NZ750260A - Antitumor agent and antitumor effect enhancer - Google Patents
Antitumor agent and antitumor effect enhancerInfo
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- NZ750260A NZ750260A NZ750260A NZ75026014A NZ750260A NZ 750260 A NZ750260 A NZ 750260A NZ 750260 A NZ750260 A NZ 750260A NZ 75026014 A NZ75026014 A NZ 75026014A NZ 750260 A NZ750260 A NZ 750260A
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Abstract
Provided is a novel method for treating a cancer using an FTD/TPI combination drug, which shows remarkably excellent antitumor effect. An antitumor agent, in which a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1 : 0.5 and an anti-VEGF antibody or anti-EGFR antibody are administered in combination
Description
DESCRIPTION
ANTITUMOR AGENT AND ANTITUMOR EFFECT ENHANCER
The present application is a divisional application from
New Zealand patent application number , the entire
disclosure of which is incorporated herein by reference.
Technical Field
The present invention relates to an antitumor agent
ning a ation drug of trifluridine and tipiracil
hydrochloride, and an anti-VEGF antibody or anti-EGFR antibody,
and an antitumor effect enhancer of an anti-VEGF antibody or
anti-EGFR dy.
Background Art
Trifluridine (also known as ,,-trifluorothymidine.
Hereinafter, also referred to as "FTD") manifests mor
effects by DNA synthesis inhibition from an action of inhibiting
thymidylate production and by DNA function blocking from
incorporation into DNA. Meanwhile, tipiracil hydrochloride
(chemical name:
-chloro[(2-iminopyrrolidineyl)methyl]pyrimidine
-2,4(1H,3H)-dione hydrochloride. Hereinafter , also referred
to as "TPI") has an action of ting thymidine
orylase. It is known that mor effect of FTD is
enhanced by TPI that suppresses in vivo decomposition of FTD
by thymidine phosphorylase (Patent Literature 1). Currently,
an antitumor agent ning FTD and TPI at a molar ratio of
1 : 0.5 nafter, also referred to as an "FTD/TPI
combination drug") is under development as a therapeutic agent
for a solid cancer such as colorectal cancer (Non-Patent
Literatures 1 and 2).
Furthermore, combination therapies to enhance the
antitumor effect of an FTD/TPI combination drug have been
studied, and the combined effect of the combination drug and
irinotecan and oxaliplatin have been suggested so far
(Non-Patent Literatures 3 and 4).
Meanwhile, in recent years, development of a drug
targeting a molecule involved in angiogenesis or cell
proliferation such as Vascular Endothelial Growth Factor
(hereinafter, VEGF) and Epidermal Growth Factor Receptor
(hereinafter, EGFR) is actively performed. For example, as a
molecular target drug for VEGF, bevacizumab, which is an
anti-VEGF humanized monoclonal antibody, is clinically used as
a therapeutic agent for a carcinoma such as colorectal cancer,
all cell lung cancer, breast cancer and renal cell cancer.
In addition, as a molecular target drug for EGFR, cetuximab,
which is an anti-EGFR human/mouse chimeric monoclonal antibody,
is clinically used as a therapeutic agent for colorectal cancer
and head and neck cancer, and mumab, which is an anti-EGFR
human-type fully monoclonal antibody, is clinically used as a
therapeutic agent for colorectal cancer, respectively
(Non-Patent Literatures 5, 6 and 7).
As described above, although developments of a therapy
including an FTD/TPI combination drug are energetically
performed, a ation y using an FTD/TPI combination
drug and a molecular target drug for VEGF or EGFR, is not known
at all.
Citation List
Patent Literature
Patent Literature 1: WO 96/30346 A
Non-Patent tures
Non-Patent Literature 1: Invest New Drugs 26(5): 445-54, 2008.
Non-Patent Literature 2: Lancet Oncol. : 993-1001, 2012.
Non-Patent Literature 3: Eur J Cancer. 43(1): 175-83, 2007.
Non-Patent Literature 4: Br J . 96(2): 231-40, 2007.
Non-Patent Literature 5: Curr Oncol Rep. 14(4): 277-84, 2012.
Non-Patent Literature 6: Curr Cancer Drug Targets. 10(1):
80-95, 2010.
Non-Patent Literature 7: Pathol Oncol Res. 16(2): 143-8, 2010.
Summary of ion
Technical m
An object of the present invention is to provide a novel
method for treating a cancer using an I combination drug,
which shows remarkably excellent antitumor effect and less
adverse s.
Solution to Problem
In consideration of such situations, the t
inventors found that concomitant use of an FTD/TPI combination
drug and an anti-VEGF antibody or anti-EGFR antibody suppresses
occurrence of adverse effects and remarkably enhances the
antitumor effect of the anti-VEGF antibody or anti-EGFR
antibody.
That is, the present invention provides the following [1]
to [21].
An antitumor agent, wherein a combination drug containing
trifluridine and tipiracil hydrochloride at a molar ratio of
1 : 0.5 and an anti-VEGF antibody or anti-EGFR antibody are
administered in ation.
The antitumor agent according to [1], wherein the
anti-VEGF dy is bevacizumab.
The antitumor agent according to [1] or [2], wherein the
anti-EGFR dy is cetuximab or panitumumab.
The antitumor agent according to any one of [1] to [3],
wherein target cancer is colorectal cancer, lung cancer, breast
cancer, atic cancer, or gastric .
An antitumor effect er including a combination drug
containing trifluridine and cil hydrochloride at a molar
ratio of 1 : 0.5 for enhancing the antitumor effect of an
anti-VEGF antibody or anti-EGFR antibody.
An antitumor agent including a combination drug
containing trifluridine and tipiracil hydrochloride at a molar
ratio of 1 : 0.5 for treating a cancer patient administered with
an anti-VEGF antibody or anti-EGFR antibody.
