[go: up one dir, main page]

WO2010131769A1 - Traitement de cancers gastriques de type diffus à l'aide de s-1 et de cisplatine - Google Patents

Traitement de cancers gastriques de type diffus à l'aide de s-1 et de cisplatine Download PDF

Info

Publication number
WO2010131769A1
WO2010131769A1 PCT/JP2010/058400 JP2010058400W WO2010131769A1 WO 2010131769 A1 WO2010131769 A1 WO 2010131769A1 JP 2010058400 W JP2010058400 W JP 2010058400W WO 2010131769 A1 WO2010131769 A1 WO 2010131769A1
Authority
WO
WIPO (PCT)
Prior art keywords
cisplatin
gastric cancer
days
administered
diffuse
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2010/058400
Other languages
English (en)
Inventor
Taro Furuie
Takeshi Tahara
Kaku Saito
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taiho Pharmaceutical Co Ltd
Original Assignee
Taiho Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taiho Pharmaceutical Co Ltd filed Critical Taiho Pharmaceutical Co Ltd
Publication of WO2010131769A1 publication Critical patent/WO2010131769A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the treatment of gastric cancers using a combination therapy of S-I and cisplatin.
  • it relates to an improved method of treating patients with diffuse-type gastric cancer by administering S-I and cisplatin to a patient in need of such treatment.
  • Gastric cancer is the fourth most common cancer worldwide, behind lung, breast, and colorectal cancers, and is the second most common cause of cancer-related deaths, with an estimate of 800,000 deaths annually (Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin 2008;58(2):71-96; Parkin DM Bray F, Ferlay J, Pisani P. Global Cancer Statistics, 2002. CA Cancer J Clin 2005 ;55(2):74- 108). The incidence and mortality rates of gastric cancer vary greatly between regions.
  • the histology of gastric cancer is an important prognostic factor in advanced gastric cancer.
  • the World Health Organization (WHO) histopathological classification of gastric cancer differentiates by groups: well-differentiated, moderately-differentiated, poorly- differentiated, signet ring cell cancer, and mucinous-type. According to Lauren's classification, gastric cancer is divided into two categories: intestinal type, and diffuse type.
  • diffuse-type gastric cancer may be characterized by non-cohesive single or small nests of cells with little or no gland formation, carcinoma with solid sheets, tight clusters, and cords of cells being evident, carcinoma with signet ring differentiation, small cell cancer with absent to minimal intracellular mucin, anaplastic cells with little intracellular mucin, or extracellular mucin with pure signet ring cell morphology.
  • intestinal-type gastric cancer includes the pure intestinal-type gastric cancer based on Lauren's classification as well as the papillary, tubular, and part of mucinous histology described by the WHO classification.
  • mixed-type gastric cancer includes tumors with histologic features of unclassified/indeterminate carcinoma under the Lauren classification, as well as mixed histology with a component of diffuse-type gastric cancer as described above and a component of intestinal-type gastric cancer as described above.
  • Recently published data indicate that the survival of patients with diffuse-type gastric cancer is significantly worse compared to those with intestinal type.
  • Park et al. (2008) reviewed retrospectively medical records of 2,275 patients who underwent gastric resection. The overall cumulative five-year survival rates for these patients were 67% for intestinal type gastric cancer versus 54% for poorly-differentiated, or diffuse, gastric cancer.
  • 5-fluorouracil is the mainstay of combination chemotherapies developed and tested in advanced gastric cancer.
  • 5 -FU is administered via continuous intravenous infusion (CIV) over five to 21 days depending on the combination chemotherapy.
  • FAM (5-FU, doxorubicin, and mitomycin), EAP (etoposide, doxorubicin, cisplatin), FAMTX (5-FU, doxorubicin, methotrexate), CF (cisplatin, 5-FU), ELF (etoposide, 5-FU, leucoporin), ECF (epirubicin, cisplatin, 5-FU), and more recently some combinations with new citotoxic drugs, including DCF (docetaxel, cisplatin, and 5-FU), IF (irinotecan, 5-FU), XP (capecitabine and cisplatin), and EOX (epirubicin, oxaliplatin, and capecitabine).
  • DCF docetaxel, cisplatin, and 5-FU
  • IF irinotecan
  • 5-FU XP (capecitabine and cisplatin)
  • EOX epirubicin, oxaliplatin
  • the present invention relates to an improved method for treating a diffuse-type or a mixed-type gastric cancer in a patient in need of such treatment, which comprises (i) administering to the patient an effective amount of S-I and (ii) administering to the patient an effective amount of cisplatin.
