NZ740252A - Antitumor agent including low-dose irinotecan hydrochloride hydrate - Google Patents

Abstract

Provided is a combination therapy which provides i) the combination of trifluridine (trifluorothymidine / TFT / FTD) and tipiracil hydrochloride (thymidine phosphorylase inhibitor / TPI); in combination with ii) irinotecan hydrochloride hydrate (CPT-11). The combination therapy is characterised in that the FTD/TPI combination drug is provided for administration at a reduced does amount of trifluridine (in the range of 35 to 70 mg/m2/day) combined with CPT-11 provided for administration at a dose in the range of 45 to 144 mg/m2/day.

Description

ANTITUMOR AGENT INCLUDING LOW-DOSE IRINOTECAN HYDROCHLORIDE This application is a divisional application of New Zealand application No. 712689, the contents of which are to be taken as incorporated herein by nce. New Zealand application No. 712689 claims the benefit of Japanese Application No. 2013-066074, filed 27 March 2013, the entire contents of which are also incorporated herein by reference.

Technical Field The present invention relates to an antitumour agent using a trifluridine/tipiracil hloride combination drug in combination with irinotecan hydrochloride hydrate, and to an agent for potentiating the antitumor effect of irinotecan hydrochloride hydrate. ound Art Trifluridine (also called:a,a,a-trifluorothymidine. after, also referred to as "FTD") exerts an antitumor effect due to an action for inhibiting thymidylate formation and an action for inhibiting DNA synthesis by incorporation into DNA. On the other hand, tipiracil hydrochloride (chemical name: -chloro[(2-iminopyrrolidinyl)methyl]-pyrimidine-2,4( 1H,3H)-dione hydrochloride. Hereinafter, also referred to as "TPI") has an action for inhibiting thymidine phosphorylase.

It has been previously described that the antitumor effect of FTD is potentiated by TPI suppressing the degradation of FTD in vivo caused by thymidine phosphorylase (Patent Literature 1). Currently, an antitumor agent containing FTD and TPI in a molar ratio of 1:0.5 (hereinafter referred to as "FTD/TPI combination drug") is under development as a therapeutic agent for solid cancers, for example, colorectal cancer (Non Patent Literatures 1 and 2).

Further, irinotecan hydrochloride hydrate nafter, also referred to as "CPT-11") is a camptothecin derivative whose active metabolite is SN-38 and which suppresses the synthesis and ription of DNA by inhibiting topoisomerase I, thereby to exert an antitumor effect. CPT-11 is clinically used as a therapeutic agent for a wide range of cancer types including, for example, small cell lung cancer, non-small cell lung cancer, cervical , ovarian cancer, gastric cancer, ctal cancer, breast cancer, squamous cell carcinoma, and ant lymphoma (Non Patent Literature 3).

Further, when FTD and SN-38 were allowed to act on a colorectal cancer cell line, a synergistic xicity was observed and thus a combination therapy using an FTD/TPI ation drug and CPT-11 has been expected (Non Patent Literature 4).

Citation List Patent Literature Patent Literature 1: WO 96/30346 Non Patent Literature Non Patent Literature 1: Invest New Drugs 26 (5): 445-54, 2008.

Non Patent Literature 2: Lancet Oncol. 13 (10): 01, 2012.

Non Patent Literature 3: Oncologist. 6(1): 66-80, 2001.

Non Patent ture 4: Eur J Cancer. 43(1): 175-83, 2007.

Summary of Invention Technical Problem The object of the present invention is to provide a novel combination y for solid cancers using an FTD/TPI combination drug which exhibits remarkable antitumor s, and few side effects.

Solution to Problem In view of this situation, when a combination therapy comprising repeating a 28-day cycle consisting of two times of -days’ administration at a dose of 70 mg/m2/day with 2-days’ rest of an I combination drug, followed by rest of the drug administration for 2 weeks, and an administration of CPT-11 at a dose of 150 mg/m2/day once in 2 weeks was performed in a colorectal cancer patient on the basis of the dose at which effects of each drug have previously been reported as in Reference Example described later, only about 30% of the predetermined amount of CPT-11 could be administered because side effects such as neutropenia, diarrhea, and body weight loss appeared strongly.

