WO2014157443A1 - イリノテカン塩酸塩水和物を含有する抗腫瘍剤 - Google Patents
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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- A61K31/706—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 administers an FTD / TPI combination drug for 5 days to colorectal cancer patients based on the administration schedule for which each drug has already been reported as in Comparative Examples described later. After taking two days of rest, then withdrawing twice for two weeks and then performing a combination therapy that repeated a 28-day cycle in which CPT-11 was administered once every two weeks, side effects appeared strongly. CPT-11 could be administered only about 30% of the planned dose. In general, since the antitumor effect is proportional to the total dose, the present inventors have conducted studies on administration schedules that can suppress the occurrence of side effects and can administer a predetermined amount.
- a combination therapy that repeats the administration schedule of one cycle in 14 days, in which the FTD / TPI combination drug is administered for 5 days and then withdrawn for 9 days and CPT-11 is administered once every 2 weeks, is preferable. It has been found that the occurrence of side effects such as neutropenia, diarrhea, and weight loss can be suppressed, and a predetermined dose can be administered, resulting in excellent antitumor effects.
- the present invention provides the following [1] to [26].
- a compound containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 is administered from the first day to the fifth day in an amount of 20-80 mg / m 2 / day in terms of trifluridine, Anti-solid cancer, characterized in that irinotecan hydrochloride hydrate is administered at 50 to 200 mg / m 2 / day on the first day, and one cycle of the administration schedule is repeated once or twice or more for 14 days.
- Tumor agent is administered from the first day to the fifth day in an amount of 20-80 mg / m 2 / day in terms of trifluridine, Anti-solid cancer, characterized in that irinotecan hydrochloride hydrate is administered at 50 to 200 mg / m 2 / day on the first day, and one cycle of the administration schedule is repeated once or twice or more for 14 days.
- An antitumor effect enhancer comprising a combination drug containing trifluridine and tipiracil hydrochloride in 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 was administered from the first day to the fifth day in an amount of 20-80 mg / m 2 / day in terms of trifluridine,
- Antitumor effect enhancement characterized by the fact that one cycle of the administration schedule of irinotecan hydrochloride hydrate is administered at 50 to 200 mg / m 2 / day on the first day for 14 days, and is repeated once or twice or more Agent.
- 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 compound containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 was administered from the first day to the fifth day in an amount of 20-80 mg / m 2 / day in terms of trifluridine, An antitumor agent characterized in that an irinotecan hydrochloride hydrate is administered at 50 to 200 mg / m 2 / day on the first day, and a one-cycle administration schedule is repeated once or twice or more for 14 days.
- a kit preparation comprising an antitumor agent comprising a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 and instructions for use,
- the instructions for use include a compound containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 for solid cancer patients from the first day to the fifth day in a trifluridine equivalent amount of 20 to Administered 80 mg / m 2 / day,
- a kit preparation characterized in that the administration schedule of one cycle is described for 14 days in which irinotecan hydrochloride hydrate is administered at 50 to 200 mg / m 2 / day on the first day.
- the drug was administered from the first day to the fifth day in an amount of 20-80 mg / m 2 / day in terms of trifluridine,
- a combination preparation characterized in that the administration schedule of one cycle is repeated once or twice or more in 14 days in which irinotecan hydrochloride hydrate is administered at 50 to 200 mg / m 2 / day on the first day.
- 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 in an amount of 20-80 mg / m 2 / day in terms of trifluridine
- an antitumor effect potentiator comprising a combination drug containing trifluridine and tipiracil hydrochloride in 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 was administered from the first day to the fifth day in an amount of 20-80 mg / m 2 / day in terms of trifluridine,
- irinotecan hydrochloride hydrate is administered at a dose of 50 to 200 mg / m 2 / day on the first day for 14 days, wherein one cycle of the administration schedule is repeated once or twice or more.
