WO2002030427A1

WO2002030427A1 - Oral dosage forms for administration of the combination of tegafur, uracil, folinic acid, and vinorelbine and method of using the same

Info

Publication number: WO2002030427A1
Application number: PCT/US2001/031796
Authority: WO
Inventors: Pierre Fumoleau; Jacques Bonneterre; Pierre Kerbrat; Pierre Fargeot; Regine Deportefety; Florence Garet
Original assignee: Bristol-Myers Squibb Company
Priority date: 2000-10-13
Filing date: 2001-10-11
Publication date: 2002-04-18
Also published as: AU2002213119A1

Abstract

The invention provides a dosage form and a method of administering an anti-tumor composition comprising tegafur, uracil, and folinic acid to potentiate the coadministration with vinorelbine.

Description

ORAL DOSAGE FORMS FOR ADMINISTRATION OF THE

COMBINATION OF TEGAFUR. URACIL. FOLINIC ACID. AND

VINORELBINE AND METHOD OF USING THE SAME

Related Applications

This application claims the benefit under Title 35 U.S.C. Section 119(e) of U.S. Provisional Patent Application Nos. 60/240,475, filed October 13, 2000 and 60/245,805, filed November 3, 2000.

Field Of The Invention

The present invention is directed to an oral dosage form(s) for administration to a warm blooded animal of the combination of tegafur, uracil, and folinic acid to potentiate coadministered vinorelbine for the treatment of tumors.

Background Of The Invention 5-Fluorouracil (5-FU) is a known anti-tumor agent. The combination of 5-fluorouracil and folinic acid is a known treatment for cancers including, but not limited to, breast and colorectal cancer. Tegafur (1- (2-tertrahydrofuryl)-5- fluorouracil) is a prodrug of 5-fluorouracil. In vivo, 5-fluorouracil is rapidly inactivated by the enzyme dihydropyridine dehydrogenase (DPD). Uracil competitively inhibits DPD metabolism of 5-FU generated from tegafur. Thus, coadministration of uracil with tegafur results in higher exposures of active 5- FU as compared to tegafur alone. It is known that 5-fluorouracil cannot be administered orally.

U.S. Patent No. 4,328,229 discloses an anti-cancer composition containing 1-(2-tetrahydrofuryl)-5-fluorouracil ("tegafur") and uracil. The composition is used for delivery of 5-fluorouracil to a tumor sensitive to 5- fluorouracil in a warm-blooded animal. It is disclosed that the composition can be administered in a variety of dosage forms including an oral dosage form.

U.S. Patent No. 5,534,513 discloses an anti-tumor composition containing tegafur and uracil in a molar ratio of 1 :4. This anti-tumor composition is stated to be further potentiated by the administration of folinic acid or a pharmaceutically acceptable salt thereof. It is disclosed in the '513 patent that the combination can be administered in a variety of dosage forms including an oral dosage form.

Vinorelbine is a known anti-tumor agent which at least operates to inhibit polymerization of tubulin into microtubules.

It has been observed that 5-fluorouracil can enhance the activity of vinorelbine. However, because 5-fluorouracil cannot be administered orally, the mode of administration for this combination therapy requires a more invasive form of administration such as by intravenous injection, and therefore typically requires administration by trained medical personnel. It would be an advance in the art of treating tumors, especially metastatic breast cancer, if a therapy could be developed employing a potentiated form of vinorelbine through the action of 5-fluorouracil in a convenient dosage form for oral administration.

Summary Of The Invention The present invention is directed to a dosage form(s) suitable for oral administration to a mammal for the treatment of tumors, especially metastatic breast cancer, that exhibits an enhanced effect in combination with vinorelbine. In particular, there is provided in accordance with the present invention a dosage form(s) suitable for oral administration to a mammal having a tumor comprising an effective amount of each of tegafur, uracil, and folinic acid or a pharmaceutically acceptable salt thereof to a patient undergoing treatment with vinorelbine, wherein said dosage form(s) is a potentiator of vinorelbine. In a preferred form of the invention, tegafur and uracil are present in respective amounts sufficient for tegafur to effectively and efficiently convert to 5-fluorouracil. In a particularly preferred form of the invention tegafur and uracil are present in a molar ratio of about 1 :4 (hereinafter referred to as "UFT").

