OA17078A

OA17078A - New pediatric uses of cabazitaxel.

Info

Publication number: OA17078A
Application number: OA1201400369
Authority: OA
Inventors: Sukhvinder S Sidhu; Patricia Vrignaud
Original assignee: Aventis Pharma S.A.
Priority date: 2012-02-10
Filing date: 2013-02-08
Publication date: 2016-03-23

Abstract

The present invention relates to the compound of formula (I) : <img file="OA17078A_A0001.tif"/> which may be in the form of an anhydrous base, a hydrate or a solvate, for its use for the treatment of pediatric cancers.

Description

NEW PEDIATRIC USES OF CABAZITAXEL

The présent invention concems new pédiatrie uses of cabazitaxel. It also $ concems a new method for treating children and young adults.

Over the past 20 years, there has been some increase in the incidence of children diagnosed with ail forms of invasive cancer. Long-term trends in incidence for leukemias and brain tumors, the most common childhood cancers, show patterns ίο that are somewhat different from the others. Incidence of childhood leukemias appeared to rise in the early 1980s. Rates in the succeeding years hâve shown no consistent upward ordownward trend.

While leukemia is the most common pédiatrie malignancy, brain tumors are the most common solid tumors, representing 21% of ail cancers in children, followed is by neuroblastoma (8.3%), nephroblastoma (5.9%), bone tumors (4.6%) such as

Osteosarcoma, Ewing’s, and soft tissue sarcoma (3.7%) [K.Pritchard-Jones et al. Eur. J. Cancer42: 2183-2190 (2006)].

Although chemotherapy improves disease-free survival of patients with osteosarcomas the long-term overall survival benefit remains unproven. 20 Chemotherapy is not efficient in chondrosarcome and its rôle is currently more limited for patients with soft-tissue sarcomas. Medulloblastoma Is the most common malignant brain tumour occurring in children, adolescents and young adults, with a response rate of *40% to temozolomide. Nevertheless, the improvement In the treatment of childhood brain tumors is particulariy critical in tumor types for which 25 outcome remains poor (such as high-grade gliomas).

There is thus an urgent and unmet need to find new antitumoral treatments in the pédiatrie indication.

Among the taxoid dérivatives with antitumoral activity, one may cite cabazitaxel.

In particular, WO96/30355 discloses taxoids dérivatives, including cabazitaxel, useful as antitumoral agents. This document also discloses a long list of other drugs that may be used as co-treatments with such taxoids.

I

W02010/128258 dis cl os es an antitumoral combination comprising cabazitaxel and capecitabine In the treatment of metastatic breast cancer for patients progressing after a previous treatment by anthracyclines and taxanes.

WO2011/051894 discloses the use of cabazitaxel In combination with prednisone or prednisolone in the treatment of prostate cancer.

The aim of the présent invention is thus to provide with a new therapeutic option for treating pédiatrie cancers.

The aim of the présent invention is to provide evidence of activity of cabazitaxel in pédiatrie sarcomas, using tumor models directly obtained from fresh tumors of pédiatrie patients (J.J. Tentler, A. Choon Tan, C.D. Weekes, A. Jimeno, S. Leong, T.M. Pitts, J.J. Arcaroli, WA. Messersmith and S.G. Eckhardt. Patient· derived tumour xenografts as models for oncology drug development. Nature Reviews Clinical Oncology 2012,9: 338-350).

The présent Invention relates to a compound of formula (I):

IS

(D which may be in the form of an anhydrous base, a hydrate or a solvaté, for its use for the treatment of pédiatrie cancers.

The présent invention Is based on an improved antitumoral activity of cabazitaxel, which may be in the form of an anhydrous base, a hydrate or a solvaté, In comparison with docetaxel in preclinical pédiatrie models.

Indeed the présent inventors hâve now demonstrated that the efficacy of cabazitaxel is better than that of docetaxel in this pédiatrie indication.

In the présent invention, the term 'pédiatrie cancers’ refers to cancers or tumors occumng in children and young adults.

The présent Invention also relates to the above-mentloned compound for its 35 use for the treatment of pédiatrie solid tumors.

IS

In the présent invention, the terni “pédiatrie solid tumors’ refera to solid tumore occurring In children and young adults.

The présent invention also relates to the above-mentioned compound for its use for the treatment of high grade gliomas, such as glioblastomas.

The term “high-grade glioma’ (or malignant glioma) refera to tumors that are classified as Grade III (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, anaplastic ependymoma) or Grade IV (glioblastoma).

According to an embodiment, the pédiatrie solid tumors are chosen from the group consisting of anaplastic astrocytomas, glioblastomas, anaplastic oiigodendrogliomas, oligoastrocytomas, anaplastic ependymomas, nephroblastoma, medulloblastomas, neuroblastomas, Wilm’s tumors, rhabdomyosarcomes, chondrosarcomas, Ewing's sarcomas and osteosarcomas.

According to an embodiment, the présent invention relates to the abovementioned compound for its use for the treatment of rhabdomyosarcoma (such as Human Rhabdomysarcoma RH-30).

According to an embodiment, the présent invention relates to the abovementioned compound for its use for the treatment of Ewing’s tumor (such as Human Ewing’s sarcoma TC71, and Human Ewing’s sarcoma SK-ES-1 or Human Ewing's sarcoma DM101).

According to an embodiment, the présent invention relates to the abovementioned compound for its use for the treatment of osteosarcomas (such as human osteosarcoma DM77 or human osteosarcoma DM113).

The présent Invention also relates to a method for treating pédiatrie cancers comprising the administration of a therapeutically efficient amount of the abovementioned compound to a patient in need thereof.

Cabazitaxel is an antitumoral agent of the taxoid family and has the following

It may be In the form of anhydrous base, a hydrate or a solvaté.

