Indian Patents. 256894:ANTITUMOR COMBINATIONS CONTAINING A VEGF INHIBITOR AND 5FU

Title of Invention	ANTITUMOR COMBINATIONS CONTAINING A VEGF INHIBITOR AND 5FU
Abstract	The invention concerns antitumor combinations consisting of VEGF inhibitor associated 5-flurouracil or with a 5-fluropyrimidin therapeutically useful for treating neoplastic diseases.

Full Text	WO 2006/059012 PCT/FR2005/003005 1 ANTITUMOR COMBINATIONS CONTAINING A VEGF-INHlBITING AGENT AND 5FU OR A DERIVATIVE THEREOF The present invention relates to combinations of a VEGF inhibitor and a chemotoxic agent of the class of 5-fluorouracil or 5-fluoropyrimidines that are useful in the treatment of neoplastic diseases. VEGF inhibitors, which are inhibitors of vascular endothelial growth factor, are, in the majority of cases, biological products chosen from soluble receptors, antisenses, RNA aptamers and antibodies. The 5-fluoropyrimidine derivatives are chosen from 5-fluorouracil, capecitabine or gemcitabine, which exhibit notable antitumoral and antileukemia properties; they are particularly useful in the treatment of ovarian cancer, breast cancer, lung cancer or colon cancer. The present combination is directed in particular toward the treatment of colon cancer or stomach cancer. The description and the preparation of the VEGF inhibitor preferably used in the invention, which is a VEGF-Trap chimeric protein, is described in patent application WO00/75319. There are several embodiments of the chimeric protein. The embodiment corresponding to VEGF-Trap is that described in Figure 24 (sequence). The VEGF-Trap used in the invention is a fusion protein comprising the VEGFR1 signal sequence fused to the Ig domain D2 of the VEGFR1 receptor, itself fused to the Ig domain D3 of the VEGFR2 receptor, in turn fused to the Fc domain of IgGl, also called VEGFRlR2-FcACl orFltlD2.FK1D3.Fc∆Cl. In general, the doses used, which depend on factors specific to the individual to be treated, are between 20 and 800 micrograms per kilo when the administration is carried out subcutaneously and from 2 to 20 micrograms per kilo when the administration is carried out intravenously or, optionally, intranasally at a lower dose of the order of 0.01 picogram to 1 mg per kilo. The 5-fluorouracil is generally used intravenously at a dose of between 500 mg/m2 and 5000 mg/m2 per week; as regards the 5-fluoropyrimidine derivatives such as capecitabine, they are generally used, for the latter, orally at a dose of between 500 and 3000 mg/m2 generally administered in two daily doses. Gemcitabine is generally used intravenously at a dose of between 500 and 2000 mg/m2 per week. An article by H Hurwitz, L Fehrenbacher, W Novotny, T Cartwright, J Hainsworth, W Heim, J Berlin, A Baron, S Griffing, E Holmgren, N Ferrara, G Fyfe, WO 2006/059012 PCT/FR2005/003005 2 B Rogers, R Ross, F Kabbinavar published in "The New England Journal of Medicine" has described a clinical trial proving a better survival rate when the combination of bevacizumab with irinotecan, 5FU and leucovorin is used compared with the same combination containing no bevacizumab. Nothing proves, in this clinical trial, that the improvement in survival rate comes from the combination of 5FU with the bevacizumab; it may just as well come from the combination of irinotecan or of leucovorin with the bevacizumab, or may come from the quadruple combination. Now, as it is known that each of the anticancer agents brings, along with its therapeutic effect, toxic side effects, it appears to be opportune to limit their presence as much as possible, especially when the same effect can be obtained in the absence of at least one of them. In the present case, it is known that irinotecan leads to considerable diarrhea, which has sometimes led to the treatment having to be stopped. Furthermore, this article does not prove any synergistic effect within Corbett's meaning, i.e. an effect that cannot be obtained with each of the elements of the combination used alone at its maximum tolerated dose. It has now been found, and it is this that forms the subject of the present invention, that the effectiveness of VEGF inhibitors can be considerably improved when they are administered in combination with at least one substance therapeutically useful in anticancer treatments that has a mechanism of action different from that of the VEGF inhibitors. Moreover, since the activity of the products depends on the doses used, it is possible to use higher doses and to increase the activity by decreasing the phenomena of toxicity or delaying their appearance through the combination with the VEGF inhibitors or with their analogs of other therapeutically active substances, of growth factors of hematopoietic type, such as G-CSF or GM-CSF, or certain interleukins. More particularly, the invention relates to the combinations of VEGF-Trap with 5-fiuorouracil or derivatives thereof