WO2014157444A1 - 低用量イリノテカン塩酸塩水和物を含有する抗腫瘍剤 - Google Patents
低用量イリノテカン塩酸塩水和物を含有する抗腫瘍剤 Download PDFInfo
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
Definitions
- the present invention relates to an antitumor agent comprising a combination of trifluridine and tipiracil hydrochloride and irinotecan hydrochloride hydrate, and an antitumor effect enhancer of irinotecan hydrochloride hydrate.
- Trifluridine also known as ⁇ , ⁇ , ⁇ -trifluorothymidine; hereinafter referred to as “FTD”
- FTD Trifluridine
- tipiracil hydrochloride chemical name: 5-chloro-6-[(2-iminopyrrolidin-1-yl) methyl] pyrimidine-2,4 (1H, 3H) -dione hydrochloride, hereinafter also referred to as “TPI”
- TPI thymidine phosphorylase inhibitory action.
- Patent Document 1 An antitumor agent containing FTD and TPI at a molar ratio of 1: 0.5 (hereinafter also referred to as “FTD / TPI combination agent”) is being developed as a therapeutic agent for solid cancers such as colorectal cancer ( Non-Patent Documents 1 and 2).
- CPT-11 Irinotecan hydrochloride hydrate
- CPT-11 is a camptothecin derivative having SN-38 as an active metabolite, and inhibits topoisomerase I to suppress DNA synthesis and transcription, Demonstrate antitumor effect.
- CPT-11 is clinically used as a therapeutic agent for a wide range of cancer types such as small cell lung cancer, non-small cell lung cancer, cervical cancer, ovarian cancer, gastric cancer, colorectal cancer, breast cancer, squamous cell carcinoma, and malignant lymphoma. (Non-patent Document 3).
- Non-Patent Document 4 When FTD and SN-38 were allowed to act on a colorectal cancer cell line, synergistic cytotoxicity was confirmed, and therefore a combination therapy of an FTD / TPI combination drug and CPT-11 is expected.
- An object of the present invention is to provide a novel solid cancer combination therapy using an FTD / TPI combination agent that exhibits a remarkable antitumor effect and has few side effects.
- the present inventor based on the doses that have already been reported to be effective for each drug, as described in Comparative Examples described later, for patients with colorectal cancer, 70 mg / m 2 days / day for 5 days followed by 2 days of rest, followed by 2 weeks of rest, followed by a 28-day cycle of CPT-11 administered once every 2 weeks at 150 mg / m 2 / day
- side effects such as neutropenia, diarrhea, and weight loss appeared strongly, so CPT-11 could be administered only at about 30% of the expected amount.
- an FTD / TPI combination drug is administered in an amount of 35 to 70 mg / m 2 / in FTD equivalent for solid cancer patients. It was found that the combination therapy in which CPT-11 was administered at 45 days and CPT-11 was administered at 45 to 144 mg / m 2 / day suppressed the occurrence of side effects and had excellent antitumor effects.
- the present invention provides the following [1] to [32].
- a compounding agent containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 is administered in an amount of 35 to 70 mg / m 2 / day in terms of trifluridine, and irinotecan hydrochloride hydrate is 45 to 144 mg / m
- the antitumor agent according to [1], wherein a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 is administered at a dose of 70 mg / m 2 / day in terms of trifluridine.
- a compound containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 was administered from the first day to the fifth day and from the eighth day to the twelfth day, and CPT-11
- the antitumor agent according to any one of [1] to [4], wherein a 28-day administration cycle is administered once or twice or more on the first day and the fifteenth day.
- An antitumor effect enhancer comprising a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 for enhancing the antitumor effect of irinotecan hydrochloride hydrate on solid cancer patients.
- a compound containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 is administered in an amount of 35 to 70 mg / m 2 / day in terms of trifluridine, and irinotecan hydrochloride hydrate is 45 to 144 mg / m 2 / day.
- An antitumor agent comprising a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 for treating a solid cancer patient to which irinotecan hydrochloride hydrate has been administered,
- a compounding agent containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 is administered in an amount of 35 to 70 mg / m 2 / day in terms of trifluridine
- a kit preparation comprising an antitumor agent comprising a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 and instructions for use, According to the instructions for use, a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 is administered to a solid cancer patient in an amount of 35 to 70 mg / m 2 / day in terms of trifluridine, A kit preparation characterized in that irinotecan hydrochloride hydrate is administered at 45 to 144 mg / m 2 / day.
- a combination drug comprising trifluridine and tipiracil hydrochloride for the treatment of solid cancer in a molar ratio of 1: 0.5 A compound containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 is administered in an amount of 35 to 70 mg / m 2 / day in terms of trifluridine, and irinotecan hydrochloride hydrate is 45 to 144 mg / m 2 / day.
