WO2019146130A1 - 胆道がん用抗腫瘍剤および胆道がんの処置方法 - Google Patents
胆道がん用抗腫瘍剤および胆道がんの処置方法 Download PDFInfo
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Definitions
- the present invention relates to an antitumor agent for biliary tract cancer, and a method for treating biliary cancer.
- Compound A (2-Deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (hereinafter sometimes referred to as “compound A”) has excellent antitumor activity, It is known that it is useful as an antitumor agent (patent document 1). Compound A is also known to have strong antitumor activity even when orally administered to mice (Non-patent Documents 1 to 3). In addition, salts, prodrugs, injections and methods of production of Compound A are also known (Patent Documents 2 to 6).
- Biliary cancer is a highly invasive cancer that originates from biliary epithelial cells. Biliary tract cancer is often found at an advanced stage in many cases due to poor clinical symptoms at the early onset, and its prognosis is poor. As treatment for biliary tract cancer, surgical resection is the only complete curative treatment, but recurrence rates are high. In addition, although chemotherapy is given for inoperable cases or recurrent cases, the treatment effect is often inadequate.
- An object of the present invention is to provide an antitumor agent for biliary tract cancer, which has an effect on biliary tract cancer, and a method for treating biliary tract cancer.
- an antitumor agent for biliary tract cancer which comprises 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or a prodrug thereof.
- the antitumor agent according to (1) wherein the biliary tract cancer is bile duct cancer.
- One dose is 20 mg / m 2 or more, and after one week administration for 3 weeks, the course for taking a rest at week 4 is repeated multiple times, any of (1) to (3) The antitumor agent described in 1).
- the antitumor agent according to (4), wherein the single dose is 40 mg / m 2 to 200 mg / m 2 .
- the antitumor agent according to (4), wherein the single dose is 80 mg / m 2 to 150 mg / m 2 .
- a therapeutically effective dose of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof is administered to a subject (a mammal including human)
- Methods of treating biliary cancer, or A method of administering an antitumor agent to a biliary cancer patient comprising: The method wherein the antitumor agent comprises 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof.
- the biliary tract cancer is bile duct cancer.
- A A method for using 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof for the treatment of biliary cancer, Administering a therapeutically effective dose to a subject (a mammal, including a human) in need of such treatment.
- B biliary tract comprising administering to the subject a therapeutically effective dose of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof Treatment methods.
- C Use of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof for the production of an antitumor agent for biliary tract cancer.
- D 1- (2-Deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof for use in the treatment of biliary tract cancer.
- Compound A exerts a therapeutic effect on biliary tract cancer. That is, according to the present invention, an antitumor agent for biliary tract cancer and a method for treating biliary tract cancer, which are effective for biliary tract cancer are provided.
- FIG. 1 shows the results of diagnostic imaging for cholangiocarcinoma patient 1.
- FIG. 2 shows the results of diagnostic imaging for cholangiocarcinoma patient 2.
- FIG. 3 is a graph showing the rate of change of the major axis of the tumor relative to Baseline in patients with cholangiocarcinoma 1-6.
- FIG. 4 is a graph showing the Cmax value of the plasma concentration of a patient receiving Compound A in a clinical test.
- the range represented by “to” includes the values at both ends, unless otherwise specified.
- the "subject” is a human, mouse, monkey, domestic animal or other mammal in need of the prevention or treatment, preferably a human in need of the prevention or treatment.
- prevention refers to inhibition of onset, reduction in risk of onset or delay in onset, and the like.
- Treatment refers to amelioration or suppression (maintenance or delay) of the disease or condition to be treated.
- Treatment refers to prevention or treatment for various diseases.
- tumor is meant a benign or malignant tumor.
- cancer tumor is meant a tumor that is close to the normal cells from which the tumor cells and their sequences are derived and is not invasive or metastatic.
- malignant tumor refers to a tumor which is invasive or metastatic, in which the morphology of the tumor cells and their sequences are different from those of the normal cells from which they are derived.
- the present invention relates to an antitumor agent for biliary tract cancer, which comprises 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (compound A) or a salt or prodrug thereof. is there.