The chemical name of cabazitaxel is 4a-acetoxy-2a-benzoyloxy-5p,20-epoxy1 p-hydroxy-7p,10p-dimethoxy-9-oxo-11 -taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. Cabazitaxel is synonymously known as (2a₁5p,7p,10p,13a)-4-acetoxy-13-(((2R,3S)-3-[(tertbutoxycarbonyl)amino]-2s hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax11-en-2-yl benzoate.

This compound and a préparative method thereof are described In WO96/30355, EP0817779 and US5847170.

Cabazitaxel may be administered in base form (cf. above formula), or in the ίο form of a hydrate. It may also be a solvaté, Le. a molecular complex characterized by the incorporation of a crystallization solvent into the crystal of the molécule of the active principle (see in this respect page 1276 of J. Pharm. Sci. 1975, 64(8), 12691288).

In the présent invention, the above-mentioned compound may be in the form i î of an acetone solvaté.

According to an embodiment, the acetone solvaté comprises from 5% to 8% by weight of acetone.

In particular, the above-mentioned compound may be the acetone solvaté described in W02005/02846.

It may be an acetone solvaté of cabazitaxel containing from 5% to 8% and preferably from 5% to 7% by weight of acetone (% means content of acetone/content of acetone+cabazitaxel x 100). An average value of the acetone content Is 7%, which approximately represents the acetone stoichiometry, which Is 6.5% for a solvaté containing one molécule of acetone.

The procedure described below allows the préparation of an acetone solvaté of cabazitaxel: 940 ml of purified water are added at 20 ± 5'C (room température) to a solution of 207 g of 4a-acetoxy-2a-benzoyloxy-5p,20-epoxy-ip-hydroxy-7p,10pdimethoxy-9-oxo-11 -taxen-13a-yl (2R,3S)-3-fert-butoxycarbonylamtno-2-hydroxy-3phenylpropionate at about 92% by weight in about 2 litres of acetone, followed by

3o seeding with a suspension of 2 g of 4a-acetoxy-2a-benzoyloxy-5p,20-epoxy-iphydroxy-7p,10p-dimethoxy-9-oxo-11-taxen-13a-yl(2R,3S)-3-fert-butoxycarbonylamino-2-hydroxy-3-phenylpro-pionate isolated from acetone/water in a mixture of 20 ml of water and 20 ml of acetone. The resulting mixture is stirred for about 10 to 22 hours, and 1.5 litres of purified water are added over 4 to 5 hours. This mixture Is stirred for 60 to 90 minutes, and the suspension is then filtered under reduced pressure. The cake is washed on the filter with a solution prepared from 450 m! 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 4a-acetoxy-2a-benzoyloxy-5ft,20-epoxy-iphydroxy-7P,10p-dimethoxy-9-oxo-11-taxen-13a-yl (2R,3S)-3-fert-butoxycarbonyls amino-2-hydroxy-3-pheny!propionate acetone containing 0.1% water and 7.2% acetone (theoretical amount: 6.5% for a stoichiometric solvaté) are obtained.

In the présent invention, the above-mentioned compound may be administered by parentéral route.

to According to an embodiment, the compound of formula (I) is administered by

Intravenous route.

Cabazitaxel may be administered parenterally, such as via intravenous administration. A galenical form of cabazitaxel suitable for administration by intravenous infusion is that In which the cabazitaxel Is dissolved In water In the 15 presence of excipients chosen from surfactants, cosolvents, glucose or sodium chloride, etc. For example, a galenical form of cabazitaxel may be prepared by diluting a premix solution of cabazitaxel contained in a stérile vial (80 mg of cabazitaxel + 2 ml of solvent + Polysorbate 80) with a stérile vial containing a solution of 6 ml of water and éthanol (13% by weight of 95% éthanol) in order to 2o obtain 8 ml of a solution ready to be rediluted in a perfusion bag. The concentration of cabazitaxel in this ready-to-redilute solution is about 10 mg/ml. The perfusion is then prepared by injecting the appropriate amount of this ready-to-redilute solution into the perfusion bag containing water and glucose (about 5%) or sodium chloride (about 0.9%).

Antitumor activity

The better antitumor activity of cabazitaxel as compared to docetaxel according to the invention is demonstrated by the head to head évaluation at same dosages and/or at equi-toxic dosages in low passage patient-derived pédiatrie 30 cancer xenografts or In pédiatrie cancer models.

In the reported examples supporting this invention, vials of the clinical formulation of cabazitaxel and docetaxel were used. Docetaxel was diluted into 0.9% sodium chloride. Each vial of cabazitaxel, 60 mg/1.5 mL was first mixed with the entire contents of supplied diluent [13% (w/w) aqueous solution of éthanol]. The 35 résultant solution contains 10 mg/mL of cabazitaxel. Stock solution of cabazitaxel was then diluted in 0.9% sodium chloride.

This efficacy may be quantified, for example, as changes in tumor volume for each treated (T) and control (C) group, which are calculated for each animal and each day by subtracting the tumor volume on the day of first treatment (staging day) from the tumor volume on the specified observation day. This allows calculating the s tumor growth inhibition: ΔΤ/Δ0 = (médian delta Tl médian delta C) x 100. Individual tumor volume changes from baseline are thereafter analyzed by a non-parametric two-way ANOVA-TYPE (with factors: group and repeated days) followed by a posthoc contrasts analysis, with Bonferroni-Holm adjustment for multiplicity, comparing ail treated groups to the control group. Additionally, a non parametric two-way io ANOVA-TYPE (with factors: treated group and repeated days) was performed and followed by a contrast analysis, with Bonferroni-Holm adjustment for multiplicity, to compare at each day the effects of docetaxel and cabazitaxel when administered at the same dose or at equi-toxic doses. A probability less than 5% (p<0.05) was considered as significant.

h Based on the National Cancer Institute (NCI) standards, a ΔΤ/ΔΟ 40% is the minimal level required to déclare activity.

