ANTITUMOR COMBINATION INCLUDING
CABAZITAXEL AND CAPECITABINE
The present invention relates to an antitumor combination combining
cabazitaxel and capecitabine in the treatment of metastatic breast cancer in
patients progressing after prior treatment with anthracyclines and taxanes.
[Prior art and technical problem]
Breast cancer affects a large part of the female population throughout the
world: 1.15 million cases worldwide in 2002; it is predicted that it will affect
1.4 million cases in 2010 (CA cancer J.Clin. 2005, 55, 74-108). It is the
most common cancer in women.
Metastatic breast cancer (MBC) is generally treated with anthracycline- and
taxane-based chemotherapy ("Concise Review for clinicians: advances in
screening, diagnosis and treatment of breast cancer" Mayo clinic
proceedings 2004, 76,810-816).
The cancer can become resistant to the agents used, in particular to
taxanes, which limits the possible treatment options. Several mechanisms
of taxane resistance have been described (expression of P-glycoprotein
P-gp, mdr-1 gene, modified taxane metabolism, tubulin gene mutation,
etc.): see Drug Resistance Updates 2001, 4(1), 3-8; J.CIin.Onc. 1999,
77(3), 1061-1070.
For patients in whom the cancer has progressed after a previous treatment
based on anthracyclines and/or taxanes (75% of patients develop
resistance to this treatment), capecitabine in monotherapy or the
combination combining capecitabine and docetaxel is indicated (J.CIin.Onc.
2002, 20(12), 2812-2823).
It has also been observed that cabazitaxel (or XRP6258) can be effective
in the treatment of taxane-resistant metastatic breast cancer ("A multicenter
phase II study of XRP6258 administered as a 1-h i.v. infusion every 3
weeks in taxane-resistant metastatic breast cancer patients" Ann.Oncol.
2008, 19(9), 1547-1552).

Furthermore, in the conclusion of the abstract entitled "In vitro induction of
Thymidine Phosphorylase by XRP6258, a new taxoid" presented at the
French Pharmacology Society Conference in Clermont-Ferrand from April 9
to 11, 2008, the following is specified: "XRP6258 induces TP expression,
especially with MCF-7 breast carcinoma cells. This induction might be
clinically relevant in the field of XRP6258/capecitabine combination,
assessed in patients with breast cancer, as predictive of an increased
cytotoxicity in the tumor cells for the combination.".
There is still a need to find and optimize novel therapeutic options in
patients in whom the cancer has progressed after previous treatment with
anthracyclines and taxanes.
The present invention meets this need by providing a novel antitumor
pharmaceutical combination comprising cabazitaxel and capecitabine, for
which it has been necessary to determine the doses of each drug and the
suitable administration scheme, so as to obtain a well-tolerated
combination which does not exacerbate the toxicity of each of the two
antitumor agents and which allows the treatment of patients progressing
after a prior treatment with anthracyclines and taxanes, in order to evaluate
the antitumor activity thereof.
[Brief description of the invention]
The invention relates to an antitumor pharmaceutical combination
comprising cabazitaxel having the formula

and capecitabine having the formula


wherein both of said antitumor agents may be in the form of a base, in the
form of a pharmaceutically acceptable acid salt or in the form of a hydrate
or of a solvate, intended for the treatment of metastatic breast cancer in
patients progressing after a prior treatment with anthracyclines and
taxanes.
Cabazitaxel can in particular be in the form of an acetone solvate. More
particularly, the acetone solvate of cabazitaxel contains between 5 and 8%
by weight of acetone, preferably between 5 and 7%.
The combination comprises an effective amount of cabazitaxel and an
effective amount of capecitabine.
The cabazitaxel can be administered at a dose (defined for each
administration) of between 15 and 25 mg/m2.
The capecitabine can be administered twice a day at a dose (defined for
each administration) of between 675 and 1250 mg/m2, more especially
between 825 and 1000 mg/m2.
The cabazitaxel can be administered by infusion at a dose of between 15
and 25 mg/m2 and the capecitabine is administered orally twice a day for
14 days at a dose (defined for each administration) of between 675 and
1250 mg/m2, more especially between 825 and 1000 mg/m2, this cycle of
administration of the two antitumor agents being repeated with a gap
between two administrations of cabazitaxel of 3 weeks, which gap can be
extended by 1 to 2 weeks depending on the tolerance to the preceding
administration of cabazitaxel.
The invention also relates to the use of cabazitaxel and capecitabine of
formula for preparing the abovementioned antitumor pharmaceutical
combination.