  • S-I is a 1:0.4:1 molar mixture of Tegafur to Gimeracil to Oteracil potassium, and is always dosed on the amount of tegafur in the S-I.
  • the S-I is administered at least twice daily in a total daily amount of about 20 mg/m 2 to about 80 mg/m 2 of Tegafur in S-I.
  • the total daily amount of S-I is initially administered in an amount of about 30 mg/m 2 to about 80 mg/m 2 of Tegafur in S-I, subject to possible reduction in the event of unwanted side effects. More preferably, the S-I is initially administered at least twice daily in a total daily amount of about 50 mg/m 2 to about 70 mg/m 2 of Tegafur in S-I.
  • the doses of S-I are provided in equal amounts. Such doses may be administered for about 7 to about 28 consecutive days within a period of about 14 to about 35 days. While the cisplatin may be administered once at any point in the about 14 to about 35 day period, it is typically more convenient to administer cisplatin on the first day or the eighth day the S-I dose is administered.
  • S-I may be administered for about 21 consecutive days in a period of about 28 days, particularly when the patient is a Caucasian patient, along with about 75 mg/m 2 of cisplatin, which is also administered once within the 28 day period.
  • S-I may be administered at least one hour before or one hour after a meal.
  • S-I is preferably administered perorally.
  • the cisplatin is administered intravenously.
  • the cisplatin is administered once in a period of about 28 to about 35 days. More preferably, cisplatin is administered once in a period of about 28 days.
  • the cisplatin is administered as a dose of about 50 mg/m 2 to about 100 mg/m 2 . More preferably, the cisplatin is administered as a dose of about 60 mg/m 2 to about 80 mg/m 2 .
  • the present invention can be used when the diffuse-type gastric cancer is an advanced diffuse-type gastric cancer, including when the advanced diffuse-type gastric cancer is a metastatic diffuse-type gastric cancer.
  • the present invention can be used when the mixed-type gastric cancer is an advanced mixed-type gastric cancer, including when the advanced mixed-type gastric cancer is a metastatic mixed-type gastric cancer.
  • the method according to the present invention is a first line therapy, that is, the advanced diffuse-type gastric cancer or advanced mixed-type gastric cancer has not been previously treated with chemotherapy, except for neo-adjuvant or adjuvant chemotherapy.
  • the patient has not lost more than 10% of his or her baseline weight prior to the beginning of treatment.
  • the present invention relates to a method for treating an advanced diffuse-type or mixed-type gastric cancer in a patient in need of such treatment which comprises (i) perorally administering to the patient S-I in an amount of about 10 mg/m 2 to about 40 mg/m 2 of Tegafur in the S-I twice daily at least one hour before or after a meal for about 7 to about 28 consecutive days within a period of about 14 to about 35 days, and (ii) intravenously administering to the patient about 50 mg/m 2 to about 100 mg/m 2 of cisplatin once in a period of about 28 to about 35 days.
  • the present invention relates to a method for treating an advanced diffuse-type gastric cancer or advanced mixed-type gastric cancer which has not been previously treated with chemotherapy in a patient in need of such treatment which comprises (i) perorally administering to the patient S-I in an amount of about 15 mg/m 2 to about 40 mg/m 2 per dose of Tegafur in the S-I. Most preferably, the patient is administered the S-I in an amount of about 25 mg/m 2 to about 35 mg/m 2 per dose of Tegafur in the S-I.
  • the present invention also relates to use of a combination of first preparation consisting of therapeutically effective amount of S-I, wherein said S-I is a pharmaceutical composition containing Tegafur, Gimeracil, and Oteracil potassium at a molar ration of 1:0.4:1, and second preparation containing therapeutically effective amount of cisplatin for preparation of medicament for the treatment of a diffuse-type gastric cancer or a mixed gastric cancer.
  • the present invention relates to a kit for the treatment of a diffuse-type gastric cancer or a mixed gastric cancer, comprising a first preparation consisting of therapeutically effective amount of S-I, wherein said S-I is a pharmaceutical composition containing Tegafur, Gimeracil, and Oteracil potassium at a molar ration of 1:0.4:1, and a second preparation containing therapeutically effective amount of cisplatin.