such as capecitabine or gemcitabine. It also relates to the combinations also including folinic acid generally combined with 5-FU. The improved effectiveness of a combination according to the invention can be demonstrated by determining the therapeutic synergism. A combination shows therapeutic synergism if it is therapeutically superior to one or other of the constituents used at its optimum dose [T.H. Corbett et al., Cancer Treatment Reports, 66,1187 (1982)]. In order to demonstrate the effectiveness of a combination, it may be necessary to compare the maximum tolerated dose of the combination with the WO 2006/059012 PCT/FR2005/003005 3 maximum tolerated dose of each of the individual constituents in the study under consideration. This effectiveness can be quantified, for example by the logjo of the killed cells, which is determined according to the following formula: log10killed cells = T-C (days)/3.32 x Td in which T-C represents the delay in growth of the cells, which is the average time, in days, for the tumors of the treated group (T) and the rumors of the control group (C) to reach a predetermined value (1 g, for example) and Td represents the time, in days, required for the volume of the tumor to double in the control animals [T.H. Corbett et al., Cancer, 40, 2660.2680 (1977) : F.M. Schabel et al., Cancer Drug Development, Part B, Methods in Cancer Research, 17, 3-51, New-York, Academic Press Inc. (1979)]. A product is considered to be active if logjo killed cells is greater than or equal to 0.7. A product is considered to be very active if the logjo killed cells is greater than 2.8. The combination, used at its own maximum tolerated dose, in which each of the constituents will be present at a dose generally less than or equal to its maximum tolerated dose, which show therapeutic synergy when the log10 killed cells is greater than the value of log10 killed cells of the best constituent when it is administered alone. The effectiveness of the combinations on solid tumors can be determined experimentally in the following way: 30 to 60 mg of an MC 13/C mammary tumor fragment are transplanted bilaterally, subcutaneously, into the animals subjected to the experiment, generally mice, on day 0. The animals bearing the tumors are randomized before being subjected to the various treatments and controls. In the case of treatment to advanced tumors, the tumors are left to develop until the desired size, the animals having insufficiently developed tumors being eliminated. The animals selected are divided up randomly so as to undergo the treatments and the controls. Animals not bearing tumors can also be subjected to the same treatments as the tumor-bearing animals in order to be able to dissociate the toxic effect from the actual effect on the tumor. The chemotherapy generally begins from 3 to 22 days after the tumor transplant, according to the type of tumor, and the animals are observed every day. The various groups of animals are weighed three or four times a week until the maximum weight loss is WO 2006/059012 PCT/FR2005/003005 4 obtained, and then the groups are weighed at least once a week until the end of the trial. The tumors are measured two or three times a week until the tumor reaches approximately 2 g or until the animal's death if the latter occurs before the tumor reaches 2 g. The animals are autopsied when they are sacrificed. The antitumor activity is determined as a function of the various parameters recorded. To study the combinations on leukemias, a given number of cells are transplanted into the animals and the antitumor activity is determined by the increase in survival time of the treated mice compared with the controls. A product is considered to be active if the increased survival time is greater than 27% and it is considered to be very active if it is greater than 75% in the case of P388 leukemia. By way of examples, the following tables give the results obtained with combinations of VEGF-Trap and 5-fluorouracile used at their optimum dose. The present invention also relates to the pharmaceutical compositions containing the combinations according to the invention. The products that constitute the combination can be administered simultaneously, separately or spread out over time so as to obtain the maximum effectiveness of the combination; it being possible for each administration to have a variable duration ranging from complete rapid administration to continuous infusion. It results therefrom that, for the purpose of the present invention, the combinations are not only limited to those which are obtained by physical combination of the constituents, but also to those which allow a separate administration which may be simultaneous or spread out over time. The compositions according to the invention are preferably compositions that can be administered parenterally. However, these compositions may be