The tumor doubling time (in days; Td) was estimated from the plot of the log linear growth of the control group tumors in exponential growth (100 to 1000 mm³range) [T-H. Corbett et al., Cancer, 40: 2660-2680 (1977); F.M. Schabel et al., 20 Cancer Drug Development, Part B, Methods in Cancer Research, 17: 3-51, New

York, Academie Press Inc. (1979)].

This efficacy may also be quantified by the number of tumor régressions observed after therapy. Individual mice reporting a tumor volume £50% of the Day 0 25 measurement for two consecutive measurements over a seven day period were considered partial responders (PR). Individual mice lackîng palpable tumors (< 4x4 mm² for two consecutive measurements over a seven day period) were class'rfied as complété responders (CR); a CR that persisted until study completion was considered a tumor-free survivor (TFS).

Efficacy could also be determined at study completion, using tumor growth delay (T-C) in days, which is calculated using the médian time to endpoint (ΜΤΓΕ) value for each treatment (T) group versus control (C). A Log Rank multiple comparison test with Bonferroni-Holm adjustment for multiplicity was applied on individual TTE to compare the treated groups to the control group.

«

The efficacy of cabazitaxel in comparison with docetaxel on pédiatrie patientderived tumor xenografts was determined experimentally in the following manner

The animais subjected to the experiment are subcutaneously grafted unilaterally with approxlmately 30 mg of a tumor fragment from low passage s pédiatrie patient-derived tumor xenografts. The animais are implanted with a human patient-derived pédiatrie tumor xenografted in immuno-compromised mice (Harian; nu/nu). Several days post tumor Implantation, mice are randomized according to their tumor burden to the different groups of treatments and contrais. The agents are dosed intravenously at 5.8, 9.3,15 or 24.2 mg/kg every 4 days for a total of 3 doses io (q4dx3) to mice bearing a tumor burden at start of therapy (day 0) ranged from 125 to 250 mm³.

Beginning Day 0, animais were observed daily and weighed twice weekly using a digital scale; data including Individual and mean gram weights (Mean We ± SD), mean percent weight change versus Day 0 were recorded for each group. is Animal deaths were recorded daily and designated as drug-related (D), technical (T), tumor related (B), or unknown (U) based on weight loss and gross observation; single agent or combination groups reporting a mean >20% for a period of 7 days and/or >10% mortality were consldered above the maximum tolerated dose (MTD) for that treatment on the evaluated regimen.

The efficacy of cabazitaxel in comparison with docetaxel on pédiatrie solid tumors was determined experimentally in the following manner

The animais subjected to the experiment are subcutaneously grafted unilaterally with approxlmately 30 mg of a tumor fragment on day 0. The animais are 25 implanted with a human tumor xenografted in immunocompromized mice. Several days post tumor implantation, mice are randomized according to their body weight to the different groups of treatments and contrais. The animais are observed every day. The different animal groups are weighed daily during treatment until the maximum weight loss is reached and subséquent full weight recovery has occurred. 30 The groups are then weighed once or twice a week until the end of the trial.

The tumors are measured 1 to 5 times a week, depending on the tumor doubling time, until the tumor reaches approximately 1,000 mm³, or until the animal dies (if this occurs before the tumor reaches 1,000 mm³). The animais are necropsied immediately after euthanasia or death.

The antttumor actîvity is determined in accordance with the different ’ parameters recorded.

DESCRIPTION OF THE FIGURES

Figure 1 represents the body weight change during the évaluation of the 5 antitumor activity of cabazitaxel and docetaxel against human RH-30 bearing SCID female mice (example 1). Curves represent means at each day for each group.

It represents the body weight change (%) over time (days post-implantation).

The curve with continuous line corresponds to control; the curve with dotted line (--) corresponds to docetaxel at 14.5 mg/kg; the curve with continuous line to and a white triangle (Δ) corresponds to docetaxel at 9 mg/kg; the curve with continuous line and a white circle (o) corresponds to docetaxel at 5.6 mg/kg; the curve with continuous line and a white square (□) corresponds to docetaxel at 3.5 mg/kg; the curve with dotted line (— ) corresponds to cabazitaxel at 14.5 mg/kg; the curve with dotted line and a black triangle (a) corresponds to cabazitaxel at 9 ts mg/kg; the curve with dotted line and a black circle (·) corresponds to cabazitaxel at

5.6 mg/kg; the curve with dotted line and a black square () corresponds to cabazitaxel at 3.5 mg/kg; and the black triangles indicate the treatment IV.

Figure 2 represents the antitumor activity of cabazitaxel and docetaxel against human RH-30 bearing SCID female mice (example 1). Curves represent médians at each day for each group.

It represents the tumor volume (mm³) over time (days post-implantation).

The curve with continuous line corresponds to control; the curve with dotted line (--) corresponds to docetaxel at 14.5 mg/kg; the curve with continuous line and a white triangle (Δ) corresponds to docetaxel at 9 mg/kg; the curve with continuous line and a white circle (o) corresponds to docetaxel at 5.6 mg/kg; the curve with continuous line and a white square (□) corresponds to docetaxel at 3.5 mg/kg; the curve with dotted line (— ) corresponds to cabazitaxel at 14.5 mg/kg; the curve with dotted line and a black triangle (a) corresponds to cabazitaxel at 9 mg/kg; the curve with dotted line and a black circle (·) corresponds to cabazitaxel at

Figure 3 represents the body weight change during the évaluation of the 35 antitumor activity of cabazitaxel and docetaxel against human TC-71 bearing SCID female mice (example 2). Curves represent means at each day for each group.

It represents the body weight change (%) over time (days post-implantation).

The curve with continuous line corresponds to control; the curve with dotted line (--) corresponds to docetaxel at 14.5 mg/kg; the curve with continuous line and a white triangle (Δ) corresponds to docetaxel at 9 mg/kg; the curve with s continuous line and a white circle (o) corresponds to docetaxel at 5.6 mg/kg; the curve with continuous line and a white square (□) corresponds to docetaxel at 3.5 mg/kg; the curve with dotted line (— ) corresponds to cabazitaxel at 14.5 mg/kg; the curve with dotted line and a black triangle (a) corresponds to cabazitaxel at 9 mg/kg; the curve with dotted line and a black circle (·) corresponds to cabazitaxel at io 5.6 mg/kg; the curve with dotted line and a black square () corresponds to cabazitaxel at 3.5 mg/kg; and the black triangles indicate the treatment IV.