There is also disclosed a method of orally administering an anti-tumor effective amount of the combination of tegafur and uracil, preferably as UFT, and folinic acid or a pharmaceutically acceptable salt thereof to a mammal undergoing vinorelbine therapy for the treatment of a tumor especially tumors associated with metastatic breast cancer.

The present invention further provides a method for the synergistic treatment of cancer, such as metastatic breast cancer, which comprises orally administering a synergistically effective amount of tegafur, uracil, and folinic acid or a pharmaceutically acceptable salt thereof, such as calcium folinate, to a mammal undergoing treatment with vinroelbine.

Brief Description of the Drawings

Figure 1 shows the plasma concentrations of tegafur on days 1 , 8 and 15 during cycles 1 and 2 in patients who received dose levels of 300 mg, 400 mg and 500 mg of UFT.

Figure 2 shows the plasma concentrations of 5-fluorouracil on days 1 ,

8 and 15 during cycles 1 and 2 in patients who received dose levels of 300 mg, 400 mg and 500 mg of UFT.

Figure 3 shows the correlation (r² = 0.8607) between plasma concentrations of uracil and 5-fluorouracil (5-FU).

Figure 4 shows the pharmacokinetic effect on 5-fluorouracil (5-FU) when UFT was administered at levels 1-5 with or without vinorelbine. Figure 5 shows the pharmacokinetic effect on uracil when UFT was administered at levels 1-5 with or without vinorelbine.

Figure 6 shows the pharmacokinetic effect on tegafur when UFT was administered at levels 1-5 with or without vinorelbine.

Figure 7 shows the dose limited toxicity of 5-fluorouracil (5-FU) in a sampling of twelve patients during a first cycle of treatment administration for dose levels 1 and 2 of vinorelbine administered on days 1 , 8, and 15.

Figure 8 shows the dose limited toxicity 5-fluorouracil (5-FU) in a sample of seven patients during a first cycle of treatment administration for dose level 5 of vinorelbine administered on days 1 and 8.

Figure 9 shows the dose limited toxicity of 5-fluorouracil (5-FU) in a sample of seven patients during a first cycle of treatment administration for dose level 5 of vinorelbine administered on days 1 and 8.

Detailed Description Of The Invention The administration of the combination of tegafur and uracil in amounts sufficient to convert tegafur to 5-fluorouracil (preferably a molar ratio of about 1 :4) can be administered orally. It was unexpectedly discovered that oral administration of this combination produced sufficient 5-fluorouracil that potentiation of vinorelbine would take place despite the inability of 5- fluorouracil itself to be effectively administered orally. This was surprising because the combination of tegafur and uracil is not totally absorbed in the gut. Thus, it was unexpected that there would be a sufficient blood circulating concentration of 5-fluorouracil available to potentiate vinorelbine.

The oral dosage form(s) used in the present invention provides significant advantages over administering the combination by other modes of administration which are more invasive. In the treatment of tumors, a potential reduction in the cost of therapy because skilled medical personnel are not required to administer the drug and the psychological benefits afforded a patient by taking an oral medication provide significant benefits for patient care.

The dosage forms for all oral administration include tablets, powders, granules, and the like. Excipients and additives which may be used include, but are not limited to, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium, kaolin, crystalline cellulose, salicylic acid, methylcellulose, glycerol, sodium alginate, arabic gum and the like. Conventional binders may be used such as glucose solutions, starch solutions, gelatine solutions, and the like. Disintegrators may be used including, but not limited to, dry starch, sodium alginate, agar powder, calcium carbonate, and the like. Absorbents which may be used include, but are not limited to, starch, lactose, kaolin, bentonite, and the like. Lubricants which may be used include, but are not limited to, purified talc, stearic acid salts, boric acid powder, polyethylene glycol and the like.