- Salts include pharmaceutically acceptable salts, and in particular, mineral acid salts, organic carboxylates and sulfonates.
- Preferred salts include mineral and sulfonate salts.
- Mineral acid salts include, for example, hydrochlorides, hydrobromides, hydroiodides, nitrates, phosphates and sulfates, with hydrochlorides, hydroiodides, nitrates or sulfates being preferred.
- Hydrochloride is more preferred.
- organic carboxylates include formate, acetate, citrate, oxalate, fumarate, maleate, succinate, malate, tartrate, aspartate, trichloroacetate and the like Trifluoroacetic acid salt is mentioned.
- sulfonate examples include methanesulfonate, benzenesulfonate, p-toluenesulfonate, mesitylenesulfonate and naphthalenesulfonate, with methanesulfonate being preferred.
- the salt of compound A may be an anhydride, a hydrate or a solvate. As referred to herein simply as “salts”, the form may be an anhydride, hydrate or solvate.
- the term “anhydride” as used herein refers to the case where it is in neither hydrate nor solvate state, unless otherwise stated. Water of crystallization, water of hydration, and a salt of Compound A having no interacting solvent, which are substances which do not form hydrates or solvates originally, are included in the “anhydride” in the present invention. .
- Anhydride is also referred to as "anhydrate.”
- the salt of compound A is a hydrate
- the number of hydration water is not particularly limited, and may be a monohydrate, a dihydrate or the like.
- solvates include methanolate, ethanolate, propanolate and 2-propanolate.
- Particular preferred salts of Compound A are: Methanesulfonic acid salt of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine; Hydrochloride salt of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine; As well as the anhydride of any of the above mentioned salts.
- prodrug refers to a compound or a salt thereof in which a functional group functioning as a prodrug is cleaved by a reaction in the body with enzymes such as gastric juice after administration to be converted into a compound exhibiting a desired pharmacological activity.
- Groups forming a prodrug include, for example, groups described in Stella VJ et al., Prodrugs: Challenges and Rewards. Parts 1 and 2, 2007, American Association of Pharmaceutical Principles.
- the prodrug of Compound A refers to a compound or a salt thereof which is converted to Compound A or its phosphate compound by a reaction with an enzyme or gastric juice under physiological conditions in vivo.
- a prodrug of Compound A the description of WO 2016/068341 can be incorporated and referred to, and the contents thereof are incorporated herein. More specifically, for example, the thionucleoside derivative represented by the general formula [1] described in WO 2016/068341 or a salt thereof is incorporated in the present specification, and the preferred range thereof is also WO 2016 It is the same as that described in Japanese Patent Publication No.
- the compound A or a salt or prodrug thereof may be used alone or in combination of two or more.
- Compound A can be produced, for example, by the method described in Patent Document 1 and Journal of Organic Chemistry, 1999, vol. 64, p7912-7920.
- the salt of Compound A or a hydrate or solvate thereof can be produced, for example, by the method described in Patent Document 4.
- the prodrug of compound A can be produced, for example, by the method described in WO 2016/068341.
- the compound A or a salt or prodrug thereof according to the present invention can be used as an antitumor agent and as an active ingredient of a pharmaceutical composition.
- an antitumor agent for biliary tract cancer which comprises 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof.
- Biliary cancer is preferably bile duct cancer, more preferably extrahepatic cholangiocarcinoma or intrahepatic cholangiocarcinoma.
- the antitumor agent of the present invention generally comprises an emulsifier, surfactant, solubilizer, suspending agent, tonicity agent, buffer, preservative, antioxidant, stabilizer, absorption enhancer, etc. It may contain an agent.
- the administration route of the antitumor agent of the present invention includes intravenous, intraarterial, intrarectal, intraperitoneal, intramuscular, intratumoral or intravesical injection, oral administration, transdermal administration and / or suppository, etc. Can be mentioned. Methods of administration include administration by syringe or infusion.
- the dose and number of doses of Compound A or a salt or prodrug thereof can be administered in 1 to 2000 mg / m 2 per day in divided doses.
