The present invention relates to a method for treating a cancer comprising orally administering a composition containing α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5 at a dose of 20 to 80 mg/m2/day in terms of FTD in 2 to 4 divided portions per to patients in need of the treatment.
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0. 18. A method for treating colorectal cancer in a human patient, comprising orally administering a composition comprising α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5 at a dose of 70 mg/m2/day in terms of FTD in 2 divided portions per day at a dosing interval of 6 hours or more wherein the administration of said dose is for 5 days followed by 2 days off treatment in a one-week dosing schedule wherein m2 is the human patient's body surface area.
0. 19. A method for treating colorectal cancer in a human patient, comprising orally administering a composition comprising α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5 at a dose of 70 mg/m2/day in terms of FTD in 2 divided portions per day at a dosing interval of 6 hours or more comprising two cycles of daily administration of said composition for 5 days followed by 2 days off treatment in a week, and subsequent 2 weeks off treatment dosing schedule wherein m2 is the human patient's body surface area.
0. 28. A method for treating at least one of a digestive cancer and a breast cancer in a human patient, comprising orally administering a composition comprising α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5 at a dose of 70 mg/m2/day in terms of FTD in 2 divided portions per day at a dosing interval of 6 hours or more comprising two cycles of daily administration of said composition for 5 days followed by 2 days off treatment in a week, and subsequent 2 weeks off treatment dosing schedule wherein m2 is the human patient's body surface area.
1. A method for treating at least one of a digestive cancer and a breast cancer, comprising
orally administering a composition comprising α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5 at a dose of 50 to 70 mg/m2/day in terms of FTD in 2 or 3 divided portions per day to a human patient in need of treatment of at least one of a digestive cancer and a breast cancer,
wherein the administration of a daily dose of said composition is in 2 or 3 portions per day for 5 days followed by 2 days off treatment in the week on a one-week dosing schedule wherein m2 is the human patient's body surface area.
2. The method according to of
0. 3. A method for treating at least one of a digestive cancer and a breast cancer, comprising
orally administering a composition comprising
α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5 at a dose of 50 to 70 mg/m2/day in terms of FTD in 2 or 3 divided portions per day to a human patient in need of treatment of at least one of a digestive cancer and a breast cancer,
wherein the α,α,α-trifluorothymidine incorporated into the target site DNA of the cancer one day after the oral administration is present in an amount that is at least a factor of 1.72 greater than the amount of α,α,α-trifluorothymidine incorporated into the target site DNA of the cancer after an equal amount of α,α,α-trifluorothymidine is orally administered in a single dose after one day.
0. 4. A method for treating at least one of a digestive cancer and a breast cancer, comprising:
orally administering a composition comprising
α,α,α-trifluorothymidine and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5 at a dose of 50 to 70 mg/m2/day in terms of α,α,α-trifluorothymidine in 2 or 3 divided portions per day to a human patient in need of treatment of at least one of a digestive cancer and a breast cancer,
wherein the α,α,α-trifluorothymidine incorporated into the target site DNA of the cancer after three days of orally administering the α,α,α-trifluorothymidine is present in an amount that is at least a factor of 1.69 greater than the amount of the α,α,α-trifluorothymidine incorporated into the target site DNA when the oral administration is carried out in a single dose for three days.
0. 5. The method according to
0. 6. The method according to
0. 8. The method according to
0. 9. The method according to
10. The method according to of
0. 11. The method according to
0. 12. The method according to
0. 13. The method of claim 10, wherein the digestive cancer is colorectal cancer.
0. 14. The method of claim 10, wherein the digestive cancer is gastric cancer.
0. 15. The method of claim 10, wherein the digestive cancer is pancreatic cancer.
0. 16. The method of claim 10, wherein the digestive cancer is esophageal cancer.
0. 17. The method of claim 10, wherein the digestive cancer is liver cancer.