As a result of repeated studies on administration schedule which can suppress the occurrence of side effects and in which a predetermined amount can be administered, the present inventors have found that a combination therapy comprising stering an FTD/TPI combination drug at a dose in the range of 35 to 70 mg/m 2/day as a reduced amount of FTD, and CPT-11 at a dose in the range of 45 to 144 mg/m2/day to a solid cancer t suppresses the occurrence of side effects and exerts a superior antitumor effects.

That is, the present ion provides the ing: An antitumor agent for solid cancers, wherein a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered, using a reduced amount of trifluridine, at a dose in the range of 35 to 70 mg/m2/day, and irinotecan hydrochloride hydrate is administered at a dose in the range of 45 to 144 mg/m 2/day.

The mor agent according to [1], wherein the combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered at a dose of 70 day using a reduced amount of trifluridine.

The mor agent according to [1] or [2], wherein irinotecan hydrochloride e is administered at a dose in the range of 75 to 120 mg/m2/day.

The antitumor agent according to any one of [1] to , wherein the solid cancer is colorectal cancer, lung cancer, breast cancer, pancreatic cancer, or gastric cancer.

The antitumor agent according to any one of [1] to , wherein one cycle of an administration schedule, in which, in a period of 28 days, a combination drug ning trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered on Days 1 to 5 and on Days 8 to 12, and CPT-11 is administered on Day 1 and on Day 15, is repeated once or twice or more times.

An agent for potentiating antitumor effect 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 in a solid cancer patient, wherein the combination drug containing trifluridine and tipiracil hloride in a molar ratio of 1:0.5 is administered, using a reduced amount of trifluridine, at a dose in the range of 35 to 70 mg/m2/day, and irinotecan hydrochloride hydrate is stered at a dose in the range of 45 to 144 mg/m2/day.

An antitumor agent sing a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 for ng a solid cancer patient who has received irinotecan hydrochloride hydrate, wherein the combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered, using a reduced amount of trifluridine, at a dose in the range of 35 to 70 mg/m 2/day, and irinotecan hydrochloride hydrate is stered at a dose in the range of 45 to 144 mg/m2/day.

A kit preparation comprising an antitumor agent containing a combination drug of trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 and an instruction for use, wherein the instruction for use describes that the combination drug of trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is to be administered to a solid cancer patient, using a reduced amount of trifluridine, at a dose in the range of 35 to 70 mg/m2/day, and irinotecan hloride hydrate is to be administered at a dose in the range of 45 to 144 mg/m2/day.

A combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 for treating a solid cancer, wherein the combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered, using a reduced amount of trifluridine at a dose in the range of 35 to 70 mg/m2/day, and irinotecan hydrochloride hydrate is stered at a dose in the range of 45 to 144 mg/m2/day.

The combination drug according to [9], wherein the combination drug containing trifluridine and tipiracil hloride in a molar ratio of 1:0.5 is administered, using a reduced amount of trifluridine, at a dose of 70 mg/m 2/day.

The combination drug according to [9] or [10], n irinotecan hydrochloride hydrate is administered at a dose in the range of 75 to 120 mg/m2/day.

The combination drug ing to any one of [9] to , wherein the solid cancer is colorectal cancer, lung cancer, breast cancer, pancreatic cancer, or gastric cancer.

The combination drug according to any one of [9] to , wherein one cycle of an administration schedule, in which, in a period of 28 days, the combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered on Days 1 to 5 and on Days 8 to 12, and CPT-11 is administered on Days 1 and 15, is repeated once or twice or more times.

A combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 for enhancing the mor effect of irinotecan hydrochloride hydrate in a solid cancer patient, n the combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered, using a reduced amount of ridine, at a dose in the range of 35 to 70 mg/m2/day, and irinotecan hydrochloride hydrate is administered at a dose in the range of 45 to 144 day.

A combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 for treating a solid cancer patient who has received irinotecan hydrochloride hydrate, wherein the combination drug ning trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered, using a reduced amount of trifluridine, at a dose in the range of 35 to 70 mg/m2/day, and irinotecan hydrochloride hydrate is administered at a dose in the range of 45 to 144 mg/m 2/day.