- a compound containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 was administered from the first day to the fifth day and from the eighth day to the twelfth day, and CPT-11
- a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 for enhancing the antitumor effect of irinotecan hydrochloride hydrate on solid cancer patients A compound containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 is administered in an amount of 35 to 70 mg / m 2 / day in terms of trifluridine, and irinotecan hydrochloride hydrate is 45 to 144 mg / m 2 / day.
- a combination drug administered is administered.
- a combination preparation comprising trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 for treating a solid cancer patient to whom irinotecan hydrochloride hydrate has been administered,
- a compounding agent containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 is administered in an amount of 35 to 70 mg / m 2 / day in terms of trifluridine
- a combination preparation comprising irinotecan hydrochloride hydrate administered at 45 to 144 mg / m 2 / day.
- a compound containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 was administered from the first day to the fifth day and from the eighth day to the twelfth day, and CPT-11
- an antitumor effect potentiator comprising a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 for enhancing the antitumor effect of irinotecan hydrochloride hydrate on solid cancer patients
- a compound containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 is administered in an amount of 35 to 70 mg / m 2 / day in terms of trifluridine, and irinotecan hydrochloride hydrate is 45 to 144 mg / m 2 / day.
- an antitumor agent comprising a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 for treating a solid cancer patient to which irinotecan hydrochloride hydrate has been administered Because A compounding agent containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 is administered in an amount of 35 to 70 mg / m 2 / day in terms of trifluridine, Use wherein irinotecan hydrochloride hydrate is administered at 45 to 144 mg / m 2 / day.
- a compound containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 is administered to a solid cancer patient in an amount of 35 to 70 mg / m 2 / day in terms of trifluridine, and irinotecan hydrochloride hydrate Is administered at a dose of 45 to 144 mg / m 2 / day.
- the method according to [23], wherein the compounding agent containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 is administered at 70 mg / m 2 / day in terms of trifluridine.
- a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 was administered from the first day to the fifth day and from the eighth day to the twelfth day, and CPT-11
- a method for enhancing the antitumor effect of irinotecan hydrochloride hydrate on solid cancer patients A compound containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 is administered in an amount of 35 to 70 mg / m 2 / day in terms of trifluridine, and irinotecan hydrochloride hydrate is 45 to 120 mg / m 2 / day.
- a method for treating a solid cancer patient administered with irinotecan hydrochloride hydrate, A compounding agent containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 is administered in an amount of 35 to 70 mg / m 2 / day in terms of trifluridine, A method wherein irinotecan hydrochloride hydrate is administered at 45 to 120 mg / m 2 / day.
- An antitumor agent for solid cancer comprising administering a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 and irinotecan hydrochloride hydrate,
- the dosage of the combination containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 is 50% to 100% of the recommended dosage in monotherapy;
- An antitumor agent wherein the dose of irinotecan hydrochloride hydrate is 25% to 80% of the recommended dose in monotherapy.
- the antitumor agent of the present invention it is possible to carry out cancer treatment exhibiting a high antitumor effect while suppressing the onset of side effects, thus leading to long-term survival of the patient.
- FIG. 4 is a view showing an antitumor effect by the combined use of FTD / TPI combination agent 150 mg / kg / day and CPT-11 25 mg / kg / day. It is a figure which shows the antitumor effect by combined use of FTD * TPI combination agent 150mg / kg / day and CPT-11 10mg / kg / day.
- FIG. 4 is a view showing an antitumor effect by the combined use of FTD / TPI combination drug 75 mg / kg / day and CPT-11 50 mg / kg / day.
- FIG. 4 is a view showing an antitumor effect by the combined use of FTD / TPI combination drug 75 mg / kg / day and CPT-11 25 mg / kg / day. It is a figure which shows the anti-tumor effect by combined use of FTD * TPI combination agent 75 mg / kg / day and CPT-11 10 mg / kg / day. It is a figure which shows the survival rate in Day70 in each combined administration group of FTD * TPI combination agent 150 mg / kg / day and CPT-11 50, 70, or 100 mg / kg / day.
- FTD and TPI of the present invention are each known compounds, and can be synthesized, for example, according to the method described in WO96 / 30346.
- a compounding agent containing FTD and TPI at a molar ratio of 1: 0.5 is also known (Non-Patent Documents 1 and 2).
- CPT-11 of the present invention is a known compound and can be synthesized according to the method described in Japanese Patent No. 3004077.
- Commercial products such as Kampto (registered trademark) (Yakult Honsha Co., Ltd.) may also be used.
- the administration schedule of the antitumor agent of the present invention is not particularly limited as long as the effect of the present invention is exhibited.
- a compounding agent containing FTD and TPI at a molar ratio of 1: 0.5 is used from the first day to the fifth day.
- CPT-11 is administered on the 1st and 15th days, and the 28-day 1-cycle administration schedule is repeated once or twice or more. Is preferred.
- the dose of the FTD / TPI combination agent in the present invention is 50% to 100% of the recommended dose in monotherapy for humans, and 100% is particularly preferred from the viewpoint of the balance between antitumor effects and side effects.