  • first preparation consisting of therapeutically effective amount of S-I, wherein said S-I is a pharmaceutical composition containing Tegafur, Gimeracil, and Oteracil potassium at a molar ration of 1 :0.4: 1, and second preparation containing therapeutically effective amount of cisplatin for the treatment of a diffuse-type gastric cancer or a mixed gastric cancer.
  • Figure 1 shows the difference in the overall survival in patients with diffuse-type of advanced gastric cancer and a limited number of patients with mucinous-type gastric cancer when treated with S-1/cisplatin as compared with the overall survival in patients with diffuse- type of advanced gastric cancer when treated with 5-FU/cisplatin.
  • Figure 2 shows the difference between overall survival in patients with metastatic disease/diffuse-type of advanced gastric cancer and a limited number of patients with mucinous- type gastric cancer, and less than 10% baseline weight loss when treated with S-1/cisplatin as opposed to when treated with 5-FU/cisplatin.
  • S-I is an oral fluoropyrimidine that combines Tegafur (FT), which is an oral prodrug of 5 -FU, with two modulators, Gimeracil (CDHP), which inhibits 5 -FU degradation by DPD inhibition, and Oteracil potassium (Oxo), which inhibits 5-FU phosphorylation in the digestive tract.
  • FT Tegafur
  • CDHP Gimeracil
  • Oxo Oteracil potassium
  • S-I is a fixed combination in a 1:0.4:1 molar ratio of Tegafur to Gimeracil to Oteracil potassium.
  • S-I is generally administered perorally.
  • S-I is more fully described in U.S. Patent Application 2008/0166427, the entirety of which is herein incorporated by reference.
  • a powerful DPD inhibitor such as Gimeracil
  • S-I has undergone Phase 1 and early Phase 2 evaluation in Japan.
  • S-I was investigated as an oral agent for once daily administration. Single dose administration in the range of 25 to 200 mg (as Tegafur) has been studied. S-I was investigated at a schedule in which the drug was given twice daily for 28 days, followed by 2 weeks recovery. 6 of 11 patients (2 of whom had gastric cancer) were reported to experience tumor reduction at all dose levels studied (50 to 100 mg). Thus far, Phase 2 studies have been performed in patients with advanced gastric cancer at 50 mg and 75 mg of S-I per patient.
  • WHO World Health Organization
  • S-I was administered orally twice a day in doses of up to 60 mg/m2/day of S-I for up to 28 consecutive days, followed by a 7-day recovery period. Antitumor activity was demonstrated and the results were consistent with those seen in the Japanese studies. However, unexpectedly higher toxicity was seen in the USA/EU studies as compared with the Japanese studies. A possible explanation for the differences in toxicity reported in the Japanese studies as compared with the USA/EU studies could be the potential differences in the conversion rate of Tegafur to 5-FU in Caucasian patients as compared with Japanese patients. Comparison of the 5-FU pharmacokinetic parameters of S-I suggests that the Caucasian population tends to demonstrate higher 5-FU concentrations with the same dose of S-I as compared with Japanese patients.
  • Cisplatin is a heavy metal compound with cytotoxic activity. It inhibits DNA precursors, to a lesser extent it inhibits protein and RNA synthesis, and it causes intra-strand crosslinking of DNA, which is the primary mechanism of action. Because cisplatin cytotoxicity does not appear to be cell-cycle dependent, its toxicity is similar in all phases of the cell cycle.
  • cytotoxic anti-cancer agents including 5-FU, have been shown to be supra-additive or synergistic with cisplatin in vitro or in vivo. The basis for 5-FU interaction with cisplatin is unclear.
  • the present invention relates to a method for treating a diffuse-type or a mixed- type gastric cancer. It has been found that a combination therapy including both cisplatin and S-I is effective in treating advanced gastric cancer, and that this combination therapy is particularly effective in treating gastric cancer classified as diffuse-type gastric cancer.
  • An open-label, international, multicenter, two-arm, parallel, randomized Phase III study was conducted in which the efficacy and safety of a combination regimen of S-I and cisplatin was compared to the efficacy and safety of a combination regimen of 5-FU and cisplatin in patients with advanced gastric cancer that was previously untreated with chemotherapy. Patients were stratified by the type of disease (e.g.