Figure 4 represents the antitumor activity of cabazitaxel and docetaxel against human TC-71 bearing SCID female mice (example 2). Curves represent médians at is each day for each group.

It represents the tumor volume (mm³) over time (days post-implantation).

The curve with continuous line corresponds to control; the curve with dotted line (--) corresponds to docetaxel at 14.5 mg/kg; the curve with continuous line and a white triangle (Δ) corresponds to docetaxel at 9 mg/kg; the curve with 2o continuous line and a white circle (o) corresponds to docetaxel at 5.6 mg/kg; the curve with continuous line and a white square (□ ) corresponds to docetaxel at 3.5 mg/kg; the curve with dotted line (— ) corresponds to cabazitaxel at 14.5 mg/kg;

the curve with dotted line and a black triangle (*) corresponds to cabazitaxel at 9 mg/kg; the curve with dotted line and a black circle (·) corresponds to cabazitaxel at

Figure 5 represents the body weight change during the évaluation of the antitumor activity of cabazitaxel and docetaxel against human SK-ES-1 bearing 30 SCID female mice (example 3). Curves represent means at each day for each group.

It represents the body weight change (%) over time (days post-implantation).

The curve with continuous line corresponds to control; the curve with dotted line (--) corresponds to docetaxel at 14.5 mg/kg; the curve with continuous line as and a white triangle (Δ) corresponds to docetaxel at 9 mg/kg; the curve with continuous line and a white circle (o) corresponds to docetaxel at 5.6 mg/kg; the ίο curve with continuous line and a white square (□ ) corresponds to docetaxel at 3.5 mg/kg; the curve with dotted line (— ) corresponds to cabazitaxel at 14.5 mg/kg; the curve with dotted line and a black triangle (^A) corresponds to cabazitaxel at 9 mg/kg; the curve with dotted line and a black circle (·) corresponds to cabazitaxel at s 5.6 mg/kg; the curve with dotted line and a black square () corresponds to cabazitaxel at 3.5 mg/kg; and the black triangles indicate the treatment IV.

Figure 6 représente the antitumor activity of cabazitaxel and docetaxel against human SK-ES-1 bearing SCID female mice (example 3). Curves represent médians îo at each day for each group.

It represents the tumor volume (mm³) over time (days post-implantation).

The curve with continuous line corresponds to control; the curve with dotted line (--) corresponds to docetaxel at 14.5 mg/kg; the curve with continuous line and a white triangle (Δ) corresponds to docetaxel at 9 mg/kg; the curve with is continuous line and a white circle (o) corresponds to docetaxel at 5.6 mg/kg; the curve with continuous line and a white square (□) corresponds to docetaxel at 3.5 mg/kg; the curve with dotted line (— ) corresponds to cabazitaxel at 14.5 mg/kg;

Figure 7 represents the antitumor activity of cabazitaxel and docetaxel against human DM77 osteosarcoma in nude female mice (example 4). Curves represent 25 médians at each day for each group.

It represents the tumor volume (mm³) over time (days post first treatment).

The curve with continuous line corresponds to control; the curve with dotted line (--) corresponds to docetaxel at 24.2 mg/kg; the curve with continuous line and a white triangle (Δ) corresponds to docetaxel at 15 mg/kg; the curve with 30 continuous line and a white circle (o) corresponds to docetaxel at 9.3 mg/kg; the curve with continuous line and a white square (□ ) corresponds to docetaxel at 5.8 mg/kg; the curve with dotted line (— ) corresponds to cabazitaxel at 24.2 mg/kg; the curve with dotted line and a black triangle ( a) corresponds to cabazitaxel at 15 mg/kg; the curve with dotted line and a black circle (·) corresponds to cabazitaxel at 35 9.3 mg/kg; the curve with dotted line and a black square () corresponds to cabazitaxel at 5.8 mg/kg; and the black triangles indicate the IV treatment.

Figure 8 represents the antitumor activity of cabazitaxel and docetaxel against human DM113 osteosarcoma in nude female mice (example 5). Curves represent médians at each day for each group.

s It represents the tumor volume (mm³) over time (days post first treatment).

The curve with continuous line corresponds to control; the curve with dotted line (--) corresponds to docetaxel at 24.2 mg/kg; the curve with continuous line and a white triangle (A) corresponds to docetaxel at 15 mg/kg; the curve with continuous line and a white circle (o) corresponds to docetaxel at 9.3 mg/kg; the io curve with continuous line and a white square (□ ) corresponds to docetaxel at 5.8 mg/kg; the curve with dotted line (---) corresponds to cabazitaxel at 24.2 mg/kg;

the curve with dotted line and a black triangle ( ) corresponds to cabazitaxel at 15 mg/kg; the curve with dotted line and a black circle (·) corresponds to cabazitaxel at 9.3 mg/kg; the curve with dotted line and a black square () corresponds to is cabazitaxel at 5.8 mg/kg; and the black triangles indicate the IV treatment.

Figure 9 represents the antitumor activity of cabazitaxel and docetaxel against human DM101 Ewing’s sarcoma in nude female mice (example 6). Curves represent médians at each day for each group.

2o It represents the tumor volume (mm³) over time (days post first treatment).

The curve with continuous line corresponds to control; the curve with dotted line (--) corresponds to docetaxel at 24.2 mg/kg; the curve with continuous line and a white triangle (A) corresponds to docetaxel at 15 mg/kg; the curve with continuous line and a white circle (o) corresponds to docetaxel at 9.3 mg/kg; the 25 curve with continuous line and a white square (□ ) corresponds to docetaxel at 5.8 mg/kg; the curve with dotted line (— ) corresponds to cabazitaxel at 24.2 mg/kg; the curve with dotted line and a black triangle ( corresponds to cabazitaxel at 15 mg/kg; the curve with dotted line and a black circle (·) corresponds to cabazitaxel at 9.3 mg/kg; the curve with dotted line and a black square () corresponds to 30 cabazitaxel at 5.8 mg/kg; and the black triangles indicate the IV treatment.