- the daily dose is preferably 20 mg / m 2 or more, preferably 40 mg / m 2 or more, and preferably 60 mg / m 2 or more.
- the upper limit value of the daily dose is preferably 200 mg / m 2 , more preferably 150 mg / m 2 , still more preferably 120 mg / m 2 , and particularly preferably 100 mg / m 2 .
- the daily dose is more preferably 40 mg / m 2 to 200 mg / m 2 , still more preferably 40 mg / m 2 to 150 mg / m 2 , still more preferably 80 mg / m 2 to 150 mg / m 2 And still more preferably 80 mg / m 2 to 120 mg / m 2 .
- it is not limited to these doses and frequency of administration.
- one dose can be 20 mg / m 2 or more, and after one week administration for 3 weeks, the course of withdrawal can be repeated multiple times for the 4th week.
- the single dose is the same as the daily dose described above, but preferably 40 mg / m 2 to 200 mg / m 2 , more preferably 40 mg / m 2 to 150 mg / m 2 And more preferably 80 mg / m 2 to 150 mg / m 2 .
- Examples of the dosage form of the antitumor agent for biliary tract cancer of the present invention include liquid pharmaceutical preparations, such as injections.
- the dosage forms can each be prepared by conventional formulation methods known to those skilled in the art.
- the liquid pharmaceutical preparation preferably contains compound A or a salt thereof, a polyhydric alcohol having a molecular weight of 100 or less, and water.
- the content of Compound A or a salt thereof is preferably 1 to 50 mg / mL, more preferably 5 to 50 mg / mL, and particularly preferably 10 to 30 mg / mL.
- the polyhydric alcohol having a molecular weight of 100 or less is preferably a polyhydric alcohol having 3 or 4 carbon atoms, more preferably glycerin, propylene glycol or butanediol, and particularly preferably glycerin.
- examples of butanediol include 1,2-butanediol, 1,3-butanediol, 1,4-butanediol and 2,3-butanediol, and 1,3-butanediol is particularly preferable.
- the lower limit of the molecular weight of polyhydric alcohol is not particularly limited, it is generally 50 or more.
- the content of polyhydric alcohol having a molecular weight of 100 or less is preferably 0.5 to 10% by mass, more preferably 0.5 to 5% by mass, and more preferably 1.0 to 2.5. More preferably, it is mass%.
- the pH of the liquid pharmaceutical preparation is preferably 1.5 to 6.9, more preferably 1.5 to 6.5, still more preferably 2.0 to 6.5, Is more preferably from 0 to 5.0, still more preferably from 2.0 to 4.0, particularly preferably from 2.6 to 3.2, 2.8 to 3.0 Most preferably.
- the liquid pharmaceutical preparation the description of WO 2017/150511 can be incorporated and referred to, and the contents thereof are incorporated herein.
- the suitable composition of a liquid pharmaceutical preparation and a suitable compounding ratio are also the same as the thing as described in international publication 2017/150511.
- the antitumor agent for biliary tract cancer of the present invention can be effectively used for the treatment of biliary tract cancer.
- the antitumor agent for biliary tract cancer of the present invention can be used as an anticancer agent.
- the present invention relates to a method for administering an antitumor agent to a biliary tract cancer patient, wherein the antitumor agent is 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine Or a method comprising the salt or prodrug thereof.
- the present invention is a method for using 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof for the treatment of biliary cancer.
- a method comprising the step of administering a therapeutically effective dose to a subject (a mammal, including a human) in need of such treatment.
- the subject may be a patient who has received gemcitabine as a prior treatment.
- the subject may be a patient who has been given gemcitabine as a prior treatment and a patient who has not shown an effect higher than Partial Response.
- the subject may be a patient who has been given combination chemotherapy including gemcitabine as prior treatment.
- the subject may be a patient who received combination chemotherapy including gemcitabine as a pretreatment, and a patient who did not show an effect higher than Partial Response.
- the subject may be a patient who has undergone other chemotherapy.
