Treatment for terminal pancreatic cancer

Abstract

To provide a novel treatment option with high safety for pancreatic cancer patients who are in third-line treatment or subsequent treatment stages.SOLUTION: A compounded preparation of potassium citrate and sodium citrate hydrate for use in a treatment method for pancreatic cancer patients in third-line or later-line treatment.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the treatment of patients with terminal pancreatic cancer for which no other therapeutic options exist. The present invention also relates to the use of a combination of potassium citrate and sodium citrate hydrate for treating patients with pancreatic cancer in the third line or later of treatment. [Background technology]

[0002] The present inventors have previously discovered and reported that cancer progression can be suppressed by neutralizing the acidic cancer microenvironment (hereinafter referred to as "TME") with an alkaline agent (Patent Documents 1, 2, 3, Non-Patent Document 1).

[0003] Patent Document 1 discloses a combination medicine containing a urinary alkalinizing agent and vitamin C for use in the treatment or remission of advanced and / or terminal pancreatic cancer, non-small cell lung cancer, or pleural mesothelioma, in which the urinary alkalinizing agent is orally administered daily at a dose of 3 to 15 g / day that alkalizes the urine, and vitamin C is parenterally administered at a dose of 25 to 50 g / day.

[0004] Patent Document 2 discloses an oral composition containing sodium bicarbonate and magnesium oxide, or citric acid or a salt thereof, for use in the treatment or remission of cancer, or the prevention of cancer recurrence or metastasis, wherein the cancer is lung cancer, lymphoma, pancreatic cancer, breast cancer, stomach cancer, or rectal cancer, and sodium bicarbonate is orally administered daily at a dose of 1 to 15 g / day, magnesium oxide is orally administered daily at a dose of 1 to 5 g / day, or citric acid or a salt thereof is orally administered daily at a dose of at least 1 g / day.

[0005] Patent Document 3 discloses a pharmaceutical composition containing a combination of potassium citrate and sodium citrate hydrate for use in enhancing the effects of anticancer drugs, which does not contain vitamin C as an active ingredient for enhancing the effects of the anticancer drugs. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent No. 6359198 [Patent Document 2] Japanese Patent No. 6826737 [Patent Document 3] Japanese Patent No. 6802598 [Non-patent literature]

[0007] [Non-Patent Document 1] Hideki Ando, ​​Kiyoshi Ejima, Tatsuhiro Ishida, et al., Biol.Pharm.Bull. Volume 44, pp. 844-852 (2021) Summary of the Invention [Problem to be solved by the invention]

[0008] As the population ages, the number of pancreatic cancer patients is rapidly increasing, but there are currently no approved pharmaceutical treatments for patients with terminal pancreatic cancer who are at or after the third line of treatment. Because the condition of pancreatic cancer patients after the third line of treatment is poor, the use of anticancer drugs with strong side effects is inappropriate, and safer treatments are needed.

[0009] Therefore, an object of the present invention is to provide a new, highly safe therapeutic method for pancreatic cancer patients who are undergoing third-line or later treatment. [Means for solving the problem]

[0010] As a result of intensive research conducted by the inventors to solve the above problems, they have found that a combination drug of potassium citrate and sodium citrate hydrate (hereinafter sometimes referred to as "DFP-17729" in this specification) can be used as an alkaline agent that neutralizes the acidic cancer microenvironment, which has almost no side effects and leads to a life-prolonging effect in patients with pancreatic cancer receiving third-line or later treatment, and can be provided as a new treatment for patients with pancreatic cancer receiving third-line or later treatment.

[0011] The present invention is based on these findings and includes the following inventions. [1] A combination of potassium citrate and sodium citrate hydrate for use in the third-line or later treatment of patients with pancreatic cancer. [2] A combination of [1], administered orally four times a day at a dose of 1,389 mg of potassium citrate and 1,170 mg of sodium citrate hydrate. [3] A combination drug of [1] or [2] used in combination with an anticancer drug.