A kit preparation including a combination drug containing
trifluridine and tipiracil hydrochloride at a molar ratio of
1 : 0.5, and an instruction manual, wherein
the instruction manual describes that the combination
drug containing trifluridine and tipiracil hydrochloride at a
molar ratio of 1 : 0.5 is administered in combination with the
anti-VEGF antibody or anti-EGFR antibody to a cancer patient.
A combination drug containing trifluridine and tipiracil
hydrochloride at a molar ratio of 1 : 0.5 for enhancing the
mor effect of an EGF antibody or anti-EGFR
antibody.
A combination drug containing trifluridine and tipiracil
hydrochloride at a molar ratio of 1 : 0.5 for treating a cancer
patient administered with an anti-VEGF antibody or anti-EGFR
antibody.
The combination drug according to [8] or [9], wherein the
anti-VEGF antibody is bevacizumab.
The combination drug ing to any one of [8] to [10],
wherein the anti-EGFR antibody is cetuximab or panitumumab.
The combination drug according to any one of [8] to [11],
wherein target cancer is colorectal cancer, lung cancer, breast
cancer, pancreatic cancer, or gastric cancer.
Use of a combination drug containing trifluridine and
tipiracil hydrochloride at a molar ratio of 1 : 0.5 for producing
an antitumor effect enhancer ing the antitumor effect of
an anti-VEGF antibody or anti-EGFR antibody.
Use of a combination drug containing ridine and
tipiracil hloride at a molar ratio of 1 : 0.5 for producing
an antitumor agent for a cancer patient administered with an
anti-VEGF antibody or anti-EGFR antibody.
The use according to [13] or [14], wherein the anti-VEGF
antibody is bevacizumab.
The use according to any one of [13] to [15], n the
anti-EGFR antibody is cetuximab or panitumumab.
The use according to any one of [13] to [16], wherein the
target cancer is ctal cancer, lung cancer, breast cancer,
pancreatic cancer, or gastric .
A method for treating a cancer, ing administering
a combination drug containing trifluridine and tipiracil
hydrochloride at a molar ratio of 1 : 0.5 and an anti-VEGF
antibody or anti-EGFR antibody in combination.
The method according to [18], wherein the anti-VEGF
antibody is bevacizumab.
The method for treating according to [18], wherein the
anti-EGFR antibody is cetuximab or panitumumab.
The method for treating according to any one of [18] to
, wherein target cancer is colorectal , lung cancer,
breast cancer, pancreatic cancer, or gastric .
The use, in the manufacture of a medicament, of a
combination of ridine and tipiracil hydrochloride at a
molar ratio of 1:0.5, and an anti-VEGF antibody or anti-EGFR
antibody selected from bevacizumab, cetuximab and panitumumab
as active ingredients for the treatment of a target cancer tumor,
wherein the daily dose of the combination of FTD/TPI in the
medicament on a day of administration is from 11 to 80 day
as FTD and
(a) the daily dose of bevacizumab on the administration day is
from 1.10 to 10 mg/kg/day;
(b) the daily dose of cetuximab on the administration day is
from 44 to 400 mg/kg/day, and
(c) the daily dose of mumab on the administration day is
from 0.67 to 6 mg/kg/day;
wherein the target cancer tumor is digestive cancer or breast
cancer.
ageous Effects of Invention
According to the antitumor agent of the present
invention, it is possible to perform a cancer treatment
suppressing outbreak of e effects and exerting high
antitumor effect, and thus bring long time survival of a cancer
patient.
Brief Description of Drawings
Fig. 1 is a figure illustrating the combinatorial effect
of an FTD/TPI combination drug and bevacizumab with respect to
colon cancer.
Fig. 2 is a figure illustrating the combinatorial effect
of an FTD/TPI combination drug and bevacizumab with respect to
colon cancer.
Fig. 3 is a figure rating the combinatorial effect
of an FTD/TPI combination drug and bevacizumab with respect to
colon cancer.
Fig. 4 is a figure illustrating the atorial effect
of an FTD/TPI combination drug and bevacizumab with respect to
colon cancer.
Fig. 5 is a figure illustrating the combinatorial effect
of an FTD/TPI ation drug and bevacizumab with respect to
colon cancer.
Fig. 6 is a figure illustrating the combinatorial effect
of an FTD/TPI combination drug and zumab with respect to
colon cancer.
Fig. 7 is a figure illustrating the combinatorial effect
of an I combination drug and cetuximab with respect to
colon cancer.
Fig. 8 is a figure illustrating the combinatorial effect
of an FTD/TPI combination drug and cetuximab with respect to
colon cancer.
Fig. 9 is a figure illustrating the combinatorial effect
of an FTD/TPI combination drug and cetuximab with respect to
colon cancer.
Fig. 10 is a figure illustrating the combinatorial effect
of an FTD/TPI combination drug and cetuximab with respect to
colon .
Fig. 11 is a figure illustrating the combinatorial effect
of an FTD/TPI combination drug and cetuximab with respect to
colon cancer.
Fig. 12 is a figure illustrating the combinatorial effect
of an FTD/TPI combination drug and cetuximab with t to
colon cancer.
Fig. 13 is a figure illustrating the combinatorial effect
of an I combination drug and cetuximab with respect to
colon cancer.
Fig. 14 is a figure illustrating the combinatorial effect
of an FTD/TPI combination drug and panitumumab with respect to
colon cancer.
Fig. 15 is a figure illustrating the combinatorial effect
of an FTD/TPI combination drug and panitumumab with respect to
colon cancer.
Fig. 16 is a figure illustrating the combinatorial effect
of an FTD/TPI combination drug and panitumumab with respect to
colon cancer.
Fig. 17 is a figure illustrating the combinatorial effect
of an FTD/TPI combination drug and panitumumab with respect to
colon .