- 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 Because 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 in an amount of 20-80 mg / m 2 / day in terms of trifluridine, Use wherein irinotecan hydrochloride hydrate is administered at a dose of 50 to 200 mg / m 2 / day on the first day for 14 days, wherein one cycle of the administration schedule is repeated once or twice or more.
- a compound containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 is 20 to 80 mg / m in terms of trifluridine from the first day to the fifth day.
- 2 / day administration Treatment of solid cancer, characterized in that irinotecan hydrochloride hydrate is administered at 50 to 200 mg / m 2 / day on the first day, and a one-cycle dosing schedule is repeated once or twice or more for 14 days Method.
- a method 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 was administered from the first day to the fifth day in an amount of 20-80 mg / m 2 / day in terms of trifluridine, A method, wherein a cycle of administration is repeated once or twice or more for 14 days in which irinotecan hydrochloride hydrate is administered at 50 to 200 mg / m 2 / day on the first day.
- a method for treating a solid cancer patient administered with irinotecan hydrochloride hydrate 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 in an amount of 20-80 mg / m 2 / day in terms of trifluridine, A method, wherein a cycle of administration is repeated once or twice or more for 14 days in which irinotecan hydrochloride hydrate is administered at 50 to 200 mg / m 2 / day on the first day.
- a compounding agent containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5, and containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 from the first day to the fifth day Administered at the recommended dosage in monotherapy
- the irnotecan hydrochloride hydrate is administered at the recommended dose in the irinotecan hydrochloride hydrate monotherapy on the first day, and the administration schedule of one cycle is repeated once or twice or more in 14 days.
- An antitumor agent for solid cancer is administered at the recommended dose in the irinotecan hydrochloride hydrate monotherapy on the first day, and the administration schedule of one cycle is repeated once or twice or more in 14 days.
- 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.
- administration schedule (1) and (2) It is a figure which shows administration schedule (1) and (2).
- the black circle is the date of administration.
- 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 campto (registered trademark, Yakult Co., Ltd.) may also be used.
- a combination drug containing FTD and TPI at a molar ratio of 1: 0.5 is administered from the first day to the fifth day, and CPT-11 is administered on the first day.
- the administration schedule of one cycle per day is repeated once or twice or more.
- a combination dose of FTD / TPI recommended for monotherapy with mice and CPT-11 recommended dose for monotherapy for mice were administered to mice according to the above administration schedule. In that case, excellent anti-tumor effect and suppression of side effects could be achieved.
- the FTD / TPI combination and CPT-11 doses to humans in the administration schedule of the present invention are the recommended doses for FTD / TPI combination and CPT-11 monotherapy for humans. . That is, the dose of FTD from the first day to the fifth day is 20 to 80 mg / m 2 / day, and 40 to 70 mg / m 2 / day is more preferable from the viewpoint of the balance between the antitumor effect and side effects. 70 mg / m 2 / day is particularly preferable.
- the dose of CPT-11 on the first day is 50 to 200 mg / m 2 / day as irinotecan hydrochloride hydrate, and is preferably 100 to 180 mg / m 2 / day from the viewpoint of the balance between antitumor effects and side effects.
- 150 to 180 mg / m 2 / day is more preferable, and 180 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 is formulated by dividing each active ingredient into a plurality of dosage forms. . 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 and manufactured. 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), wherein an FTD / TPI combination drug and CPT-11 are administered based on the above administration schedule
- the present invention relates to an antitumor effect potentiator comprising an FTD / TPI combination agent.
- the antitumor effect potentiator has a preparation form of the antitumor agent.
- the present invention also provides a method for treating a solid cancer patient (particularly a colorectal cancer patient) administered with CPT-11, wherein an FTD / TPI combination drug and CPT-11 are administered based on the above administration schedule.
- the present invention relates to an antitumor agent comprising the FTD / TPI combination drug.
- the antitumor agent has the above-described preparation form.
- the present invention also relates to a kit preparation containing an FTD / TPI combination and an instruction manual describing that an FTD / TPI combination and CPT-11 are administered based on the above administration schedule.
