazine -1 (6H) -carboxamide is administered to the patient at the same time, separately, sequentially or at a time lag.
  • “simultaneously” means that the respective components are administered within the same period or exactly at the same time or by the same route of administration. “Separately” means that each component is administered at different dosing intervals or frequencies, or by different routes of administration. “Sequentially” means that the respective components are administered in any order within a period of time, by the same or different routes of administration. “At a time lag” means that each component is administered at the same or different route of administration, with an interval for each administration of each component.
  • the One of the administration forms in the combined administration of the present invention is lenvatinib and (6S, 9aS) -N-benzyl-8-( ⁇ 6- [3- (4-ethylpiperazin-1-yl) azetidin-1-yl] ] Pyridin-2-yl ⁇ methyl) -6- (2-fluoro-4-hydroxybenzyl) -4,7-dioxo-2- (prop-2-en-1-yl) hexahydro-2H-pyrazino [2, 1-c] [1,2,4] triazine-1 (6H) -carboxamide is administered orally.
  • the combined administration of the present invention comprises lenvatinib and (6S, 9aS) -N-benzyl-8-( ⁇ 6- [3- (4-ethylpiperazin-1-yl) azetidin-1-yl] pyridine-2- Yl ⁇ methyl) -6- (2-fluoro-4-hydroxybenzyl) -4,7-dioxo-2- (prop-2-en-1-yl) hexahydro-2H-pyrazino [2,1-c] [ It may be performed simultaneously with the administration of the pharmaceutical composition for tumor treatment other than 1,2,4] triazine-1 (6H) -carboxamide, separately, sequentially or at a time interval.
  • the pharmaceutical composition for tumor treatment of the present invention can be formulated, for example, by the method described in the 16th revision Japanese Pharmacopoeia (JP), US Pharmacopoeia (USP) or European Pharmacopoeia (EP).
  • JP Japanese Pharmacopoeia
  • USP US Pharmacopoeia
  • EP European Pharmacopoeia
  • the target tumor in the present invention is, for example, breast cancer, thyroid cancer, hepatocellular carcinoma (HCC), colon cancer (CRC), renal cell carcinoma (RCC), head and neck cancer, endometrial cancer or Although it is a melanoma, it is not specifically limited to these.
  • the target tumor is thyroid cancer.
  • the thyroid cancer that is a target in one embodiment of the present invention is thyroid undifferentiated cancer (ATC).
  • ATC thyroid undifferentiated cancer
  • the target tumor is hepatocellular carcinoma.
  • Example 1 Transtumor effect of a combined use of E7386 and lenvatinib mesylate in a transgenic mouse (MMTV-Wnt-1) spontaneously transplanted breast cancer model Wnt-1 is expressed locally in mammary epithelial cells Spontaneous breast cancer was collected from the transgenic mice (MMTV-Wnt-1, Jackson Laboratories), and transplanted into tigercars (C57BL / 6J, Charles River, Japan) as a background strain.
  • mice When the transplanted subcultured tumor reached about 1.5 g, it was excised and fragmented to about 30 mg, and the control group, E7386 12.5, 25 or 50 mg / kg alone administration group, lenvatinib mesylate 10 mg / kg The mice were transplanted subcutaneously into the body side of 5 mice (C57BL / 6J) in each group of the single administration group and the combination administration group of E7386 12.5, 25 or 50 mg / kg and lenvatinib mesylate 10 mg / kg.
  • E7386 (12.5, 25 or 50 mg / kg, twice daily, 14 days oral administration) and lenvatinib mesylate (10 mg / kg, once daily, 14 Daily orally) alone or in combination and administered to a single administration group or a combination administration group, respectively.
  • E7386 was dissolved in 0.1 mol / L hydrochloric acid
  • lenvatinib mesylate was dissolved in 3 mmol / L hydrochloric acid.
  • 0.1 mol / L hydrochloric acid (twice a day for 14 days) was administered.
  • the administration start date was 1 day, and on the 4th, 8th, 11th, and 15th day, the major axis and the minor axis of the tumor generated in each mouse were measured with a Digimatic caliper (Mitsutoyo).
  • Tumor volume and specific tumor volume (RTV) were calculated according to the following formula.