0. 20. The method of claim 19, wherein the patient's body surface area is calculated by a formula selected from the group consisting of:
i.) body surface area (m2)=([Height(cm)×Weight(kg)]/3600)1/2
ii.) body surface area (m2)=0.20247×Height(m)0.725×Weight(kg)0.425
iii.) body surface area (m2)=0.007184×Height(cm)0.725×Weight(kg)0.425
iv.) body surface area (m2)=0.024265×Height(cm)0.3964×Weight(kg)0.5378
v.) body surface area (m2)=0.0235×Height(cm)0.42246×Weight(kg)0.51456
vi.) body surface area(m2)=0.0003207×Height(cm)0.3×Weight(gram)(0.7285−(0.0188×LOG(gram)).
0. 21. The method of claim 19, wherein the patient's body surface area is calculated by the formula body surface area (m2)=([Height(cm)×Weight(kg)]/3600)1/2.
0. 22. The method of claim 19, wherein the patient's body surface area is calculated by the formula body surface area (m2)=0.20247×Height(m)0.725×Weight(kg)0.425.
0. 23. The method of claim 7, wherein the dose is 70 mg/m2/day of FTD.
0. 24. The method of claim 7, wherein the dose is 50 mg/m2/day of FTD.
0. 25. The method of claim 1, wherein the two divided portions are administered at a dosage interval of six hours or more.
0. 26. The method of claim 23, wherein the two divided portions are administered at a dosage interval of six hours or more.
0. 27. The method of claim 24 wherein the two divided portions are administered at a dosage interval of six hours or more.
0. 29. The method of claim 13, wherein the dose is 70 mg/m2/day of FTD.
0. 30. The method of claim 14, wherein the dose is 70 mg/m2/day of FTD.
0. 31. The method of claim 15, wherein the dose is 70 mg/m2/day of FTD.
0. 32. The method of claim 16, wherein the dose is 70 mg/m2/day of FTD.
0. 33. The method of claim 17, wherein the dose is 70 mg/m2/day of FTD.
0. 34. The method of claim 13, wherein the 2 divided portions are administered at a dosage interval of 6 hours or more.
0. 35. The method of claim 14, wherein the 2 divided portions are administered at a dosage interval of 6 hours or more.
0. 36. The method of claim 15, wherein the 2 divided portions are administered at a dosage interval of 6 hours or more.
0. 37. The method of claim 16, wherein the 2 divided portions are administered at a dosage interval of 6 hours or more.
0. 38. The method of claim 17, wherein the 2 divided portions are administered at a dosage interval of 6 hours or more.
0. 39. The method of claim 35, wherein the dose is 70 mg/m2/day of FTD.
0. 40. The method of claim 36, wherein the dose is 70 mg/m2/day of FTD.
0. 41. The method of claim 37, wherein the dose is 70 mg/m2/day of FTD.
0. 42. The method of claim 38, wherein the dose is 70 mg/m2/day of FTD.
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For example, when the body surface area of a cancer patient 175 cm high and 70 kg in weight is calculated by the above formula of item 1, the area is determined to be [175 (cm)×70(kg)]/3600)1/2=1.84 (m2). The assumption that the dose of 60 mg/m2/day is used in the patient gives 1.84×60=111 mg, whereby the total daily dose is set to 110 mg which will be administered in 2 to 4 divided portions.
The composition of the present invention is administered in an oral dose of 20 to 80 mg/m2/day in terms of FTD in 2 to 4 divided portions; however, the dose is preferably given in 2 to 3 divided portions. A dosage interval for the composition is preferably 6 hours or more.
For the method of the invention, a dosing schedule in one week can be daily administration, but, in terms of burden relief on patients, is preferably daily dosing for 5 days followed by 2 days off treatment in the week, more preferably two cycles of daily dosing for 5 days followed by 2 days off treatment in the week, and subsequent 2 weeks off treatment.