The better antitumor activity of cabazitaxel as compared to docetaxel, according to the invention, is demonstrated as illustrated in the 6 following examples.

Example 1: ANTITUMOR ACTIVITY OF CABAZITAXEL AND DOCETAXEL AGAINST HUMAN RHABDOMYOSARCOMA RH-30 IN SC1D FEMALE MICE.

s In this example, the better antitumor activity of cabazitaxel as compared to docetaxel for tumor growth inhibition was demonstrated in vivo.

The selected tumor model was a human rhabdomyosarcoma RH-30, xenografted in SCID mice [Douglass EC, et al. Cytogenet Cell Genet. 1987; 45(3-

4):14855.].

io Cabazitaxel and docetaxel were weighed for each treatment and dissolved in éthanol. Treatment solutions were prepared first by mixing 1 volume of ethanolic stock solution and 1 volume of polysorbate 80, then by adding 18 volumes of glucose 5% In water.

Cabazitaxel and docetaxel were administered intravenously on days 14 and is 18 after tumor implantation.

The results of the experiments are reported below in Tables 1, 2 & 3 and in Figures 1 & 2.

The tumor doubling time (in days; Td) was estimated from the plot of the log linear growth of the control group tumors in exponentiel growth (100 to 1,000 mm³ range) and the number of tumor régressions observed after therapy. Tumor doubling time was 3.2 days.

The following end points were used:

- Toxicity was declared at dosages Inducing £ 20% body weight loss or i 10 % dru g death;

- Relative tumor growth Inhibition was determined on day 27 post tumor implantation when the médian tumor size in the control group was 1148 mm’;

- Antitumor efficacy was determined by calculating the AT/AC value in percent, according to the above mentioned formula;

-Tumor régressions (as expîained above);

- Statistical analysis performed as expîained above.

i

Table 1 Evaluation of the efficacy of docetaxel and cabazitaxel in SCID female mice bearing human rhabdomyosarcome RH-30.

Agent	Route/ Dosage InmL/kg per Injection	Dosage in mg/kg per Injection (total dose)	SchecUs Indays	Dmgdeath (Day ofdeath)	Average body weight change fn % per mouse at nadir (day cf nadir)		PvaÉje <pByZ7y	î 1 Bfctoÿcd HepretaOsn
ΔΤ/Δ0 ln% (day 27)	Partial	Complété	Omortee suvtas at day 120
		14.5(29)		08	•15.0(24)	<0	66	66	66	pO.0001	Hjÿtyacthe
		9.0(18)		06	-8 0 (25)	7	66	66	56	pC.0001	Vayacthe
CABAZITAXEL	IV (16)		14; 18
		5 8(11.2)		06	-15 3(28)	0	56	26	06	pO.0001	Hÿtyacfce
		3 5(7.0)		06	-10.1 (24)	24	08	06	06	pO.0001	Adte
		14.5 (29)		06	-17.6(27)	1	56	36	06	pO.0001	Vatyacfce
DOCETAXEL	IV (18)	9.0 (18)	14; 18	08	-11.2(25)	<0	2/8	06	06	p<10001	Hÿtyadk®
		5 8(11.2)		06	•12.1 (25)	<0	46	06	06	p<10001	H&iyacfce
		3.5 (7.0)		06	-1 8(15)	77	06	06	06	P-Q5534	tacte
Control	-	-	-	06	-2.2(19)	-	0/8	06	06
Tumor doubilng time	3.2 days. Tumor size at start of therapy was 108-392mm^J, with a médian tumor burden per group of 188-198 mm¹,
Mice average weight Due to body weight heterogenerty (range: DOCETAXEL· 19.73-24 51 g; CAZABITAXEL	•20 54-24.72 g) dosages were adjusted to the Individual body
weights.
Abbreviations used, ΔΤ/Δ0· ratio of médian tumor volume changes from baseline between treated and control groups.
• Statistical analysis: p-value obtained with a contrast analysis versus control with Bonferroni-Holm adjustment for multiplicity after Anova-Type on tumor volume changes from
baseilne.

The médian tumor burden at start of therapy was 188 to 198 mm³. Cabazitaxel and docetaxel were administered as single agents by IV tail vein injection on day 14 and day 18 post tumor at the following doses: 14.5, 9.0, 5.6 and 3.5 mg/kg per injection (Table 1).

Cabazitaxel and docetaxel were well tolerated, with a maximum 15.3% bw! on day 28 for cabazitaxel and 17.6% bwl on day 27 for docetaxel (Table 1 and Figure 1).

Cabazitaxel and docetaxel were both highly active, AT/AC £ 0% on day 27 io (p<0.0001) at 14.5 and 5.6 mg/kg per injection for cabazitaxel and 9.0 and 5.6 mg/kg per injection for docetaxel.

Cabazitaxel at 9.0 mg/kg per injection was very active (AT/AC = 7% on day 27, p<0.0001) and docetaxel at 14.5 mg/kg per injection were also very active (AT/AC =1% on day 27, p<0.0001).

ü At 3.5 mg/kg per injection, cabazitaxel was still active (AT/AC =24% on day

27, p<0.0001), while docetaxel was inactive (AT/AC >40% on day 27, NS) (Table 1).

The effect of cabazitaxel was significant in comparison with control on days 19, 22, 25 and 27 at 14.5 mg/kg per injection, from day 18 to day 27 at 9 mg/kg per 20 injection, at days 18, 19, 22, 25 and 27 at 5.6 mg/kg per injection, on days 25 and at 3.5 mg/kg per injection.