  • Tumor volume (mm 3 ) tumor major axis (mm) ⁇ tumor minor axis 2 (mm 2 ) / 2
  • Specific tumor volume (RTV) tumor volume on the measurement day / tumor volume on the administration start day
  • RTV results of RTV are shown in Table 1 and FIGS. 1, 2 and 3.
  • the numbers in Table 1 mean the average value of RTV ⁇ standard deviation (SD).
  • SD standard deviation
  • E7386 and lenvatinib mesylate showed an excellent antitumor effect in a transgenic mouse (MMTV-Wnt-1) spontaneously transplanted breast cancer model.
  • *, *** and *** in FIG. 1, FIG. 2 and FIG. 3 are statistically significant when the combination of E7386 and lenvatinib mesylate is compared to the case where each is administered alone. Shows inhibition of tumor growth (*: p ⁇ 0.05, ***: p ⁇ 0.001, ***: p ⁇ 0.0001; Repeated measures ANOVA followed by Dunnett's type multiple comparison. ).
  • Example 2 Antitumor effect by combined use of E7386 and lenvatinib mesylate in mouse breast cancer 4T1 orthotopic transplantation model
  • Mouse breast cancer 4T1 cells (ATCC) were treated with a 5% carbon dioxide incubator at 37 ° C. The culture was performed using RPMI1640 medium (SIGMA) containing 10% FBS. When the cells were approximately 80% confluent, the cells were harvested using trypsin-EDTA. Hanks buffered saline solution was added to prepare a suspension to 1.0 ⁇ 10 7 cells / mL.
  • mice were transplanted into the right third mammary fat pad of 5 mice (C57BL / 6J, Nippon Charles River) in each group of the kg combination administration group.
  • E7386 25 mg / kg, twice daily, 14 days, oral administration
  • lenvatinib mesylate 10 mg / kg, once daily, 14 days, oral administration
  • each was administered to a single administration group or a combination administration group.
  • E7386 was dissolved in 0.1 mol / L hydrochloric acid
  • lenvatinib mesylate was dissolved in 3 mmol / L hydrochloric acid. No drug was administered to the control group.
  • Tumor volume and specific tumor volume (RTV) were calculated according to the following formula.
  • Example 3 Antitumor effect by combined use of E7386 and lenvatinib mesylate in human breast cancer MDA-MB-231 transplantation model Human breast cancer MDA-MB-231 cells (ATCC) The cells were cultured in a% carbon dioxide incubator using RPMI 1640 medium (SIGMA) containing 10% FBS. When the cells were approximately 80% confluent, the cells were harvested using trypsin-EDTA. A 50% Matrigel-containing Hanks buffered saline solution was added to the cells, and a suspension was prepared so as to have a concentration of 10.0 ⁇ 10 7 cells / mL.
  • SIGMA RPMI 1640 medium
  • mice (CAnN.Cg-Foxn1 nu / CrlCrlj, Charles River, Japan) of 5 cases in each group of the combined administration group of kg were transplanted subcutaneously on the body side.
  • E7386 25 mg / kg, twice daily, 10 days, oral administration
  • lenvatinib mesylate 10 mg / kg, once daily, 10 days, oral administration
  • each was administered to a single administration group or a combination administration group.
  • E7386 was dissolved in 0.1 mol / L hydrochloric acid
  • lenvatinib mesylate was dissolved in 3 mmol / L hydrochloric acid. No drug was administered to the control group.
  • Tumor volume and specific tumor volume (RTV) were calculated according to the following formula.
  • E7386 12.5 or 25 mg / kg single administration group E7386 12.5 or 25 mg / kg single administration group
  • lenvatinib mesylate 10 mg / kg single administration group E7386 12.5 or 25 mg / kg and Lembatinib mesylate salt was transplanted subcutaneously into the body side of 6 nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj, Charles River, Japan) in each group of 10 mg / kg combined administration group.
  • E7386 (12.5 or 25 mg / kg, twice daily, 14 days, oral administration) and lenvatinib mesylate (10 mg / kg, once daily, 14 days, oral administration) ) Alone or in combination, respectively, were administered to a single administration group or a combined administration group.
