Method of treating cancer by co-administration of anticancer agents

Abstract

The present invention relates to a method of treating cancer by co-administration of an effective amount of 1-(2-methoxy-ethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium bromide and an effective amount of one or more anticancer agents selected from the group consisting of carboplatin, cisplatin, paclitaxel, vinorelbine, gemcitabine, irinotecan, docetaxel, doxorubicin, dacarbazine and rituximab, or a retuximab-containing combination therapy selected from R-ICE and R-DHAP. The treatment method of the present invention is useful for the treatment for all solid tumors and lymphomas, preferably skin cancer, bladder cancer, breast cancer, uterine cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer and the like. Particularly, they are expected as therapeutic agents for tumor types which show resistance against existing anticancer agents.

Description

CROSS-REFERENCE TO RELATED APPLICATION

bellow below the limit of palpation.

6) Statistical Analysis

Values are expressed as the mean±the standard error of the mean (SEM). Tumor volume and body weight on day 35 were compared between each single compound group and combination group using the Student's t-test. P values of less than 5% are considered significant. SAS software was used for data processing.

7) Results

When the anti-tumor activity of YM155 in combination with docetaxel was examined, the combination of YM155 at 2 mg/kg/day with docetaxel at 20 mg/kg/day completely inhibited tumor growth (>100%), and induced complete regression by 100% (Table 2 and FIG. 1-(a)). YM155 treatment alone inhibited tumor growth by 99% on day 35. Docetaxel also exhibited complete inhibition (>100%) of tumor growth, and induced tumor regression by 52% on day 35. During the 5 weeks of observation, YM155 or docetaxel treatment group showed tumor regression only during the first few weeks which was followed by successive tumor regrowth during the last few weeks. On the other hand, YM155 in combination with docetaxel showed complete regression of the tumors in all cases on day 35. No statistically significant decrease in body weight was observed in the combination group as compared to docetaxel group (FIG. 1-(d)).

TABLE 2
			Antitumor	Number of
	Tumor Volume (mm3)	Body Weight (g)	Activity	Complete
Treatment Groups	day 0	day 35	day 35	(% inh/% reg )	Regressions
Vehicle Control	120.9 ± 7.0	2848.0 ± 185.1	26.56 ± 0.56	—	0/8
YM155	121.4 ± 6.9	142.3 ± 16.9	26.13 ± 0.56	99%/—	0/8
Docetaxel	121.4 ± 7.0	58.0 ± 20.4	24.95 ± 0.54	>100%/52%	0/8
YM155 + Docetaxel	121.1 ± 7.2	0.0 ± 0.0¶,##	24.11 ± 0.66#N.S.	>100%/100%	8/8
Values are expressed as the mean ± SEM (n = 8).
¶P < 0.05 versus Docetaxel group,
##P < 0.01 versus YM155 group,
#P < 0.05 versus YM155 group,
N.S.no significance from Docetaxel group, respectively (Student's t-test).

8) Discussion

Results of this study indicate that YM155 significantly potentiate the anti-tumor activity of docetaxel without an increase in systemic toxicity, which is evidenced by overt symptoms such as body weight loss. The results also suggest that YM155 in combination with docetaxel is tolerated by mice, and that makes a strong combination for the treatment of cancer.

Test Example 2

The following study was conducted in the same way as Test Example 1 except for the administration timing.

A) The first day of administration was designated day 0, and observation continued until day 35. Each group (n=8) was treated as follows.

Vehicle control group Vehicle

YM155 group           YM155 2 mg/kg/day (7-day sc continuous
                      infusion)
Docetaxel group       Docetaxel 20 mg/kg/day (iv bolus on day 7, 11,
                      and 15)
Combination group     YM155 2 mg/kg/day → Docetaxel 20 mg/kg/day

For 7-day sc continuous infusion, an osmotic pump containing either YM155 or physiological saline, was implanted in the dorsum of each animal while under anesthesia. The vehicle control group received a 7-day sc continuous infusion of physiological saline starting on day 0, and iv bolus injection of physiological saline on days 7, 11 and 15. The YM155 group received a 7-day sc continuous infusion of YM155 at 2 mg/kg/day starting on day 0 and iv bolus injection of physiological saline on days 7, 11 and 15. The docetaxel group received iv bolus injection of docetaxel at 20 mg/10 mL/kg on days 7, 11 and 15, as well as a 7-day sc continuous infusion of physiological saline starting on day 0. The combination group received both compounds instead of the vehicle, similarly to the YM155 and docetaxel groups.
Results