- the dose of CPT-11 is 25% to 80% of the recommended dose in monotherapy for humans, preferably 40% to 80%, and preferably 50% to 80% from the viewpoint of the balance between antitumor effects and side effects. More preferred is 50% to 70%.
- the recommended dose of monotherapy for FTD / TPI combination therapy for humans is 70 mg / m 2 / day
- the dose of FTD is 35 to 70 mg / m 2 / day, which has antitumor effects and side effects.
- 70 mg / m 2 / day is particularly preferable.
- the recommended dose of CPT-11 in monotherapy for humans varies depending on the dosing schedule, but is, for example, 150 to 180 mg / m 2 / day when administered every 2 weeks. Therefore, when the recommended dose is 180 mg / m 2 / day (for example, digestive organ cancer, lung cancer, breast cancer, cervical cancer, ovarian cancer, etc., colorectal cancer and pancreatic cancer are preferred).
- the dose of CPT-11 is 45 to 144 mg / m 2 / day, preferably 72 to 144 mg / m 2 / day, more preferably 90 to 144 mg / m 2 / day from the viewpoint of the balance between antitumor effects and side effects. 90 to 126 mg / m 2 / day is particularly preferable.
- the recommended dose is 150 mg / m 2 / day (for example, digestive organ cancer, lung cancer, breast cancer, cervical cancer, ovarian cancer, etc., cervical cancer, ovarian cancer, stomach cancer and colorectal cancer are
- the dose of CPT-11 of the present invention is preferably 37.5 to 120 mg / m 2 / day, and preferably 60 to 120 mg / m 2 / day from the viewpoint of the balance between antitumor effects and side effects, -120 mg / m 2 / day is more preferable, and 75 to 105 mg / m 2 / day is particularly preferable.
- the recommended dose for monotherapy of CPT-11 for humans is 100 to 125 mg / m 2 / day.
- the recommended dose is 100 mg / m 2 / day (for example, digestive organ cancer, lung cancer, breast cancer, cervical cancer, ovarian cancer, etc., small cell lung cancer, non-small cell lung cancer, breast cancer, cervical, etc. Cancer, ovarian cancer, gastric cancer, and colorectal cancer are preferable)
- the dose of CPT-11 of the present invention is 25 to 80 mg / m 2 / day, and 40 to 80 mg from the viewpoint of the balance between the antitumor effect and side effects.
- / M 2 / day is preferable, 50 to 80 mg / m 2 / day is more preferable, and 50 to 70 mg / m 2 / day is particularly preferable.
- CPT- The dose of 11 is 31.25 to 100 mg / m 2 / day, and is preferably 50 to 100 mg / m 2 / day, and preferably 62.5 to 100 mg / m 2 / day from the viewpoint of the balance between antitumor effects and side effects. Is more preferable, and 62.5 to 87.5 mg / m 2 / day is particularly preferable.
- the recommended dose for monotherapy of CPT-11 for humans is 350 mg / m 2 / day (for example, digestive cancer, lung cancer, breast cancer, cervical cancer or ovarian cancer). And colorectal cancer is preferred). Therefore, the dose of CPT-11 of the present invention is 87.5 to 280 mg / m 2 / day, and preferably 140 to 280 mg / m 2 / day from the viewpoint of the balance between antitumor effect and side effects, and 175 to 280 mg. / M 2 / day is more preferable, and 175 to 245 mg / m 2 / day is particularly preferable.
- the target of the antitumor agent of the present invention is solid cancer, specifically, head and neck cancer, digestive organ cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (eg, gallbladder / bile duct cancer), pancreatic cancer. , Small intestine cancer, colon cancer (colorectal cancer, colon cancer, rectal cancer, etc.), lung cancer, breast cancer, ovarian cancer, uterine cancer (cervical cancer, uterine body cancer, etc.), renal cancer, bladder cancer, prostate cancer, etc. Is mentioned.
- digestive organ cancer esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (eg, gallbladder / bile duct cancer), pancreatic cancer.
- lung cancer breast cancer, ovarian cancer
- uterine cancer cervical cancer, uterine body cancer,
- the solid cancer includes not only the primary tumor but also a tumor derived from the solid cancer that has metastasized to other organs (eg, liver).
- the antitumor agent of the present invention may be used for postoperative adjuvant chemotherapy performed for preventing recurrence after surgically removing a tumor.
- the antitumor agent of the present invention divides each active ingredient into a plurality of dosage forms.
- Formulate It is preferable to formulate FTD and TPI as a compounding agent and CPT-11 as a single agent.
- each preparation may be manufactured and sold in one package suitable for combined administration, and each preparation is divided into separate packages. May be sold.
- an oral agent a tablet, a coated tablet, a powder, a granule, a capsule, a liquid agent etc.
- injection Examples include suppositories, suppositories, patches, ointments and the like.
- the combination of FTD and TPI is preferably an oral preparation, and CPT-11 is preferably an injection.