  • E7386 was dissolved in 0.1 mol / L hydrochloric acid
  • lenvatinib mesylate was dissolved in 3 mmol / L hydrochloric acid.
  • 0.1 mol / L hydrochloric acid (twice a day for 14 days) was administered.
  • the administration start date was 1 day, and on the 4th, 8th, 11th, and 15th day, the major axis and the minor axis of the tumor generated in each mouse were measured with a Digimatic caliper (Mitsutoyo).
  • Tumor volume and specific tumor volume (RTV) were calculated according to the following formula.
  • Tumor volume (mm 3 ) tumor major axis (mm) ⁇ tumor minor axis 2 (mm 2 ) / 2
  • Specific tumor volume (RTV) tumor volume on the measurement day / tumor volume on the administration start day
  • 0.1 mL of the resulting cell suspension was added to the control group, E7386 12.5, 25 or 50 mg / kg single administration group, lenvatinib mesylate 10 mg / kg single administration group, and E7386 12.5, 25 or Nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj, Charles River Japan) of 5 cases in each group of 50 mg / kg and lenvatinib mesylate 10 mg / kg were administered to the body side subcutaneously.
  • E7386 (12.5, 25, or 50 mg / kg, twice daily for 14 days, oral administration) and lenvatinib mesylate (10 mg / kg, once daily, for 14 days) Oral administration) alone or in combination was administered to the single administration group or the combination administration group, respectively.
  • E7386 was dissolved in 0.1 mol / L hydrochloric acid
  • lenvatinib mesylate was dissolved in 3 mmol / L hydrochloric acid.
  • 0.1 mol / L hydrochloric acid (twice a day for 14 days) was administered.
  • Tumor volume and specific tumor volume (RTV) were calculated according to the following formula.
  • Example 6 Antitumor effect by combined use of E7386 and lenvatinib mesylate in human hepatocellular carcinoma SNU398 transplantation model Human hepatocellular carcinoma SNU398 (ATCC) was placed in a 5% carbon dioxide incubator at 37 ° C. Then, culture is performed using RPMI 1640 medium (SIGMA) containing 10% FBS. When the cells are about 80% confluent, trypsin-EDTA is used to harvest the cells. A 50% Matrigel-containing Hank's buffered saline solution is added to the cells, and a suspension is prepared so as to be 5.0 ⁇ 10 7 cells / mL.
  • SIGMA RPMI 1640 medium
  • E7386 oral administration
  • lenvatinib mesylate oral administration
  • Tumor volume and specific tumor volume (RTV) are calculated according to the following formula.
  • Example 6-1 Antitumor effect by combined use of E7386 and lenvatinib mesylate in human hepatocellular carcinoma SNU398 transplantation model Human hepatocellular carcinoma SNU398 cells (ATCC)
  • the cells were cultured in a% carbon dioxide incubator using RPMI1640 medium (WAKO) containing 10% FBS. When the cells were approximately 80% confluent, the cells were harvested using trypsin-EDTA. A 50% Matrigel-containing Hank's buffered saline solution was added to the cells, and a suspension was prepared so as to be 5.0 ⁇ 10 7 cells / mL.
  • E7386 (12.5, 25 or 50 mg / kg once daily for 14 days orally) and lenvatinib mesylate (10 mg / kg once daily for 14 days) Oral administration) alone or in combination was administered to a single administration group or a combination administration group, respectively.
  • E7386 was dissolved in 0.1 mol / L hydrochloric acid
  • lenvatinib mesylate was dissolved in 3 mmol / L hydrochloric acid. No drug was administered to the control group.
  • the administration start date was 1 day, and on the 6th, 9th, 12th and 15th day, the major axis and the minor axis of the tumor generated in each mouse were measured with a Digimatic caliper (Mitsutoyo).
  • Tumor volume and specific tumor volume (RTV) were calculated according to the following formula.
