Note: Descriptions are shown in the official language in which they were submitted.
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TITLE
A COMBINED THERAPY COMPRISING AN INDOLOPYRROLOCARBAZOLE
DERIVATIVE AND ANOTHER ANTITUMOR AGENT
DESCRIPTION OF THE INVENTION
The present invention relates to the field of the
neoplastic diseases therapy. In particular, this
invention relates to a method for treating cancer in a
subject in need of such a treatment, said method
comprising the administration to the patient of a
therapeutically effective amount of an
indolopyrrolocarbazole derivative together with another
antitumor agent. The present invention further relates
to pharmaceutical compositions and packaging units,
which comprise an indolopyrrolocarbazole derivative and
another antitumoral agent.
Cancer is one of the major causes of death in humans
and animals; surgery, radiation and chemotherapy are
the useful means to fight cancer.
In particular, combined chemotherapy, designed to treat
cancer using more than one drug in combination or in
association, is a well-known modality to optimise the
treatment regimen of neoplastic diseases.
There is therefore a need of selecting new antitumor
combinations of known pharmaceutical agents that are
particularly suitable for treating patients suffering
from a cancer.
The present invention meets this need by providing a
pharmaceutical combination comprising an
indolopyrrolocarbazole derivative, i.e. edotecarin or a
pharmaceutically acceptable salt thereof and another
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antitumor agent chosen between docetaxel and
capecitabine.
It has now been found that the efficacy of the
combination according to the invention is greater than
the efficacy that could have been achieved with either
type of combination partner administered alone.
Therefore, it is an object of the present invention a
combined preparation for simultaneous, separate or
sequential use in cancer treatment, comprising a
pharmaceutical composition comprising edotecarin or a
pharmaceutically acceptable salt thereof and at least a
pharmaceutically acceptable excipient and a
pharmaceutical composition comprising docetaxel and at
least a pharmaceutically acceptable excipient.
A further object of the present invention is a combined
preparation for simultaneous, separate or sequential
use in cancer treatment, comprising a pharmaceutical
composition comprising edotecarin and at least a
pharmaceutically acceptable excipient and a
pharmaceutical composition comprising capecitabine and
at least a pharmaceutically acceptable excipient.
Edotecarin (CAS RN 174402-32-5), i.e. 12-(3-D-
glucopyranosyl-2,10-dihydroxy-6-{[2-hydroxy-1-
hydroxymethyl)ethyl]amino}-12,13-dihydro-6H-indolo[2,3-
a]pyrrole[3,4-c]carbazole-5,7-dione, is an
indolopyrrolocarbazole derivative also known as ED-749
or J-107088 having the following formula:
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o ""
r~o t
off
OH
Edotecarin can be prepared, for example, according to
the method described in the European Patent no.
545,195, in the European patent application No.
95917506 both to Banyu Pharm. C0. LTD., or in
Tetrahedron (2001) 57, 8917-23.
According to the present invention, edotecarin can be
present in the form of a pharmaceutically acceptable
salt. A pharmaceutically acceptable salt is, according
to the present invention, any salt of acid or basic
addition which maintains the biological effectiveness
and the properties of edotecarin and which is formed by
a suitable non toxic acid or base. Examples of
pharmaceutically acceptable salts of addition with
acids, both with inorganic acids, such as hydrochloric
and methansulfonic acid and with organic acids, such as
acetic, citric, tartaric and malefic acid.
Capecitabine (CAS RN 154361-50-9) having the following
formula
O
HN~O~~
N ~ F
O'o _N
HaC~,
~' H
HO' ~OH
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is a pro-drug of 5-fluorouracyl, which Hoffmann-La
Roche has developed and launched for the treatment of
breast and colon-rectum cancer in major worldwide
markets.
Capecitabine can be prepared, for example, following
the methods described in the European patent No.
602,454 and US patent No. 5,472,949, both to Hoffmann-
La Roche.
Capecitabine is commercially available as XELODA°.