[0012] [4] A treatment method for patients with pancreatic cancer as a third-line or later treatment, comprising administering a combination of potassium citrate and sodium citrate hydrate to patients with pancreatic cancer who are eligible for third-line or later treatment. [5] The method for treating [4], comprising orally administering the combination drug in amounts of 1389 mg of potassium citrate and 1170 mg of sodium citrate hydrate four times a day. [6] The method of treatment according to [4] or [5], further comprising administering an anticancer agent.

[0013] [7] Use of potassium citrate and sodium citrate hydrate in the manufacture of a potassium citrate-sodium citrate hydrate combination for use in third-line or later treatment of patients with pancreatic cancer. [8] The use of [7], wherein the combination drug is orally administered four times a day in an amount of 1389 mg of potassium citrate and 1170 mg of sodium citrate hydrate per dose. [9] The use of [7] or [8], wherein the combination drug is used in combination with an anticancer drug in the treatment method. [Effects of the Invention]

[0014] According to the present invention, a new, highly safe therapeutic method can be provided for pancreatic cancer patients who have received third-line or later treatment. Furthermore, the present invention can provide an alkaline agent that can neutralize the acidic cancer microenvironment, which has almost no side effects and leads to a life-prolonging effect for pancreatic cancer patients who have received third-line or later treatment. [Brief explanation of the drawings]

[0015] [Figure 1-1] Figure 1-1 shows the results of a Phase I / II clinical trial of DFP-17729 conducted at multiple centers in Japan in patients with metastatic pancreatic cancer, as well as the results of stratified analysis, which are described in detail below as examples. [Figure 1-2] Continued from Figure 1-1. [Figure 1-3] Continued from Figure 1-1. [Figure 2] Figure 2(A) is a graph showing median survival times for pancreatic cancer treatments beyond the third line, based on a subgroup analysis of Phase I and II studies combined. Figure 2(B) is a graph showing median survival times for pancreatic cancer treatments beyond the fourth line, based on a subgroup analysis of Phase I and II studies combined. DETAILED DESCRIPTION OF THE INVENTION

[0016] In the present invention, DFP-17729 is characterized by being used in a treatment method for pancreatic cancer patients from the third line onwards.

[0017] When anticancer drug therapy is administered for inoperable cancer, the initial anticancer drug treatment is generally referred to as initial (primary) or first-line therapy, and is typically administered until the drug becomes ineffective or becomes unusable due to side effects. The drug is then discontinued, and a different anticancer drug is used for second-line therapy. When the drug becomes ineffective or becomes unusable due to side effects, the drug is discontinued and a different anticancer drug is used for treatment. This is typically referred to as third-line therapy. Similarly, when the drug becomes ineffective or becomes unusable due to side effects, a different drug is used for treatment, and fourth, fifth, and sixth-line therapy (but not limited to these) are administered. In the present invention, the term "therapeutic method after the third-line treatment" refers to a therapeutic method performed after the second-line treatment, and includes third-line treatment and / or subsequent treatments (e.g., fourth-line treatment, fifth-line treatment, sixth-line treatment, etc., but is not limited to these).

[0018] In the present invention, DFP-17729 can contain potassium citrate and sodium citrate hydrate in any ratio. For example, when administered in divided doses (for example, 2 to 5 times (for example, 2, 3, 4, or 5 times)), 6000 mg to 3500 mg of potassium citrate and 5000 mg to 3000 mg of sodium citrate hydrate per day can be contained in amounts that allow for convenient administration per dose, depending on the dosage form. As a particularly preferred example, DFP-17729 can be used in the form of a combined powder. When made into a dosage form, it can contain 463 mg of potassium citrate and 390 mg of sodium citrate hydrate per gram (dry weight), and when made into a combination tablet dosage form, it can contain 231.5 mg of potassium citrate and 195 mg of sodium citrate hydrate per tablet (dry weight). In the present invention, commercially available combination agents may be used, and for example, Uralyt (registered trademark)-U combination powder and Uralyt (registered trademark) combination tablets (manufactured by Nippon Chemiphar Co., Ltd.) can be suitably used.

[0019] In addition to potassium citrate and sodium citrate hydrate, DFP-17729 may also contain other ingredients, as needed, that are commonly used in the manufacture of pharmaceuticals, such as excipients, binders, disintegrants, lubricants, diluents, stabilizers, isotonicity agents, pH adjusters, buffers, solubilizers, suspending agents, colorants, flavoring agents, odor masking agents, coating agents, preservatives, antiseptics, and antioxidants.