  • Tumor volume (mm 3 ) tumor major axis (mm) ⁇ tumor minor axis 2 (mm 2 ) / 2
  • Specific tumor volume (RTV) tumor volume on the measurement day / tumor volume on the administration start day
  • Example 7 Anti-tumor effect by combined use of E7386 and lenvatinib mesylate in human hepatocellular carcinoma HepG2 subcutaneous transplant model Human hepatocellular carcinoma HepG2 cells (JCRB cell bank) were The cells were cultured in a 5% carbon dioxide incubator using DMEM-Low glucose medium (WAKO) containing 10% FBS. When the cells were approximately 80% confluent, the cells were harvested using trypsin-EDTA. To this cell, 50% Matrigel-containing phosphate buffered saline was added, and a suspension was prepared so as to be 10.0 ⁇ 10 7 cells / mL.
  • WAKO DMEM-Low glucose medium
  • mice (CAnN.Cg-Foxn1 nu / CrlCrlj, Charles River, Japan) of 5 cases in each group of the combined administration group of kg were transplanted subcutaneously on the body side.
  • E7386 50 mg / kg, once daily for 14 days, oral administration
  • lenvatinib mesylate 10 mg / kg, once daily, for 14 days, oral administration
  • each was administered to a single administration group or a combination administration group.
  • E7386 was dissolved in 0.1 mol / L hydrochloric acid
  • lenvatinib mesylate was dissolved in 3 mmol / L hydrochloric acid. No drug was administered to the control group.
  • Tumor volume and specific tumor volume (RTV) were calculated according to the following formula.
  • Example 8 Antitumor effect by combined use of E7386 and lenvatinib mesylate in human colon cancer strain Colo-205 transplantation model Human colon cancer strain Colo-205 cells (ATCC)
  • the cells were cultured in a% carbon dioxide incubator using RPMI1640 medium (WAKO) containing 10% FBS. When the cells were approximately 80% confluent, the cells were harvested using trypsin-EDTA. A Hanks buffered saline solution was added to the cells, and a suspension was prepared so as to be 5.0 ⁇ 10 7 cells / mL.
  • mice (CAnN.Cg-Foxn1 nu / CrlCrlj, Charles River, Japan) of 5 cases in each group of the combined administration group of kg were transplanted subcutaneously on the body side.
  • E7386 50 mg / kg, once daily, 11 days, oral administration
  • lenvatinib mesylate 10 mg / kg, once daily, 11 days, oral administration
  • each was administered to a single administration group or a combination administration group.
  • E7386 was dissolved in 0.1 mol / L hydrochloric acid
  • lenvatinib mesylate was dissolved in 3 mmol / L hydrochloric acid. No drug was administered to the control group.
  • Tumor volume and specific tumor volume (RTV) were calculated according to the following formula.
  • 0.1 mL of the obtained cell suspension was added to a control group, an E7386 50 mg / kg single administration group, a lenvatinib mesylate 10 mg / kg single administration group, and an E7386 50 mg / kg and a lenvatinib mesylate 10 mg / kg.
  • Six nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj, Charles River, Japan) of each group in the kg combined administration group were transplanted subcutaneously on the body side.
  • E7386 50 mg / kg, once daily for 14 days, oral administration
  • lenvatinib mesylate 10 mg / kg, once daily, for 14 days, oral administration
  • each was administered to a single administration group or a combination administration group.
  • E7386 was dissolved in 0.1 mol / L hydrochloric acid
  • lenvatinib mesylate was dissolved in 3 mmol / L hydrochloric acid. No drug was administered to the control group.
  • the major axis and the minor axis of the tumor generated in each mouse were measured with a Digimatic caliper (Mitsutoyo).
  • Tumor volume and specific tumor volume were calculated according to the following formula.
  • Tumor volume (mm 3 ) tumor major axis (mm) ⁇ tumor minor axis 2 (mm 2 ) / 2
  • Specific tumor volume (RTV) tumor volume on the measurement day / tumor volume on the administration start day
  • Example 10 Antitumor effect by combined use of E7386 and lenvatinib mesylate in human head and neck cancer SCC15 transplantation model
  • Human head and neck cancer SCC15 cells (ATCC) were treated with a 5% carbon dioxide incubator at 37 ° C. The culture is performed using RPMI1640 medium (SIGMA) containing 10% FBS. When the cells are about 80% confluent, trypsin-EDTA is used to harvest the cells. A 50% Matrigel-containing Hank's buffered saline solution is added to the cells, and a suspension is prepared so as to be 5.0 ⁇ 10 7 cells / mL.