  • S-1/cisplatin S-I, 25 mg/m 2 twice a day from Day 1 through Day 21, and cisplatin, 75 mg/m 2 on Day 1 of treatment, repeated every four weeks, with a maximum of 6 cycles of cisplatin.
  • 5-FU/cisplatin 5-FU, 1000 mg/m 2 /24 hours on Days 1 through 5 and cisplatin, 100 mg/m 2 on Day 1, repeated every 4 weeks, with a maximum of 6 cycles of cisplatin.
  • the primary objective of this study was to compare the overall survival of S-I + cisplatin therapy to 5-FU + cisplatin therapy in patients with advanced gastric cancer.
  • the key secondary endpoints were overall response rate and progression-free survival analyzed for the full analysis set of the study population, as well as the safety and tolerability of the two chemotherapy regimens.
  • weight loss has been recognized as increasing the risk of death in cancer patients. It has been demonstrated that weight loss in patients receiving chemotherapy is associated with reduced survival. Patients with metastatic gastrointestinal cancers who present with weight loss receive less chemotherapy than patients without weight loss (Andreyev et al., Eur J Cancer 34(4), 503-9, 1998; DeWys et al. Am J Med. 69, 491-7, 1980; Ross PJ, Ashley S, when undergoing chemotherapy for lung cancers? Br J Cancer 2004;90, 1905-11).
  • a patient with a diffuse-type or mixed-type gastric cancer is treated by administering an effective amount of S-I and an effective amount of cisplatin to the patient.
  • the diffuse-type or mixed-type gastric cancer may be a diffuse-type or mixed-type gastric cancer at any stage of the disease.
  • the diffuse- type or mixed-type gastric cancer may be in an advanced stage.
  • an advanced gastric cancer is a stage II, III, or IV cancer.
  • the cancer which is to be treated by the invented method may have reached a metastatic disease state when the S-1/cisplatin combination is administered.
  • the method of the present invention may be used as a first-line, or as a neoadjuvant or adjuvant, therapy in the treatment of diffuse-type or mixed-type gastric cancers.
  • the method of the present invention may also be used as a second (or more)-line therapy to treat a patient who has previously received treatment for diffuse-type or mixed-type gastric cancer, including, but not limited to, tumor resection, radiation treatment, or prior chemotherapy.
  • S-I may be administered perorally.
  • S-I may be administered in an initial dose of about 20 mg/m 2 to about 80 mg/m 2 of Tegafur in S-I per day.
  • S-I may be given in an initial dose of about 30 mg/m 2 to about 80 mg/m 2 of Tegafur in S-lper day.
  • S-I may be given in an initial dose of about 50 mg/m 2 to about 70 mg/m 2 of Tegafur in S-I per day.
  • This dose may be administered in at least two separate doses, such that S-I is administered at least twice daily.
  • S-I may be given to the patient twice daily in two doses each of about 10 mg/m 2 to about 40 mg/m 2 of Tegafur in S-I, such that the total daily dose of S-I is about 20 mg/m 2 to about 80 mg/m 2 of Tegafur in S-I.
  • S-I may be initially given to the patient twice daily in two doses each of about 15 mg/m 2 to about 40 mg/m 2 of Tegafur in S-I, such that the total daily dose of S-I is about 30 mg/ m 2 to about 80 mg/m 2 of Tegafur in S-I.
  • S-I may be initially given to the patient twice daily in two doses each of about 25 mg/m 2 to about 35 mg/m 2 of Tegafur in S-I, such that the total daily dose of S-I is about 50 mg/m 2 to about 70 mg/m 2 of Tegafur in S-I.
  • the dose of S-I may be adjusted downward in case the patient experiences any adverse effects due to the administration of S-I.
  • S-I may be given in a dosing regimen which includes a dosing period and a rest period. In one embodiment of the present invention, S-I is given to a patient at least twice daily for a period of about 7 to about 28 days, followed by a rest period of about 7 to about 14 days.
  • the dosing period and the rest period combined are not shorter than 28 days.
  • S-I is administered at least twice daily for about 21 days.
  • the patient should not receive any doses of S-I. This results in the S-I being administered for about 21 consecutive days within a period of about 28 to about 35 days. Further, some patients may respond better to a shorter rest period, whereas other patients may respond better to a longer rest period.
  • a rest period of 14 days may be more appropriate.
  • a 7-day rest period may be more appropriate.