- the target may be a patient whose improvement is not expected by other chemotherapy. According to the present invention, the improvement effect can be obtained even for a patient who can not expect the therapeutic effect conventionally as described above.
- the present invention comprises the administration of a therapeutically effective dose of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof to a subject.
- a therapeutically effective dose of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof to a subject.
- the present invention relates to the use of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof for the preparation of an antitumor agent for biliary tract cancer I will provide a.
- the present invention provides 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof for use in the treatment of biliary tract cancer.
- Example 1 ⁇ Preparation of Methanesulfonate of Compound A>
- the methanesulfonic acid salt of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (hereinafter also referred to as compound A) is described in WO 2013/146833
- the compound was synthesized according to the method of (See Example 22 described in paragraph 0487 to paragraph 0492) and used in the following tests.
- ⁇ Preparation of Liquid Pharmaceutical Composition> The methanesulfonate salt of Compound A was dissolved in an appropriate amount of water for injection, and the pH was adjusted using a 1 mol / L aqueous sodium hydroxide solution.
- Compound A was administered by intravenous injection once a week from the first week to the third week, and the dosing cycle was repeated with no dosing at the fourth week. Specifically, Compound A was administered on days 1, 8, and 15, with 28 days as one cycle, and the cycle consisting of 28 days was repeated. The dose per single dose of Compound A was 40 mg / m 2 to 135 mg / m 2 .
- CR Complete Response
- PR Partial Response
- SD Stable Disease
- PD Progressive Disease
- Bile duct cancer patient 3 is a biliary duct cholangiocarcinoma.
- the starting dose was 60 mg / m 2, but then changed to 90 mg / m 2. SD has been maintained for over 32 weeks.
- the cholangiocarcinoma patient 6 is an intrahepatic cholangiocarcinoma.
- the starting dose was 135 mg / m 2, but then changed to 90 mg / m 2 because the side effects such hypotension and Utagukinchisho was observed. Furthermore, due to neutropenia, it was changed to 67.5 mg / m 2 . After that, we have been able to maintain SD for over 34 weeks.
- ECOG means Eastern Cooperative Oncology Group
- Gem-Cis means combination chemotherapy with gemcitabine and cisplatin
- Gem-Capecitabine means combination chemotherapy with gemcitabine and capecitabine.
- cholangiocarcinoma 1-2 since multiple prior treatments (treatment history) were performed, they were also described.
- the ECOG of bile duct cancer patient 1 was 0, and the ECOG of bile duct cancer patients 2 to 6 was 1.
- FIG. 3 is a graph showing the change rate of the major axis of the tumor relative to Baseline in patients with cholangiocarcinoma 1 to 6 (FIG. 3).
- FIG. 4 is a graph showing Cmax values of plasma concentrations of 38 patients who received Compound A in a clinical test including cholangiocarcinoma patients (FIG. 4). Also in clinical trials, the most common drug-related AEs in two or more patients were fever, nausea, chills, itching, rash, dry skin, skin abrasions, and fatigue.
- the antitumor agent of the present invention is useful as an antitumor agent having a therapeutic effect on biliary tract cancer.