Description of Embodiments
The antitumor agent of the present invention is
terized in that an FTD/TPI combination drug and an
anti-VEGF antibody or GFR antibody are administered in
combination. Another antitumor agent may be further
administered in combination as long as the FTD/TPI combination
drug and the anti-VEGF antibody or anti-EGFR antibody are
stered in ation.
FTD and TPI in the t invention are known compounds,
respectively, and can be synthesized, for example, in
accordance with the method described in the pamphlet of WO
96/30346 A. In addition , a combination drug containing FTD and
TPI at a molar ratio of 1 : 0.5 is also known (Non-Patent
Literatures 1 and 2).
VEGF recognized by the "anti-VEGF antibody" in the
present invention may be any one of VEGF-A, VEGF-B, ,
VEGF-D, VEGF-D, , PLGF (placental growth factor)-1 and
PLGF-2, which are of human VEGF family, and is preferably human
VEGF-A. The base ce and the amino acid sequence of human
VEGF-A are registered as the accession numbers NM001171623 and
NP001165094, respectively in GenBank, and information of these
ces may be used in the present invention.
EGFR recognized by the "anti-EGFR antibody" in the
present invention is preferably human EGFR. Meanwhile , the
base sequence and the amino acid sequence of human EGFR are,
registered as the accession numbers NM005228 and NP005219,
respectively in GenBank, and information of these sequences may
be used in the present invention.
In addition, the VEGF antibody" and the "anti-EGFR
antibody" in the present invention may be a monoclonal antibody
or may be a polyclonal antibody, or may be an antibody fragment
such as Fab, Fab' and F(ab')2. Furthermore, the anti-VEGF
antibody may be an extracellular domain of the VEGF receptor.
In addition, the origin of these antibodies is preferably a
human chimeric antibody, a humanized dy or a human
dy from the viewpoint of reducing the immunogenicity.
The VEGF antibody" and the "anti-EGFR antibody" in
the present invention can be usually manufactured in accordance
with a method for manufacturing an antibody known in the field.
A commercially available antibody may be also used.
The "anti-VEGF antibody" in the present invention is not
ularly limited if it is an antibody specifically
recognizing VEGF, and exemplified by bevacizumab, aflibercept,
ranibizumab and icrucumab, and is preferably bevacizumab.
Commercially available products may be also used as these
antibodies.
The "anti-EGFR antibody" in the present invention is not
particularly limited if it is an antibody specifically
recognizing EGFR, and exemplified by cetuximab, mumab,
mab, nimotuzumab, zalutumumab and mumab, and is
preferably cetuximab or panitumumab. Commercially available
products may be also used as these antibodies.
The daily dose of the FTD/TPI combination drug in the
antitumor agent of the present ion on the administration
day is preferably from 17 to 115%, more preferably from 50 to
100%, more preferably from 70 to 100%, and particularly
preferably 100% to the recommended dose in the case of single
administration of the I ation drug to a cancer
patient from the viewpoint of the action of enhancing the
antitumor effect of the anti-VEGF antibody or anti-EGFR
antibody by the I combination drug. Specifically, the
dose of the FTD/TPI combination drug is ably from 11 to
80 mg/m2/day, more preferably from 35 to 70 mg/m2/day, more
preferably from 50 to 70 mg/m2/day, and particularly preferably
70 mg/m2/day as FTD.
The daily dose of bevacizumab in the antitumor agent of
the present invention on the administration day is preferably
from 4 to 100%, more preferably from 11 to 100%, and particularly
preferably from 34 to 100% to the recommended dose in the case
of single stration of bevacizumab to a cancer patient from
the viewpoint of the action of enhancing the antitumor effect
by the FTD/TPI combination drug. Specifically, the dose of
bevacizumab is preferably from 0.4 to 15 mg/kg/day, more
preferably from 0.4 to 10 mg/kg/day, more preferably from 1.10
to 10 mg/kg/day, and particularly preferably from 3.4 to 10
mg/kg/day.
The daily dose of cetuximab in the antitumor agent of the
present invention on the administration day is preferably from
4 to 100%, more preferably from 11 to 100%, and particularly
preferably from 50 to 100% to the recommended dose in the case
of single administration of cetuximab to a cancer patient from
the viewpoint of the action of enhancing the antitumor effect
of cetuximab by the I combination drug. Specifically,
the dose of cetuximab is preferably from 15 to 400 mg/m2/day,
more preferably from 44 to 400 day, and particularly
preferably from 200 to 400 mg/m2/day.
The daily dose of panitumumab in the antitumor agent of
the present ion on the administration day is preferably
from 4 to 100%, more preferably from 11 to 100%, and particularly
preferably from 34 to 100% to the recommended dose in the case
of single administration of panitumumab to a cancer patient from
the int of the action of ing the antitumor effect
of panitumumab by the FTD/TPI combination drug. Specifically,
the daily dose of panitumumab is preferably from 0.23 to 6
mg/kg/day, more ably from 0.67 to 6 mg/kg/day, and
particularly preferably from 2.03 to 6 mg/kg/day.
The "administration in combination" in the present
invention means that the FTD/TPI combination drug and an
anti-VEGF antibody or anti-EGFR antibody are administered in
combination within a certain period within a range of achieving
the effect of the present ion of enhancing the antitumor
effect of an anti-VEGF antibody or anti-EGFR antibody while
ssing outbreak of adverse effects. Specific
administration schedule of the antitumor agent of the t
invention can be ly selected depending on, for example,
carcinoma or stage of disease. The administration schedule of
the FTD/TPI combination drug is preferably five day
administration every day and two day withdrawal that is repeated
twice, and then two week withdrawal. The stration
schedule of the EGF antibody or anti-EGFR antibody is
preferably administration once every one to three weeks. Such
administration schedule may be implemented once, or repeated
twice or more.