- the antitumor agent in the present invention can be prepared by a generally known method using a pharmaceutically acceptable carrier according to the administration form.
- a pharmaceutically acceptable carrier include various types commonly used for ordinary drugs, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonic agents, pH.
- examples include regulators, buffers, stabilizers, colorants, flavoring agents, and flavoring agents.
- the present invention also enhances the antitumor effect of CPT-11 on solid cancer patients (especially colorectal cancer patients), characterized in that an FTD / TPI combination drug and CPT-11 are administered based on the above dose.
- the present invention relates to an antitumor effect potentiator comprising an FTD / TPI combination drug.
- the antitumor effect potentiator has a preparation form of the antitumor agent.
- the present invention also treats a solid cancer patient (especially a colorectal cancer patient) administered with CPT-11, wherein an FTD / TPI combination drug and CPT-11 are administered based on the above dose.
- the present invention relates to an antitumor agent comprising an FTD / TPI combination drug.
- the antitumor agent has the above-described preparation form.
- the present invention also provides an FTD / TPI combination drug and instructions for administration of the FTD / TPI combination drug and CPT-11 based on the above dosage for solid cancer patients (particularly colorectal cancer patients).
- the present invention relates to a kit preparation containing
- the “instruction for use” may be anything that describes the above-mentioned dose, and it does not matter whether there is a legal binding force. Specifically, an attached document, a pamphlet, etc. are illustrated.
- a kit preparation including instructions for use includes instructions for use printed together with the antitumor agent even if the instructions for use are printed and attached to the kit preparation package. It may be a thing.
- irinotecan hydrochloride hydrate (CPT-11: Campto Injection (registered trademark), Yakult Honsha Co., Ltd.) has been reported dead at 111 mg / kg / day (Basic and Clinical, (1990), Vol. 24, No. 14, 7-17), and irinotecan hydrochloride hydrate was prepared at 80 and 100 mg / kg / day.
- the administration of the drug was started from Day 3, the FTD / TPI combination drug was orally administered for 5 days, and the drug was suspended for 2 days for 6 weeks, and CPT-11 was administered from the tail vein once a week for 6 weeks.
- the number of surviving mice in each group was confirmed, and the survival time of each group was compared. The results are shown in Table 1.
- mice had a long survival time in the 100 mg / kg / day group, so the recommended dose (RD) of CPT-11 in mice was irinotecan hydrochloride hydrate. 100 mg / kg / day. Therefore, 100 mg / kg / day in mice corresponds to RD 150-180 mg / m 2 / day in humans.
- RD recommended dose
- the RD of the FTD / TPI combination in mice is 150 mg / kg / day in terms of FTD. Therefore, 150 mg / kg / day (FTD equivalent) in mice corresponds to RD 70 mg / m 2 / day (FTD equivalent) in humans.
- CPT-11 (Kampto (registered trademark) Note, Yakult Honsha Co., Ltd.) was prepared as irinotecan hydrochloride hydrate at 10, 25 and 50 mg / kg / day.
- the FTD / TPI combination was orally administered daily to Day 1-14, and CPT-11 was administered to Day 1 and Day 8 via the tail vein.
- the FTD / TPI combination drug and CPT-11 were administered at the same dosage and administration schedule as the single agent administration group.
- Table 2 shows a list of each drug administration group.
- the FTD / TPI combination drug (mixture of FTD and TPI at a molar ratio of 1: 0.5) was prepared so that the FTD was 150 mg / kg / day (recommended dose).
- CPT-11 (Kampto Injection (registered trademark), Yakult Honsha Co., Ltd.) was prepared as irinotecan hydrochloride hydrate at 50, 70 and 100 mg / kg / day.
- combination administration was started from Day 3, FTD / TPI combination drug was orally administered for 5 days, and 2 days were withdrawn for 6 weeks, and CPT-11 was administered via the tail vein once a week for 6 weeks. I went for a week.
- the number of surviving mice in each group at Day 70 was confirmed, and the survival rate of each group was compared. The survival rate of each group at Day 70 is shown in FIG.
- the survival rate at Day 70 was 100%, whereas FTD / TPI was 100%.
- the combination drug was 150 mg / kg / day and CPT-11 was 100 mg / kg / day, side effects were strongly observed, and the survival rate at Day 70 was extremely reduced to 30%.
- Example 3 According to Example 1, a combined administration test of FTD / TPI combination drug and CPT-11 was conducted in place of the human gastric cancer line (SC-2) as the cell line.
- FTD / TPI combination (mixture with a molar ratio of FTD to TPI of 1: 0.5) is 75 and 150 mg / kg / day (recommended dose) as FTD, CPT-11 is 40 and irinotecan hydrochloride hydrate. It adjusted so that it might become 80 mg / kg / day.
- Table 3 The results are shown in Table 3.