Use of a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 for manufacturing an mor agent against solid cancers, wherein the combination drug containing trifluridine and cil hydrochloride in a molar ratio of 1:0.5 is administered, using a reduced amount of trifluridine, at a dose in the range of 35 to 70 mg/m2/day, and irinotecan hydrochloride hydrate is stered at a dose in the range of 45 to 144 mg/m 2/day.

The use according to claim 16, wherein the combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered, using a reduced amount of trifluridine, at a dose of 70 mg/m2/day.

The use according to [16] or [17], wherein irinotecan hydrochloride hydrate is administered at a dose in the range of 75 to 120 mg/m2/day.

The use according to any one of [16] to [18], wherein the solid cancer is ctal , lung cancer, breast cancer, pancreatic cancer, or gastric cancer.

The use ing to any one of [16] to [19], wherein one cycle of an administration schedule, in which, in a period of 28 days, the combination drug ning trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered on Days 1 to 5 and on Days 8 to 12, and CPT-11 is administered on Days 1 and 15, is repeated once or twice or more times.

Use for manufacturing an agent for potentiating antitumor effect comprising a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 to potentiate the antitumor effect of irinotecan hydrochloride hydrate in a solid cancer patient, wherein the combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is stered, using a reduced amount of trifluridine, at a dose in the range of 35 to 70 mg/m2/day, and irinotecan hydrochloride hydrate is administered at a dose in the range of 45 to 144 mg/m 2/day.

Use for manufacturing an mor agent comprising a ation drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 to treat a solid cancer patient who has ed irinotecan hydrochloride hydrate, wherein the combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered, using a reduced amount of trifluridine, at a dose in the range of 35 to 70 mg/m2/day, and irinotecan hloride hydrate is administered at a dose in the range of 45 to 144 mg/m 2/day.

A method for treating a solid cancer, wherein a combination drug ning trifluridine and tipiracil hloride in a molar ratio of 1:0.5 is administered, using a reduced amount of trifluridine, to a solid cancer patient at a dose in the range of 35 to 70 mg/m2/day, and irinotecan hloride hydrate is administered at a dose in the range of 45 to 144 mg/m2/day.

The method according to [23], wherein the combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered at a dose of 70 mg/m2/day, using a reduced amount of trifluridine.

The method according to [23] or [24], wherein irinotecan hydrochloride hydrate is administered at a dose in the range of 75 to 120 mg/m2/day.

The method according to any one of [23] to [25], wherein the solid cancer is colorectal cancer, lung cancer, breast cancer, pancreatic cancer, or gastric cancer.

The method according to any one of [23] to [26], wherein one cycle of an administration schedule, in which, in a period of 28 days, the combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered on Days 1 to 5 and on Days 8 to 12 and CPT-11 is administered on Days 1 and 15, is repeated once or twice or more times.

A method for ing the antitumor effect of irinotecan hydrochloride hydrate against solid cancer patients, n a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered, using a reduced amount of trifluridine, to a solid cancer patient at a dose in the range of 35 to 70 mg/m2/day, and irinotecan hydrochloride hydrate is administered at a dose in the range of 45 to 144 mg/m2/day.

A method for treating a solid cancer patient who has received irinotecan hydrochloride hydrate, n a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered, using a reduced amount of ridine, at a dose in the range of 35 to 70 mg/m2/day to a solid cancer t, and irinotecan hydrochloride hydrate is administered at a dose in the range of 45 to 144 day.

An antitumor agent for solid cancers, wherein a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is administered in combination with irinotecan hydrochloride hydrate, wherein the dose of the combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is 50% to 100% of the recommended dose in the monotherapy, and the dose of irinotecan hydrochloride hydrate is 25% to 80% of the recommended dose in the monotherapy.

The antitumor agent according to [30], wherein the dose of the combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 is 100% of the recommended dose in the monotherapy.

The mor agent according to [30] or [31], wherein the dose of irinotecan hydrochloride hydrate is 50% to 70% of the recommended dose in the erapy.