administered orally. The compositions for parenteral administration are generally sterile pharmaceutically acceptable solutions or suspensions which may optionally be prepared extemporaneously at the time of use. For the preparation of nonaqueous solutions or suspensions, natural plant oils such as olive oil, sesame oil or paraffin oil or injectable organic esters such as ethyl oleate can be used. The aqueous sterile solutions may consist of a solution of the product in water. The aqueous solutions are suitable for intravenous administration insofar as the pH is suitably adjusted and isotonicity is effected, for example by means of a sufficient amount of sodium WO 2006/059012 PCT/FR2005/003005 5 chloride or glucose. The sterilization can be carried out by heating or by any other means that does not impair the composition. The combinations may also be in the form of liposomes or in the form of a combination with carriers such as cyclodextrins or polyethylene glycols. In the combinations according to the invention, file application of these constituents may be simultaneous, separate or spread out over time, it is particularly advantageous for the amount of VEGF-Trap derivative to represent from 2 to 80% by weight of the combination, it being possible for this content to vary according to the nature of the substance combined, to the desired effectiveness and to the nature of the cancer to be treated. The combinations according to the invention are particularly useful in the treatment of colon and/or stomach cancers. In particular, they may have the advantage of being able to use the constituents at doses that are much lower than those at which they are used alone. The following example illustrates a combination according to the invention. EXAMPLE Ampoules of 1 cm3 containing 25 mg of VEGF-Trap, which are diluted in a phosphate buffer, are prepared, according to the usual technique, for subcutaneous administration. 0.2 ml per mouse is prepared, according to the usual technique, for intravenous administration, from a commercial solution of 5 cm containing 250 mg of 5 FU to be diluted with 5% glucose in water. These solutions are administered simultaneously, after suitable dilution, by infusion. The treatment can be repeated several times per day or per week until partial or complete remission or recovery. WO 2006/059012 PCT/FR2005/003005 6 Dosage in mg/kg/day Death due % (total dost ; in mg/kg) to the weight % T/C T-C lck scVEGF- iv5-FU treatment loss at days Trap (day 4,11, the (day 4, 7, 18) lowest 11, 14, 18,21) point 40 (240) 0/5 2.3 4 12.7 1.4 25 (150) - 0/5 1.1 8 13.9 1.5 10 (60) - 0/5 1.1 9 12.1 1.3 2.5 (15) - 0/5 0.9 32 5.2 0.6 145 (435) 1/5 8.7 Toxic - - - 90 (270) 0/5 4.8 0 12.5 1.3 - 55.8 (167.4) 0/5 1.1 12 7.8 0.8 - 34.6 (103.8) 0/5 + 2.3 34 4.6 0.5 40 (240) 90 (270) 0/5 8.0 0 25.2 2.7 25 (150) 90 (270) 0/5 9.6 0 24.8 2.7 10 (60) 90 (270) 0/5 7.4 0 23.1 2.5 10 (60) 55.8 (167.4) 0/5 4.4 0 16.5 1.8 10 (60) 34.6 (103.8) 0/5 5.4 1 20.0 2.2 2.5 (15) 90 (270) 0/5 7.0 0 20.4 2.2 2.5 (15) 55.8 (167.4) 0/5 2.0 0 18.0 1.9 2.5 (15) 34.6 (103.8) 0/5 2.0 6 11.7 1.3 BCM-1428 (05/28/04 - 07.30.2004): tumor doubling time = 2.8 days. Average time for 750 mg on controls = 22.2 d. Treatment period = 18 d for VEGF-Trap and combination, and 15 days for 5-FU. Abbreviations used: T/C = inhibition of tumor growth at day 24, (T-C) delay of tumor growth, lck = log cells killed. WO 2006/059012 PCT/FR2005/003005 7 WHAT IS CLAIMED IS 1 - Combinations containing a VEGF inhibitor with at least 5-fluorouracil or a 5-fluoropyrimidine derivative that is therapeutically useful in the treatment of neoplastic diseases. 2 - Combinations containing a VEGF inhibitor with 5-fluorouracil or capecitabine or gemcitabine. 3 - The combinations as claimed in claim 2, containing a VEGF inhibitor with fluorouracil. 4 - The combinations as claimed in claim 3, containing a VEGF-Trap inhibitor with 5-fluorouracil. 5 - The combinations as claimed in one of claims 1 to 4, characterized in that they also contain folinic acid. 6 - The combinations as claimed in one of claims 1 to 5, characterized in that they contain from 2 to 80% by weight of VEGF-Trap. 7 - Products containing a VEGF inhibitor and at least one therapeutically useful substance as defined in one of claims 1 to 5, in the treatment of neoplastic diseases, as a combined preparation for simultaneous use, separate use or use spread out over time in anticancer therapy. 8 - Combinations containing a VEGF inhibitor with at least 5-flurorouracil or a 5-fluoropyrimidine derivative and folinic acid with the exclusion of any other chemotoxic derivative exhibiting a therapeutically synergistic effect in the treatment of neoplastic diseases. The invention concerns antitumor combinations consisting of VEGF inhibitor associated 5-flurouracil or with a 5-fluropyrimidin therapeutically useful for treating neoplastic diseases.