  • S-I is administered at least one hour before or at least one hour after a meal. It has been found that the plasma concentrations of Oteracil potassium, one component of S-I, are significantly higher when S-I is taken at least one hour before or at least one hour after a meal. Assuming that Oteracil potassium is important for protection of the gastro-intestinal tract, this suggests it may be optimal to administer S-I under fasting conditions. For this reason, S-I should not be taken within one hour of a meal.
  • cisplatin may be administered intravenously. Cisplatin may be administered in conventional forms for intravenous administration as is well known to those in the art.
  • cisplatin is administered in an initial dose of about 50 mg/m 2 to about 100 mg/m 2 .
  • cisplatin is administered in an initial dose of about 60 mg/m 2 to about 80 mg/m 2 .
  • cisplatin is administered in a single dose, followed by a rest period of about 28 to about 35 days.
  • cisplatin may be administered in a dose of about 75 mg/m 2 . During this rest period, the patient should receive no cisplatin.
  • One may wish to provide a patient with a lower dose of cisplatin if the patient experiences adverse events related to the administration of cisplatin at the initial dose.
  • a patient may receive multiple doses of cisplatin over the course of time, so long as there is a rest period between those doses.
  • Both cisplatin and S-I should be administered to the patient within the same period of about 28 to about 35 days. However, it is not necessary to administer the dose of cisplatin at the same time as the first dose of S-I is administered to the patient. Instead, the dose of cisplatin should be administered once within a period of about 28 to about 35 days, and the doses of S-I should be administered 21 consecutive days within a period of about 28 to about 35 days.
  • S-I may be administered in various peroral dosage forms, including (but not limited to) tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, etc. These may be prepared by conventional methods, using suitable pharmaceutically acceptable carriers. Examples of useful carriers are those widely used in the manufacture of conventional pharmaceutical compositions, such as fillers, extenders, binders, disintegrators, surfactants, lubricants and like diluents and excipients.
  • various excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.; binders such as simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, gum arabic powder, gum tragacanth powder, etc.; disintegrators such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene-sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc.; antidisintegrators such as sucrose, stearic acid, cacao butter, hydrogenated oil, etc.; absorption promotors such as quaternary ammonium bases, sodium lauryl sulf
  • the tablets may be in the form of coated tablets such as sugar-coated tablets, gelatin- coated tablets, enteric-coated tablets, film-coated tablets, or double or multi-layer tablets, etc.
  • Capsules are manufactured by mixing the antitumor composition with any of the carriers mentioned above and encapsulating the mixture in hard gelatin capsule, soft capsule or other capsules.
  • Cisplatin may be administered in intravenous dosage forms such as liquid.
  • the preparation containing cisplatin may be prepared by conventional methods, using suitable pharmaceutically acceptable carriers. Examples of useful carriers are those widely used in the manufacture of conventional pharmaceutical compositions, such as diluents, and buffer agents.
  • Cisplatin may be provided in a liquid form, that .is administered intravenously as itself, or a solid form, that is prepared in a liquid form before use.
  • the present invention will be further illustrated by reference to the following examples, which are not intended to be limiting.
  • 1,053 patients with untreated, advanced gastric/gastroesophogeal adenocarcinoma were randomized 1:1 to receive either S-1/cisplatin or 5-FU/cisplatin.
  • Patients who received S- 1/cisplatin were treated with 25 mg/m 2 of Tegaf ⁇ ir in S-I, in the form of an oral capsule, twice daily (at least one hour before, or one hour after, a meal) on days 1 through 21 of the treatment cycle, followed by a 7 day rest period, as well as 75 mg/m 2 of cisplatin, in the form of continuous intravenous infusion, on day 1 of the treatment cycle, followed by a 28 day rest period.
  • Patients with untreated, advanced diffuse-type or mixed-type gastric/gastroesophogeal adenocarcinoma are randomized 2:1 to receive S-1/cisplatin or 5- FU/cisplatin, respectively. Patients with locally advanced disease and patients with more than 10% weight loss within 3 months prior to the study are excluded from the patient population.