Use of trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 in the preparation of an antitumor medicament for the treatment of solid cancers, - n the mor medicament is adapted to administer trifluridine and tipiracil hydrochloride at a dose in the range of 35 to 70 mg/m2/day, and - wherein the antitumor medicament is adapted to administer trifluridine and tipiracil hydrochloride in combination with ecan hloride hydrate at a dose in the range of 45 to 130 mg/m2/day.

Use of irinotecan hydrochloride hydrate and a ation drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 in the manufacture of an agent for the treatment of cancers by potentiating the antitumor effect of the ecan hydrochloride hydrate which is formulated for stration at a dose in the range of 45 to 144 mg/m2/day in a solid cancer patient, wherein the agent comprises the combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 which is formulated for administration of trifluridine at a dose in the range of 35 to 70 mg/m2/day.

Use of a combination drug in the preparation of an agent for the treatment of cancers by potentiating the antitumor effect of the ecan hydrochloride hydrate preset in a t, and - wherein the combination drug contains trifluridine and tipiracil hloride in a molar ratio of 1:0.5, and - wherein the agent is formulated for use in combination with irinotecan hydrochloride hydrate for administration at a dose in the range of 45 to 144 mg/m2/day, and - wherein the agent contains trifluridine and tipiracil hydrochloride in a molar ratio of 1:0.5 which is formulated for administration of trifluridine at a dose in the range of 35 to 70 mg/m2/day.

The use, in the manufacture of an antitumor medicament, of a combination of ridine and tipiracil hydrochloride in a molar ratio of 1:0.5, and irinotecan hydrochloride hydrate as active ingredients for the treatment of solid cancers, - wherein the antitumor medicament is adapted to administer the combination of trifluridine and tipiracil hydrochloride at a dose in the range of 35 to 70 mg/m2/day, and - wherein the antitumor medicament is adapted to administer the combination of trifluridine and tipiracil hydrochloride, in combination with irinotecan hydrochloride hydrate at a dose in the range of 45 to 130 day.

Advantageous Effects of Invention ing to the antitumor agent of the present invention, it is possible to perform cancer treatment exhibiting a high antitumor effect while suppressing the onset of side s, thereby ing long-term survival in patients.

Brief Description of Drawings Fig. 1 is a graph showing an antitumor effect by combination use of an I combination drug at a dose of 150 mg/kg/day and CPT-11 at a dose of 50 mg/kg/day.

Fig. 2 is a graph showing an antitumor effect by combination use of an FTD/TPI combination drug at a dose of 150 mg/kg/day and CPT-11 at a dose of 25 mg/kg/day.

Fig. 3 is a graph showing an antitumor effect by combination use of an FTD/TPI combination drug at a dose of 150 mg/kg/day and CPT-11 at a dose of 10 mg/kg/day.

Fig. 4 is a graph g an antitumor effect by combination use of an FTD/TPI combination drug at a dose of 75 mg/kg/day and CPT-11 at a dose of 50 mg/kg/day.

Fig. 5 is a graph showing an antitumor effect by combination use of an FTD/TPI combination drug at a dose of 75 mg/kg/day and CPT-11 at a dose of 25 mg/kg/day.

Fig. 6 is a graph g an antitumor effect by combination use of an FTD/TPI combination drug at a dose of 75 mg/kg/day and CPT-11 at a dose of 10 mg/kg/day.

Fig. 7 is a graph showing survival rate at Day 70 in each combined administration group of an FTD/TPI combination drug at a dose of 150 mg/kg/day and CPT-11 at a dose of 50, 70, or 100 mg/kg/day.

Description of Embodiments FTD and TPI of the present ion are both previously described nds and can be synthesized, for example, according to the method bed in WO 96/30346. A combination drug of FTD and TPI in a molar ratio of 1:0.5 has also been previously described (Non Patent Literatures 1 and 2).

CPT-11 of the present invention is a previously described compound and can be synthesized according to the method bed in Japanese Patent No. 3,004,077. Also, the commercially available product, for example, CAMPTO (registered trademark, Yakult Honsha Co., Ltd.), may be used.

The administration schedule of the antitumor agent of the present invention is not particularly limited as long as the effects of the present invention are achieved, and one cycle in which, in a period of 28 days, a combination drug containing FTD and TPI in a molar ratio of 1:0.5 is administered on Days 1 to 5 and on Days 8 to 12, and CPT-11 is administered on Days 1 and 15, is preferably repeated once or twice or more times.