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Abstract
Description
さらに、結腸直腸癌の細胞株に対してFTDとSN-38を作用させたところ、相乗的な細胞毒性が確認されたことから、FTD・TPI配合剤とCPT-11の併用療法が期待されている(非特許文献4)。
〔2〕トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤が、トリフルリジン換算量で70mg/m2/dayで投与される〔1〕記載の抗腫瘍剤。
〔3〕イリノテカン塩酸塩水和物が、75~120mg/m2/day投与される〔1〕又は〔2〕記載の抗腫瘍剤。
〔4〕固形癌が、結腸直腸癌、肺癌、乳癌、膵癌又は胃癌である〔1〕~〔3〕のいずれかに記載の抗腫瘍剤。
〔5〕トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤を第1日目から第5日目までと第8日目から第12日目まで投与し、CPT-11を第1日目と第15日目に投与する28日間1サイクルの投与スケジュールを1回又は2回以上繰り返すことを特徴とする〔1〕~〔4〕のいずれかに記載の抗腫瘍剤。
〔6〕固形癌患者に対するイリノテカン塩酸塩水和物の抗腫瘍効果を増強するための、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤からなる抗腫瘍効果増強剤であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする抗腫瘍効果増強剤。
〔7〕イリノテカン塩酸塩水和物を投与された固形癌患者を治療するための、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤からなる抗腫瘍剤であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、
イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする抗腫瘍剤。
〔8〕トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤を含む抗腫瘍剤と使用説明書を含むキット製剤であって、
使用説明書には、固形癌患者に対して、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、
イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることが記載されていることを特徴とするキット製剤。
〔9〕固形癌治療のためのトリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする配合剤。
〔10〕トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤が、トリフルリジン換算量で70mg/m2/dayで投与される〔9〕記載の配合剤。
〔11〕イリノテカン塩酸塩水和物が、75~120mg/m2/day投与される〔9〕又は〔10〕記載の配合剤。
〔12〕固形癌が、結腸直腸癌、肺癌、乳癌、膵癌又は胃癌である〔9〕~〔11〕のいずれかに記載の配合剤。
〔13〕トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤を第1日目から第5日目までと第8日目から第12日目まで投与し、CPT-11を第1日目と第15日目に投与する28日間1サイクルの投与スケジュールを1回又は2回以上繰り返すことを特徴とする〔9〕~〔12〕いずれかに記載の配合剤。
〔14〕固形癌患者に対するイリノテカン塩酸塩水和物の抗腫瘍効果を増強するための、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする配合剤。
〔15〕イリノテカン塩酸塩水和物を投与された固形癌患者を治療するための、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、
イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする配合剤。
〔16〕トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する合剤の固形癌に対する抗腫瘍剤製造のための使用であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする使用。
〔17〕トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤が、トリフルリジン換算量で70mg/m2/dayで投与される〔16〕記載の使用。
〔18〕イリノテカン塩酸塩水和物が、75~120mg/m2/day投与される〔16〕又は〔17〕記載の使用。
〔19〕固形癌が、結腸直腸癌、肺癌、乳癌、膵癌又は胃癌である〔16〕~〔18〕のいずれかに記載の使用。
〔20〕トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤を第1日目から第5日目までと第8日目から第12日目まで投与し、CPT-11を第1日目と第15日目に投与する28日間1サイクルの投与スケジュールを1回又は2回以上繰り返すことを特徴とする〔16〕~〔19〕のいずれかに記載の使用。
〔21〕固形癌患者に対するイリノテカン塩酸塩水和物の抗腫瘍効果を増強するための、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤からなる抗腫瘍効果増強剤製造のための使用であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする使用。
〔22〕イリノテカン塩酸塩水和物を投与された固形癌患者を治療するための、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤からなる抗腫瘍剤製造のための使用であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、
イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする使用。
〔23〕固形癌患者に対してトリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする固形癌の治療方法。
〔24〕トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤が、トリフルリジン換算量で70mg/m2/dayで投与される〔23〕記載の方法。