Docetaxel (CAS RN 114977-28-5) having the following
formula:
H3G OH
_...." d ~ t
HAG ~ N
is a synthetic derivative of paclitaxel, developed and
launched by Aventis Pharma. The preparation of
docetaxel is described, for example, in the European
Patents No. 253,738 and 253,739 and in the
International patent application WO 92/09589, all to
Rhone-Poulenc.
Docetaxel is commercially available as TAXOTERE°.
The terms "treating" or "to treat" mean to alleviate
symptoms, eliminate the causation either on a temporary
or permanent basis, or to prevent or slow the
appearance of symptoms.
.~!
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The term "treatment" includes, according to the present
invention, alleviation, elimination, of the cause and
prevention of the cancer.
Besides being useful for human treatment, these
combinations are also useful for the treatment of other
mammals, among them horses, dogs, cats, mice, ovines,
swine, etc.
The combined preparations according to the present
invention can be used in cancer treatment.
The term "cancer" according to the present invention
includes all types of cancer, as those listed in the
National Cancer Institute (NCI) Web Site, at the
following Internet address:
http://www.nci.nih.gov/cancerinfo/types/ and comprises,
for instance, breast cancer, colon cancer, colorectal
cancer, liver cancer, pancreatic cancer, renal cancer,
uterine cancer, head and neck cancer, brain cancer,
ovarian cancer, prostate cancer, testicular cancer,
kidney cancer, lung cancer, stomach cancer, oesophageal
cancer, bladder cancer, bone cancer, skin cancer,
limphoma, malignant melanoma, neuroblastoma, glioma,
multiform glioblastoma and the like.
The term "therapeutically-effective" is intended to
qualify the amount of each agent for use in the
combination therapy, which will achieve the goal of
improvement in disease severity and the frequency of
incidence over treatment of each agent by itself,
and/or of amelioration of adverse side effects
typically associated with alternative therapies.
The administration of the constituents of the combined
preparation according to the present invention can be
made simultaneously, separately or sequentially in any
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order. Namely, the present invention intends to embrace
administration of edotecarin or a pharmaceutically
acceptable salt thereof with capecitabine or docetaxel
in a sequential manner in a regimen that will provide
beneficial effects of the drug combination, and intends
as well to embrace co-administration of these agents in
a substantially simultaneous manner, such as in a
single dosage unit having a fixed ratio of these active
agents or in multiple, separate dosage units for each
agent, where the separate dosage units can be taken
together contemporaneously, or taken within a period of
time sufficient to receive a beneficial effect from
both of the constituents of the combination.
Therefore, it is an additional object of the present
invention the use of edotecarin or of a
pharmaceutically acceptable salt thereof and of
capecitabine in the preparation of a medicament for use
against cancer, wherein edotecarin or a
pharmaceutically acceptable salt thereof and
capecitabine are administered simultaneously,
separately or sequentially.
It is yet another object of the present invention the
use of edotecarin or a pharmaceutically acceptable salt
thereof and of docetaxel in the preparation of a
medicament for use against cancer, wherein edotecarin
or a pharmaceutically acceptable salt thereof and
docetaxel are administered simultaneously, separately
or sequentially.
The constituents of the combined preparation according
to the present invention can be administered to the
patient in any manner that is medically acceptable from
the medical viewpoint, including orally, parenterally
and with loco-regional therapeutic approaches, such as
implants.
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Oral administration includes the administration of the
constituents of the combined preparation according to
the invention in a suitable pharmaceutical form for
oral use, such as tablets, capsules, suspensions,
solutions, emulsions, powders, granules, syrups and the
like.
Parenteral administration includes the administration
of the constituents of the combined preparation
according to the invention in a suitable pharmaceutical
form for sub-cutaneous, intramuscular or intravenous
use. Implants include, for example, intrarterial
implants.
For example, edotecarin or a pharmaceutically
acceptable salt thereof may be administered in a
suitable pharmaceutical form for intravenous use,
docetaxel may be administered in a suitable
pharmaceutical form for intravenous use and
capecitabine may be administered in a suitable
pharmaceutical form for oral use.