Global p values were p<0.0001, p<0.0001, p<0.0001 & p=0.0473 respectively for each dose (Table 2 and Figure 2).

In this study, docetaxel had a significant effect in comparison with control on days 19, 22, 25 and 27 at 14.5 and 9 mg/kg per injection, on days 25 and 27 at 5.6 mg/kg per injection. Global p values were p<0.0001, p<0.0001 & p=0.0005, respective for each dose (Table 2 and Figure 2).

Table 2 Antitumor activity of cabazitaxel and docetaxel against human rhabdomyosarcome RH-30 bearing SCID mice: Comparison of each agent versus control group.

Tumor volume changes from baseline:

Médian (nMad) and Anova-Type followed by a contrat analysis versus control on tumor volume changes from baseline

Group	Day
Global	18	19	20	22	25	27
Control	-	327 (83) n-8	437 (149.7) n-8	403(106.7) n-8	852.5(418 8) n-8	757.5(281.7) n-8	956 5 (588 6) n-8
Cabazitaxel 14.5 mg/kg	-	217.5 (87.5) n=6	146(138 6) n-6	359 (285 4) n-6	272(180.1) n-6	86 5(318) n=6	-13.5(281) n-6
	p<0001	p-0 0996	p-0 0012	p-0 5335	p-0 0071	p<0001	p<.0001
Cabazitaxel 9 mg/kg	-	138 5 (34 8) n-6	139 5(482) n«6	215 5 (88 2) n-6	129 5 (45.2) n-6	78.5 (174.9) n-6	82.5 (102.3) n-6
	p< 0001	p-0 0047	p<.0001	p-0 0042	p<0001	p<.0001	p<0001
Cabazitaxel 5.6 mg/kg	-	164(304) n=6	203(80.1) n-6	302 5 (220 2) n-6	192 5(196 4) n-6	22 (147.5 ) n-6	0(130 5) n=6
	p<0001	p-0 0076	p-0.0003	p-0.1708	p-0 0016	p«.OOÛ1	p<.0001
Cabazitaxel 3.5 mg/kg	-	307(356) n-6	433.5 (232) n=6	601 (114.2) n-6	418(258) n-6	280 (168 3) n-6	229(78 6) n-6
	p-0 0473	p-0 8325	p-10000	p-1.0000	p-0.2529	p-0 0043	p<0001
Docetaxel 14.5 mg/kg	-	166 5 (87.5) n-6	195 (83) n-6	247 (126) n-6	172(64 5) n-6	154.5(54 9) n-6	13 (67.5) n-6
	p<.0001	p-0 0828	p-0 0042	p-0.1178	p-0 0009	p<0001	p<.0001
Docetaxel 9 mg/kg	-	202 (98 6) n-6	202(71.9) n-6	325(181.6) n-6	290.5 (139.4) n-6	115 5(120 8) n=6	-50 5(60) n-6
	p<.0001	p-0.3352	p-0 0293	p-0 8168	p-0 027	p<.0001	p< 0001
Docetaxel 5.5 mg/kg	-	216(84 5) n-6	289 (57.1) n-6	409 5(109 7) n-6	405 5 (226 8) n-6	•30 5 (68 2) n-6	-73 (51.1) n-6
	p»0 0005	p-0.604	p-0 6497	p-1 0000	p-0 2529	p<0001	p< 0001
Docetaxel 3.6 mg/kg	-	236 5 (125.3) n-6	477(157.9) n-6	475(198.7) n-6	495 5 (276 5) n-6	621.5(318) n-6	736 (288.4) n-6
	p-0 0473	p-0 8325	p-1.0000	p-1 0000	p-0.2529	p-0.0043	p<.0001

p-value: obtained with a contrat analysis versus control with Bonferronl-Holm adjustment for multiplidty after Anova-Type on tumor volume changes from baseline

Table 3 Antitumor activity of cabazitaxel and docetaxel against human rhabdomyosarcoma RH-30 bearing SCID mlce: Comparison of the agents at the same dose ________________

Tumor volume changes from baseline: Médian (nMad) and Anova-Type followed by a contrast analysis on tumor volume changes from baseline