[Description of the invention]
Definitions
• pharmaceutically acceptable acid: organic or inorganic acid having a
low toxicity (see Pharmaceutical salts J.Pharm.Sci. 1977, 66, 1-19);
• effective amount: amount of a pharmaceutical compound producing
an effect on the cancer treated.
As regards cabazitaxel, it belongs to the taxoid family and has the
formula:

It has the chemical name: 4α-acetoxy-2α-benzoyloxy-5p,20-epoxy-1β-
hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxy-
carbonylamino-2-hydroxy-3-phenylpropionate. This compound and a
method of preparation are described in document WO 96/30355.
Cabazitaxel can be administered in the form of a base (cf. formula above),
in the form of a pharmaceutically acceptable acid salt or in the form of a
hydrate. It can also be a solvate, i.e. a molecular complex characterized by
the incorporation of the crystallization solvent into the crystal of the
molecule of the active ingredient (in this respect, see page 1276 of
J.Pharm.Sci. 1975, 64(8), 1269-1288). In particular, it may be an acetone
solvate, more particularly the one described in WO 2005/028462. It may be
an acetone solvate of cabazitaxel containing between 5 and 8% by weight
of acetone, preferably between 5 and 7% (% signifies acetone
content/acetone+cabazitaxel content x 100). An average value of the
acetone content is 7%, which represents more or less acetone
stoichiometry, which is 6.5% for a solvate comprising one acetone
molecule. The procedure described below makes it possible to prepare an
acetone solvate of cabazitaxel:

940 ml of purified water are added, at 20 + 5°C ambient temperature, to a
solution of 207 g of 4-acetoxy-2α-benzoyloxy-5p,20-epoxy-1-hydroxy-
7β,10β-dimethoxy-9-oxotax-11-en-13α-yl, at approximately 92% by weight
in approximately 2 liters of acetone, and then seeding is carried out with a
suspension of 2g of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-
7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonyl-
amino-2-hydroxy-3-phenylpropionate isolated in acetone/water in a mixture
of 20 ml of water and 20 ml of acetone. The mixture is left to stir for
approximately 10 to 22 hours and 1.5 liters of purified water are added over
the course of 4 to 5 hours. The mixture is left to stir for 60 to 90 minutes
and then the suspension is filtered under reduced pressure. The cake is
washed on a filter with a solution prepared from 450 ml of acetone and
550 ml of purified water and then oven-dried at 55°C under reduced
pressure (0.7 kPa) for 4 hours. 197 g of 4-acetoxy-2α-benzoyloxy-5β,20-
epoxy-1 -hydroxy-7β, 10β-dimethoxy-9-oxotax-11 -en-13α-yl (2R,3S)-3-tert-
butoxycarbonylamino-2-hydroxy-3-phenylpropionate acetone containing
0.1% of water and 7.2% of acetone are obtained (theoretically 6.5% for a
stoichiometric solvate).
Cabazitaxel is administered parenterally, such as by intravenous
administration, as a bolus or by infusion. A galenical form of cabazitaxel
suitable for administration by infusion is the form wherein the cabazitaxel is
in solution in water in the presence of excipients chosen from surfactants,
cosolvents, glucose or sodium chloride, etc. For example, a galenical form
of cabazitaxel can be prepared by dilution of a premix solution of
cabazitaxel contained in a sterile vial (80 mg of cabazitaxel + 2 ml of
solvent + polysorbate 80) with a sterile vial containing a solution of 6 ml of
water and ethanol (13% by weight of 95% ethanol) so as to obtain 8 ml of a
solution ready for redilution in a drip bag. The concentration of cabazitaxel
in this ready-for-redilution solution is approximately 10 mg/ml. The infusion
is then prepared by injecting the appropriate amount of this ready-for-
redilution solution into the drip bag containing water and glucose
(approximately 5%) or sodium chloride (approximately 0.9%).
As regards capecitabine (CAS RN 154361-50-9), it is sold by the
company Roche under the trademark Xeloda®. It is a prodrug of 5-fluoro-
uracil:


and has the chemical name: 5'-deoxy-5-fluoro-N4-(pentyloxycarbonyl)-
cytidine N-[1 -(5-deoxy-beta-D-ribofuranosyl)-5-fluoro-2-oxo-1,2-dihydro-
pyrimidin-4-yl]carbamic acid pentyl ester. This compound is described in
EP 0602454 or US 5472949. Capecitabine can be administered in the form
of a base (cf. formula above), in the form of a pharmaceutically acceptable
acid salt or in the form of a hydrate or of a solvate.
A galenical form of capecitabine suitable for oral administration is, for
example, the product sold under the trademark Xeloda® in the form of
tablets containing 150 or 500 mg of capecitabine and anhydrous lactose as
excipient.
As regards the combination, it consists in combining cabazitaxel and
capecitabine in the form of two distinct pharmaceutical preparations. The
combination can be used in the treatment of metastatic breast cancer, in
particular for patients who still have the cancer after a treatment based on
anthracyclines and/or taxanes.
The combination is administered repeatedly according to a protocol which
depends on the patient to be treated (body surface area, tolerance to the
previous cycle, etc.). The cabazitaxel can be administered to the patient by
infusion according to an intermittent scheme with a gap between each
administration of 3 weeks, that can be extended by 1 to 2 weeks depending
on the tolerance to the preceding administration. The capecitabine can, for
its part, be administered daily, for example in the form of two intakes per
day, for a period of 14 days. During a cycle, the 1st intake of capecitabine
can coincide with the administration of cabazitaxel.
An example of the protocol is as follows: the cabazitaxel is administered by
infusion over a period of approximately 1 hour on a given day D1 (1st day
of the cycle). The capecitabine is administered orally twice a day, in the

morning and evening, from day D1 to day D14 (from the 1st to the 14th day
of the cycle). This cycle consisting in administering both the cabazitaxel (on
D1) and the capecitabine (from D1 to D14) is then repeated with a gap of
3 weeks (extendable by 1 to 2 weeks).
The cabazitaxel and capecitabine doses administered each time to the
patient depend on various parameters: body surface area, tolerance to the
previous cycle, etc. The cabazitaxel can be administered at a dose (defined
for each administration) of between 15 and 25 mg/m2. The capecitabine
can be administered twice a day at a dose (defined for each administration)
of between 675 and 1250 mg/m2, more especially between 825 and
1000 mg/m2.
Preferably, the recommended dose is 20 mg/m2 of cabazitaxel on the first
day of treatment and 2 x 1000 mg/m2/day of capecitabine from the first to
the fourteenth day, this cycle of administration of the two antitumor agents
being repeated with a gap between two cabazitaxel administrations of
3 weeks, which gap can be extended by 1 to 2 weeks depending on the
tolerance to the previous administration of cabazitaxel.
[Example]
A phase l/lI study was carried out in four study centers in Europe.
Part 1: the maximal administered dose (MAD) and the recommended dose
(RD) of cabazitaxel in combination with capecitabine were determined.
Part 2: the antitumor activity and the characterization of the tolerance
profile were determined at the recommended dose.
The pharmacokinetics (PK), including the drug interaction study, were also
studied.
Patients
Main inclusion criteria for patients

The main inclusion criteria were an age of 18 or older, a histologically
proven metastatic or locally recurrent breast cancer that was inoperable, an
Eastern Cooperative Oncology Group performance status (ECOG PS) of 0
to 2, prior exposure to taxanes and to anthracyclines, and adequate
hematological, renal and hepatic function. For part 2, the patients selected
had to have at least 1 measurable lesion according to the RECIST
guidelines (J Natl Cancer Inst 2000, 92, 205-216).
The main exclusion criteria were a simultaneous cancer, more than one
chemotherapy treatment for metastatic cancer, prior exposure to
capecitabine, or uncontrolled significant comorbid conditions.
Thirty-three patients with metastatic breast cancer were included in the
study, all previously treated with anthracyclines and taxanes: 15 patients
for part 1 and 18 for part 2.
The characteristics relating to the patients treated are specified in Table I.