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Abstract
Description
(1) 1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを含む胆道がん用抗腫瘍剤。
(2) 胆道がんが胆管がんである、(1)に記載の抗腫瘍剤。
(3) 胆管がんが肝外胆管がんまたは肝内胆管がんである、(1)または(2)に記載の抗腫瘍剤。
(4) 1回の投与量が20mg/m2以上であり、週1回の投与を3週間行った後に4週目は休薬するコースを複数回繰り返す、(1)から(3)の何れか一に記載の抗腫瘍剤。
(5) 1回の投与量が40mg/m2~200mg/m2である、(4)に記載の抗腫瘍剤。
(6) 1回の投与量が80mg/m2~150mg/m2である、(4)に記載の抗腫瘍剤。
(7) 注射剤である、(1)から(6)の何れか一に記載の抗腫瘍剤。
胆道がん患者に抗腫瘍剤を投与する方法であって、
抗腫瘍剤が、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを含む、方法。
(9) 胆道がんが胆管がんである、(8)に記載の方法。
(10) 胆管がんが肝外胆管がんまたは肝内胆管がんである、(8)または(9)に記載の方法。
(11) 1回の投与量が20mg/m2以上であり、週1回の投与を3週間行った後に4週目は休薬するコースを複数回繰り返す、(8)から(10)の何れか一に記載の方法。
(12) 1回の投与量が40mg/m2~200mg/m2である、(11)に記載の方法。
(13) 1回の投与量が80mg/m2~150mg/m2である、(11)に記載の方法。
(14) 抗腫瘍剤が注射剤である、(8)から(13)の何れか一に記載の方法。
(B) 1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグの治療有効用量を、対象に投与することを含む、胆道がんの処置方法。
(C) 胆道がん用抗腫瘍剤の製造のための、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグの使用。
(D) 胆道がんの治療において使用するための、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグ。
「対象」とは、その予防もしくは治療を必要とするヒト、マウス、サル、家畜等の哺乳動物であり、好ましくは、その予防もしくは治療を必要とするヒトである。
「予防」とは、発症の阻害、発症リスクの低減または発症の遅延などを意味する。
「治療」とは、対象となる疾患または状態の改善または進行の抑制(維持または遅延)などを意味する。
「処置」とは、各種疾患に対する予防または治療などを意味する。
「腫瘍」とは、良性腫瘍または悪性腫瘍を意味する。
「良性腫瘍」とは、腫瘍細胞およびその配列がその由来する正常細胞に近い形態をとり、浸潤性または転移性のない腫瘍を意味する。
「悪性腫瘍」とは、腫瘍細胞の形態やその配列がその由来する正常細胞と異なっており、浸潤性または転移性を示す腫瘍を意味する。
本発明は、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシン(化合物A)またはその塩もしくはプロドラッグを含む、胆道がん用抗腫瘍剤である。
まず、化合物Aまたはその塩もしくはプロドラッグについて説明する。
塩としては、薬学的に許容される塩が挙げられ、具体的には、鉱酸塩、有機カルボン酸塩およびスルホン酸塩が挙げられる。好ましい塩としては、鉱酸塩およびスルホン酸塩が挙げられる。
1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンのメタンスルホン酸塩;
1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンの塩酸塩;
ならびに上記の塩のいずれかの無水物。
プロドラッグを形成する基としては、例えば、Stella VJら、Prodrugs: Challenges and Rewards. Parts 1 and 2、2007年、American Association of Pharmaceutical Scientistsに記載されている基が挙げられる。
化合物Aのプロドラッグとしては、国際公開第2016/068341号公報の説明を援用および参酌でき、これらの内容は本願明細書に組み込まれる。
より具体的には、例えば、国際公開第2016/068341号公報に記載の一般式[1]で表わされるチオヌクレオシド誘導体またはその塩が本願明細書に組み込まれ、その好適な範囲も国際公開第2016/068341号公報に記載のものと同一である。
本発明にかかる化合物Aまたはその塩もしくはプロドラッグは、抗腫瘍剤として、また医薬組成物の有効成分として用いることができる。
本発明によれば、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを含む、胆道がん用抗腫瘍剤が提供される。