In any case, the selection of the route, of the dosage,
of the time interval and of the order of administration
of the constituents of the combined preparation
according to the present invention can be determined by
a person skilled in the medical art. Such selection can
vary, inter alia, according to the particular
pharmaceutical composition of edotecarin or of a
pharmaceutically acceptable salt thereof which is used,
according to the particular pharmaceutical composition
of capecitabine which is used or according to the
particular pharmaceutical composition of docetaxel
which is used, on the type, severity and extension of
the cancer being treated, on the sex, age, and on the
particular clinical conditions of the patient at the
time of the treatment.
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When edotecarin or a pharmaceutically acceptable salt
thereof and capecitabine or docetaxel are provided
together with a pharmaceutically acceptable carrier, a
pharmaceutical composition is formed. Said
pharmaceutical composition which therefore comprises
edotecarin or a pharmaceutically acceptable salt
thereof and capecitabine or docetaxel as active agents,
a carrier or a pharmaceutically acceptable excipient,
is suitable for treating cancer.
Therefore, it is a further object of the present
invention a pharmaceutical composition, which comprises
edotecarin or a pharmaceutically acceptable salt
thereof and capecitabine or docetaxel as active agents,
and at least a carrier or a pharmaceutically acceptable
excipient, for cancer treatment.
Pharmaceutically acceptable carriers or excipients to
be used in the preparation of a pharmaceutical
composition according to the invention are well known
to a skilled person in the art of formulating compounds
in the form of pharmaceutical compositions. For
example, said pharmaceutical compositions can usually
contain, for instance, pharmaceutically acceptable
salts, buffering agents, preservatives and/or
compatible carriers.
The terms "pharmaceutically acceptable carrier" refers
herein to one or more conventional compatible solid or
liquid filling agents, diluting substances or
encapsulating substances which are suitable for
administration to mammals, among them humans.
Pharmaceutical compositions suitable for parenteral
administration are formulated in a sterile form.
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The amount of active ingredient contained in the
aforesaid pharmaceutical compositions according to the
present invention may vary, depending quite amply on
many factors such as the route of administration and
the vehicle; for example, a single dosage unit may
contain from 0.5 to 500 mg of edotecarin or a
pharmaceutically acceptable salt thereof and from 10 to
1,000 mg of capecitabine or from 1 mg to 100 mg of
docetaxel.
The technique for the preparation of the pharmaceutical
compositions according to the present invention is to
be considered conventional and well known by those
skilled in the art.
A further aspect of the present invention relates to a
method for the treatment of cancer, which comprises
administering to a mammal a therapeutically effective
amount of edotecarin or of a pharmaceutically
acceptable salt thereof and capecitabine, in amounts
effective to produce a synergistic anti-cancer effect.
In a particular aspect, the present invention relates
to a method for treating a cancer in a patient in need
thereof, said method comprising the administration to
said patient of edotecarin or a pharmaceutically
acceptable salt thereof and of capecitabine, in amounts
effective to produce a synergistic anti-cancer effect.
Yet another aspect of the present invention relates to
a method for the treatment of cancer, which comprises
administering to a mammal a therapeutically effective
amount of edotecarin or of a pharmaceutically
acceptable salt thereof and docetaxel, in amounts
effective to produce a synergistic anti-cancer effect.
In another particular aspect, the present invention
relates to a method for treating a cancer in a patient
in need thereof, said method comprising the
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administration to said patient of edotecarin or a
pharmaceutically acceptable salt thereof and of
docetaxel, in amounts effective to produce a
synergistic anti-cancer effect.
The terms "a synergistic anti-cancer effect" refers to
a greater than additive anti-cancer effect which is
produced by a combination of two active and which
exceeds that which .would otherwise results from
individual administration of either active alone.
In the method according to the present invention the
amount of edotecarin or a pharmaceutically acceptable
salt thereof together with the amount of capecitabine
or docetaxel constitute an amount effective for the
treatment of cancer.
In the method of the present invention, the
administration of edotecarin or of a pharmaceutically
acceptable salt thereof can vary from about 0.1 mg/m2
to about 100 mg/m2 per body surface area of an adult,
preferably from about 10 mg/m2 to about 50 mg/m2 per
body surface area of an adult.