Full Text

WO 2006/059012 PCT/FR2005/003005
1
ANTITUMOR COMBINATIONS CONTAINING A VEGF-INHlBITING AGENT
AND 5FU OR A DERIVATIVE THEREOF
The present invention relates to combinations of a VEGF inhibitor and a
chemotoxic agent of the class of 5-fluorouracil or 5-fluoropyrimidines that are useful
in the treatment of neoplastic diseases.
VEGF inhibitors, which are inhibitors of vascular endothelial growth factor,
are, in the majority of cases, biological products chosen from soluble receptors,
antisenses, RNA aptamers and antibodies. The 5-fluoropyrimidine derivatives are
chosen from 5-fluorouracil, capecitabine or gemcitabine, which exhibit notable
antitumoral and antileukemia properties; they are particularly useful in the treatment
of ovarian cancer, breast cancer, lung cancer or colon cancer. The present
combination is directed in particular toward the treatment of colon cancer or stomach
cancer.
The description and the preparation of the VEGF inhibitor preferably used in
the invention, which is a VEGF-Trap chimeric protein, is described in patent
application WO00/75319. There are several embodiments of the chimeric protein.
The embodiment corresponding to VEGF-Trap is that described in Figure 24
(sequence). The VEGF-Trap used in the invention is a fusion protein comprising the
VEGFR1 signal sequence fused to the Ig domain D2 of the VEGFR1 receptor, itself
fused to the Ig domain D3 of the VEGFR2 receptor, in turn fused to the Fc domain of
IgGl, also called VEGFRlR2-FcACl orFltlD2.FK1D3.Fc∆Cl.
In general, the doses used, which depend on factors specific to the individual
to be treated, are between 20 and 800 micrograms per kilo when the administration is
carried out subcutaneously and from 2 to 20 micrograms per kilo when the
administration is carried out intravenously or, optionally, intranasally at a lower dose
of the order of 0.01 picogram to 1 mg per kilo.
The 5-fluorouracil is generally used intravenously at a dose of between 500
mg/m2 and 5000 mg/m2 per week; as regards the 5-fluoropyrimidine derivatives such
as capecitabine, they are generally used, for the latter, orally at a dose of between 500
and 3000 mg/m2 generally administered in two daily doses. Gemcitabine is generally
used intravenously at a dose of between 500 and 2000 mg/m2 per week.
An article by H Hurwitz, L Fehrenbacher, W Novotny, T Cartwright, J
Hainsworth, W Heim, J Berlin, A Baron, S Griffing, E Holmgren, N Ferrara, G Fyfe,