液状医薬製剤は、化合物Aまたはその塩と、分子量100以下の多価アルコールと、水と、を含有することが好ましい。
液状医薬製剤において、化合物Aまたはその塩の含有量は、1~50mg/mLであることが好ましく、5~50mg/mLであることがより好ましく、10~30mg/mLであることが特に好ましい。
分子量100以下の多価アルコールは、炭素数3または4の多価アルコールであることが好ましく、グリセリン、プロピレングリコールまたはブタンジオールであることがより好ましく、グリセリンであることが特に好ましい。なお、ブタンジオールとしては、1,2-ブタンジオール、1,3-ブタンジオール、1,4-ブタンジオール、2,3-ブタンジオールが挙げられるが、1,3-ブタンジオールが特に好ましい。多価アルコールの分子量の下限は特に限定されないが、一般的には50以上である。
液状医薬製剤の分子量100以下の多価アルコールの含有量は、0.5~10質量%であることが好ましく、0.5~5質量%であることがより好ましく、1.0~2.5質量%であることがさらに好ましい。
液状医薬製剤は、pHが1.5~6.9であることが好ましく、1.5~6.5であることがより好ましく、2.0~6.5であることがより一層好ましく、2.0~5.0であることがさらに好ましく、2.0~4.0であることがさらに一層好ましく、2.6~3.2であることが特に好ましく、2.8~3.0であることが最も好ましい。
液状医薬製剤としては、国際公開第2017/150511号公報の説明を援用および参酌でき、これらの内容は本願明細書に組み込まれる。なお、液状医薬製剤の好適な組成や好適な配合比も国際公開第2017/150511号公報に記載のものと同一である。
対象としては、前治療としてゲムシタビンを投与された患者であり、Partial Response以上の効果が認められなかった患者でもよい。
対象としては、前治療としてゲムシタビンを含む併用化学療法が実施された患者でもよい。
対象としては、前治療としてゲムシタビンを含む併用化学療法が実施された患者であり、Partial Response以上の効果が認められなかった患者でもよい。
対象としては、他の化学療法が実施された患者でもよい。
対象としては、他の化学療法では改善が見込めない患者でもよい。
本発明によれば、上記のような従来は治療効果が見込めない患者に対しても、改善効果が得られる。
<化合物Aのメタンスルホン酸塩の調製>
1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンのメタンスルホン酸塩(以下、化合物Aとも言う)を、国際公開第2013/146833号パンフレットに記載の方法(段落0487~段落0492に記載の実施例22を参照)に準じて合成し、以下の試験で用いた。
<液状医薬組成物の調製>
化合物Aのメタンスルホン酸塩を適量の注射用水に溶かし、1mol/L水酸化ナトリウム水溶液を用いてpHを調整した。化合物Aの濃度が20mg/mLとなるように適量の注射用水を加えて混合した。
また1.5質量%の濃度になるようにグリセリン(メルク社製、分子量92)を添加した。この液状医薬製剤のpHは、2.9であった。この液をメンブランフィルター(0.22μm)を用いてろ過し、液状医薬製剤を得た。
この液状医薬製剤を、以下の治療で用いた。なお、治療は、米国テキサス州立大学MDアンダーソンがんセンター(以下、MDACC)および米国コロラド州デンバー市にあるサラ・キャノン研究所(以下、SCRI)で行った。
胆管がん患者に対して、第1週目~第3週目までは週一回、化合物Aを静脈注射により投与し、第4週目は投薬しないという投薬サイクルを繰り返した。具体的には、28日間を1サイクルとして、第1日目、第8日目および第15日目に化合物Aを投与し、この28日間からなるサイクルを繰り返した。化合物Aの一回の投与当たりの投与量は、40mg/m2~135mg/m2とした。
MRI(核磁気共鳴画像法;magnetic resonance imaging)による画像診断により評価対象を確認し、以下の基準で判定した。
CR(Complete Response):腫瘍が完全に消失した状態
PR(Partial Response):腫瘍の大きさの和が30%以上減少した状態
SD(Stable Disease):腫瘍の大きさが変化しない状態
PD(Progressive Disease):腫瘍の大きさの和が20%以上増加かつ絶対値でも5mm以上増加した状態、あるいは新病変が出現した状態
化合物Aを1回の投与当たり40mg/m2で投与した胆管がん(肝内胆管がん)患者1名において、4サイクル(16週間)後に31%の腫瘍縮小効果が確認された(図1)。また、1回の投与量を60mg/m2、90mg/m2と増量した場合でもPRが確認された。この患者は、前治療として、ゲムシタビンおよびシスプラチンの併用化学療法を受けていたが、前治療の結果はPDであった。患者の年齢、性別、治療施設、1回の投与量、治療歴、本発明の治療効果などを表1に示す。以下、同様。