- the “instruction manual” may be any document that describes the above-mentioned administration schedule, regardless of whether or not 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 As described in Table 1, in mice, CPT-11 was 100 mg / kg / day, and the survival time was long. Therefore, the recommended dose (RD) of CPT-11 in mice was 100 mg / kg / day. is there. 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 in humans.
- Irinotecan hydrochloride hydrate (CPT-11: Campto Injection, Yakult Honsha Co., Ltd.) was prepared as irinotecan hydrochloride hydrate at 100 mg / kg / day.
- the FTD / TPI combination drug was orally administered daily to Day 1-5 and Day 8-12, and CPT-11 was administered to Day 1 and Day 15 from the tail vein.
- the FTD / TPI combination was orally administered daily on Day 1-5 and Day 15-19, and CPT-11 was administered on Day 1 and Day 15 via the tail vein.
- the FTD / TPI combination drug and CPT-11 monotherapy group were administered with the same dosage and administration schedule as the corresponding drugs in the combination administration group (FIG. 1).
- body weight [body weight: BW] was measured over time as an index of toxicity, and the average weight change rate [body weight change: BWC (%)] of Day n with respect to Day 0 was calculated by the following formula (n: 2 times) The day of body weight measurement carried out per week, which corresponds to Day 29 which is the final evaluation day), and diarrhea of individual mice was observed during the test period. The results are shown in FIGS.
- Example 2 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 (a mixture of FTD and TPI at a molar ratio of 1: 0.5) is 75 and 150 mg / kg / day (recommended dose) as FTD, and CPT-11 is 100 mg / day as irinotecan hydrochloride hydrate. It was prepared to be kg / day (recommended dose). The results are shown in Table 2.
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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)。
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする固形癌に対する抗腫瘍剤。
〔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40~70mg/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、100~180mg/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〕記載の抗腫瘍剤。
〔5〕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で含有する配合剤を含む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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする抗腫瘍効果増強剤。
〔6〕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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする抗腫瘍剤。
〔7〕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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが記載されていることを特徴とするキット製剤。
〔8〕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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする配合剤。
〔9〕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40~70mg/m2/dayで投与される〔8〕記載の配合剤。
〔10〕イリノテカン塩酸塩水和物が、100~180mg/m2/day投与される〔8〕又は〔9〕記載の配合剤。
〔11〕固形癌が、結腸直腸癌、肺癌、乳癌、膵癌又は胃癌である〔8〕~〔10〕のいずれかに記載の配合剤。
〔12〕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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする配合剤。
〔13〕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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする配合剤。
〔14〕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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする使用。
〔15〕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40~70mg/m2/dayで投与される〔14〕記載の使用。
〔16〕イリノテカン塩酸塩水和物が、100~180mg/m2/day投与される〔14〕又は〔15〕記載の使用。
〔17〕固形癌が、結腸直腸癌、肺癌、乳癌、膵癌又は胃癌である〔14〕~〔16〕のいずれかに記載の使用。
〔18〕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で含有する配合剤を含む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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする使用。