Tegafur, uracil, and folinic acid preferably provided as the calcium salt "calcium folinate" (leucovorin) are present in the oral dosage form(s) in an amount from about 1 to 70% by weight based on the total weight of the oral dosage form(s). The dosage of each active ingredient for administration on a daily basis is from about 0J to 100 mg/kg/day, preferably about 1 to 30 mg/kg/day for tegafur. The preferred dosage for uracil is from about 1 to 50 mg/kg/day. For UFT, i.e. the 1 :4 combination of tegafur and uracil, the dosage is from about 100 to 800 mg/day based on tegafur, preferably from about 300 to 500 mg/day based on tegafur. Folinic acid or a pharmaceutically acceptable salt thereof may be administered in an amount from about 0.1 to 500 mg/kg/day, but preferably is administered as calcium folinate in a fixed dose of about 90 mg/day. The oral dosage form(s) may be administered in a single dose(s) or in divided doses typically up to 3 times a day. Vinorelbine is typically administered in a non-oral mode of administration, typically parenteral infusion including intravenous infusion. Based on body surface area, the dosage may range from about 5 to 100 mg/m²/day, preferably from about 15 to 25 mg/m²/day.

Those of ordinary skill in the art would have the knowledge to adjust the above stated dosage ranges for UFT, folinic acid or a pharmaceutically acceptable salt thereof, and vinorelbine as needed based on body surface area and/or in the event of toxicity. In accordance with the present invention, the combination of tegafur and uracil (e.g. UFT) results in a sufficient amount of 5-fluorouracil available to potentiate vinorelbine to improve the availability and potency of vinorelbine in the treatment of tumors, especially tumors associated with metastatic breast cancer.

The following examples are exemplary of the claimed invention, but are not intended to limit the invention as encompassed by the full disclosure of the invention set forth herein.

EXAMPLE 1

This study assessed the in vivo maximum tolerated dose (MTD), the side effect profile, the toxicity profile, the dose limiting toxicity (DLT) of vinorelbine combined with UFT (tegafur and uracil in a molar ratio of 1:4) plus folinic acid in the form of oral calcium folinate (leucovorin), and the determination of the main pharmacokinetic parameters and any potential drug interaction when vinorelbine and UFT/folinic acid are administered in combination.

A standard phase I trial was conducted with escalating doses of UFT and vinorelbine with a fixed dose of calcium folinate (leucovorin) at 90 mg/day. Up to five dose levels each having at least 3 patients comprised the test patient study. Entry criteria for the study included, but was not limited to, a histological or cytological confirmed metastatic breast cancer, no concurrent radiotherapy, one prior chemotherapy regimen for metastatic disease, no prior treatment with continuous infusion of 5-FU and/or vinca-alkaloid in either adjuvant or metastatic setting, ECOG performance status of 0-2, no brain metastatic disease, and adequate hematological, renal and hepatic function.

The dosages for UFT, calcium folinate and vinorelbine for each level are escalated as shown below in Table 1. Table 1

The treatments were given on a three-week cycle until progressive disease or unacceptable toxicity occurred. UFT and calcium folinate were given orally on days 1-21 of each cycle; vinorelbine was administered intravenously on days 1 , 8 and 15 of each cycle for dose levels 1 and 2, and on days 1 and 8 for dose levels 3-5. The regimen was repeated every four weeks. Prophylactic granulocyte colony stimulating factor was not routinely given.