In the method of the present invention, the
administration of capecitabine can vary from about
mg/m2 to about 10000 mg/m~ per body surface area of
an adult, preferably from about 500 mg/m2 to about
2500 mg/m~ per body surface area of an adult.
In the method of the present invention, the
administration of docetaxel can vary from about
0.5 mg/m2 to about 500 mg/m2 per body surface area of
an adult, preferably from about 10 mg/m~ to about
100 mg/m2 per body surface area of an adult.
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The present invention also provides a therapeutic kit
which comprises, in suitable packaging units, a
pharmaceutical composition comprising edotecarin or a
pharmaceutically acceptable salt thereof and a
pharmaceutical composition comprising capecitabine or
docetaxel, present within individual packaging units or
within distinct packaging units.
As a particular example, a kit according to the
invention comprises a pharmaceutical composition
comprising edotecarin or a pharmaceutically acceptable
salt thereof and a pharmaceutical composition
comprising capecitabine or docetaxel, within distinct
packaging units.
The kits according to the invention are intended for
use in anti-cancer therapy, as defined above.
The efficacy of the combined preparations according to
the invention can be demonstrated by determining a
therapeutic synergy among the constituents of the
combination, for example as set out in the experimental
part that follows.
EXPERIMENTAL PART
Immune depressed (Nu/Nu) mice, bearing human SKBR-3
human breast carcinoma implanted sub-cutaneously, were
treated with the compounds in question with following
treatment scheme:
Edotecarin 3 mg/Kg was administered intravenously on
day 9 and 16;
Docetaxel 5 mg/Kg was administered intravenously on day
8, 12 and 15;
Capecitabine 370 mg/Kg was administered orally from day
to day 23.
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The treatments started when the tumors were measurable
(day 8 from tumor cell injection: tumor weight mean for
all the groups was 0.18 g).
Tumour measurements were taken by a calliper 1-2 times
a week. These tumor measurements were converted to mg
tumor weight by following formula:
length (rnm) x width 2 (natn)
Tumour weight =
2
Statistical analysis were carried out on the tumor
weights measured at different days in the mice treated
with the combination of edotecarin + capecitabine or
edotecarin + docetaxel in comparison with the
measurements obtained in mice treated with the
corresponding drugs as single agents. P values resulted
from a Mann Whitney test always <0.01, indicated a
therapeutic advantage (synergism) of the combined
treatments in comparison of the administration of each.
compound alone.
Antitumor response to the actives alone or in
combination was also assessed by evaluating the tumor
growth delay, namely the time taken by the tumours of
the different treatment groups to reach the
predetermined weight of (1 g) (T-C).
The obtained results are reported in the Table below.
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Table
Time to T-C
Synergistic
Treatment reach 1 g (days)Expecte
(days) d T-C effect
control 13.2
Edotecarin 3 mg/Kg*19.6 6.4
Docetaxel 5 mg/Kg**17.3 4.1
docetaxel 5 mg/Kg**
+ edotecarin 3 33.5 20.3 10.5 YES
mg/Kg*
capecitabine 370
mg/Kg*** 36.3 23.1
edotecarin 3 mg/Kg*
+ capecitabine 48.1 34.9 29.5 YES
370
mg/Kg***
* treatments IV on day 9 and 16
** treatments IV 'on day 8, l2, 15
*** treatments OS from day 10 to day 23
Edotecarin combined with docetaxel produced a
synergistic effect: the T-Cs was higher than that
expected by the simple addition of the T-Cs obtained
with the two compounds as single agent (20.3 days when
the expected T-Cs was 10.5 days). Also the result
obtained for the combination with capecitabine was
considered as synergistic (T-C - 34.9 days in
comparison with an expected T-C = 29.5).
The above-reported data show that the administration of
edotecarin in combination with docetaxel or
capecitabine result in a synergistic anti-cancer effect
by providing an unexpected increase in the tumor of
growth delay.