Examples of the target cancer of the antitumor agent of
the present invention include specifically head and neck
cancer, digestive cancer (for example, geal cancer,
gastric cancer, duodenal cancer, liver cancer, bile duct cancer
(for e, gallbladder or bile duct cancer), pancreatic
cancer, small intestinal cancer, and colon cancer (for example,
colorectal cancer, colon cancer and rectal cancer)), lung
cancer, breast cancer, ovary cancer, uterine cancer (for
example, cervical cancer and corpus uteri cancer), renal
cancer, bladder cancer, and tic cancer. Among them, the
target cancer of the antitumor agent of the present invention
is preferably digestive cancer, lung cancer or breast cancer,
more preferably colorectal , lung cancer, breast cancer,
pancreatic cancer, or gastric cancer, and particularly
preferably colorectal cancer from the viewpoint of the
antitumor effect and the adverse effects. The cancer herein
includes not only cancers at a primary lesion, but also cancers
spread to other organs (for example, liver). In addition , the
antitumor agent of the present invention may be used in
postoperative adjuvant herapy med for preventing
relapse after surgical extraction of the tumor, or may be a
pre-operative adjuvant chemotherapy previously performed for
surgical extraction of the tumor.
The antitumor agent of the present invention is
formulated in multiple dosage forms separately for each active
ingredient since the administration means and administration
les are different by each active ingredient and all active
ingredients cannot be formulated together in one dosage form.
It is preferred that FTD and TPI are formulated as a combination
drug, and the anti-VEGF antibody and GFR dy as a
single active ingredient preparation.
Each preparation may be produced and sold together in one
package suitable for administration in combination, or each
preparation may be produced and sold in a separate e
respectively as long as each active ingredient is administered
according to the dose of the present invention.
The dosage form of the antitumor agent of the present
invention is not particularly limited, and can be suitably
selected ing on the therapeutic purpose. Examples of t he
dosage form of the antitumor agent of the t invention
include ically an oral agent (for example, a tablet, a
coated tablet, a powder, a granule, a capsule, and a liquid),
an injection, a suppository, a patch, and an ointment. The
FTD/TPI combination drug is preferably an oral agent, and the
anti-VEGF dy and anti-EGFR antibody is preferably an
injection, and ularly ably an injection for
intravenous administration.
The antitumor agent of the present invention can be
usually ed according to a known method using
pharmaceutically acceptable carriers depending on the dosage
form thereof. Examples of such carrier include various
carriers generally used in conventional drugs, for example an
excipient, a binder, a disintegrator, a lubricant, a diluent,
a solubilizer, a suspending agent, a tonicity agent, a pH
adjusting agent, a buffer, a stabilizer, a colorant, a flavoring
agent, and an odor improving agent.
In addition, the present invention also relates to an
mor effect enhancer including an FTD/TPI combination drug
for enhancing the antitumor effect of an anti-VEGF antibody or
anti-EGFR antibody in a cancer patient (particularly, patient
with colorectal cancer). The antitumor effect enhancer has the
dosage form of the antitumor agent described above.
The present invention also relates to an antitumor agent
including an FTD/TPI combination drug for ng a cancer
patient administered with an anti-VEGF antibody or anti-EGFR
antibody (particularly, a t with colorectal cancer).
The antitumor agent has the dosage form described above.
The present invention also relates to a kit preparation
ing an FTD/TPI combination drug and an instruction manual
describing that the FTD/TPI combination drug is administered
in combination with an anti-VEGF antibody or anti-EGFR to a
cancer patient (particularly, a t with colorectal
cancer). The uction manual" herein may describe the dose
bed above, preferably recommending the dose described
above, whether it is legally bound or not. Specifically,
examples of the instruction manual include a e insert,
and a pamphlet. In addition , the ction manual in the kit
preparation including the instruction manual may be embedded
by printing onto the package of the kit preparation, or may be
enclosed along with the antitumor agent in the package of the
kit preparation.
The present invention also relates to a method for
treating a cancer, which is characterized by administering an
FTD/TPI combination drug and an anti-VEGF antibody or anti-EGFR
in combination. The antitumor agent containing an I
combination drug and an anti-VEGF antibody or anti-EGFR has the
dosage form of the antitumor agent described above.
Examples
Next, the present invention will be further described
with es and nce Examples more specifically.
Reference Example
The culture cells of a human colon cancer cell line
(KM20C) (1 107 cells/mouse) were transplanted into the
abdominal cavity of a five to six ld BALB/cA Jcl-nu mouse.
The mouse was allocated into each group such that the average
weight of each group was equal, and the day when the grouping
(n = 10) was implemented was assumed to be Day 0.
An FID/TPI combination drug (a mixture of FTD and TPI at
a molar ratio of 1 : 0.5) was prepared to give 75, 100, 150,
300 and 450 mg/kg/day as FTD. The drug administration was
initiated from Day 3, and oral administration of the I
combination drug for five days every day and two day withdrawal
were performed for six weeks.
As an index of the antitumor effect, the number of the
surviving mice in each group was checked, and the survival time
of each group was compared. The results are shown in Table 1.
[Table 1]
Dose ILS b)
Drug Treatment a)
No. of Survival time
(mg/kg/day) s (day) Mean SD (%)
Control - - 10 40.0 4.3 -
Five day oral administration with
FTD/TPI combination drug 75 10 25.0
two day rest (b.i.d) 50.0 9.1
Five day oral administration with
FTD/TPI combination drug 100 10
two day rest (b.i.d) 75.8 42.6 89.5
Five day oral administration with
FTD/TPI combination drug 150 10 214.3
two day rest (b.i.d) 125.7 64.8
Five day oral administration with
FTD/TPI combination drug 300 10
two day rest (b.i.d) 75.6 17.5 89.0
Five day oral administration with
FTD/TPI combination drug 450 10
two day rest (b.i.d) 54.1 18.3 35.3
As described in Table 1, in the mice, the survival time
was longer in the group of 150 mg/kg/day as FTD for the FTD/TPI
combination drug. From this , the recommending dose (RD) of the
FTD/TPI combination drug in a mouse is 150 mg/kg/day as FTD.