WO 2006/059012 PCT/FR2005/003005
2
B Rogers, R Ross, F Kabbinavar published in "The New England Journal of
Medicine" has described a clinical trial proving a better survival rate when the
combination of bevacizumab with irinotecan, 5FU and leucovorin is used compared
with the same combination containing no bevacizumab. Nothing proves, in this
clinical trial, that the improvement in survival rate comes from the combination of
5FU with the bevacizumab; it may just as well come from the combination of
irinotecan or of leucovorin with the bevacizumab, or may come from the quadruple
combination. Now, as it is known that each of the anticancer agents brings, along with
its therapeutic effect, toxic side effects, it appears to be opportune to limit their
presence as much as possible, especially when the same effect can be obtained in the
absence of at least one of them. In the present case, it is known that irinotecan leads to
considerable diarrhea, which has sometimes led to the treatment having to be stopped.
Furthermore, this article does not prove any synergistic effect within Corbett's
meaning, i.e. an effect that cannot be obtained with each of the elements of the
combination used alone at its maximum tolerated dose.
It has now been found, and it is this that forms the subject of the present
invention, that the effectiveness of VEGF inhibitors can be considerably improved
when they are administered in combination with at least one substance therapeutically
useful in anticancer treatments that has a mechanism of action different from that of
the VEGF inhibitors.
Moreover, since the activity of the products depends on the doses used, it is
possible to use higher doses and to increase the activity by decreasing the phenomena
of toxicity or delaying their appearance through the combination with the VEGF
inhibitors or with their analogs of other therapeutically active substances, of growth
factors of hematopoietic type, such as G-CSF or GM-CSF, or certain interleukins.
More particularly, the invention relates to the combinations of VEGF-Trap
with 5-fiuorouracil or derivatives thereof such as capecitabine or gemcitabine. It also
relates to the combinations also including folinic acid generally combined with 5-FU.
The improved effectiveness of a combination according to the invention can
be demonstrated by determining the therapeutic synergism.
A combination shows therapeutic synergism if it is therapeutically superior
to one or other of the constituents used at its optimum dose [T.H. Corbett et al.,
Cancer Treatment Reports, 66,1187 (1982)].
In order to demonstrate the effectiveness of a combination, it may be
necessary to compare the maximum tolerated dose of the combination with the

WO 2006/059012 PCT/FR2005/003005
3
maximum tolerated dose of each of the individual constituents in the study under
consideration. This effectiveness can be quantified, for example by the logjo of the
killed cells, which is determined according to the following formula:
log10killed cells = T-C (days)/3.32 x Td
in which T-C represents the delay in growth of the cells, which is the average time, in
days, for the tumors of the treated group (T) and the rumors of the control group (C)
to reach a predetermined value (1 g, for example) and Td represents the time, in days,
required for the volume of the tumor to double in the control animals [T.H. Corbett et
al., Cancer, 40, 2660.2680 (1977) : F.M. Schabel et al., Cancer Drug Development,
Part B, Methods in Cancer Research, 17, 3-51, New-York, Academic Press Inc.
(1979)]. A product is considered to be active if logjo killed cells is greater than or
equal to 0.7. A product is considered to be very active if the logjo killed cells is
greater than 2.8.
The combination, used at its own maximum tolerated dose, in which each of
the constituents will be present at a dose generally less than or equal to its maximum
tolerated dose, which show therapeutic synergy when the log10 killed cells is greater
than the value of log10 killed cells of the best constituent when it is administered
alone.
The effectiveness of the combinations on solid tumors can be determined
experimentally in the following way:
30 to 60 mg of an MC 13/C mammary tumor fragment are transplanted
bilaterally, subcutaneously, into the animals subjected to the experiment, generally
mice, on day 0. The animals bearing the tumors are randomized before being
subjected to the various treatments and controls. In the case of treatment to advanced
tumors, the tumors are left to develop until the desired size, the animals having
insufficiently developed tumors being eliminated. The animals selected are divided up
randomly so as to undergo the treatments and the controls. Animals not bearing
tumors can also be subjected to the same treatments as the tumor-bearing animals in
order to be able to dissociate the toxic effect from the actual effect on the tumor. The
chemotherapy generally begins from 3 to 22 days after the tumor transplant, according
to the type of tumor, and the animals are observed every day. The various groups of
animals are weighed three or four times a week until the maximum weight loss is