〔25〕イリノテカン塩酸塩水和物が、75~120mg/m2/day投与される〔23〕又は〔24〕記載の方法。
〔26〕固形癌が、結腸直腸癌、肺癌、乳癌、膵癌又は胃癌である〔23〕~〔25〕のいずれかに記載の方法。
〔27〕トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤を第1日目から第5日目までと第8日目から第12日目まで投与し、CPT-11を第1日目と第15日目に投与する28日間1サイクルの投与スケジュールを1回又は2回以上繰り返すことを特徴とする〔23〕~〔26〕のいずれかに記載の方法。
〔28〕固形癌患者に対するイリノテカン塩酸塩水和物の抗腫瘍効果を増強するための方法であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~120mg/m2/day投与されることを特徴とする方法。
〔29〕イリノテカン塩酸塩水和物を投与された固形癌患者を治療するための方法であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、
イリノテカン塩酸塩水和物が45~120mg/m2/day投与されることを特徴とする方法。
〔30〕トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤とイリノテカン塩酸塩水和物を併用投与することを特徴とする固形癌に対する抗腫瘍剤であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤の投与量が、単独療法における推奨投与量の50%~100%であり、
イリノテカン塩酸塩水和物の投与量が、単独療法における推奨投与量の25%~80%である抗腫瘍剤。
〔31〕トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤の投与量が、単独療法における推奨投与量の100%である〔30〕記載の抗腫瘍剤。
〔32〕イリノテカン塩酸塩水和物の投与量が、単独療法における推奨投与量の50%~70%である〔30〕又は〔31〕記載の抗腫瘍剤。
本発明のCPT-11は公知の化合物であり、特許第3004077号公報に記載の方法に準じて合成することができる。また、カンプト(登録商標)(株式会社ヤクルト本社)などの市販品を用いても良い。
すなわち、FTD・TPI配合剤のヒトに対する単独療法における推奨投与量は70mg/m2/dayであることから、FTDの投与量は35~70mg/m2/dayであり、抗腫瘍効果と副作用のバランスの観点から、70mg/m2/dayが特に好ましい。
CPT-11のヒトに対する単独療法における推奨投与量は、投与スケジュールによって異なるが、例えば、2週間毎の投与の場合、150~180mg/m2/dayである。よって、その推奨投与量が180mg/m2/dayのとき(例えば、消化器癌、肺癌、乳癌、子宮頸癌又は卵巣癌等が挙げられ、結腸直腸癌及び膵癌が好ましい)は、本発明のCPT-11の投与量は45~144mg/m2/dayであり、抗腫瘍効果と副作用のバランスの観点から、72~144mg/m2/dayが好ましく、90~144mg/m2/dayがより好ましく、90~126mg/m2/dayが特に好ましい。また、その推奨投与量が150mg/m2/dayのとき(例えば、消化器癌、肺癌、乳癌、子宮頸癌又は卵巣癌等が挙げられ、子宮頸癌、卵巣癌、胃癌及び結腸直腸癌が好ましい)は、本発明のCPT-11の投与量は37.5~120mg/m2/dayであり、抗腫瘍効果と副作用のバランスの観点から、60~120mg/m2/dayが好ましく、75~120mg/m2/dayがより好ましく、75~105mg/m2/dayが特に好ましい。
また、1週間毎の投与の場合、CPT-11のヒトに対する単独療法における推奨投与量は100~125mg/m2/dayである。よって、その推奨投与量が100mg/m2/dayのとき(例えば、消化器癌、肺癌、乳癌、子宮頸癌又は卵巣癌等が挙げられ、小細胞肺癌、非小細胞肺癌、乳癌 、子宮頸癌、卵巣癌、胃癌及び結腸直腸癌が好ましい)は、本発明のCPT-11の投与量は25~80mg/m2/dayであり、抗腫瘍効果と副作用のバランスの観点から、40~80mg/m2/dayが好ましく、50~80mg/m2/dayがより好ましく、50~70mg/m2/dayが特に好ましい。また、その推奨投与量が125mg/m2/dayのとき(例えば、消化器癌、肺癌、乳癌、子宮頸癌又は卵巣癌等が挙げられ、結腸直腸癌が好ましい)は、本発明のCPT-11の投与量は31.25~100mg/m2/dayであり、抗腫瘍効果と副作用のバランスの観点から、50~100mg/m2/dayが好ましく、62.5~100mg/m2/dayがより好ましく、62.5~87.5mg/m2/dayが特に好ましい。
また、3週間毎の投与の場合、CPT-11のヒトに対する単独療法における推奨投与量は350mg/m2/dayである(例えば、消化器癌、肺癌、乳癌、子宮頸癌又は卵巣癌等が挙げられ、結腸直腸癌が好ましい)。よって、本発明のCPT-11の投与量は87.5~280mg/m2/dayであり、抗腫瘍効果と副作用のバランスの観点から、140~280mg/m2/dayが好ましく、175~280mg/m2/dayがより好ましく、175~245mg/m2/dayが特に好ましい。
ヒト大腸癌株(KM20C)の培養細胞(1×107cells/マウス)を生後5~6週齢のBALB/cA Jcl-nuマウスの腹腔内に移植し、各群の平均体重が均等になるように各群にマウスを割り付け、群分け(n=10)を実施した日をDay 0とした。
FTD・TPI配合剤(FTDとTPIのモル比1:0.5の混合物)は、FTDとして75、100、150、300及び450mg/kg/dayとなるように調製した。イリノテカン塩酸塩水和物(CPT-11:カンプト注(登録商標)、株式会社ヤクルト本社)は、111mg/kg/dayで死亡例が報告されていることから(基礎と臨床、(1990)、Vol.24、No.14、7~17)、イリノテカン塩酸塩水和物として80及び100mg/kg/dayとなるように調製した。薬剤の投与はDay 3から開始し、FTD・TPI配合剤は5日間連日経口投与・2日間休薬を6週間行い、CPT-11は週に1回の尾静脈から投与を6週間行った。
抗腫瘍効果の指標として、各群のマウスの生存数を確認し、各群の生存期間を比較した。結果を表1に示す。
ヒト大腸癌株(KM20C)を生後5~6週齢のBALB/cA Jcl-nuマウスの右側胸部に移植した。腫瘍移植後に腫瘍の長径(mm)および短径(mm)を測定し、腫瘍体積(tumor volume:TV)を算出後、各群の平均TVが均等になるように各群にマウスを割り付け、群分け(n=6)を実施した日をDay0とした。