In contrast, RD of the FTD/TPI combination drug in human is 70
mg/m2/day as FTD. From this, 150 mg/kg/day in a mouse
corresponds to 70 mg/m2/day in human.
With bevacizumab, the doses of 1.25 and 5, 20 mg/kg were
stered into the abdominal cavity for three weeks every
seven days using nude mice lanted with a human breast
cancer cell line MX-1, and the optimal dose was studied. From
the report (Bevacizumab Interview Form) that 5 mg/kg gave the
highest tumor growth tion rate, and the effect reached
the peak at a higher dose than the dose, RD of bevacizumab in
a mouse is 5 mg/kg/day. In contrast, RD of bevacizumab in human
is 10 mg/kg/day. From this, 5 mg/kg/day in a mouse ponds
to 10 mg/kg/day in human.
With cetuximab, the doses of 0.5 and 1 mg/dose were
injected intravenously for five weeks every three days using
nude mice transplanted with a human renal cell cancer cell line
SK-RC-29, and the optimal dose was studied. From the report
(Clinical cancer research (1998) 4, 2957-2966) that 1 mg/dose
(corresponding to 40 mg/kg when the weight of mouse is assumed
to be 25 g) gave the highest tumor growth inhibition rate, RD
of cetuximab in a mouse is 40 mg/kg/day. In contrast, RD of
cetuximab in human is 400 mg/m2/day. From this , 40 mg/kg/day
in a mouse corresponds to 400 mg/m2/day in human.
With panitumumab, the doses of 20, 200, 500 and 1000
g/dose were injected intravenously twice every week for five
weeks using nude mice transplanted with a human colon cancer
cell line HT29, and the optimal dose was studied. From the
report umumab iew Form) that the effect reached the
peak at a dose equal to or higher than 200 g/dose (corresponding
to 8 mg/kg when the weight of a mouse is assumed to be 25 g),
RD of panitumumab in a mouse is 8 mg/kg. In contrast, RD of
mumab in human is 6 mg/kg/day. From this , accordingly,
8 mg/kg/day in a mouse corresponds to 6 mg/kg/day in human.
Example 1
A human colon cancer cell line (KM20C) was transplanted
onto the right chest of a five to six week-old BALB/cA Jcl-nu
mouse. The length (mm) and the breadth (mm) of the tumor after
the tumor transplantation were ed, and the tumor volume
(TV) was calculated. Then, the mouse was allocated into each
group such that the average TV in each group was equal, and the
day when the grouping (n = 6 to 7) was implemented was assumed
to be Day 0.
The administration dose of the drug was 10 mL/kg, and the
FTD/TPI combination drug (a mixture of FTD and TPI at a molar
ratio of 1 : 0.5) was prepared to be 150 mg/kg/day as the dose
of FTD. Bevacizumab (Avastin injection, Chugai Pharmaceutical
Co., Ltd.) was prepared to be 0.20, 0.55, 1.7 and 5 mg/kg/day.
The FTD/TPI combination drug was orally administered on Days
1 to 14 every day, and bevacizumab was administered into the
nal cavity for two weeks at a frequency of twice a week
from Day 1. To the combination-treated group, the FTD/TPI
combination drug and bevacizumab were administered in the same
doses and the same administration schedules as those of the
single agent-treated group.
As an index of the antitumor effect, the TV in each group
was calculated, and the relative tumor volume (RTV) for Day 0
was obtained from the equation below and plotted. The
logical s of RTV were compared among no treatment
group (control), an FTD/TPI ation drug-treated group, a
bevacizumab-treated group, and a FTD/TPI combination drug and
bevacizumab combination-treated group. In addition , the
weight loss as the toxicity was ted. The results are
shown in Table 2 and Figs. 1 to 4.
TV (mm3) = (length breadth2)/2
RTV = (TV on evaluation day)/(TV on Day 0)
[Table 2]
RTV a) Body weight change c)
Drug Dose (mg/kg/day) IR b) (%)
(mean SD) (%, mean SD)
Control - 13.58 3.54 - 1.3 5.2
FTD/TPI combination drug 150 8.65 3.03 36.3 -4.9 4.6
Bevacizumab 0.20 8.93 2.79 34.3 9.7 5.1
Bevacizumab 0.55 9.71 4.99 28.5 3.2 6.0
Bevacizumab 1.7 8.19 2.29 39.7 5.2 6.7
zumab 5 8.34 1.82 38.6 1.8 4.6
I combination drug + Bevacizumab 150 + 0.20 7.01 2.17 48.4 -7.2 7.4
FTD/TPI combination drug + Bevacizumab 150 + 0.55 5.13 0.62 *# 62.2 -5.2 5.7
FTD/TPI combination drug + Bevacizumab 150 + 1.7 5.43 1.31 *# 60.1 -2.6 6.0
FTD/TPI combination drug + Bevacizumab 150 + 5 5.11 1.90 *## 62.4 -3.7 9.4
Next, a test was performed in the same manner using a human
breast cancer cell line (MC-2). Here, the FTD/TPI combination
drug (a mixture of FTD and TPI at a molar ratio of 1 : 0.5) was
ed to be 25 and 50 mg/kg/day as the dose of FTD, and
bevacizumab was prepared to be 1.5 mg/kg/day. The results are
shown in Table 3 and Figs. 5 to 6.