At least 3 patients were entered at each dose level before escalating to the next level. After all patients had safely completed one cycle of treatment, the dose was escalated. The study continued to each progressive level until the maximum tolerated dose (MTD) was experienced. The MTD was defined as the dose level at which greater than 2/3 or 3/6 of the patients experienced a dose limiting toxicity (DLT) during the first cycle of treatment. The DLT was

defined as follows: a. Febrile neutropenia, or b. Grade 4 neutropenia for more than seven days, or c. Grade 4 thrombocytopenia prolonged or complicated by bleeding or requiring platelet transfusion, or d. Grade 3/4 non-hematological toxicity including nausea, vomiting, diarrhea despite appropriate treatment, excluding alopecia and fatigue, or e. Inability to take full UFT and calcium folinate doses for more than 3 days out of a 21 day cycle, or f . A treatment delay of greater than 29 days prior to the start of the next cycle of treatment, or g. An inability to take 1 of the 2 doses (dose levels 3-5), or 3 doses (dose levels 1-2) of vinorelbine due to toxicity effects.

Patients qualified for the test protocol if they met the following criteria:

a. Histological or crytological confirmed advanced/metastatic breast cancer b. One prior chemotherapy regimen for metastatic disease c. Evidence of disease progression, either clinical or biological d. No prior treatment with continuous infusion of 5-FU and/or vinca- alkaloid in either adjuvant or metastatic setting.

e. Age > 18 and PS < 2

f. Adequate hematological, hepatic, and renal functions g. Written informed consent

The results for six patients that were entered at each of levels 1 and 2 as defined in Table 1 above, including the mean number of cycles progressed, and the number of patients at each dose level exhibiting DLT, are shown below in Table 2.

Table 2

As indicated in Table 2 above, the first MTD was reached at dose level 2 where 20 mg/m² of vinorelbine was administered on days 1, 8 and 15, and 300 mg/day of UFT and 90 mg/day calcium folinate were administered for 21 days. The DLT included neutropenia and the inability to take one out of the three doses of vinorelbine and/or full doses of UFT and calcium folinate during more than 3 days out of the 21 day treatment cycle.

The results for the three, nine and seven patients that were entered at respective dose levels 3, 4, and 5 as defined in Table 1 above, including the mean number of cycles progressed, and the number of patients at each dose level exhibiting DLT, are shown below in Table 3. Table 3

As further dosage levels of vinorelbine were administered for days 1 and 8, the second MTD was reached at dose level 5. Accordingly, it was determined that elimination of one vinorelbine administration permitted increases in the UFT dosage.

The hematological toxicity profile of the patients is shown for each dose level in Table 4.

Table 4

The nonhematological toxicity profile of the patients is shown in Table 5.

Table 5

For the 26 patients currently undergoing assessment, their response to treatment was assessed according to the criteria established by the World Health Organization ("WHO") as described in Miller, A.B. et al., Cancer 11 (1981). A complete response which is defined as the disappearance of ail tumor lesions as confirmed by two independent observations at least four weeks apart, has been observed in one patient (3.85%). A partial response, which is defined as a decrease of at least 50% in the sizes of tumor lesions, was observed in 4 patients (15.4%). A stable disease situation, i.e. one in which there was no change in the disease (i.e. a decrease in tumor size of less than 50% which there was no change in the disease (i.e. a decrease in tumor size of less than 50% or an increase in tumor size of less than 25%) confirmed by two independent observations at least 4 weeks apart, was observed in 10 patients (38.5%). A progressive disease situation was observed in 11 patients (42.3%). This latter category includes the appearance of any new, previously unidentified lesions or the occurrence of malignant pleural effusion or ascites and/or an increase by at least 25% in the size of one or more measurable lesions.

The test patients were evaluated in the following manner: • Patients receiving at least one cycle of treatment were evaluated

for toxicity.

• Patients receiving at least 2 cycles of treatment or who

developed rapid tumor progression or who died of progressive disease were evaluated for response. Also patients who discontinued treatment, or who died, due to a treatment related toxicity prior to response evaluation were considered evaluated for response.