The method of the invention is intended for cancers including, but not limited to, esophageal, gastric, liver, gallbladder-bile duct, pancreatic, colorectal, head and neck, lung, breast, cervical, ovarian, bladder, prostate cancers, cancer of the testicles, soft tissue and bone sarcomas, skin cancer, malignant lymphoma, leukemia, and brain tumor, preferably malignant solid cancers such as gastric, pancreatic, breast, colorectal, head and neck, gallbladder-bile duct and lung cancers.
According to the method of the present invention, a much more favorable therapeutic effect may be obtained against cancer despite the use of the reduced dose, compared to conventional once-a-day administration. This is due to an increased amount of FTD incorporated into target site DNA resulting from administration at a daily dose in 2 to 4 divided portions. In addition, the method of the invention has facilitated the management of side effects.
Next, the present invention is described in further detail with reference to examples. However, this invention should not be construed to be limited to these examples in any manner.
FTD
20.00
mg
TPI-1
9.42
Lactose
70.00
Crystalline cellulose
3.50
Magnesium stearate
1.00
Talc
1.00
Corn starch
3.50
Hydroxypropylmethylcellulose
25.00
Per tablet
133.42
mg
A tablet was prepared in the preceding compounding ratio according to the ordinary method.
FTD
15.00
mg
TPI-1
7.07
Lactose
45.00
Carboxymethylcellulose
5.00
Magnesium stearate
2.00
Titanium oxide
0.50
Hydroxypropylmethylcellulose
1.00
Polyethylene glycol 4000
0.50
per tablet
85.07
mg
A tablet was prepared in the preceding compounding ratio according to the ordinary method.
FTD
30.00
mg
TPI-1
14.13
Lactose
85.00
Corn starch
100.00
Hydroxypropylcellulose
2.50
Per divided dose of powders
231.63
mg
A granule was prepared in the preceding compounding ratio according to the ordinary method.
FTD
10.00
mg
TPI-1
4.71
Lactose
24.00
Crystalline cellulose
12.50
Magnesium stearate
1.00
Per capsule
52.21
mg
A capsule was prepared in the preceding compounding ratio according to the ordinary method.
Effects of single- and divided-dosing of TAS-102 on the incorporation of FTD into DNA in mice bearing the human gastric cancer cell line NUGC-3 were studied.
Our previous data demonstrated that, when TAS-102 (the composition containing FTD and TPI in a molar ratio of 1:0.5) was orally administered to the mice at a dose of 50 mg/kg in terms of FTD, FTD levels in cancer cells could be maintained at a several-micro molar range for several hours. From this finding, we supposed that, when FTD, being divided into three times (totally, 150 mg/kg/day), would be administered at intervals of every 3 hours, tumor could contact with FTD at a several-micro molar range for 5 hours or more. Then, TAS-102 containing [3H]-labeled FTD was orally administered to the cancer-bearing mice at a dose of 150 mg/kg/day in terms of FTD, and the amount of FTD incorporated into the cancer cell DNA was quantitatively determined. The results are shown in
At one day after single- or divided-dosing, the amount of FTD in the DNA in the divided-dosing group was significantly increased as compared to that in the single-dosing group (p=0.002). In addition, the divided-dosing of FTD for further three consecutive days produced a significant increase in the amount of FTD in the DNA (p=0.03). These results suggested that the amount of FTD incorporated into cancer cell DNA could be enhanced by such a divided-dosing modality of TAS-102.
Antitumor effects of single- and 3 divided-dosing of TAS-102 were studied in a cancer-bearing mouse model.