化合物Aを1回の投与当たり60mg/m2で投与した胆管がん(肝内胆管がん)患者1名においては、2サイクル後に31%の腫瘍縮小効果が確認され、4サイクル後に41%の腫瘍縮小効果が確認された(図2)。この患者は、前治療として、ゲムシタビンおよびシスプラチンの併用化学療法、並びにゲムシタビンおよびカペシタビンの併用化学療法を受けていた。前治療の結果はSDであった。詳細は、表1に示す。
胆管がん患者3は、胆管胆管がん(bile duct cholangiocarcinoma)である。開始投与量は60mg/m2であったが、その後、90mg/m2に変更した。32週以上にわたりSDを維持できている。
胆管がん患者6は、肝内胆管がん(intrahepaticcholangiocarcinoma)である。開始投与量は135mg/m2であったが、その後、低血圧および疑菌血症といった副作用がみられたことから90mg/m2に変更した。さらに好中球減少症により、67.5mg/m2に変更した。その後、34週以上にわたりSDを維持できている。
胆管がん患者1~6の年齢、性別、治療施設、1回の投与量、前治療(治療歴)、ECOG、本発明の治療効果などを表1に示す。
胆管がん患者を含む臨床試験で化合物Aを投与された38患者の血漿中濃度のCmax値を示したグラフである(図4)。また臨床試験では、2人以上の患者で最も一般的な薬物関連AEは、発熱、吐き気、悪寒、かゆみ、かぶれ、乾燥皮膚、皮膚剥離、および疲労がみられた。
Claims (14)
- 1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを含む胆道がん用抗腫瘍剤。
- 胆道がんが胆管がんである、請求項1に記載の抗腫瘍剤。
- 胆管がんが肝外胆管がんまたは肝内胆管がんである、請求項1または2に記載の抗腫瘍剤。
- 1回の投与量が20mg/m2以上であり、週1回の投与を3週間行った後に4週目は休薬するコースを複数回繰り返す、請求項1から3の何れか一項に記載の抗腫瘍剤。
- 1回の投与量が40mg/m2~200mg/m2である、請求項4に記載の抗腫瘍剤。
- 1回の投与量が80mg/m2~150mg/m2である、請求項4に記載の抗腫瘍剤。
- 注射剤である、請求項1から6の何れか一項に記載の抗腫瘍剤。
- 1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグの治療有効用量を、対象に投与することを含む、胆道がんの処置方法。
- 胆道がんが胆管がんである、請求項8に記載の方法。
- 胆管がんが肝外胆管がんまたは肝内胆管がんである、請求項8または9に記載の方法。
- 1回の投与量が20mg/m2以上であり、週1回の投与を3週間行った後に4週目は休薬するコースを複数回繰り返す、請求項8から10の何れか一項に記載の方法。
- 1回の投与量が40mg/m2~200mg/m2である、請求項11に記載の方法。
- 1回の投与量が80mg/m2~150mg/m2である、請求項11に記載の方法。
- 抗腫瘍剤が注射剤である、請求項8から13の何れか一項に記載の方法。
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2018
- 2018-03-01 TW TW107106844A patent/TW201932119A/zh unknown
- 2018-03-01 AU AU2018404329A patent/AU2018404329B2/en active Active
- 2018-03-01 CA CA3089728A patent/CA3089728C/en active Active
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023008511A1 (ja) | 2021-07-29 | 2023-02-02 | 富士フイルム株式会社 | Bap1およびpbrm1の少なくとも1つの機能低下を有する腫瘍に対する医薬組成物および抗腫瘍剤 |
KR20240028451A (ko) | 2021-07-29 | 2024-03-05 | 후지필름 가부시키가이샤 | Bap1 및 pbrm1 중 적어도 하나의 기능 저하를 갖는 종양에 대한 의약 조성물 및 항종양제 |
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US20200352973A1 (en) | 2020-11-12 |
AU2018404329B2 (en) | 2021-09-09 |
MX2018002611A (es) | 2019-07-30 |
AU2018404329A1 (en) | 2020-08-13 |
CA3089728A1 (en) | 2019-08-01 |
CA3089728C (en) | 2023-01-10 |
TW201932119A (zh) | 2019-08-16 |
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