a includes adrenal, soft tissue, peritoneum, pericardial effusion.
ECOG PS: Eastern Cooperative Oncology Group performance status; ER:
estrogen receptor; PgR: progesterone receptor; HER2: human epidermal
growth factor receptor.
Pharmacokinetics:
The pharmacokinetic parameters were calculated for cabazitaxel,
capecitabine and their metabolites (Cmax, Tmax, AUC0-iast, AUC, t½λ).
Blood samples were collected at various times in part 1 of the study and
tested by liquid chromatography coupled to mass spectrometry methods.
The pharmacokinetic analysis did not reveal any apparent interaction
between cabazitaxel and capecitabine; the pharmacokinetics of cabazitaxel
and of its metabolite do not appear to be affected by the coadministration
of capecitabine, and vice versa.
Part 1: determination of the maximal administered dose (MAD) and of the
recommended dose (RD) of cabazitaxel in combination with capecitabine.
The dose-limiting toxicities (DLTs), i.e. the list of events to be monitored,
which make it possible to guide the dose escalation, were first of all

predefined in the protocol in accordance with the NCI-CTCAE classification
scale, version 3.
The increase in doses was studied in groups of three patients as long as
no DLT was observed. If a DLT was noted in a patient, the group was
extended to six patients, the MAD being reached if at least 2 patients
suffered a DLT. The RD was defined as the highest dose at which less than
33% of the patients exhibited a DLT.
First dose level:
- 3 patients - cabazitaxel 20 mg/m2 (D1) and capecitabine 825 mg/m2 twice
a day(D1-14)
- 1 DLT of grade 4 neutropenia type for more than 7 days in one patient
was observed
- group extended to 6 patients without further DLTs.
Second dose level:
- 3 patients - cabazitaxel 20 mg/m2 (D1) and capecitabine 1000 mg/m2
twice a day (D1-14)
- no DLT observed.
Third dose level:
- 3 patients - cabazitaxel 25 mg/m2 (D1) and capecitabine 1000 mg/m2
twice a day (D1-14)
- 1 DLT of grade 4 neutropenia type for more than 7 days in one patient
was observed

- group extended to 6 patients - a second DLT of the same type in another
patient was observed.
The MAD was consequently defined as being: cabazitaxel 25 mg/m2 and
capecitabine 1000 mg/m2.
The RD was consequently defined as being: cabazitaxel 20 mg/m2 and
capecitabine 1000 mg/m2.
Part 2: Study of the antitumor activity and characterization of the tolerance
profile at the recommended dose
The patients included in part 2 of the study were treated with the RD.
The main criterion for evaluating efficacy was the objective response rate
(ORR).
The objective response rate is defined, according to the RECIST guidelines
(J Natl Cancer Inst 2000, 92, 205-216), as the proportion of patients with a
confirmed complete response (CR) or partial response (PR), divided by the
total number of patients in the analysis population.
The secondary criteria for evaluating efficacy were the duration of response
(DR) and the time to progression (TTP).
The time to progression (TTP) is defined, according to the RECIST
guidelines (J Natl Cancer Inst 2000, 92, 205-216), as the time elapsed
between the first date of administration of the combination and the date of
the first documentation of progression of the disease.
The duration of response (DR) is defined, according to the RECIST
guidelines (J Natl Cancer Inst 2000, 92, 205-216), as the time elapsed
between the date of the first documentation of an objective response (CR

or PR) and the date of the first documentation of progression of the disease
or the occurrence of a death.
The capecitabine is administered orally twice a day, in the morning and
evening, from day D1 to day D14 (from the 1st to the 14th day of the cycle).
Two hours after the administration in the morning, the cabazitaxel is
administered by infusion (iv) over a period of approximately 1 hour on day
D1 (1st day of the cycle). This cycle consisting in administering both the
cabazitaxel (on D1) and the capecitabine (from D1 to D14) is then repeated
every three weeks.
Table II gives details of a concrete example of a cycle.