In order to confirm whether an increased incorporation of FTD into DNA as shown in
When TAS-102 was administered at almost the same total dose in single- and divided-dosing (thrice a day at intervals of 3 hours) modalities, a significant antitumor effect, as compared to the control group, was observed in all the group treated with TAS-102 except for the group of mice bearing the PAN-12 cell line given TAS-102 at 150 mg/kg in a single-dosing modality. In addition, the divided-dosing of TAS-102 thrice a day at 30 mg/kg/dosing or 50 mg/kg/dosing increased the inhibition rate (IR). At the higher dosage of TAS-102 (150 mg/kg/day), the divided-dosing significantly enhanced the antitumor effect of TAS-102 against not only the cell line relatively high sensitive (AZ-521) to but also the cell line relatively low sensitive (PAN-12) to the single-dosing of TAS-102. In this respect, body weight loss used as a toxicological parameter was estimated to be −15% or less in a relative body weight loss ratio, indicating that such treatments were all tolerable.
Therapeutic effects of TAS-102 were studied by oral administration once a day at a daily dose of 100 mg/m2 in terms of FTD (trial 1) or at a daily dose of 70 mg/m2 in 3 divided portions (trial 2) to cancer patients.
These trials were performed using patients with digestive cancer which is refractory to standard therapy or for which no curative therapy exists, in order to evaluate, principally, the safety of the TAS-102 administrations, representing a phase I clinical trial for determining the recommended dose (RD) at which TAS-102 can be safely administered without causing problematic side effects in phase II clinical trials carried out in each type of cancer. This phase I trial was also designed to evaluate, if possible, therapeutic effects of the administrations against tumors. For therapeutic effects against tumors, tumor-shrinking effects were determined on the basis of the comprehensive evaluation of target lesions (lesions of a measurable size, or more, depending on slice thickness) and nontarget lesions (all lesions other than the target lesions), referring to the RECIST evaluation method (Journal of the National Cancer Institute, 2000, Vol 92, No. 3, 205-216). For the trial, PR (partial response) means at least a 30% decrease in the sum of the longest diameters of target lesions, maintained for a certain period of time (typically, 4 weeks) during which no progression of nontarget lesions is observed. PD (progressive disease) means at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started, or unequivocal progression of existing nontarget lesions or the appearance of a new lesion(s). SD (stable disease) means neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, the stopping of tumor growth, and no progression of tumor. MR (minor response) means a tumor shrinkage of less than 30%; however, it refers to a case maintaining a shrinkage near the percentage (a shrinkage of a 15% range), or temporarily showing a therapeutic response equivalent to PR.
The results obtained are provided in
A phase I clinical trial was performed using patients with breast cancer, as described in Example 3.
Therapeutic effects of TAS-102 were studied by oral administration twice a day at 60 mg/m2/day in terms of FTD (trial 3) or twice a day at 50 mg/m2/day (trial 4) to patients with breast cancer, which was refractory to standard therapy or for which no curative therapy was available.
The results obtained are shown in
TABLE 1
RTV1) (mean ± SD)
IR2) (%)
B.W.C.3) (%)
AZ-521
NUGC-3
PAN-12
AZ-521
NUGC-3
PAN-12
AZ-521
NUGC-3
PAN-12
SID4), 100
8.57 ± 2.94
6.84 ± 2.38
8.59 ± 1.32
45.7
31.5
28.1
4.5
3.8
−5.0
TID5), 30 × 3
6.71 ± 2.65
4.93 ± 1.03
9.33 ± 2.31
57.5
54.8
31.3
−0.6
−1.3
−7.1
SID, 150
5.86 ± 1.79
5.54 ± 1.37
7.34 ± 1.55
62.9
44.4
21.9
1.0
−2.3
−7.4
TID, 50 × 3
2.93 ± 0.66*6)
4.08 ± 1.24
5.05 ± 1.74*
81.4
62.7
53.0
−4.2
−13.8
−14.0
1)Relative tumor volume (a ratio of the estimated tumor volume on the day of response evaluation to the tumor volume on the day of animal allocation)
2)Inhibition Rate (an inhibition rate in tumor growth)
3)Body Weight Change (a ratio of the increased body weight to the body weight on the animal allocation day)
4)Once-a-day dosing
5)Thrice-a-day divided-dosing
6)Significantly different from the SID group at ± probability level of less than 0.05.
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