As shown in Reference Example and Examples described later, when 50% to 100% of the recommended dose of FTD/TPI combination drug in the monotherapy in mice was administered to mice in combination with 25% to 80% of the recommended dose of CPT-11 in the monotherapy in mice, or antitumor effects and suppression of side effects could be achieved. Thus, the dose of FTD/TPI ation drug is 50% to 100%, especially preferably 100%, of the recommended dose in the monotherapy in humans from the int of a balance n antitumor effects and side s. The dose of CPT-11 is 25% to 80%, preferably 40% to 80%, more preferably 50% to 80%, especially preferably 50% to 70%, of the recommended dose in the monotherapy in humans from the viewpoint of a balance between antitumor effects and side In other words, since the recommended dose of FTD/TPI combination drug in the monotherapy in humans is 70 mg/m2/day, the dose of FTD is 35 to 70 mg/m2/day, and from the viewpoint of a balance n antitumor effects and side effects, the dose of FTD is especially ably 70 mg/m2/day.

The recommended dose of CPT-11 in the erapy in humans may vary depending on the administration schedules, for example, for administration every two weeks, the dose of CPT-11 is 150 to 180 mg/m2/day. Thus, when the recommended dose of CPT-11 is 180 mg/m2/day (for example, for gastrointestinal cancer, lung cancer, breast cancer, cervical cancer, or ovarian cancer, preferably for colorectal cancer and pancreatic cancer), the dose of CPT-11 according to the present ion is in the range of 45 to 144 mg/m2/day, and from the viewpoint of a balance between mor effects and side effects, the dose of CPT-11 is preferably in the range of 72 to 144 mg/m2/day, more preferably in the range of 90 to 144 mg/m2/day, and especially preferably in the range of 90 to 126 mg/m2/day. Also, when the recommended dose is 150 mg/m2/day (for example, for gastrointestinal cancer, lung cancer, breast cancer, cervical cancer, or ovarian cancer, preferably for cervical cancer, ovarian cancer, c cancer, and colorectal cancer), the dose of CPT-11 according to the present invention is in the range of 37.5 to 120 mg/m 2/day and from the viewpoint of a balance between antitumor s and side effects, the dose of CPT-11 is preferably in the range of 60 to 120 mg/m2/day, more preferably in the range of 75 to 120 mg/m 2/day, and especially preferably in the range of 75 to 105 mg/m 2/day.

Further, in the case of administration every week, the recommended dose of CPT-11 in the monotherapy in humans is 100 to 125 mg/m2/day. While the recommended dose is 100 mg/m2/day (for example, for gastrointestinal cancer, lung cancer, breast cancer, cervical cancer, or ovarian cancer, preferably for small cell lung cancer, non-small cell lung cancer, breast cancer, cervical cancer, ovarian cancer, gastric cancer, and ctal cancer), the dose of CPT-11 ing to the present invention is in the range of 25 to 80 day and from the viewpoint of a balance between antitumor effects and side effects, the dose of CPT-11 is preferably 40 to 80 mg/m2/day, more preferably 50 to 80 mg/m2/day, and especially ably 50 to 70 mg/m2/day.

In addition, when the recommended dose is 125 mg/m2/day (for e, for gastrointestinal cancer, lung cancer, breast cancer, cervical cancer or n cancer, and preferably for colorectal cancer), the dose of CPT-11 according to the present invention is in the range of 31.25 to 100 mg/m2/day and from the int of a balance between antitumor effects and side effects, the dose of CPT-11 is preferably in the range of 50 to 100 mg/m2/day, more preferably in the range of 62.5 to 100 mg/m2/day, and especially preferably in the range of 62.5 to 87.5 mg/m 2/day.

In addition, in the case of administration every three weeks, the ended dose of CPT-11 in the monotherapy in humans is 350 mg/m2/day (for example, for gastrointestinal cancer, lung cancer, breast cancer, cervical cancer, or ovarian cancer, and ably for colorectal cancer). Whereas, the dose of CPT-11 according to the present invention is in the range of 87.5 to 280 mg/m2/day and from the int of a balance between antitumor effects and side effects, the dose of CPT-11 is preferably in the range of 140 to 280 mg/m2/day, more preferably in the range of 175 to 280 day, and especially preferably in the range of 175 to 245 mg/m2/day.