  • Patients who receive S-1/cisplatin are treated with 25 mg/m 2 of Tegafur in S-I, in the form of an oral capsule, twice daily (at least one hour before, or one hour after, a meal) on days 1 through 21 of the treatment cycle, followed by a 7 day rest period, as well as with 75 mg/m 2 of cisplatin, in the form of continuous intravenous infusion, on day 1 of the treatment cycle, followed by a 28 day rest period.
  • Patients who receive 5-FU/cisplatin are treated with a 1000 mg/m 2 per day continuous intravenous infusion of 5 -FU per day over a period of 5 days, followed by a 23 day rest period, as well as with a 100 mg/m 2 continuous intravenous infusion of cisplatin on day 1, followed by a 28 day rest period.
  • Patients with untreated, advanced diffuse-type or mixed-type gastric/gastroesophogeal adenocarcinoma are randomized 2:1 to receive S-I or 5-FU, respectively. Patients with locally advanced disease and patients with more than 10% weight loss within 3 months prior to the study are excluded from the patient population. Patients who receive S- 1 are treated with 25 mg/m 2 of Tegafur in S- 1 , in the form of an oral capsule, twice daily (at least one hour before, or one hour after, a meal) for a total daily amount of 50 mg/ m 2 on days 1 through 21 of the treatment cycle, followed by a 7 day rest period.
  • Patients who receive 5-FU are treated with a 1000 mg/m 2 per day continuous intravenous infusion of 5-FU per day over a period of 5 days, followed by a 23 day rest period. Overall survival analyses for superiority are performed. Patients with diffuse- type or mixed-type gastric cancer given the S-1/cisplatin treatment regimen have a statistically superior overall survival to those given the 5-FU/cisplatin treatment regimen. S-I is also found to have lower mortality risk than 5-FU. In addition, S-I shows a favorable safety and tolerability to 5-FU. It is concluded that S-I demonstrates superior overall survival to 5-FU in patients with diffuse-type or mixed-type of metastatic gastric cancer.
  • S-I administered with or without cisplatin, should be effective in treating diffuse-type gastric cancers and mixed-type gastric cancers, along with treating other diffuse-type cancers in general.
  • Other cancers that present with a diffuse-type histology include the following: colorectal cancer, bladder cancer, pancreatic cancer, biliary cancer, appendix cancer, esophageal cancer, non-small cell lung cancer (NSCLC), and breast cancer.
  • S-I can be administered to a patient at least twice daily in a total daily amount of about 20 mg/m 2 to about 80 mg/m 2 of Tegafur in S-I.
  • the total daily amount of S-I initially administered to the patient is about 30 mg/m 2 to about 80 mg/m 2 of Tegafur in S-I, subject to possible reduction in the event of unwanted side effects.
  • S-I may be administered to a patient at least twice daily in a total daily amount of 50 mg/m 2 to 70 mg/m 2 of Tegafur in S-I.
  • S-I may be provided in peroral formulations as described above for the treatment of diffuse-type gastric cancer or mixed-type gastric cancer.
  • S-I may be administered to the patient at least twice daily for a period of about 7 to about 28 days, followed by a rest period of about 7 to about 14 days.
  • Japanese patients generally respond better to a dosing regimen that including administering S-I at least twice daily for a period of about 28 days followed by a rest period of about 14 days, such that S-I is administered over about 28 consecutive days in a 42 day period.
  • Other, non- Japanese patients may respond better to a dosing regimen that includes administering S-I at least twice daily for a period of about 14 days followed by a rest period of about 7 days, such that S-I is administered over about 14 consecutive days in a 21 day period.
  • S-I may be provided in peroral formulations as described above for the treatment of diffuse-type gastric cancer or mixed-type gastric cancer.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un procédé amélioré permettant de traiter le cancer gastrique de type diffus ou un cancer gastrique de type mixte, notamment les cancers gastriques avancés de type diffus et de type mixte et les cancers gastriques métastatiques de type diffus et de type mixte, par administration de S-1 et de cisplatine à des patients ayant besoin de traitement pour un cancer gastrique de type diffus ou un cancer gastrique de type mixte.
PCT/JP2010/058400 2009-05-13 2010-05-12 Traitement de cancers gastriques de type diffus à l'aide de s-1 et de cisplatine Ceased WO2010131769A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17782409P 2009-05-13 2009-05-13
US61/177,824 2009-05-13