WO 2006/059012 PCT/FR2005/003005
4
obtained, and then the groups are weighed at least once a week until the end of the
trial.
The tumors are measured two or three times a week until the tumor reaches
approximately 2 g or until the animal's death if the latter occurs before the tumor
reaches 2 g. The animals are autopsied when they are sacrificed.
The antitumor activity is determined as a function of the various parameters
recorded.
To study the combinations on leukemias, a given number of cells are
transplanted into the animals and the antitumor activity is determined by the increase
in survival time of the treated mice compared with the controls. A product is
considered to be active if the increased survival time is greater than 27% and it is
considered to be very active if it is greater than 75% in the case of P388 leukemia.
By way of examples, the following tables give the results obtained with
combinations of VEGF-Trap and 5-fluorouracile used at their optimum dose.
The present invention also relates to the pharmaceutical compositions
containing the combinations according to the invention.
The products that constitute the combination can be administered
simultaneously, separately or spread out over time so as to obtain the maximum
effectiveness of the combination; it being possible for each administration to have a
variable duration ranging from complete rapid administration to continuous infusion.
It results therefrom that, for the purpose of the present invention, the
combinations are not only limited to those which are obtained by physical
combination of the constituents, but also to those which allow a separate
administration which may be simultaneous or spread out over time.
The compositions according to the invention are preferably compositions
that can be administered parenterally. However, these compositions may be
administered orally.
The compositions for parenteral administration are generally sterile
pharmaceutically acceptable solutions or suspensions which may optionally be
prepared extemporaneously at the time of use. For the preparation of nonaqueous
solutions or suspensions, natural plant oils such as olive oil, sesame oil or paraffin oil
or injectable organic esters such as ethyl oleate can be used. The aqueous sterile
solutions may consist of a solution of the product in water. The aqueous solutions are
suitable for intravenous administration insofar as the pH is suitably adjusted and
isotonicity is effected, for example by means of a sufficient amount of sodium

WO 2006/059012 PCT/FR2005/003005
5
chloride or glucose. The sterilization can be carried out by heating or by any other
means that does not impair the composition. The combinations may also be in the
form of liposomes or in the form of a combination with carriers such as cyclodextrins
or polyethylene glycols.
In the combinations according to the invention, file application of these
constituents may be simultaneous, separate or spread out over time, it is particularly
advantageous for the amount of VEGF-Trap derivative to represent from 2 to 80% by
weight of the combination, it being possible for this content to vary according to the
nature of the substance combined, to the desired effectiveness and to the nature of the
cancer to be treated.
The combinations according to the invention are particularly useful in the
treatment of colon and/or stomach cancers. In particular, they may have the advantage
of being able to use the constituents at doses that are much lower than those at which
they are used alone.
The following example illustrates a combination according to the invention.
EXAMPLE
Ampoules of 1 cm3 containing 25 mg of VEGF-Trap, which are diluted in a
phosphate buffer, are prepared, according to the usual technique, for subcutaneous
administration.
0.2 ml per mouse is prepared, according to the usual technique, for
intravenous administration, from a commercial solution of 5 cm containing 250 mg
of 5 FU to be diluted with 5% glucose in water.
These solutions are administered simultaneously, after suitable dilution, by
infusion.
The treatment can be repeated several times per day or per week until partial
or complete remission or recovery.