[Table 3]
Body weight change c)
Drug Dose (mg/kg/day) RTV a) (mean SD) IR b) (%)
(%, mean SD)
Control - 5.20 1.43 - 12.0 2.7
FTD/TPI combination drug 25 3.39 0.52 34.7 7.1 1.9
FTD/TPI combination drug 50 2.70 0.26 48.1 7.9 1.8
Bevacizumab 1.5 3.06 0.88 41.1 7.7 3.7
FTD/TPI combination drug + zumab 25 + 1.5 1.99 0.70 **# 61.7 9.1 2.9
FTD/TPI combination drug + Bevacizumab 50 + 1.5 1.52 0.16 **## 70.8 8.6 1.2
As shown in Tables 2 to 3 and Figs. 1 to 6, remarkable
enhancement for the antitumor effect was seen when the FTD/TPI
combination drug was 25 to 150 mg/kg/day (corresponding to 11
to 70 day in human) as FTD, and bevacizumab was 0.20 to
mg/kg/day (corresponding to 0.40 to 10 mg/kg/day in human),
and statistically significant synergistic mor effect was
obtained when zumab was 0.55 to 5 mg/kg/day
(corresponding to 1.10 to 10 mg/kg/day in human).
Any treated group showed an acceptable degree of the
weight loss, and no increase of the adverse effect was found
caused by the administration in combination. In the test using
KM20C, the weight loss was found to be -4.9% in the I
combination drug-treated group while it was found to be -2.6
to -3.7% in the combination FTD/TPI combination drug-treated
group and 1.7 to 5 mg/kg/day of bevacizumab combination-treated
group, and thus the weight loss decreased. Also in the test
using MC-2, similar s were obtained. Whereas
administration antitumor agents in combination usually
increase adverse effects as the antitumor effect increases,
with the present invention, e effects decreases while the
antitumor effect increases, which is a very surprising result.
In addition, the effect of delaying tumor growth by
concomitant use of the FTD/TPI combination drug was checked
(Clin Cancer Res. 2000; 6(2): 701-8.; J Radiat Res. 2007; 48(3):
187-95.; Invest New Drugs. 2008; 26(1): 1-5.; J Radiat Res.
2011; 52(5): 646-54.). With respect to the time period during
which the tumor volume doubled from Day 0 (namely, RTV becomes
2), the results of the combination-treated group were predicted
from the single agent-treated group of Figs. 5 and 6. The
"length of days till RTV actually reached 2" of the single
agent-treated group were summarized in Table 4. The h
of days till RTV actually reached 2" was calculated under the
assumption that RTV on the ement day when RTV firstly
exceeded 2 changes according to a linear function from RTV on
the measurement day immediately before the day.
[Table 4]
FTD/TPI combination Bevacizumab Length of
drug (mg/kg/day) /day) Days (day)
0 7.35
50 0 7.33
0 1.5 7.71
Table 5 summarizes the "expected length of days" for RTV
of the combination-treated group to reach 2, and the "actual
length of days" for RTV to reach 2.
[Table 5]
I Bevacizumab Expected Actual length
combination drug (mg/kg/day) length of days of days (day)
(mg/kg/day) (day)
1.5 15.07 15.11
50 1.5 15.05 26.25
Particularly, in the combination-treated group where the
FTD/TPI combination drug was 50 mg/kg/day and zumab was
1.5 mg/kg/day, the "actual length of days" till RTV reached 2
were 7.33 days and 7.71 days in each of the single agent-treated
groups. Accord ingly, under the assumption that the actions and
effects of the FTD/TPI combination drug and bevacizumab are not
antagonistic, the "expected length of days" till RTV reached
2 in the combination-treated group was 15.05 days, which is the
sum of the time periods. However, the "actual length of days"
till RTV reached 2 was, singly, 26.25 days. These results
show that the action of enhancing the antitumor effect of
bevacizumab by the FTD/TPI combination drug is synergistic.
Example 2
A human colon cancer cell line (Co-3) was transplanted
onto the right chest of a five to six week-old BALB/cA Jcl-nu
mouse. The length (mm) and the breadth (mm) of the tumor after
the tumor transplantation were measured, and the tumor volume
(TV) was calculated. Then, the mouse was allocated into each
group such that the average TV in each group was equal, and the
day when the ng (n = 3 to 7) was ented was assumed
to be Day 0.
The administration dose of the drug was 10 mL/kg, and the
FTD/TPI combination drug (a mixture of FTD and TPI at a molar
ratio of 1 : 0.5) was prepared to be 75, 150 mg/kg/day as the
dose of FTD. Cetuximab (ERBITUX injection, Merck Serono Co.,
Ltd.) was prepared to be 1.5, 4.4 and 40 mg/kg/day. The FTD/TPI
ation drug was orally stered on Days 1 to 14 every
day, and cetuximab was administered into the nal cavity
for 2 weeks at a frequency of twice a week from Day 1. To the
combination-treated group, the FTD/TPI combination drug and
cetuximab were stered in the same doses and the same
administration schedules as those of the single agent-treated
group.
As an index of the antitumor effect, TV on Days 5, 8, 12
and 15 in each group was calculated, and the relative tumor
volume (RTV) for Day 0 was obtained according to the formula
of e 1 and plotted. The chronological changes of RTV were
compared of no treatment group (control), the FTD/TPI
combination drug-treated group, and the cetuximab-treated
group and the FTD/TPI combination drug and cetuximab
combination-treated group. In addition, the weight loss as the
toxicity was evaluated. The results are shown in Tables 6 to
7 and Figs. 7 to 10.