Publications (1)

Publication Number Publication Date
WO2010131769A1 true WO2010131769A1 (fr) 2010-11-18

Family

ID=43085137

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2010/058400 Ceased WO2010131769A1 (fr) 2009-05-13 2010-05-12 Traitement de cancers gastriques de type diffus à l'aide de s-1 et de cisplatine

Country Status (2)

Country Link
TW (1) TW201039816A (fr)
WO (1) WO2010131769A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2671590A4 (fr) * 2011-01-31 2014-09-03 Taiho Pharmaceutical Co Ltd Composition contenant du tégafur pour une posologie unique quotidienne ou un jour sur deux

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007534634A (ja) * 2004-04-29 2007-11-29 大鵬薬品工業株式会社 テガフールの投与に起因する消化器毒性を軽減する方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007534634A (ja) * 2004-04-29 2007-11-29 大鵬薬品工業株式会社 テガフールの投与に起因する消化器毒性を軽減する方法

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
EMMANUELLE COMETS ET AL.: "Comparison of the Pharmacokinetics of S-1, an Oral Anticancer Agent, in Western and Japanese Patients", JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS, vol. 30, no. 4, 2003, pages 257 - 283 *
H. WATAYA ET AL.: "A new antitumor drug: S-1", GEKKAN KOKYUKIKA, vol. 7, no. 5, 2005, pages 496 - 501 *
K. TSUTSUMI ET AL.: "Saihatsu shinko igan ni taisuru Sl wo chushin to shita kagakuryouhou no kentou (Investigation of Sl-based chemotherapy against recurrent or advanced gastric cancer)", JOURNAL OF JAPAN SURGICAL SOCIETY, vol. 104, 2003, pages 638 *
T. KONDO ET AL.: "Antitumor Effect of S-1 and Cisplatin Treatment against Human Gastric Cancer Xenografted in Nude Mice", GAN TO KAGAKU RYOHO, vol. 24, no. 9, 1997, pages 1103 - 1108 *
W. KOIZUMI ET AL.: "Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer", BRITISH JOURNAL OF CANCER, vol. 89, 2003, pages 2207 - 2212 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2671590A4 (fr) * 2011-01-31 2014-09-03 Taiho Pharmaceutical Co Ltd Composition contenant du tégafur pour une posologie unique quotidienne ou un jour sur deux