Day

Cabazitaxel 3.5 mg/kg

Docetaxel 3.5 mg/kg

P value

Cabazitaxel 5.5 mg/kg

Docetaxel 5.5 mg/kg

P value

Cabazitaxel 9 mg/kg

Docetaxel 9 mg/kg

P value

Cabazitaxel 14.5 mg/kg

Docetaxel 14.8 mg/kg

P value

18

307 (35 6) n=6

236 5 (125.3) n=6

0.4525

164 (30.4) o=6

218(64.5)0=6

0.0294

138 5(34 8) o=6

202 (98 6) o=6

00891

217.5 (87.5) n=6

168.5 (87.5) n=6

0 9728

19

433.5 (232) n=6

477(157.9) n=6

0 5377

203 (80.1) r>=6

289 (57.1)0=6

0 0086

139 5(48 2) n=6

202 (71 9) o=6

00167

146(138 6) n=6

195(83) n=6

0 6549

20

601 (114 2) n=6

475 (198.7) n=6

0 5365

302 5 (220.2) 0=6

409 5(109 7) o=6

00993

215 5(88.2) 0=6

325 (181.6) o=6

0 0495

359 (285 4) n=6

247 (126) n=6

0 8251

22

418(258) n=6

495 5 (278.5) n=6

0 5872

192.5(196.4) o=6

405.5 (226 8) 0=6

0.1388

129 5(45 2) 0=8

290 5(1394) o=6

0 0672

272(180.1) n=8

172 (64 5) n=6

0.7155

25

280 (168.3) n=8

621.5 (318) n=6

0.1899

22(147.5) n=6

-30 5 (68.2) 0=6

0 9608

78 5(174.9) o=8

115 5(120 8) o=6

0 5782

86 5(318) n=6

154 5(54.9) n=6

0.4871

27

229 (78 6) n=6

736 (288 4) n=6

<0001

0(1305) n=6

-73 (51.1) 0=6

04408

82.5(102.3) o=6

-50 5 (80) o=8

0 8153

-13 5(281) n=6

13(67.5) n=6

0 7016

29

356 5 (362 5) n=6

905.5 (41.5) 0=6

0 0022

106(147.5) 0=6

-47 (89.7) 0=6

0 6123

62.5 (91.9) 0=6

119 5(164 6) o=8

0.1300

-107(150 5) n=6

87(100 8) n=6

0 0712

33

-85(117.1) o=6

67 (262-4) n=8

0 0469

•129(142.3) 0=6

272 (328 9) o=6

0 0002

•180(68) n=6

17(1112) n=6

<0001

35

-120(986) n=8

129(281.7) 0=8

00030

-180 (94 9) 0=6

253 5(210 5) o=6

<0001

194(74.1) n=6

-80 (63 8) n=6

00034

39

-139 (113.4) n=6

454 5 (348.4) o=6

<0001

•189 5(66.7) o=6

676(4996) n=8

<0001

-194(74.1) n=6

-112(57,8) n=6

0 0275

41

-157(113.4) o=6

712 (361 B) n=6

<.0001

-189 5 (86 η o=6

904.5 (636) n=6

<0001

-194(74.1) n=6

-96(786) n=6

0 0264

43

•104 5(114 2) o=6

1039 5 (526 3) 0=6

<.0001

-189 5(68.7) o=6

909 (523 4) o=6

<0001

-194(74,1) n=8

-72 5 (146) n=6

00191

48

-194(74.1)

18.5 (270 6)

00048

n=6

50

-194(74.1)

485 (487.8)

<0001

n=6

p-value: obtained with a contrast analysis to compare the compounds atthe same tested dose aftw2-wayAncva-Type on tumor volume changes from baseline on the two corresponding groups

Upon comparison between cabazitaxel and docetaxel treatment at the équivalent doses, a significant différence was observed with regards to improved antitumor activity for cabazitaxel.

• At 14.5 mg/kg per injection a significant différence was observed between docetaxel and cabazitaxel from day 33 to day 50.

• At 9.0 mg/kg per injection a significant différence was observed on days 19, 20 and from day 33 to 43.

io · At 5.6 mg/kg per injection a significant différence was observed on days 18, and from day 33 to 43.

At 3.5 mg/kg per injection a significant différence was observed on days 27 and 29 (Table 3; p <0.05).

is Tumor régressions were seen in 3 cabazitaxel groups 14.5 mg/kg per injection (6/6 CR), 9 mg/kg per injection (6/6 CR), and 5.6 mg/kg per injection (2/6 CR, 5/6 PR), and TFS (Tumor Free Survivors) on day 120 were only obtained post treatment with cabazitaxel at 14.5 mg/kg per injection (6/6), and at 9 mg/kg per Injection (5/6).

In comparison, 3/6 mice displayed CR and 5/6 PR at 14.5 mg/kg per injection

2o of docetaxel without TFS, docetaxel achieving only PR at 9 (2/6) and 5.6 mg/kg per

Injection (4/6) (Table 1 and Figure 2).

In conclusion, cabazitaxel is more active than docetaxel against the human pédiatrie tumor, rhabdomyosarcome RH-30.

2s Cabazitaxel achieves 100% CR at 2 dose levels, leading to TFS, tumor régressions being also observed at the third dose level.

In comparison, docetaxel only induces CR at the highest dose tested.

I*

Example 2: ANTITUMOR ACTIVITY OF CABAZITAXEL AND DOCETAXEL AGAINST HUMAN EWING’S SARCOMA TC-71 IN SCID FEMALE MICE.

$ In this example, the better antitumor activity of cabazitaxel as compared to docetaxel for tumor growth Inhibition was demonstrated in vivo.

The selected tumor model was a human Ewing's sarcoma TC-71, xenografted in SCID mice [Whang-Peng J, et al. Cancer Genet Cytogenet 1986 Apr io 1;21 (3):185208].

Cabazitaxel and docetaxel were weighed for each treatment and dissoived in éthanol. Treatment solutions were prepared first by mixing 1 volume of ethanolic stock solution and 1 volume of polysorbate 80, then by adding 18 volumes of is glucose 5% in water.

Cabazitaxel and docetaxel were administered Intravenously on days 12 and 16 after tumor implantation.

The results of the experiments are reported In Tables 4, 5 & 6 and in Figures 3 20 &4.

The Td in days was estimated from the plot of the log linear growth of the control group tumors in exponentiel growth (100 to 1,000 mm³ range) and the number of tumor régressions observed after therapy. Tumor doubling time was 2.5 2$ days.

The following end points were used:

- Toxicity was declared at dosages inducing 2 20% body weight loss or s 10 % drug death

3o - Relative tumor growth Inhibition was determined on day 21 post tumor implantation when the médian tumor size in the control group was 1588.5 mm³.

- Antitumor efficacy was determined by calculating the ΔΤ/AC value in percent, according to the above-mentioned formula;

- Tumor régressions (as explained above);

- Statistical analysis performed (as explained above).

Table4 Evaluation ofthe efficacy of cabazitaxel and docetaxel In SCID female mice bearing human Ewing’s sarcoma TC-71.