The target of the antitumor agent of the present invention is a solid cancer including specifically head and neck cancer, gastrointestinal cancer (esophageal cancer, c cancer, duodenal , liver cancer, biliary tract cancer (gallbladder cancer/bile duct cancer), pancreatic cancer, small inal cancer, large intestinal cancer (colorectal cancer, colon , rectal cancer), etc.), lung cancer, breast cancer, ovarian cancer, uterine cancer (cervical cancer, uterine cancer), renal cancer, bladder cancer, prostate cancer, etc. Of these, from the int of antitumor effects and side effects, the target is preferably gastrointestinal cancer, lung cancer, breast cancer, cervical cancer, or ovarian cancer; more preferably colorectal cancer, lung cancer, breast cancer, pancreatic cancer, or gastric cancer; more preferably colorectal cancer and c cancer; and particularly preferably colorectal cancer. Here, the solid cancer es not only primary tumor but also tumor derived from solid cancer that has metastasized to other organs (such as liver). Also, the antitumor agent of the present invention may be one used for postoperative nt chemotherapy that is performed for preventing the recurrence after having surgically removed the tumor.

Since the administration means and the administration le are different in each active ingredient, all the active ingredients cannot be formulated in one dosage form. Thus, the antitumor agent of the present invention is formulated separately for each active ingredient into a plurality of dosage forms.

It is preferred that FTD and TPI are formulated as a combination drug and CPT-11 is formulated as a single agent.

Further, as long as each active ient is administered according to the dose of the present invention, each preparation may be manufactured and sold together in a single package suitable for combined administration, or each ation may be manufactured and sold after being divided into a separate package.

There is no particular limitation to the dosage form of the antitumor agent of the present invention, and it can be appropriately selected depending on the therapeutic purposes and includes specifically oral preparations (tablets, coated tablets, powders, granules, es, solutions, etc.), injections, suppositories, patches, ointments, etc. An oral ation is preferable for the combination drug of FTD and TPI, and an injectable preparation is preferable for CPT-11.

Depending on the dosage form, the antitumor agent of the present invention can be usually prepared by the known method using a ceutically able carrier. Such a r includes various ones which are commonly used in conventional drugs, such as excipients, binders, egrators, lubricants, diluents, solubilizers, suspending agents, ic agents, pH adjusting agents, buffering agents, stabilizers, coloring agents, flavoring agents, and flavors.

The present invention also relates to an agent for potentiating antitumor effect comprising an FTD/TPI combination drug for enhancing the antitumor effect of CPT-11 in a solid cancer t (especially colorectal cancer patient), wherein the FTD/TPI combination drug and CPT-11 are administered on the basis of the dose mentioned above. The agent for potentiating antitumor effect has the dosage form of the above antitumor agent.

The present invention further relates to an antitumor agent comprising an FTD/TPI combination drug for treating a solid cancer patient (especially colorectal cancer patient) who has received CPT-11, wherein the FTD/TPI combination drug and CPT-11 are stered based on the dose mentioned above. The antitumor agent has the above dosage form.

The present invention furthermore relates to a kit preparation comprising an FTD/TPI combination drug and an instruction for use teaching that the FTD/TPI combination drug and CPT-11 are to be administered to a solid cancer patient (especially colorectal cancer patient) based on the dose mentioned above. Here, the term "instruction for use" may be any one as long as it describes the dose; however, an instruction for use, in which the above dose is recommended though legal binding force does not matter, is preferable. The instruction for use includes ically a package insert, a pamphlet, etc.

Also, a kit ation comprising an instruction for use may be one in which the instruction for use is d on or attached to the package of the kit preparation, or a kit preparation may be one in which an antitumor agent er with the instruction for use is enclosed in a package of the kit preparation.

EXAMPLES Then, the present ion is explained in more detail by way of Examples.