When the anti-tumor activity of YM155 in sequential combination with docetaxel was examined, the combination of YM155 at 2 mg/kg/day with docetaxel at 20 mg/kg/day completely inhibited tumor growth (>100%), and induced complete regression by 99% (Table 3 and FIG. 1-(c)). YM155 treatment alone inhibited tumor growth by 99% on day 35. Docetaxel also exhibited complete inhibition (>100%) of tumor growth, and induced tumor regression by 10% on day 35. During the 5 weeks of observation, YM155 or docetaxel treatment group showed tumor regression only during the first few weeks which was followed by successive tumor regrowth during the last few weeks. On the other hand, YM155 in combination with docetaxel showed complete regression of the tumors in all 7 cases of 8 cases, and tumor volume was significantly (P<0.01) reduced in mice treated with YM155 in combination with docetaxel as compared to each single compound treatment on day 35. No statistically significant decrease in body weight was observed in the combination group as compared to Docetaxel group (FIG. 1-(f)).

TABLE 3
	Tumor Volume (mm3)	Body Weight (g)	Antitumor Activity	Number
Treatment Groups	day 0	day 35	day 35	(% inh/% reg)	of CRs
Vehicle Control	208.5 ± 18.6	4237.0 ± 545.7	25.88 ± 0.70	—	0/8
YM155	208.5 ± 18.6	251.8 ± 50.7	26.25 ± 0.25	99%/—	0/8
Docetaxel	209.1 ± 18.3	188.8 ± 29.1	21.03 ± 0.94	>100%/10%	0/8
YM155→Docelaxel	208.6 ± 18.1	1.3 ± 1.3¶¶##	24.13 ± 0.78¶#	>100%/99%	7/8
Values are expressed as the mean ± SEM (n = 8).
¶¶P < 0.01 versus Docetaxel group,
##P < 0.01 versus YM155 group,
#P < 0.05 versus YM155 group,
¶P < 0.05 versus Docetaxel group (Student's t-test).

B) The first day of administration was designated day 0, and observation continued until day 35. Each group (n=8) was treated as follows.

Vehicle control group Vehicle

YM155 group           YM155 2 mg/kg/day (7-day sc continuous
                      infusion)
Docetaxel group       Docetaxel 20 mg/kg/day (iv bolus on day 0,
                      4, and 8)
Combination group     Docetaxel 20 mg/kg/day → YM155 2 mg/kg/day

For 7-day sc continuous infusion, an osmotic pump containing either YM155 or physiological saline, was implanted in the dorsum of each animal while under anesthesia. The vehicle control group received a 7-day sc continuous infusion of physiological saline starting on day 8, and iv bolus injection of physiological saline on days 0, 4 and 8. The YM155 group received a 7-day sc continuous infusion of YM155 at 2 mg/kg/day starting on day 8, and iv bolus injection of physiological saline on days 0, 4 and 8. The docetaxel group received iv bolus injection of docetaxel at 20 mg/10 mL/kg on days 0, 4 and 8, as well as a 7-day sc continuous infusion of physiological saline starting on day 8. The combination group received both compounds instead of the vehicle, similarly to the YM155 and docetaxel groups.

Results

When the anti-tumor activity of YM155 in sequential combination with docetaxel was examined, the combination of YM155 at 2 mg/kg/day with docetaxel at 20 mg/kg/day completely inhibited tumor growth (>100%), and induced complete regression by 97% (Table 4 and FIG. 1-(b)). YM155 treatment alone inhibited tumor growth by 61% on day 35. Docetaxel also exhibited complete inhibition (>100%) of tumor growth, and induced tumor regression by 68% on day 35. During the 5 weeks of observation, YM155 or docetaxel treatment group showed tumor regression only during the first few weeks which was followed by successive tumor regrowth during the last few weeks. On the other hand, YM155 in combination with docetaxel showed complete regression of the tumors in three cases, and tumor volume was significantly (P<0.01) reduced in mice treated with YM155 in combination with docetaxel as compared to each single compound treatment on day 35. No statistically significant decrease in body weight was observed in the combination group as compared to docetaxel group (FIG. 1-(e)).

TABLE 4
	Tumor Volume (mm3)	Body Weight (g)	Antitumor Activity	Number
Treatment Groups	day 0	day 35	day 35	of CRs	of CRs
Vehicle Control	207.7 ± 23.5	3380.8 ± 325.4	24.33 ± 0.85	—	0/8
YM155	206.9 ± 21.8	1437.5 ± 225.5	24.80 ± 1.01	61%/—	0/8
Docetaxel	210.0 ± 22.6	67.2 ± 15.1	23.84 ± 1.01	>100%/68%	0/8
Docetaxel →YM155	210.1 ± 20.4	5.5 ± 1.7¶¶,##	25.74 ± 1.13N.S., N.S.	>100%/97%	3/8
Values are expressed as the mean ± SEM (n = 8).
¶¶P < 0.01 versus Docetaxel group,
##P < 0.01 versus YM155 group,
N.S.no significance from YM155 group and Docetaxel group, respectively (Student's t-test).