〔19〕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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする使用。
〔20〕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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする固形癌の治療方法。
〔21〕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40~70mg/m2/dayで投与される〔20〕記載の方法。
〔22〕イリノテカン塩酸塩水和物が、100~180mg/m2/day投与される〔20〕又は〔21〕記載の方法。
〔23〕固形癌が、結腸直腸癌、肺癌、乳癌、膵癌又は胃癌である〔20〕~〔22〕のいずれかに記載の方法。
〔24〕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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする方法。
〔25〕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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする方法。
〔26〕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単独療法における推奨投与量で投与し、
イリノテカン塩酸塩水和物を、第1日目にイリノテカン塩酸塩水和物の単独療法における推奨投与量で投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする固形癌に対する抗腫瘍剤。
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)などの市販品を用いても良い。
後述の参考例及び実施例のとおり、マウスに対する単独療法における推奨投与量のFTD・TPI配合剤と、マウスに対する単独療法における推奨投与量のCPT-11を、上記の投与スケジュールに従いマウスに併用投与した場合、優れた抗腫瘍効果と副作用の抑制を達成できた。したがって、本発明の投与スケジュールにおけるFTD・TPI配合剤及びCPT-11のヒトへの投与量は、ヒトに対するFTD・TPI配合剤及びCPT-11の単独療法における推奨投与量であることは明らかである。
すなわち、第1日目~第5日目におけるFTDの投与量は20~80mg/m2/dayであり、抗腫瘍効果と副作用のバランスの観点から、40~70mg/m2/dayがより好ましく、70mg/m2/dayが特に好ましい。
第1日目におけるCPT-11の投与量はイリノテカン塩酸塩水和物として50~200mg/m2/dayであり、抗腫瘍効果と副作用のバランスの観点から、100~180mg/m2/dayが好ましく、150~180mg/m2/dayがより好ましく、180mg/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150mg/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、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100mg/kg/dayとなるように調製した。投与スケジュール(1)では、FTD・TPI配合剤はDay1-5及びDay8-12に連日経口投与し、CPT-11はDay1及びDay15に尾静脈から投与した。投与スケジュール(2)では、FTD・TPI配合剤はDay1-5及びDay15-19に連日経口投与し、CPT-11はDay1及びDay15に尾静脈から投与した。FTD・TPI配合剤及びCPT-11の単剤投与群は、併用投与群における対応する薬剤と同じ投与量及び投与スケジュールで投与した(図1)。
RTV=(Day29におけるTV)/(Day0におけるTV)
実施例2
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100mg/kg/day(推奨投与量)となるように調製した。結果を表2に示す。
Claims (26)
- 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日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施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40~70mg/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、100~180mg/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。
- 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で含有する配合剤を含む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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュール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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施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40~70mg/m2/dayで投与される請求項8記載の配合剤。
- イリノテカン塩酸塩水和物が、100~180mg/m2/day投与される請求項8又は9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8~10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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施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40~70mg/m2/dayで投与される請求項14記載の使用。
- イリノテカン塩酸塩水和物が、100~180mg/m2/day投与される請求項14又は15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14~16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で含有する配合剤を含む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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施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40~70mg/m2/dayで投与される請求項20記載の方法。
- イリノテカン塩酸塩水和物が、100~180mg/m2/day投与される請求項20又は21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20~22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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施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で含有する配合剤を第1日目から第5日目までトリフルリジン換算量で20~80mg/m2/day投与し、