Reference Example ed cells (1 ´ 107 cells/mouse) of human colon cancer cell line (KM20C) were intraperitoneally transplanted into 5-6 weeks old BALB/cA Jcl-nu mice after birth, and the mice were assigned to each group so that the mean body weight of each group became equal. The date on which such grouping (n=10) was performed was taken as Day 0.

An FTD/TPI combination drug (a mixture of FTD and TPI in a molar ratio of 1:0.5) was prepared so as to be 75, 100, 150, 300, and 450 mg/kg/day as FTD. Since a death case of irinotecan hydrochloride hydrate 1: CAMPTO (registered trademark) infusion, Yakult Honsha Co., Ltd.) at a dose of 111 mg/kg/day was reported (Kiso to Rinsho, (1990), Vol. 24, No. 14, 7-17), irinotecan hydrochloride hydrate was prepared so as to be 80 and 100 day. Starting the dug administration from Day 3, a 5-days’ daily oral administration of the FTD/TPI combination drug with 2-days’ rest was performed for 6 weeks, and CPT-11 was stered once in a week from the tail vein for 6 weeks.

As an index of the antitumor effect, the number of survivors of each group of mice and the survival time of each group was compared. The results are shown in Table 1.

[Table 1] 3m}: Gov - 98 0% 2.; 9% Sn 9% a; $3 Om 3. E 0.? 30 w: 2: 9: as 95 fi H a a a a a a a :33 :82 o? 9% w? 32 0.? 3m o. mo 2: .02 MES" 2 S 2 2 2 2 2 2 #7338» "3.6 65 2:8 85 83 we :2 62 we up. 35:8 .fi%-~ .aau-~ .53 .53 mo 898th Kgmfiacagmgg £3 £3 £3 £3 1 £83 £83 .gm Saginaw SHEER asgminca ing" .5. 3:. 595 Ea :8 as :8 .20 3:on 33% .93: 1%-" a": K86 awn 3953.: Soc Mo % 05.5 38 33%th n goo? fl 8. ca 8m o? 8 2: 0.5 .8 3323. :02» 83.8... :38: 3.58 £9.95 E. 5... r: u . Ed: . . 203 o 888 at 2.: 2.: :Eo :Eb $95" 3T Gama As bed in Table 1, since the life span of a 100 day administration group of CPT-11 in mice was long, the recommended dose (RD) of CPT-11 in mice is 100 mg/kg/day as irinotecan hydrochloride hydrate. Thus, the dose of 100 mg/kg/day in mice is equivalent to RD of 150 to 180 mg/m2/day in humans.

Since the life span was long in the 150 mg/kg/day (as a reduced amount of FTD) administration group of FTD/TPI combination drug, RD of the FTD/TPI combination drug in mice is 150 mg/kg/day using a d amount of FTD. Thus, 150 mg/kg/day (as a reduced amount of FTD) in mice is equivalent to RD of 70 mg/m2/day (as a reduced amount of FTD) in humans.

Example 1 Human colon cancer cell lines (KM20C) were transplanted into the right chest of 5-6 weeks old BALB/cA Jcl-nu mice after birth. After tumor transplant, the major axis (mm) and minor axis (mm) of tumor were measured, and the tumor volume (TV) was calculated. Then, the animals were assigned to each group so that the mean TV of each group becomes equal and the day when grouping (n=6) was performed was taken as Day 0.

The FTD/TPI ation drug (a mixture of FTD and TPI in a molar ratio of 1:0.5) was prepared so as to be 75 and 150 mg/kg/day as FTD. CPT-11 (CAMPTO (registered ark, Yakult Honsha Co., Ltd.) infusion) was prepared so as to be 10, 25, and 50 day as irinotecan hloride hydrate. The FTD/TPI combination drug was daily and orally administered on Days 1 to 14, and CPT-11 was administered via the tail vein on Days 1 and 8. The FTD/TPI combination drug and CPT-11 were administered to the combined administration group at the same dose according to the administration schedule as in the monotherapy group. A list of each drug administration group is shown in Table 2.

As an indicator of the antitumor effect, TV on Days 4, 8, 11, 15, 18, and 22 in each group was calculated, and the relative tumor volume (RTV) on Day 0 was ined by the following equation, and then plotted. The daily changes of the RTV of the untreated group (control), the FTD/TPI combination drug administration group, the CPT-11 administration group, and the combined administration group of FTD/TPI combination drug and CPT-11 were compared.