• Disease was assessed every 3 cycles and the response

evaluated according to WHO criteria were (Miller et al., 1981). Based on this study, the results show that when vinorelbine was administered at days 1 , 8, and 15, MTD was reached at dose level 2 (UFT - 300 mg/day for days 1-21 , calcium folinate 90 mg/day for days 1-21 and vinorelbine - 20 mg/m²). Further dose levels, in which vinorelbine was administered only at days 1 and 8, were such that MTD was reached at dose level 5 (UFT - 500 mg/day for days 1-21 , calcium folinate 90 mg/day for days 1-21 , and vinorelbine 25 mg/m²). Accordingly, it was determined that elimination of one vinorelbine administration allowed an increase in UFT dosage.

Example 2

A pharmacokinetic study of UFT plus calcium folinate in combination with vinorelbine was carried out with patients from levels 1-5 of a Phase I study as described in Example 1. The study objectives were threefold: 1) to determine the main pharmacokinetic (PK) parameters of 5-FU, uracil, tegafur, and vinorelbine; 2) to determine any potential drug interaction when UFT, calcium folinate and vinorelbine were given in combination; and 3) to determine the relationship between the PK parameters and clinical toxicity (i.e. DLT).

The selection criteria was as set forth in Example 1. UFT and calcium folinate given orally in three divided daily doses at the levels defined in Example 1 from day 1 to day 21 every four weeks. The methodology for determining the pharmacokinetic parameters includes defining the plasma pharmacokinetic profile for tegafur, uracil and 5-Fluorouracil (5-FU), and the plasma pharmacokinetic profile for vinorelbine in combination with UFT and calcium folinate. 5-Fluorouracil, uracil and tegafur plasma concentrations were determined by HPLC at cycles 1 and 2 on days 1, 8, 15 and 21 (levels 1- 2) during the first of the three daily UFT/calcium folinate dose administrations. Vinorelbine plasma concentration was determined by HPLC at cycle 1 on day 1. This aspect of the study was performed by carrying out the following two- course methodology during the course of the treatment described above. In cycle 1 , vinorelbine was infused six hours after first UFT and calcium folinate dose administration. In cycle 2, vinorelbine was infused 10 minutes before the first UFT and calcium folinate dose administration. Eight plasma samplings were taken over a 6-hour period after the first administration of UFT and calcium folinate and ten plasma samplings were taken over a 24- hour period after administration of vinorelbine.

With reference to Figure 1 , AUCo-β_h values for tegafur increased from day 1 to day 15 during cycles 1 and 2. AUC₀-6_h values increased linearly with the UFT dose level.

With reference to Figure 2, large variations of AUCo-βh values for 5- fluorouracil were observed during cycles 1 and 2. AUCo-β h values did not increase proportionally with the UFT dose level. With reference to Figure 3, AUC₀-_6h values for uracil were correlated to 5-fluorouracil AUCo-β _h values with a correlation value of r² = 0.8607.

As set forth in Table 6, the AUC₀-_6h values for vinorelbine increased with increasing dose levels, while clearance remained stable over the tested dose ranges.

Table 6

With reference to Figures 4-6, AUC₀-_6h tegafur, 5-fluorouracil and uracil, respectively, were not significantly modified when UFT was administered with or without vinorelbine.

With reference to Figure 7, at levels 1 and 2 AUC₀-6h values of fluorouracil were significantly higher (p<0.001 ) in patients with DLT

(neutropenia, anemia and nausea) as compared to patients not experiencing

DLT (1.07 μMxh versus 0.47 μMxh, respectively). The mean AUC₀-6h was

determined to be 0.66 + 0.52 μMxh (n = 46). With reference to Figures 8 and 9, at levels 3 and 4 (Fig. 8) and 5 (Fig.

9) AUCo-_6h values of 5-fluorouracil were also higher in patients experiencing

DLT (hematological toxicity), but the differences were not significant. The

mean AUC₀-_6h at levels 3-4 and 5 were determined to be 2.90 + 2.93 μMxh (n

= 30) and 3.04 ± 1.93

μMxh (n = 20), respectively.