  • SIGMA RPMI1640 medium
  • E7386 oral administration
  • lenvatinib mesylate oral administration
  • Tumor volume and specific tumor volume (RTV) are calculated according to the following formula.
  • Example 11 Anti-tumor effect by combined use of E7386 and lenvatinib mesylate in human endometrial cancer HEC-151 transplantation model Human endometrial cancer HEC-151 cells (JCRB cell bank) under conditions of 37 ° C below, it culture
  • SIGMA RPMI1640 culture medium
  • E7386 oral administration
  • lenvatinib mesylate oral administration
  • Tumor volume and specific tumor volume (RTV) are calculated according to the following formula.
  • Example 12 Tumor vascular suppressive effect by combined use of E7386 and lenvatinib mesylate in orthotopic transplantation model of mouse breast cancer 4T1
  • Mouse breast cancer 4T1 cells (ATCC) were treated with 5% carbon dioxide under the condition of 37 ° C. The cells were cultured in an incubator using RPMI 1640 medium (SIGMA) containing 10% FBS. When the cells were approximately 80% confluent, the cells were harvested using trypsin-EDTA. Hanks buffered saline solution was added to prepare a suspension to 1.0 ⁇ 10 7 cells / mL.
  • SIGMA RPMI 1640 medium
  • mice were transplanted into the right third mammary fat pad of 5 mice (C57BL / 6J, Nippon Charles River) in each group of the kg combination administration group.
  • E7386 25 mg / kg, twice daily, 14 days, oral administration
  • lenvatinib mesylate 10 mg / kg, once daily, 14 days, oral administration
  • each was administered to a single administration group or a combination administration group.
  • E7386 was dissolved in 0.1 mol / L hydrochloric acid
  • lenvatinib mesylate was dissolved in 3 mmol / L hydrochloric acid. No drug was administered to the control group.
  • tumor tissue was collected from the mice, formalin fixation of the tumor tissue was performed, and the tumor tissue was embedded in paraffin.
  • ⁇ -smooth muscle actin ( ⁇ -SMA) antibody manufactured by SIGMA
  • CD31 antibody manufactured by Dianova
  • FIG. 17 shows 10-fold enlarged immunostained images co-stained with CD31 / ⁇ -SMA (color images are shown in brown (CD31) and red ( ⁇ -SMA)).
  • 17 are the control group, the E7386 single administration group, the lenvatinib mesylate single administration group, and the combination of E7386 and lenvatinib mesylate, respectively. It is an immuno-staining image of an administration group. As a result, it was observed that the combined use of E7386 and lenvatinib mesylate significantly reduced MVD compared to the control group and the case where each was administered alone.
  • 18 shows 200-fold enlarged immunostained images co-stained with CD31 / ⁇ -SMA (shown in brown (CD31) and red ( ⁇ -SMA) in the color photograph).
  • 18 (a), (b), (c) and (d) are the control group, the E7386 single administration group, the lenvatinib mesylate single administration group, and the combination of E7386 and lenvatinib mesylate, respectively. It is an immuno-staining image of an administration group.
  • a black arrow indicates a microvessel stained with CD31.
  • a white arrow indicates a CD31 / ⁇ -SMA positive blood vessel.
  • FIG. A graph shows the average value of five tumor sections of each administration group, and error bars show standard deviation.
  • the combined use of E7386 and lenvatinib mesylate showed an excellent microvascular inhibitory effect in the orthotopic transplantation model of mouse breast cancer 4T1.
  • * And *** in FIG. 19 indicate that the combination of E7386 and lenvatinib mesylate statistically significantly suppressed microvessels compared to the case where each was administered alone (* : P ⁇ 0.05, *****: p ⁇ 0.0001; Dunnett's type multiple comparison).
  • FIG. A graph shows the average value of five tumor sections of each administration group, and error bars show standard deviation.
  • the combined use of E7386 and lenvatinib mesylate showed an excellent inhibitory effect of Pericite Coverage (blood vessel pericytes) on the orthotopic transplantation model of mouse breast cancer 4T1.