TV (mm3) = (long axis ´ (short axis)2)/2 RTV = (TV on Day 28)/(TV on Day 0) [Table 2] As shown in Figs. 1 to 6, when the dose of FTD/TPIcombination drug was in the range of 75 to 150 mg/kg/day and the dose of CPT-11 was in the range of 25 to 50 mg/kg/day, a synergistic mor effect was obtained.

Example 2 Cultured cells (1 ´ 107 cells/mouse) of a human colon cancer cell line ) were intraperitoneally transplanted into 5-6 weeks old mice after birth, BALB/cA Jcl-nu mice. The mice were assigned to each group (n=10) so that the mean body weight of each group became equal, and the day when such grouping (n=6) was performed was taken as Day 0.

A FTD/TPI combination drug (mixture of FTD and TPI in a molar ratio of 1:0.5) was prepared so as to be 150 mg/kg/day (recommended dose) as FTD. CPT-11 (CAMPTO (registered trademark) on, Yakult Honsha Co., Ltd.) was prepared so as to be 50, 70, and 100 mg/kg/day as irinotecan hloride hydrate. In each combined administration group, the combined administration was started on Day 3 and the FTD/TPI combination drug was subjected to a 5-days’ daily oral administration with 2-days’ rest for 6 weeks, and the CPT-11 was administered once a week via the tail vein for 6 weeks.

As an indicator of the antitumor effect, the number of survivors in each group of mice on Day 70 was confirmed and the survival rate of each group was compared. The survival rate of each group on Day 70 is shown in Fig. 7.

As shown in Fig. 7, in the administration group of 150 mg/kg/day of FTD/TPI combination drug and 50 or 70 mg/kg/day of CPT-11, the survival rate on Day 70 was 100%, while in the administration group of 150 mg/kg/day of FTD/TPI ation drug and 100 mg/kg/day of , side effects appeared strongly and the survival rate on Day 70 was ely lowered up to 30%.

Example 3 A combined administration test of an FTD/TPI combination drug and CPT-11 was med in the same manner as in Example 1, except that the cell line was changed to human gastric cancer cell line (SC-2). The FTD/TPI combination drug (a mixture of FTD and TPI in a molar ratio of 1:0.5) was prepared so as to be 75 and 150 mg/kg/day (recommended dose) as FTD, and CPT-11 was prepared so as to be 40 and 80 mg/kg/day as irinotecan hydrochloride hydrate. The results are shown in Table 3.

[Table 3] As shown in Table 3, when 50 to 100% of the recommended dose of FTD/TPI combination drug in the monotherapy was used in combination with 40 to 80% of the recommended dose of CPT-11 in the monotherapy for gastric cancer, a remarkable enhancement of the antitumor effect was confirmed. Also, the body weight loss was within an acceptable range.

From the above, when 50 to 100% of the recommended dose of FTD/TPI combination drug in the erapy and 25 to 80% of the ended dose of CPT-11 in the monotherapy were used in combination, it was ed that an excellent antitumor effect was exhibited while suppressing the onset of side effects.

THE

Claims (3)

CLAIMS DEFINING THE SCOPE OF THE INVENTION ARE AS FOLLOWS:

1. The use, in the cture of an antitumor ment, of a combination of trifluridine and cil hydrochloride in a molar ratio of 1:0.5, and ecan hydrochloride hydrate as active ingredients for the treatment of solid cancers, - wherein the antitumor medicament is adapted to administer the combination of trifluridine and tipiracil hloride at a dose in the range of 35 to 70 mg/m2/day, and - wherein the antitumor medicament is adapted to administer the combination of trifluridine and tipiracil hydrochloride, in combination with irinotecan hydrochloride hydrate at a dose in the range of 45 to 130 mg/m2/day.

2. The use according to claim 1, wherein the antitumor medicament is adapted to ster trifluridine at a dose of 70 mg/m2/day.

3. The use according to claim 1 or claim 2, wherein the antitumor medicament is adapted to administer irinotecan hydrochloride hydrate at a dose of 75 to