WO 2006/059012 PCT/FR2005/003005
6

Dosage in mg/kg/day Death due %
(total dost ; in mg/kg) to the weight % T/C T-C lck
scVEGF- iv5-FU treatment loss at days
Trap (day 4,11, the
(day 4, 7, 18) lowest
11, 14, 18,21) point
40 (240) 0/5 2.3 4 12.7 1.4
25 (150) - 0/5 1.1 8 13.9 1.5
10 (60) - 0/5 1.1 9 12.1 1.3
2.5 (15) - 0/5 0.9 32 5.2 0.6
145 (435) 1/5 8.7 Toxic - -
- 90 (270) 0/5 4.8 0 12.5 1.3
- 55.8 (167.4) 0/5 1.1 12 7.8 0.8
- 34.6 (103.8) 0/5 + 2.3 34 4.6 0.5
40 (240) 90 (270) 0/5 8.0 0 25.2 2.7
25 (150) 90 (270) 0/5 9.6 0 24.8 2.7
10 (60) 90 (270) 0/5 7.4 0 23.1 2.5
10 (60) 55.8 (167.4) 0/5 4.4 0 16.5 1.8
10 (60) 34.6 (103.8) 0/5 5.4 1 20.0 2.2
2.5 (15) 90 (270) 0/5 7.0 0 20.4 2.2
2.5 (15) 55.8 (167.4) 0/5 2.0 0 18.0 1.9
2.5 (15) 34.6 (103.8) 0/5 2.0 6 11.7 1.3
BCM-1428 (05/28/04 - 07.30.2004): tumor doubling time = 2.8 days. Average time
for 750 mg on controls = 22.2 d. Treatment period = 18 d for VEGF-Trap and
combination, and 15 days for 5-FU.
Abbreviations used: T/C = inhibition of tumor growth at day 24, (T-C) delay of tumor
growth, lck = log cells killed.

WO 2006/059012 PCT/FR2005/003005
7
WHAT IS CLAIMED IS
1 - Combinations containing a VEGF inhibitor with at least 5-fluorouracil or
a 5-fluoropyrimidine derivative that is therapeutically useful in the treatment of
neoplastic diseases.
2 - Combinations containing a VEGF inhibitor with 5-fluorouracil or
capecitabine or gemcitabine.
3 - The combinations as claimed in claim 2, containing a VEGF inhibitor
with fluorouracil.
4 - The combinations as claimed in claim 3, containing a VEGF-Trap
inhibitor with 5-fluorouracil.
5 - The combinations as claimed in one of claims 1 to 4, characterized in that
they also contain folinic acid.
6 - The combinations as claimed in one of claims 1 to 5, characterized in that
they contain from 2 to 80% by weight of VEGF-Trap.
7 - Products containing a VEGF inhibitor and at least one therapeutically
useful substance as defined in one of claims 1 to 5, in the treatment of neoplastic
diseases, as a combined preparation for simultaneous use, separate use or use spread
out over time in anticancer therapy.
8 - Combinations containing a VEGF inhibitor with at least 5-flurorouracil
or a 5-fluoropyrimidine derivative and folinic acid with the exclusion of any other
chemotoxic derivative exhibiting a therapeutically synergistic effect in the treatment
of neoplastic diseases.

The invention concerns antitumor combinations consisting of VEGF inhibitor associated 5-flurouracil or with a
5-fluropyrimidin therapeutically useful for treating neoplastic diseases.

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Patent Number

256894

Indian Patent Application Number

1868/KOLNP/2007

PG Journal Number

32/2013

Publication Date

09-Aug-2013

Grant Date

07-Aug-2013

Date of Filing

24-May-2007

Name of Patentee

AVENTIS PHARMA S. A.

Applicant Address

20 AVENUE RAYMOND ARON, F-92160, ANTONY

Inventors:

#	Inventor's Name	Inventor's Address
1	VRIGNAUD, PATRICIA	27 RUE DE LA CLAIRIERE F-77380, COMBS LA VILLE
2	BISSERY, MARIE-CHRISTINE	5 RUE HENRI POINCARE F-94400, VITRY SUR SIENE
3	FURFINE, ERIC	2055, QUAKER RIDGE ROAD, CROTON ON HUDSON, 10520, NEW-YORK
4	HOLASH, JOCELYN	321, CHANNING WAY, ALAMEDA, 94502, CALIFORNIA
5	CEDARBAUM, JESSE M.	28 PRYER MANOR ROD, LARCHMONT, 10538, NEW-YORK
6	CHIRON-BLONDEL, MARIELLE	13 RUE DE CASTAGNARY, F-75015, PARIS

PCT International Classification Number

A61K 38/17

PCT International Application Number

PCT/FR2005/003005

PCT International Filing date

2005-12-02

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	04/12,870	2004-12-03	France