[0020] DFP-17729 can be in any dosage form suitable for the intended administration route, but a dosage form suitable for oral administration is preferred for ease of administration. Examples of dosage forms suitable for oral administration include, but are not limited to, liquid preparations such as solutions and syrup suspensions, tablets, pills, capsules, granules, powders, etc. Liquid preparations may be dissolved in water or the like to adjust to an appropriate concentration before administration. Solid dosage forms can be coated as needed (e.g., sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, etc.).

[0021] In the present invention, the subject is a pancreatic cancer patient to whom a treatment method is to be applied as a third-line or later treatment. The subject may or may not have been administered DFP-17729 in either or both of the first-line and second-line treatments.

[0022] The dose of DFP-17729 can vary depending on factors such as the severity, age, weight, and condition of the subject, the form of DFP-17729, and the route of administration, but is preferably an amount sufficient to shift the urinary pH of the administered subject toward the alkaline side compared to before administration and / or maintain alkalinity. In the present invention, alkalinization of the urinary pH means that the urinary pH shifts toward the alkaline side compared to before administration, more preferably to a urinary pH of 7 or greater, even more preferably to 7.5 or greater, even more preferably to 8 or greater, and particularly preferably to 8.5 or greater. Furthermore, in the present invention, "maintaining alkalinization" means that the urinary pH of the subject is alkalinized for at least 1 hour, 3 hours, 6 hours, 12 hours, 18 hours, or 24 hours or more after administration of DFP-17729.

[0023] For example, the dosage of DFP-17729 is an amount equivalent to 6000 mg to 3500 mg of potassium citrate and 5000 mg to 3000 mg of sodium citrate hydrate per day (e.g., an amount equivalent to 5556 mg of potassium citrate and 4680 mg of sodium citrate hydrate; an amount equivalent to 4630 mg of potassium citrate and 3900 mg of sodium citrate hydrate; an amount equivalent to 3704 mg of potassium citrate and 3120 mg of sodium citrate hydrate) which can be orally administered multiple times a day (e.g., 2 to 5 times (e.g., 2, 3, 4, or 5 times) every day, every other day, or every few days). In a particularly preferred example, DFP-17729 is orally administered four times a day in amounts of 1389 mg of potassium citrate and 1170 mg of sodium citrate hydrate per dose.

[0024] In the present invention, DFP-17729 has a life-prolonging effect on pancreatic cancer patients receiving third-line or later treatment, and this effect can be confirmed by the fact that the survival rate (median survival time, etc.) is higher than that of pancreatic cancer patients receiving third-line or later treatment who are not administered DFP-17729.

[0025] In the present invention, DFP-17729 neutralizes the acidic cancer microenvironment, thereby prolonging the lifespan of pancreatic cancer patients receiving third-line or later treatment. The neutralizing effect can be assessed based on the urinary pH of a subject administered DFP-17729. The neutralizing effect can be determined if the subject's urinary pH becomes more alkaline than before administration and / or remains alkaline. This determination can be made by measuring the pH of urine collected after initiation of administration or after continuous administration. Furthermore, measuring the urinary pH can easily identify subjects whose cancer's acidic microenvironment can be neutralized by administration of DFP-17729, i.e., subjects who can be expected to benefit from life-prolonging effects. After selecting appropriate patients, cancer treatment based on administration of DFP-17729 can be administered to the subject.

[0026] Furthermore, in the present invention, DFP-17729 can inhibit or suppress one or more mechanisms related to cancer malignancy, proliferation, and metastasis, such as cell malignancy, cell proliferation, oncogene expression, growth factor activation, glycolysis enhancement, DNA synthesis promotion, cell cycle enhancement, apoptosis induction reduction, cell migration, angiogenesis, cancer metastasis, and drug resistance, in pancreatic cancer patients who have received third-line or later treatment, thereby quelling cancer and achieving treatment or remission, or preventing recurrence or metastasis. In particular, the effect is remarkable in refractory (advanced and / or terminal) cancers, and the survival rate (median survival time, etc.) can be significantly improved.