イリノテカン塩酸塩水和物を第1日目に50~200mg/m2/day投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施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で含有する配合剤を、第1日目から第5日目まで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単独療法における推奨投与量で投与し、
イリノテカン塩酸塩水和物を、第1日目にイリノテカン塩酸塩水和物の単独療法における推奨投与量で投与する14日間で1サイクルの投与スケジュールが1回又は2回以上繰り返して実施されることを特徴とする固形癌に対する抗腫瘍剤。
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NZ712584A NZ712584A (en) | 2013-03-27 | 2014-03-27 | Antitumor agent including irinotecan hydrochloride hydrate |
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SI201431671T SI2979701T1 (sl) | 2013-03-27 | 2014-03-27 | Ptotitumorsko sredstvo z irinotekan hidroklorid hidratom |
US14/780,269 US9616082B2 (en) | 2013-03-27 | 2014-03-27 | Antitumor agent including irinotecan hydrochloride hydrate |
EP14773672.2A EP2979701B1 (en) | 2013-03-27 | 2014-03-27 | Antitumor agent including irinotecan hydrochloride hydrate |
PL14773672T PL2979701T3 (pl) | 2013-03-27 | 2014-03-27 | Środek przeciwnowotworowy obejmujący hydrat chlorowodorku irynotekanu |
ES14773672T ES2824400T3 (es) | 2013-03-27 | 2014-03-27 | Agente antitumoral que incluye clorhidrato de irinotecán hidratado |
JP2015508648A JP5976923B2 (ja) | 2013-03-27 | 2014-03-27 | イリノテカン塩酸塩水和物を含有する抗腫瘍剤 |
LTEP14773672.2T LT2979701T (lt) | 2013-03-27 | 2014-03-27 | Priešnavikinis agentas, įskaitant irinotekano hidrochlorido hidratą |
UAA201510464A UA114840C2 (uk) | 2013-03-27 | 2014-03-27 | Протипухлинний агент, який включає гідрат гідрохлориду іринотекану |
RU2015145948A RU2657604C2 (ru) | 2013-03-27 | 2014-03-27 | Противоопухолевый агент, включающий гидрат гидрохлорида иринотекана |
AU2014245146A AU2014245146B2 (en) | 2013-03-27 | 2014-03-27 | Antitumor agent including irinotecan hydrochloride hydrate |
RS20201272A RS60958B1 (sr) | 2013-03-27 | 2014-03-27 | Antitumorski agens koji uključuje irinotekan hidrohlorid hidrat |
DK14773672.2T DK2979701T3 (en) | 2013-03-27 | 2014-03-27 | Antitumormiddel indbefattende irinotecanhydrochloridhydrat |
ZA2015/07442A ZA201507442B (en) | 2013-03-27 | 2015-10-07 | Antitumor agent including irinotecan hydrochloride hydrate |
CY20201100962T CY1123539T1 (el) | 2013-03-27 | 2020-10-13 | Παραγων κατα των ογκων που περιλαμβανει ενυδρη υδροχλωρικη ιρινοτεκανη |
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CN106551946A (zh) * | 2015-09-24 | 2017-04-05 | 江苏奥赛康药业股份有限公司 | 一种含三氟胸苷和盐酸替比嘧啶的药物组合物及制备方法 |
JP2021113228A (ja) * | 2016-02-05 | 2021-08-05 | 大鵬薬品工業株式会社 | 重度腎機能障害を有する癌患者に対する治療方法 |
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WO2015034032A1 (ja) * | 2013-09-06 | 2015-03-12 | 大鵬薬品工業株式会社 | 抗腫瘍剤及び抗腫瘍効果増強剤 |
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JP2021113228A (ja) * | 2016-02-05 | 2021-08-05 | 大鵬薬品工業株式会社 | 重度腎機能障害を有する癌患者に対する治療方法 |
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AU2014245146B2 (en) | 2017-08-31 |
EP2979701A4 (en) | 2016-11-30 |
EP2979701A1 (en) | 2016-02-03 |
AU2014245146A1 (en) | 2015-10-15 |
SI2979701T1 (sl) | 2021-02-26 |
TWI615145B (zh) | 2018-02-21 |
PT2979701T (pt) | 2020-10-20 |
RS60958B1 (sr) | 2020-11-30 |
RU2015145948A (ru) | 2017-05-04 |
ZA201507442B (en) | 2017-01-25 |
LT2979701T (lt) | 2020-11-10 |
HUE051464T2 (hu) | 2021-03-01 |
UA114840C2 (uk) | 2017-08-10 |
DK2979701T3 (en) | 2020-10-26 |
US9616082B2 (en) | 2017-04-11 |
EP2979701B1 (en) | 2020-08-26 |
KR20150136073A (ko) | 2015-12-04 |
JPWO2014157443A1 (ja) | 2017-02-16 |
KR101847252B1 (ko) | 2018-04-09 |
RU2657604C2 (ru) | 2018-06-14 |
CY1123539T1 (el) | 2022-03-24 |
PL2979701T3 (pl) | 2020-12-28 |
ES2824400T3 (es) | 2021-05-12 |
US20160045530A1 (en) | 2016-02-18 |
HRP20201691T1 (hr) | 2020-12-25 |
JP5976923B2 (ja) | 2016-08-24 |
TW201513870A (zh) | 2015-04-16 |
NZ712584A (en) | 2018-03-23 |
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