FTD・TPI配合剤(FTDとTPIのモル比1:0.5の混合物)は、FTDとして75及び150mg/kg/dayとなるように調製した。CPT-11(カンプト(登録商標)注、株式会社ヤクルト本社)は、イリノテカン塩酸塩水和物として10、25及び50mg/kg/dayとなるように調製した。FTD・TPI配合剤はDay1-14に連日経口投与し、CPT-11はDay1及びDay8に尾静脈から投与した。併用投与群は、単剤投与群と同じ投与量及び投与スケジュールでFTD・TPI配合剤とCPT-11を投与した。各薬剤投与群の一覧を表2に示した。
抗腫瘍効果の指標として、各群のDay4、8、11、15、18及び22のTVを算出し、下式によりDay0に対する相対腫瘍体積(relative tumor volume:RTV)を求めてプロットし、無処置群(control)、FTD・TPI配合剤投与群、CPT-11投与群及びFTD・TPI配合剤とCPT-11併用投与群のRTVの経日的推移を比較した。
RTV=(Day28におけるTV)/(Day0におけるTV)
ヒト大腸癌株(KM20C)の培養細胞(1×107cells/マウス)を生後5~6週齢のBALB/cA Jcl-nuマウスの腹腔内に移植し、各群の平均体重が均等になるように各群にマウスを割り付け、群分け(n=10)を実施した日をDay0とした。
FTD・TPI配合剤(FTDとTPIのモル比1:0.5の混合物)は、FTDとして150mg/kg/day(推奨投与量)となるように調製した。CPT-11(カンプト注(登録商標)、株式会社ヤクルト本社)は、イリノテカン塩酸塩水和物として50、70及び100mg/kg/dayとなるように調製した。各併用投与群では、Day3から併用投与を開始し、FTD・TPI配合剤は5日間連日経口投与・2日間休薬を6週間行い、CPT-11は週に1回の尾静脈から投与を6週間行った。
抗腫瘍効果の指標として、Day70での各群のマウスの生存数を確認し、各群の生存率を比較した。Day70での各群の生存率を図7に示す。
実施例1に準じて、細胞株をヒト胃癌株(SC-2)に代えてFTD・TPI配合剤とCPT-11の併用投与試験を行った。FTD・TPI配合剤(FTDとTPIのモル比1:0.5の混合物)は、FTDとして75及び150mg/kg/day(推奨投与量)、CPT-11は、イリノテカン塩酸塩水和物として40及び80mg/kg/dayとなるように調製した。結果を表3に示す。
Claims (32)
- トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする固形癌に対する抗腫瘍剤。
- トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤が、トリフルリジン換算量で70mg/m2/dayで投与される請求項1記載の抗腫瘍剤。
- イリノテカン塩酸塩水和物が、75~120mg/m2/day投与される請求項1又は2記載の抗腫瘍剤。
- 固形癌が、結腸直腸癌、肺癌、乳癌、膵癌又は胃癌である請求項1~3のいずれかに記載の抗腫瘍剤。
- α,α,α-トリフルオロチミジン及び5-クロロ-6-(2-イミノピロリジン-1-イル)メチル-2,4(1H,3H)-ピリミジンジオン塩酸塩をモル比1:0.5で含有する配合剤を第1日目から第5日目までと第8日目から第12日目まで投与し、CPT-11を第1日目と第15日目に投与する28日間1サイクルの投与スケジュールを1回又は2回以上繰り返すことを特徴とする請求項1~4のいずれかに記載の抗腫瘍剤。
- 固形癌患者に対するイリノテカン塩酸塩水和物の抗腫瘍効果を増強するための、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤からなる抗腫瘍効果増強剤であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする抗腫瘍効果増強剤。 - イリノテカン塩酸塩水和物を投与された固形癌患者を治療するための、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤からなる抗腫瘍剤であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、
イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする抗腫瘍剤。 - トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤を含む抗腫瘍剤と使用説明書を含むキット製剤であって、
使用説明書には、固形癌患者に対して、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、
イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることが記載されていることを特徴とするキット製剤。 - 固形癌治療のためのトリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする配合剤。 - トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤が、トリフルリジン換算量で70mg/m2/dayで投与される請求項9記載の配合剤。
- イリノテカン塩酸塩水和物が、75~120mg/m2/day投与される請求項9又は10記載の配合剤。
- 固形癌が、結腸直腸癌、肺癌、乳癌、膵癌又は胃癌である請求項9~11のいずれかに記載の配合剤。
- トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤を第1日目から第5日目までと第8日目から第12日目まで投与し、CPT-11を第1日目と第15日目に投与する28日間1サイクルの投与スケジュールを1回又は2回以上繰り返すことを特徴とする請求項9~12のいずれかに記載の配合剤。
- 固形癌患者に対するイリノテカン塩酸塩水和物の抗腫瘍効果を増強するための、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする配合剤。 - イリノテカン塩酸塩水和物を投与された固形癌患者を治療するための、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、
イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする配合剤。 - トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する合剤の固形癌に対する抗腫瘍剤製造のための使用であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする使用。 - トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤が、トリフルリジン換算量で70mg/m2/dayで投与される請求項16記載の使用。