The doses could be reduced and the treatment cycle duration could be
extended in the case of a severe adverse event (AE). The treatment was
continued until disease progression, the presence of an unacceptable AE
or the withdrawal of patient consent.
A physical examination, complete differential leukocyte and blood counts,
and blood chemistry analyses were carried out before the recruitment of
the patients and regularly during treatment. Tumor evaluation by radiology
was carried out at recruitment of the patients and every 6 weeks. The
responses were confirmed by 2 evaluations at least 4 weeks apart.
Supplementary data were collected every 6 weeks until the date the study
was stopped.
Table III summarizes the treatment characteristics of the patients at the
various dose levels tested.


Tolerance
The most common adverse events (AE) were gastrointestinal problems,
fatigue, hand-foot syndrome and hematological toxicity, which corresponds
to the profile generally expected for a taxane-capecitabine combination.
Table IV gives the results of antitumor activity at the various dose levels
tested.


Part 2 of the study confirmed the feasibility of the antitumor pharmaceutical
combination comprising cabazitaxel and capecitabine at the recommended
dose since it was observed that the combination is well tolerated and does
not exacerbate the toxicity of each of the two antitumor agents. !n addition,
encouraging antitumor activity signals were observed at this dose.
An antitumor activity was, moreover, observed at all the dose levels tested.
In total, 7 patients showed an objective response.
It is remarkable to note that 2 of the 4 patients who had a progression of
the disease as best response with the prior taxane therapy experienced a
stabilization of their cancer with the cabazitaxel and capecitabine
combination, while 4 patients who had a stabilization of their disease as
best response with the prior taxane therapy obtained an objective response
to the treatment.

CLAIMS
1. An antitumor pharmaceutical combination comprising cabazitaxel
having the formula

and capecitabine having the formula

wherein both of said antitumor agents may be in the form of a base, in the
form of a pharmaceutically acceptable acid salt or in the form of a hydrate
or of a solvate, intended for the treatment of metastatic breast cancer in
patients progressing after a prior treatment with anthracyclines and
taxanes.
2. The combination as claimed in claim 1, comprising an effective
amount of cabazitaxel and an effective amount of capecitabine.
3. The combination as claimed in claim 1 or 2, in which the cabazitaxel
is in the form of an acetone solvate.
4. The combination as claimed in claim 3, in which the acetone solvate
of cabazitaxel contains between 5 and 8% by weight of acetone, preferably
between 5 and 7%.

5. The combination as claimed in claims 1 to 4, in which the
cabazitaxel is administered at a dose (defined for each administration) of
between 15 and 25 mg/m2.
6. The combination as claimed in claims 1 to 5, in which the
capecitabine is administered twice a day at a dose (defined for each
administration) of between 675 and 1250 mg/m2.
7. The combination as claimed in claim 6, in which the capecitabine is
administered for 14 days.
8. The combination as claimed in claims 1 to 7, in which the
cabazitaxel is administered by infusion at a dose of between 15 and
25 mg/m2 and the capecitabine is administered orally twice a day for
14 days at a dose (defined for each administration) of between 675 and
1250 mg/m2, more especially between 825 and 1000 mg/m2, this cycle of
administration of the two antitumor agents being repeated with a gap
between two cabazitaxel administrations of 3 weeks, which gap can be
extended by 1 to 2 weeks depending on the tolerance to the preceding
cabazitaxel administration.
9. The combination as claimed in claim 8, in which the cabazitaxel is
administered at the dose of 20 mg/m2 on the first day of treatment and the
capecitabine is administered at the dose of 2 x 1000 mg/m2/day from the
first to the fourteenth day of treatment.
10. The combination as claimed in claim 8 or 9, in which, during a cycle,
the 1st intake of capecitabine coincides with the administration of
cabazitaxel.
11. The use of cabazitaxel having the formula


and of capecitabine having the formula

for preparing an antitumor pharmaceutical combination as defined in one of
claims 1 to 10.

ABSTRACT

The invention relates to a pharmaceutical antitumor combination including cabazitaxel and capccitabinc, wherein
both of said antitumor agents may be in the form of a base, in the form of a pharmacemically acceptable acid salt or in the form of
a hydrate or solvate, intended for the treatment of metastatic breast cancer in patients progressing after a previous treatment with
anthracyclines and taxanes.