  • * And *** in FIG. 20 indicate that the combined use of E7386 and lenvatinib mesylate statistically significantly suppressed Pericite Coverage compared to the case where each was administered alone (* : P ⁇ 0.05, *****: p ⁇ 0.0001; Dunnett's type multiple comparison).
  • Example 13 Tumor vascular inhibitory effect of E7386 in combination with lenvatinib mesylate in a subcutaneous transplantation model of human hepatocellular carcinoma HepG2
  • human hepatocellular carcinoma strain HepG2 cells 0.1 mL of the cell suspension prepared using the JCRB cell bank
  • the control group the E7386 50 mg / kg single administration group
  • the E7386 50 mg / kg and lembachi Nib mesylate salt was transplanted subcutaneously on the body side of 5 nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj, Charles River, Japan) in each group of 10 mg / kg combined administration group.
  • E7386 50 mg / kg, once daily for 14 days, oral administration
  • lenvatinib mesylate 10 mg / kg, once daily, for 14 days, oral administration
  • each was administered to a single administration group or a combination administration group.
  • E7386 was dissolved in 0.1 mol / L hydrochloric acid
  • lenvatinib mesylate was dissolved in 3 mmol / L hydrochloric acid.
  • No drug was administered to the control group.
  • Tumor tissue collected from mice after 14 days of administration was divided into tumor samples for vascular analysis. The divided tumor tissue was fixed in formalin and embedded in paraffin.
  • ⁇ -smooth muscle actin ( ⁇ -SMA) antibody manufactured by SIGMA
  • CD31 antibody manufactured by Dianova
  • PCI was remarkably increased by administration of lenvatinib mesylate alone, but it was observed that combination of lenvatinib mesylate and E7386 suppressed the increase in PCI to a level equivalent to that of the control group. .
  • MVD results are shown in FIG.
  • the graph was prepared by measuring the average value of 5 tumor sections for each administration group and then calculating the percentage (%) with the control group value as the reference value. Error bars indicate standard deviation.
  • the combined use of E7386 and lenvatinib mesylate showed an excellent microvascular inhibitory effect in a subcutaneous transplantation model of human hepatocellular carcinoma HepG2. ** and *** in FIG. 21 indicate that the combined use of E7386 and lenvatinib mesylate statistically significantly suppressed microvessels compared to the case where each was administered alone ( **: p ⁇ 0.01, ***: p ⁇ 0.0001; Dunnett's type multiple comparison).
  • FIG. A graph shows the ratio average value of PCI of 5 tumor sections of each administration group, and an error bar shows a standard deviation.
  • E7386 and lenvatinib mesylate showed an excellent Pericite Coverage (blood vessel pericyte coating) suppression effect in a human hepatocellular carcinoma HepG2 subcutaneous transplantation model. *** in FIG.

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AU2018219637A AU2018219637B2 (en) 2017-02-08 2018-02-06 Tumor-treating pharmaceutical composition
US16/465,277 US12303505B2 (en) 2017-02-08 2018-02-06 Tumor-treating pharmaceutical composition
KR1020197016853A KR102539920B1 (ko) 2017-02-08 2018-02-06 종양-치료용 약제학적 조성물
JP2018567437A JP6581320B2 (ja) 2017-02-08 2018-02-06 腫瘍治療用医薬組成物
MX2019006504A MX380144B (es) 2017-02-08 2018-02-06 Composicion farmaceutica de tratamiento de tumores.
EP18751614.1A EP3581183B1 (en) 2017-02-08 2018-02-06 Tumor-treating pharmaceutical composition
BR112019014127-8A BR112019014127A2 (pt) 2017-02-08 2018-02-06 Composição farmacêutica para tratamento de tumores
CA3044658A CA3044658A1 (en) 2017-02-08 2018-02-06 Tumor-treating pharmaceutical composition
CN201880005026.1A CN110072528B (zh) 2017-02-08 2018-02-06 治疗肿瘤的药物组合物
ES18751614T ES2971448T3 (es) 2017-02-08 2018-02-06 Composición farmacéutica para el tratamiento de tumores
RU2019120680A RU2750539C2 (ru) 2017-02-08 2018-02-06 Фармацевтическая композиция для лечения опухоли
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