[0027] In the present invention, DFP-17729 is effective by itself in treating or achieving remission of cancer, or preventing cancer recurrence or metastasis in pancreatic cancer patients after third-line treatment, but may also be used in combination with existing anticancer drugs.

[0028] In the present invention, the term "anticancer drug" is not particularly limited as long as it is used in the treatment of cancer, and examples thereof include cancer immunotherapeutic agents, cancer immune checkpoint inhibitors, cancer molecular targeted drugs, and cancer chemotherapy agents. More specifically, examples thereof include tegafur, tegafur-uracil combination drug (trade name: UFT), tegafur-gimeracil-oteracil potassium combination drug (trade name: TS-1 (registered trademark)), fluorouracil, gemcitabine (trade name: Gemzar (registered trademark)), enocitabine, carmofur, doxifluridine, cytarabine, cytarabine ocfosfate, mercaptopurine, fludarabine, capecitabine, methotrexate, cladribine, and pemetrexed (trade name: Alimta (registered trademark)). (Registered trademark), hydroxycarbamide, cyclophosphamide, thiotepa, ifosfamide, busulfan, dacarbazine, melphalan, ranimustine, nimustine, temozolomide, carboplatin, cisplatin, oxaliplatin, nedaplatin, doxorubicin, aclarubicin, idarubicin, actinomycin D, daunorubicin, zinostatin stimalamer, bleomycin, mitomycin C, pirarubicin, epirubicin, peplomycin, amrubicin, vinca alkaloids , topoisomerase inhibitors, sorafenib, erlotinib, axitinib, everolimus, sunitinib, imatinib, lapatinib, rituximab, dasatinib, bortezomib, tamibarotene, gefitinib, ibritumomab, nilotinib, temsirolimus, trastuzumab, panitumumab, tretinoin, gemtuzumab ozogamicin, crizotinib, afatinib, bevacizumab (trade name: Avastin (registered trademark)), paclitaxel (trade name: Abraxane (registered trademark)), docetaxel (trade name: Taxotere®), nivolumab (trade name: Opdivo®), pembrolizumab (trade name: Keytruda®), ipilimumab (trade name: Yervoy®), atezolizumab (trade name: Tecentriq®), [2S]-2-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoylamino]-4-methylpentanoic acid (generic name: ubenimex) (trade name: Bestatin), and lentinan are examples of anti-cancer drugs.Preferably, the anticancer drug is an immune checkpoint inhibitor, and particularly, nivolumab (trade name: Opdivo (registered trademark)), pembrolizumab (trade name: Keytruda (registered trademark)), ipilimumab (trade name: Yervoy (registered trademark)), and atezolizumab (trade name: Tecentriq (registered trademark)) are preferred.

[0029] In combination with DFP-17729, the anticancer drug can be administered at a dose that is 90%, 80%, 70%, 60%, 50%, 40%, or less lower than when the anticancer drug is administered alone, and / or with a reduced administration period and / or extended withdrawal period. This allows for the prevention or delay of side effects that may be caused by the administration of the anticancer drug (e.g., bone marrow suppression, hemolytic anemia, disseminated intravascular coagulation, fulminant hepatitis, dehydration, enterocolitis, interstitial pneumonia, stomatitis, gastrointestinal ulcer, gastrointestinal bleeding, gastrointestinal perforation, acute renal failure, mucocutaneous ocular syndrome, toxic epidermal necrolysis, neuropsychiatric disorders, acute pancreatitis, rhabdomyolysis, anosmia, etc.), and also significantly reduces the financial burden on cancer patients and the burden on national and local government health insurance finances.

[0030] Recently developed immune checkpoint inhibitors such as nivolumab are groundbreaking anticancer drugs, but their high manufacturing costs and extremely high drug prices place a heavy economic burden on cancer patients, creating a social problem. On the other hand, when used in combination with DFP-17729, it is possible to reduce the drug dosage, which is preferable as it can reduce the economic burden on cancer patients.