Also Published As

Publication number Publication date
TW201039816A (en) 2010-11-16

Similar Documents

Publication Publication Date Title
Calvo et al. Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study
US20110053879A1 (en) Picoplatin and amrubicin to treat lung cancer
Ajani et al. A multi-center phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma
Kaira et al. A phase II study of amrubicin, a synthetic 9-aminoanthracycline, in patients with previously treated lung cancer
BG107281A (bg) Комбиниран химиотерапевтичен състав
Igawa et al. Evaluation of the recommended dose and efficacy of amrubicin as second-and third-line chemotherapy for small cell lung cancer
Kobayashi et al. Pharmacokinetic study of weekly administration dose of paclitaxel in patients with advanced or recurrent gastric cancer in Japan
KR101978108B1 (ko) 암 세포의 대사 특이성에 기초하는 신규 항 악성 종양제
Petrioli et al. Feasibility of modified docetaxel, oxaliplatin, capecitabine followed by capecitabine as maintenance chemotherapy as first-line therapy for patients with metastatic gastric or gastroesophageal cancer
CN112566628A (zh) 预防和治疗癌症的药物组合物，包括棉酚、苯乙双胍和抗癌剂
Iwase et al. A phase II multi-center study of triple therapy with paclitaxel, S-1 and cisplatin in patients with advanced gastric cancer
Petrioli et al. Treatment of advanced oesophagogastric cancer with FOLFOX-4 regimen followed by leucovorin/bolus and continuous infusion 5-FU as maintenance chemotherapy in patients aged≥ 75 years with impaired performance status
Park et al. Phase I/II and pharmacokinetic study of S-1 and oxaliplatin in previously untreated advanced gastric cancer
Shimada et al. Second-line chemotherapy with combined irinotecan and low-dose cisplatin for patients with metastatic gastric carcinoma resistant to 5-fluorouracil
Thomas et al. Randomized multicentric phase II study of carboplatin/gemcitabine and cisplatin/vinorelbine in advanced non-small cell lung cancer: GFPC 99-01 study (Groupe français de pneumo-cancérologie)
Zang et al. Dose-finding study of docetaxel, oxaliplatin, and S-1 for patients with advanced gastric cancer
Sato et al. Preliminary study of fortnightly irinotecan hydrochloride plus cisplatin therapy in patients with advanced gastric and colorectal cancer
Di Lauro et al. Epirubicin, cisplatin and docetaxel combination therapy for metastatic gastric cancer
WO2010131769A1 (fr) Traitement de cancers gastriques de type diffus à l'aide de s-1 et de cisplatine
Bozkurt et al. Efficacy and safety of raltitrexed combinations with uracil-tegafur or mitomycin C as salvage treatment in advanced colorectal cancer patients: a multicenter study of Anatolian Society of Medical Oncology (ASMO)
Luo et al. Efficacy and tolerability of docetaxel and cisplatin plus S-1 for advanced gastric cancer
Xiros et al. Carboplatin plus gemcitabine in patients with inoperable or metastatic pancreatic cancer: a phase II multicenter study by the Hellenic Cooperative Oncology Group
CN108503676B (zh) 用于癌症治疗的果糖类似物及其组合物
Polyzos et al. Subsets of patients with advanced gastric cancer responding to second-line chemotherapy with docetaxel-cisplatin
Ueda et al. Phase I study of a combination of s-1 and weekly paclitaxel in patients with advanced or recurrent gastric cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10775022

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10775022

Country of ref document: EP

Kind code of ref document: A1