[Table 6]
Body weight change c)
Drug Dose (mg/kg/day) RTV a) (mean SD) IR b) (%)
(%, mean SD)
Control - 13.33 4.10 - -5.2 4.5
FTD/TPI combination drug 75 7.91 1.73 40.6 -10.6 6.4
FTD/TPI combination drug 150 6.27 0.97 53.0 -13.2 7.0
Cetuximab 40 6.90 2.52 48.2 0.2 2.8
FTD/TPI combination drug + mab 75 + 40 4.01 0.37 **## 69.9 -5.5 4.7
FTD/TPI combination drug + Cetuximab 150 + 40 3.69 0.32 **## 72.3 -5.0 4.2
[Table 7]
Body weight change c)
Drug Dose (mg/kg/day) RTV a) (mean SD) IR b) (%)
(%, mean SD)
Control - 10.19 4.70 - -2.5 6.4
I combination drug 150 4.58 1.39 55.1 -18.6 4.2
Cetuximab 1.5 4.50 1.18 55.9 -2.1 4.8
Cetuximab 4.4 4.53 1.32 55.6 -0.2 5.9
FTD/TPI combination drug + Cetuximab 150 + 1.5 3.42 0.72 66.4 -9.4 5.6
FTD/TPI combination drug + Cetuximab 150 + 4.4 2.88 0.63 *# 71.7 -14.9 5.1
Next, a test was med in the same manner using a human
colon cancer cell line (SW48). Here, cetuximab was prepared
to be 4.4, 20 and 40 mg/kg/day. The results are shown in Tables
8 to 9 and Figs. 11 to 13.
[Table 8]
Body weight change c)
Drug Dose (mg/kg/day) RTV a) (mean SD) IR b) (%)
(%, mean SD)
Control - 15.95 4.54 - 8.6 5.6
FTD/TPI ation drug 150 10.05 3.22 37.0 -5.3 1.9
Cetuximab 4.4 9.29 2.79 41.7 11.6 4.7
Cetuximab 40 5.65 1.71 64.6 10.5 5.0
FTD/TPI combination drug + Cetuximab 150 + 4.4 4.85 0.46 **## 69.6 3.6 3.4
FTD/TPI combination drug + Cetuximab 150 + 40 2.92 0.89 **## 81.7 5.4 5.1
[Table 9]
Body weight change c)
Drug Dose (mg/kg/day) RTV a) (mean SD) IR b) (%)
(%, mean SD)
Control - 16.03 7.17 - -2.5 9.5
FTD/TPI combination drug 150 11.87 3.27 25.9 -2.2 6.5
mab 20 8.01 3.66 50.1 9.9 12.0
FTD/TPI combination drug + Cetuximab 150 + 20 2.96 0.81 **## 81.6 5.1 5.4
As shown in Tables 6 to 9 and Figs. 7 to 13, remarkable
enhancement for the antitumor effect was seen when the I
combination drug was 75 to 150 mg/kg/day sponding to 35
to 70 mg/m2/day in human) as FTD, and mab was 1.5 to 40
mg/kg/day (corresponding to 15 to 400 mg/m2/day in human) and
statistically significant synergistic antitumor effect was
obtained when cetuximab was 4.4 to 40 mg/kg/day (corresponding
to 44 to 400 mg/m2/day in human).
In addition, any treated group had an acceptable degree
of the weight loss, and no increase of the adverse effect was
found from the administration in combination. In the test using
Co-3, the weight loss was found to be -13.2% (or -18.6%) in the
150 mg/kg/day FTD/TPI combination reated group, and the
weight loss was found to be -5.0% (or -9.4 to -14.9%) in the
150 mg/kg/day FTD/TPI combination drug and 1.5 to 40 mg/kg/day
cetuximab ation-treated group, and thus the weight loss
decreased. Also in the test using SW48, similar results were
obtained. Whereas administration of antitumor agents in
combination ordinarily increases adverse effects as the
antitumor effect increases, with the present invention, adverse
s decreases while the antitumor effect increases, which
is a very surprising result.
In addition, the effect of delaying tumor growth by
concomitant use of the FTD/TPI combination drug was d
(Clin Cancer Res. 2000; 6(2): 701-8.; J Radiat Res. 2007; 48(3):
187-95.; Invest New Drugs. 2008; 26(1): 1-5.; J Radiat Res.
2011; 52(5): 646-54.). With respect to the time period during
which the tumor volume doubled from Day 0 y, RTV becomes
2), the results of the combination-treated group were predicted
from the single treated group of Figs. 11 and 13. The
"length of days till RTV actually reached 2" of the single
agent-treated group were ized in Table 10. The "length
of days till RTV actually reached 2" was calculated under the
assumption that RTV on the measurement day when RTV firstly
exceeded 2 changes according to a linear function from RTV on
the measurement day immediately before the day.
[Table 10]
FTD/TPI combination Cetuximab Length of
drug (mg/kg/day) (mg/kg/day) Days (day)
150 0 3.62
0 4.4 4.32
0 40 10.34
Table 11 summarizes the expected length of days for RTV
of combination-treated group to reach 2, and the actual length
of days for RTV to reach 2.
[Table 11]
FTD/TPI Expected
Cetuximab Actual length
combination drug length of days
(mg/kg/day) of days (day)
(mg/kg/day) (day)
150 4.4 7.94 13.66
150 40 13.96 16.68
In the combination-treated group where the FTD/TPI
combination drug was 150 mg/kg/day and cetuximab was 4.4
mg/kg/day, the "actual length of days " when RTV reached 2 in
each of the single agent-treated groups were 3.62 days and 4.32
days. Accordingly , the "expected length of days" till RTV
reached 2 in the combination-treated group was 7.94 days, which
is the sum of the time periods under the tion that the
actions and effects of the FTD/TPI combination drug and
bevacizumab are not antagonistic. r, the l length
of days" till RTV reached 2 was surprisingly 13.66 days. In
addition, the "expected length of days" till RTV reached 2 in
the combination-treated group where the FTD/TPI combination
drug was 150 day and cetuximab was 20 mg/kg/day, was
obtained in the same manner from Fig. 12, which was 8.50 days.
The "actual length of days" till RTV reached 2 was 20.70 days.
These results show that the action of enhancing the antitumor
effect of bevacizumab by the FTD/TPI combination drug is
synergistic.