Test Example 3

The study was conducted in the same way as Test Example 1, except that the listed agents in Table 5 were used instead of Docetaxel according to the following dosage regimen.

TABLE 5
Anticancer Agent	Dosage Regimen	Result
Carboplatin	CBDCA	60	mg/kg/day i.v. (day 0, 1)	FIG. 2-(a) & (b)
Cisplatin	CDDP	3	mg/kg/day i.v.	FIG. 2-(c) & (d)
			(day 0-4, 7-11)
Gemcitabine	GEM	200	mg/kg/day i.v.	FIG. 3-(a) & (b)
			(day 0, 3, 6)
Vinorelbine	VNR	10	mg/kg/day i.v. (day 0, 7)	FIG. 3-(c) & (d)
Doxorubicin	DXR	10	mg/kg/day i.v. (day 0, 7)	FIG. 4-(a) & (b)
Irinotecan	CPT-11	60	mg/kg/day i.v. (day 0-4)	FIG. 4-(c) & (d)
Paclitaxel	TXT	10-15	mg/kg/day i.v. (day 0-4)	FIG. 5-(a) & (b)
(In the Table 5, i.v. means intravenous administration, for example, (day 0, 1) means once-a-day administration at the initial day of administration (day 0) and at the 1st day (day 1); (day 0-4) means once-a-day administration from the initial day of administration (day 0) to the 4th day (day 4), respectively.)

Results were shown in FIGS. 2 to 5. In the figures, values are expressed as the mean±SEM (n=8). ¶¶: P<0.01 versus an anticancer agent group YM155 group, ##: P<0.01 versus YM155 group an anticancer agent group, #: P<0.05 versus YM155 group, N.S.: no significance from YM155 group and the anticancer agent group, respectively (Student's t-test).

The respective anticancer agents were purchased as commercially available products, and prepared according to the procedure directed in package inserts to use in the tests.

Test Example 4

The study was conducted in the same way as Test Example 1, except that Dacarbazine was used instead of Docetaxel and Melanoma A375 cells were used instead of Calu 6 cells according to the following dosage regimen (n=8). Results were shown in FIG. 6.

YM155 group YM155 3 mg/kg/day (7-day sc continuous infusion)
Dacarbazine Dacarbazine 200 mg/kg, 5 times weekly, i.v.
group
Combination YM155 3 mg/kg/day (7-day sc continuous infusion) +
group       Dacarbazine 200 mg/kg, 5 times weekly, i.v.

Dacarbazine was purchased as commercially available products, and prepared according to the procedure directed in package inserts to use in the tests.

Test Example 5

The study was conducted in the same way as Test Example 1, except that R-ICE(RICE) or Rituximab(RTX) was used instead of Docetaxel, and lymphoma WSU-DLCL-2 cells were used instead of Calu 6 cells according to the following dosage regimen.

YM155 group YM155 1 mg/kg/day (7-day sc continuous infusion)

RICE group RTX 50 mg/kg, i.v. (day 0)+(IFM 200 mg/kg+ETP 10 mg/kg), i.v. (day 1.2 and 3)+CBDCA 30 mg/kg, i.v. (day 1)

YM155+RICE group YM155 1 mg/kg/day (7-day sc continuous infusion)+RTX 50 mg/kg, i.v. (day 0)+(IFM 200 mg/kg+ETP 10 mg/kg), i.v. (day 1, 2 and 3)+CBDCA 30 mg/kg, i.v (day 1).

YM155+RTX group YM155 1 mg/kg/day (7-day sc continuous infusion)+RTX 50 mg/kg, i.v. (day 0).

RTX, IFM and ETP were purchased as commercially available products, and prepared according to the procedure directed in package inserts to use in the tests. Results were shown in FIG. 7. In the figures, values are expressed as the mean±SEM (n=6). ¶¶: P<0.01 versus an anticancer agent group, ¶: P<0.05 versus an anticancer agent group, ##: P<0.01 versus YM155 group, N.S.: no significance from YM155 group and the anticancer agent group, respectively (Student's t-test). YM155 in combination with R-ICE showed complete regression of the tumors in one case, and YM155 in combination with RTX showed complete regression of the tumors in two cases.
The preliminary study was done by using the method similar to the above-mentioned YM155+RICE group, but R-DHAP was used instead of R-ICE, wherein R-DHAP was consisting of rituximab (50 mg/kg i.v., day 0 and 2), cisplatin (5 mg/kg, i.v., day 2), cytarabin (70 mg/kg, i.v., day 4). The tumor volume was significantly (P<0.01) reduced in the combination group as compared to R-DHAP group on day 18.