[0031] In the present invention, the "combination use" of DFP-17729 and an anticancer drug includes not only simultaneous administration of each component but also sequential administration of each component at predetermined intervals over the treatment period. The administration route and administration means of each component administered in combination may be the same or different. The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. [Example]

[0032] 1. Clinical trial methods (Figure 1-1 (Methods)) A multicenter, open-label Phase I / II study was conducted to evaluate the combination of potassium citrate and sodium citrate hydrate (hereinafter referred to as "DFP-17729") as a neutralizer of the acidic TME in combination with gemcitabine (hereinafter referred to as "Gem") or a combination of tegafur, gimeracil, and oteracil potassium (hereinafter referred to as "S-1").

[0033] Phase I consisted of Gem (1000 mg / m 2 to be administered intravenously on days 1, 8, and 15, repeated every 4 weeks) or S-1 (80 mg / m 2 The tolerability of combination therapy with 1,389 mg of potassium citrate and 1,170 mg of sodium citrate hydrate (administered orally four times daily) was investigated. The Phase II portion examined efficacy during patient survival.

[0034] Between November 2020 and May 2022, 39 patients were enrolled at six Japanese centers, with 6 enrolled in Phase I and 33 enrolled in Phase II. 22 patients were randomized to the investigational drug group and 11 to the control drug group. The median age of enrolled patients was 65 years (range, 49-77 years). Patients in the control drug group received either Gem or S-1 alone.

[0035] 2. Clinical trial results No serious adverse events were observed during the Phase I portion, and the study drug was well tolerated. In the Phase II portion of the study, the median survival time was 5.3 months in the test drug group and 6.3 months in the control group, and the superiority of the test group over the control group could not be verified. No serious adverse events such as grade 4 or 5 were observed in the test group. (Figure 1-2 (Results (Efficacy))

[0036] 3. Results of stratified analysis of clinical trials As shown in Figures 1-2, 1-3, and 2, in a subgroup analysis combining Phase I and Phase II data, for pancreatic cancer treatment at or after the third line, the median survival time was 8.9 months in the investigational drug group (third line or later treatment, concomitant drug S-1, urine pH 7.5 or higher, investigational drug administration period 6 weeks or longer, 11 cases), and 5.4 months in the control group (pre-treatment, third line or later treatment, concomitant drug S-1, 7 cases), revealing a significant difference (Figure 2(A)). A mediated effects analysis (a method of examining the influence of variables that mediate the causal relationship between two variables) also revealed a significant difference between urine pH and survival time in pancreatic cancer patients. Furthermore, in the treatment of pancreatic cancer from the fourth line onwards, the median survival time was 9.0 months in the test drug group (previous treatment, third line onwards, GEM-based treatment, concomitant drug S-1, 5 cases) and 6.1 months in the control group (concomitant drug S-1, 9 cases), confirming a trend towards longer survival time in the test drug group (Figure 2(B)).

[0037] 4. Conclusion Combination therapy with DFP-17729 and S-1 has been confirmed to be useful in terms of prolonging life as a treatment for pancreatic cancer from the third line onwards.

Claims

1. A combination of potassium citrate and sodium citrate hydrate for use in the third-line or later treatment of patients with pancreatic cancer.

2. 2. The combination preparation according to claim 1, which is orally administered four times a day in amounts of 1,389 mg of potassium citrate and 1,170 mg of sodium citrate hydrate per dose.

3. The combination drug according to claim 1 , which is used in combination with an anticancer drug.

4. A treatment method for pancreatic cancer patients as a third-line or later treatment, comprising administering a combination of potassium citrate and sodium citrate hydrate to a pancreatic cancer patient to whom a third-line or later treatment is applicable.

5. 5. The method of claim 4, comprising orally administering the combination drug four times a day in an amount of 1,389 mg of potassium citrate and 1,170 mg of sodium citrate hydrate per dose.

6. The method of claim 4, further comprising administering an anticancer agent.

7. Use of potassium citrate and sodium citrate hydrate in the manufacture of a potassium citrate / sodium citrate hydrate combination drug for use in third-line or later treatment methods for patients with pancreatic cancer.

8. The use according to claim 7, wherein the combination is orally administered four times a day in an amount of 1,389 mg of potassium citrate and 1,170 mg of sodium citrate hydrate per dose.

9. The use according to claim 7, wherein the combination drug is used in combination with an anticancer drug in the treatment method.

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