Example 3
A human colon cancer cell line (Co-3) was transplanted
onto the right chest of a five to six week-old BALB/cA Jcl-nu
mouse. The length (mm) and the breadth (mm) of the tumor after
the tumor transplantation were measured, and the tumor volume
(TV) was calculated. Then, the mouse was allocated into each
group such that the average TV in each group was equal, and the
day when the grouping (n = 6) was implemented was assumed to
be Day 0.
The administration dose of the drug was 10 mL/kg, and the
FTD/TPI ation drug (a mixture of FTD and TPI at the molar
ratio of 1 : 0.5) was prepared to be 150 mg/kg/day as the dose
of FTD. Panitumumab (Vectibix tered trademark)
injection, Amgen Inc.) was prepared to be 0.30, 0.89, 2.7 and
8 mg/kg/day. The FTD/TPI combination drug was orally
administered on Days 1 to 14 every day, and panitumumab was
administered into the nal cavity for two weeks at a
ncy of twice a week from Day 1. To the
combination-treated group, the FTD/TPI combination drug and
panitumumab were administered in the same doses and the same
administration schedules as those of the single agent-treated
group.
As an index of the antitumor effect, TV on Days 5, 8, 12
and 15 was calculated in each group, and the ve tumor
volume (RTV) for Day 0 was obtained according to the formula
of Example 1 and plotted. T he chronological changes of RTV were
compared of no treatment group (control), the FTD/TPI
combination drug-treated group, the panitumumab-treated group
and the combination FTD/TPI ation drug and panitumumab
treated group. In addition, the weight loss as the toxicity
was evaluated. The results are shown in Table 12 and Figs. 14
to 17.
[Table 12]
Body weight change c)
Drug Dose (mg/kg/day) RTV a) (mean SD) IR b) (%)
(%, mean SD)
Control - 23.58 11.81 - -12.8 6.0
FTD/TPI combination drug 150 15.38 3.10 34.8 -16.2 2.3
Panitumumab 0.30 18.15 6.79 23.0 -11.3 5.3
Panitumumab 0.89 15.10 7.51 35.9 -6.7 4.3
Panitumumab 2.7 12.71 4.37 46.1 -1.2 3.1
Panitumumab 8 12.97 2.33 45.0 -4.5 4.5
FTD/TPI combination drug + Panitumumab 150 + 0.30 10.66 3.84 # 54.8 -16.2 5.3
I ation drug + Panitumumab 150 + 0.89 7.92 1.77 **# 66.4 -10.6 5.0
FTD/TPI combination drug + Panitumumab 150 + 2.7 7.27 1.80 **# 69.2 -9.7 6.3
FTD/TPI combination drug + Panitumumab 150 + 8 5.90 1.96 **## 75.0 -8.7 4.4
As shown in Table 12 and Figs. 14 to 17, remarkable
enhancement for the antitumor effect was seen when the dose of
FTD/TPI combination drug was 150 mg/kg/day (corresponding to
70 mg/m2/day in human) as FTD and panitumumab was 0.3 to 8
day (corresponding to 0.23 to 6 mg/kg/day in human), and
statistically significant synergistic antitumor effect was
obtained when panitumumab was 0.89 to 8 mg/kg/day
(corresponding to 0.67 to 6 mg/kg/day in human).
In on, any treated group showed an acceptable
degree of the weight loss, and no increase of the adverse effect
was found caused by the administration in combination. The
weight loss was found to be -16.2% in the FTD/TPI combination
drug-treated group, and the weight loss was found to be 8.7 to
.6% in the combination FTD/TPI combination drug and 0.89 to
8 mg/kg/day panitumumab combination-treated group, and thus the
weight loss decreased. Whereas administration of mor
agents in combination ordinarily increases e effects as
the mor effect increases, but with the present invention,
adverse effects decreases while the antitumor effect increases,
which is a very surprising result.
From above, it was revealed that the FTD/TPI combination
drug remarkably enhances the antitumor effect of bevacizumab,
cetuximab or panitumumab while ssing outbreak of adverse
effects.
Claims (10)
1. The use, in the manufacture of a medicament, of a combination of trifluridine and tipiracil hydrochloride at a molar ratio of 1:0.5, and an anti-VEGF antibody or anti-EGFR antibody selected from bevacizumab, mab and panitumumab as active ingredients for the treatment of a target cancer tumor, wherein the daily dose of the combination of FTD/TPI in the ment on a day of administration is from 11 to 80 mg/m2/day as FTD, (a) the daily dose of bevacizumab on the administration day is from 1.10 to 10 mg/kg/day; (b) the daily dose of mab on the administration day is from 44 to 400 mg/kg/day, and (c) the daily dose of mumab on the administration day is from 0.67 to 6 mg/kg/day; wherein the target cancer tumor is digestive cancer or breast cancer.
2. The use according to claim 1, wherein the anti-VEGF antibody is bevacizumab.
3. The use according to claim 2, wherein the dose of the FTD/TPI combination drug is from 11 to 80 mg/m2/day as FTD, and the dose of bevacizumab is from 1.10 to 10 mg/kg/day.
4. The use according to claim 1, wherein the anti-EGFR antibody is cetuximab.
5. The use according to claim 4, wherein the dose of the FTD/TPI combination drug is from 11 to 80 mg/m2/day as FTD, and the dose of cetuximab is from 44 to 400 mg/kg/day.
6. The use according to claim 1, wherein the anti-EGFR antibody is panitumumab.
7. The use according to claim 6, wherein the dose of the I combination drug is from 11 to 80 mg/m2/day as FTD, and the dose of mumab is from 0.67 to 6 mg/kg/day.
8. The use according to any one of claims 1 to 7, n the target cancer tumor is colorectal cancer, pancreatic cancer, or gastric cancer.
9. The use ing to any one of claims 1 to 8, wherein the dose of the FTD/TPI combination drug is from 35 to 70 mg/m2/day as FTD.
10. The use according to any one of claims 1 to 9, wherein the dose of the FTD/TPI combination drug is 70 mg/m2/day as FTD.
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