The results of this study demonstrate the high inter- and intra-individual variability of 5-fluorouracil and uracil pharmacokinetics. Increases in AUCo-_6h values for 5-fluorouracil and uracil were more than proportional to the dose administered. Without wishing to be bound by any theory, it is suggested that the increase in AUCo-e_h values may be due to a saturation of the pyrimidine catabolic pathway due to dihydropyrimidine dehydrogenase (DPD) inhibition. No change of vinorelbine clearance was observed with increasing doses of UFT, which indicates that UFT and vinorelbine could be administered together without any relevant drug interaction. The PK-PD analysis suggests that there is a relationship at levels 1 and 2 between 5-fluorouracil AUCo-_6h values and clinical toxicity (DLT), in that, in patients who developed a DLT, 5- fluorouracil AUCo-_6h values were significantly higher than those who did not experience DLT. The omission of day 15 vinorelbine at levels 3-5 has allowed an increased UFT dosage to be utilized and increases in 5-fluorouracil AUCo- _6h. The MTD was reached at level 5, i.e. vinorelbine at 25 mg/m² on ^"days 1 and 8, UFT at 500 mg/day, and calcium folinate at 90 mg/day.

Claims

What Is Claimed Is:

1. A method of administering an anti-tumor effective amount of a combination of tegafur, uracil, and folinic acid or a pharmaceutically acceptable salt thereof, to a mammal undergoing treatment with vinorelbine comprising administering to the mammal having a tumor said combination in oral dosage form(s).

2. The method of claim 1 wherein the amount of tegafur and uracil is sufficient to produce an effective amount of 5-fluorouracil sufficient to potentiate the activity of vinorelbine.

3. The method of claim 1 wherein tegafur and uracil are present in a molar ratio of about 1 :4, respectively.

4. A dosage form suitable for administration to a mammal having a tumor and undergoing treatment with vinorelbine comprising an effective amount of each of tegafur, uracil, and folinic acid or a pharmaceutically acceptable salt thereof in oral dosage form.

5. The dosage form of claim 4 wherein the amount of tegafur and uracil is sufficient to produce an effective amount of 5-fluorouracil sufficient to potentiate the activity of vinorelbine.

6. The dosage of claim 5 wherein tegafur and uracil are present in a molar ratio of about 1 :4 sufficient to potentiate the activity of vinorelbine.

7. A method for the synergistic treatment of cancer which comprises orally administering a synergistically effective amount of tegafur, uracil, and folinic acid or a pharmaceutically acceptable salt thereof to a mammal undergoing treatment with vinorelbine.

8. The method according to claim 7 wherein the cancer is metastatic breast cancer.

9. The method according to claim 7 wherein tegafur and uracil are present in a molar ratio of about 1 :4, respectively.

10. The method according to claim 7 wherein tegafur is orally administered at a dosage of about 1 to 30 mg/kg/day, uracil is orally administered at a dosage of about 1 to 50 mg/kg/day, and calcium folinate is orally administered at a fixed dosage of about 90 mg/day.

11. The method according to claim 7 wherein the mammal is treated with vinorelbine at a dosage of about 5 to 100 mg/m²/day.

12. A method for the synergistic treatment of cancer which comprises orally administering a synergistically effective amount of UFT and folinic acid or a pharmaceutically acceptable salt thereof to a mammal undergoing treatment with vinorelbine.

13. The method according to claim 12 wherein the cancer is metastatic breast cancer.

14. The method according to claim 12 wherein UFT is orally administered at a dosage of about 100 to 800 mg/day based on tegafur, calcium folinate is orally administered at a fixed dosage of about 90 mg/day, and the mammal is treated with vinorelbine at a dosage of about 5 to 100 mg/m²/day.

15. The method according to claim 12 wherein UFT is orally administered at a dosage of about 300 to 500 mg/day based on tegafur, calcium folinate is orally administered at a fixed dosage of about 90 mg/day, and the mammal is treated with vinorelbine at a dosage of about 15 to 25 mg/m²/day.