Test Example 6

The study was conducted in the same way as Test Example 5 according to the following dosage regimen.

YM155 group YM155 2 mg/kg/day (7-day sc continuous infusion)

RICE group RTX 50 mg/kg, i.v. (day 6 and 8)+(IFM 400 mg/kg+CBDCA 30 mg/kg), i.v (day 9)+ETP 10 mg/kg, i.v (day 8, 9 and 10)

YM155→RICE group YM155 2 mg/kg/day (7-day sc continuous infusion)+RTX 50 mg/kg, i.v. (day 6 and 8)+(IFM 400 mg/kg+CBDCA 30 mg/kg), i.v. (day 9)+ETP 10 mg/kg, i.v. (day 8, 9 and 10)

Results were shown in table 6. In the table, values are expressed as the mean±SEM (n=8, RICE group: n=6). ¶¶: P<0.01 versus an RICE group, ##: P<0.01 versus YM155 group, N.S.: no significance from RICE group (Student's t-test). YM155 in combination with R-ICE showed complete regression of the tumors in six cases.

TABLE 6
	Tumor Volume (mm3)	Body Weight (g)	Antitumor Activity	Number
Treatment Groups	day 0	day 28	day 28	(% inh/% reg )	of CRs
Vehicle Control	404.4 ± 14.5	2131.5 ± 276.6	29.02 ± 0.38	—	0/8
YM155	405.1 ± 13.8	1181.3 ± 174.7	28.81 ± 0.23	45%/—	0/8
RICE	404.2 ± 13.0	1356.0 ± 371.7	29.54 ± 0.51	56%/—	0/6
YM155 → RICE	404.7 ± 12.6	17.6 ± 11.5¶¶,##	28.55 ± 0.26N.S.	>100%/96%	6/8

INDUSTRIAL APPLICABILITY

The method of the invention for treatment of cancer by co-administration of YM155 and an existing anticancer agent, in which the inhibitory action of YM155 on expression of survivin works synergistically with the anticancer effect of the existing anticancer agent, affords a high therapeutic effect for cancers and is useful in treatment of a variety of cancers to which existing anticancer agents are applied, accordingly. Thus, the method of the invention for treatment of cancer by co-administration of YM155 and an existing anticancer agent is useful in treatment of cancers, preferably all solid cancers and lymphomas, particularly skin cancer, bladder cancer, breast cancer, uterine cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and the like. Particularly, they are expected as therapeutic agents for some kinds of cancers which show resistance against existing anticancer agents.

Claims

1. A method for treatment of a cancer patient with lymphoma, which comprises administering an effective amount of 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium bromide to said patient, combined with

i) an effective amount of rituximab,

ii) a combination therapy R-ICE consisting of rituximab, ifosfamide, carboplatin and etoposide, or

iii) a combination therapy R-DHAP consisting of rituximab, cytarabine and cisplatin as anticancer agents.

2. The method as claimed in claim 1, wherein rituximab is combined with said effective amount of 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium bromide.

3. The method as claimed in claim 1, wherein said rituximab is administered as a member of a combination therapy selected from the group consisting of R-ICE and R-DHAP is combined with said effective amount of 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium bromide.

4. The method as claimed in claim 3 1, wherein said rituximab is administered as a member of a combination therapy R-ICE is combined with said effective amount of 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium bromide.

5. The method as claimed in claim 1, wherein the patient has lymphoma.

6. The method as claimed in claim 1, wherein said 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium bromide is administered intravenously by infusion at a dose of 1-10 mg/m²/day continuously for a period of 4-14 days.

7. A method as claimed in claim 6, wherein said 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-]imidazol-3-ium bromide is administered intravenously by infusion at a dose of 3-8 mg/m²/day continuously for 7 days followed by 14 days of no 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium bromide, after which the entire administration cycle can be repeated depending on the patient's conditions.

8. A kit comprising at least one cycle dosage of 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium bromide and

i) rituximab,

ii) anticancer agents for a combination therapy R-ICE consisting of rituximab, ifosfamide, carboplatin and etoposide, or

iii) anticancer agents for a combination therapy R-DHAP consisting of rituximab, cytarabine and cisplatin as anticancer agents.