- イリノテカン塩酸塩水和物が、75~120mg/m2/day投与される請求項16又は17記載の使用。
- 固形癌が、結腸直腸癌、肺癌、乳癌、膵癌又は胃癌である請求項16~18のいずれかに記載の使用。
- トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤を第1日目から第5日目までと第8日目から第12日目まで投与し、CPT-11を第1日目と第15日目に投与する28日間1サイクルの投与スケジュールを1回又は2回以上繰り返すことを特徴とする請求項16~19のいずれかに記載の使用。
- 固形癌患者に対するイリノテカン塩酸塩水和物の抗腫瘍効果を増強するための、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤からなる抗腫瘍効果増強剤製造のための使用であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする使用。 - イリノテカン塩酸塩水和物を投与された固形癌患者を治療するための、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤からなる抗腫瘍剤製造のための使用であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、
イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする使用。 - 固形癌患者に対して、トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする固形癌の治療方法。
- トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤が、トリフルリジン換算量で70mg/m2/dayで投与される請求項23記載の方法。
- イリノテカン塩酸塩水和物が、75~120mg/m2/day投与される請求項23又は24記載の方法。
- 固形癌が、結腸直腸癌、肺癌、乳癌、膵癌又は胃癌である請求項23~25のいずれかに記載の方法。
- トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤を第1日目から第5日目までと第8日目から第12日目まで投与し、CPT-11を第1日目と第15日目に投与する28日間1サイクルの投与スケジュールを1回又は2回以上繰り返すことを特徴とする請求項23~26のいずれかに記載の方法。
- 固形癌患者に対するイリノテカン塩酸塩水和物の抗腫瘍効果を増強するための方法であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする方法。 - イリノテカン塩酸塩水和物を投与された固形癌患者を治療するための方法であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤がトリフルリジン換算量で35~70mg/m2/day投与され、
イリノテカン塩酸塩水和物が45~144mg/m2/day投与されることを特徴とする方法。 - トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤とイリノテカン塩酸塩水和物を併用投与することを特徴とする固形癌に対する抗腫瘍剤であって、
トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤の投与量が、単独療法における推奨投与量の50%~100%であり、
イリノテカン塩酸塩水和物の投与量が、単独療法における推奨投与量の25%~80%である抗腫瘍剤。 - トリフルリジン及びチピラシル塩酸塩をモル比1:0.5で含有する配合剤の投与量が、単独療法における推奨投与量の100%である請求項30記載の抗腫瘍剤。
- イリノテカン塩酸塩水和物の投与量が、単独療法における推奨投与量の50%~70%である請求項30又は31記載の抗腫瘍剤。
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US10980795B2 (en) | 2012-06-13 | 2021-04-20 | Ipsen Biopharm Ltd. | Methods for treating pancreatic cancer using combination therapies comprising liposomal irinotecan |
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JPWO2014157444A1 (ja) | 2017-02-16 |
ZA201507444B (en) | 2017-01-25 |
US20160082031A1 (en) | 2016-03-24 |
ES2702911T3 (es) | 2019-03-06 |
KR20150136074A (ko) | 2015-12-04 |
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EP2979700A4 (en) | 2016-11-23 |
RU2015145997A (ru) | 2017-05-04 |
SI2979700T1 (sl) | 2019-01-31 |
EP2979700B1 (en) | 2018-09-26 |
HUE041687T2 (hu) | 2019-05-28 |
TR201819576T4 (tr) | 2019-01-21 |
EP2979700A1 (en) | 2016-02-03 |
AU2014245147B2 (en) | 2017-08-31 |
AU2014245147A1 (en) | 2015-10-15 |
JP6002835B2 (ja) | 2016-10-05 |
PT2979700T (pt) | 2018-12-27 |
UA117581C2 (uk) | 2018-08-27 |
HRP20182145T1 (hr) | 2019-03-08 |
DK2979700T3 (en) | 2019-01-21 |
RU2668125C2 (ru) | 2018-09-26 |
CY1120990T1 (el) | 2019-12-11 |
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