Agent	Route/ Dosage In mL/kg per Injection	Dosage in mgfeg per injection (total dose)	SdwdA in days	Drug death	Average body weight change inSpermouse at nadir (day of nadir)	ΔΤ/Δ0 in % (day 21)	Regnesebre Partial Complété	Timor iee suVwn et ttey120	Pvdue (Dey 21?	1 1 ni » a f ilIMT 1
		14 5 (29)		on	-9 0 (23)	<0	7/7	7/7	on	ρ<ο.οαοι	Hÿ^Acfce
		9 0(18)		0/7	-7.0(18)	<0	7/7	6/7	on	pO.0001	Hÿ^Acfce
CABAZITAXEL	IV (16)	1Z16						po.0001	Hÿ^Acfce
	5 8(11.2)	On	-7.0(18)	<0	6/7	on	on
		3 5 (7.0)		on	-2.3 (21)	27	on	on	on	p=Q0047	Acfce
		14 5 (29)		on	-12 4(23)	<0	on	2n	1/7	p<10001	Hÿ^AtAe
		90(18)		on	-10 8(23)	<0	2n	on	on	ρΟΌΟΟΙ	Hÿ^AtAe
DOCETAXEL	IV (18)	12; 16							Acfce
	5 6(11.2)	on	-13.7(22)	31	on	on	on	p=OCMOO
		3.5 (7.0)		on	-1.8(13)	77	on	on	on	frt9778	Inadve
Control	-	-	-	0/10	-0 8(13)	-	0/10	0/10	0/10
Tumor doubling time ³ 2 5 days. Tumor size at start of therapy was 126 - 294 mm*. with a médian tumor burden per group of 172 -	198 mm*.
Mice average weight Due to body weight heterogeneity (range: docetaxel · 19 70 -	24.15 g; cabazitaxel “	19 25 - 25 07 g) dosages were adjusted to individual
body weight
Abbreviations used ΔΤ/ΔΟ³	ratio of médian tumor volume changes from baseline between treated and control groups.
a) Statistlcal analysis: p-value obtained with a contrast analysis versus control with Bonferroni+folm adjustmentfor multiplicrty after Anova-Type on tumor volume
changes from baseline.

The médian tumor burden at start of therapy was 172 to 198 mm³.

Cabazitaxel and docetaxel were administered as single agents by IV tail vein injection on day 12 and day 16 post tumor at the following doses, 14.5, 9, 5.6 and s 3.5 mg/kg per injection (Table 4).

Cabazitaxel and docetaxel were well tolerated with a maximum 9% bwl on day 23 for cabazitaxel and 13.7% bwl on day 22 for docetaxel (Table 4 and Figure 3).

io Cabazitaxel and docetaxel were both highly active, ΔΤ/AC < 0% on day 21 (p<0.0001) at 14.5, 9.0 and 5.6 mg/kg per injection for cabazitaxel and at 14.5 and 9.0 mg/kg per injection for docetaxel.

Cabazitaxel at 3.5mg/kg per injection was considered active (ΔΤ/AC = 27% on day 21, p=0.0047), while docetaxel at 5.6 mg/kg per injection was considered active iî (ΔΤ/Δϋ = 31% on day 21, p=0.0400), but inactive at 3.5 mg/kg per injection,

ΔΤ/Δ0 > 40% on day 21, NS (Table 4).

Table 5 Antitumor activity of cabazitaxel and docetaxel against human Ewlng's sarcoma TC-71 bearing SCID mice: Comparison of each agent versus control group.

Tumor volume changes from baseline:

Médian (nMad) and Anova-Type followed by a contrast analysis versus control on tumor volume changes from baseline

Group	Global	14	Day 16	19	21
Control	•	157 (86) η·10	399(205.3) n«10	917.5 (396 6) n»10	1354.5 (5834) r>’10
Cabazitaxel 14.5 mg/kg	-	36 (53 4) π·7	32 (47.4) n»7	-140 (44.5) η·7	-166(32 6) n»7
	p <0001	p-0 0029	p<0001	p<0001	p<0001
Cabazitaxel 9 mg/kg	-	54(43) π·7	52 (91 9) n»7	-105 (28.7) n»7	-166 (57.8) n*7
	p<0001	p=0 012	p<0001	p<0001	p<.0001
Cabazitaxel 5.6 mg/kg	-	88(29 7) n«7	150(80.1) n«7	-16 (46) n»7	-81 (282) n^a7
	p<.0001	p*0.2155	p-00004	p< 0001	p<.0001
Cabazitaxel 3.S mg/kg	-	78 (43) n«7	194 (32 6) n«7	355(112.7) n’7	369 (93 4) n=7
	p=0 0229	p=0.1702	p-0.0676	p-0 2377	p=0 0047
Docetaxel 14.5 mg/kg	-	96(86) n«7	154(1408) n»7	-72(115 6) n«7	-130(112 7) n»7
	p<.0001	p*0.2155	p< 0001	p<0001	p<0001
Docetaxel 9 mg/kg	-	108(19 3) η·7	222(29 7) η·7	139(1515) η·7	-36(1186) 0’7
	p<0001	p-0.4719	p>0 0393	p<0001	pc.0001
Docetaxel 5.6 mg/kg	-	116(4 4) η·7	268(178) η·7	371 (150.5) n=6	415(146 6) n=6
	p=0 2527	p-06391	p-0.7707	p=0 3631	p«0 0400
Docetaxel 3.6 mg/kg	-	101 (26.7) n’7	320 (904) n«7	629 (200 2) n=7	1044(243.1) H’7
	p=0 6691	p-0 6391	p=0 8453	p=0 864	p=0 9778

p-value: obtained with a contrast analysis versus control with Bonferronl-Holm adjustment for multiplicrty after Anova-Type on tumor volume changes from baseline

The effect of cabazitaxel was significant in comparison with control from days s 14 to 21 at 14.5 and 9.0 mg/kg per injection, for days 16,19 and 21 at 5.6 mg/kg per

Injection, and on day 21 at 3.5 mg/kg per injection (Table 5 and Figure 4).

In this study, docetaxel had a significant effect in comparison with control on days 16, 19 and 21 at 14.5 and 9 mg/kg per injection (global p values of p<0.0001; Table 5 and Figure 4).

îo A significant effect was also seen on day 21 for docetaxel at 5.6 mg/kg per injection (p=0.04). Docetaxel at 3.5 mg/kg per injection had no significant effect on tumor volume changes as compared to the control group (Table 5 and Figure 4).

Table 6 Antitumor activity of cabazitaxel and docetaxel against human Ewlng's sarcoma TC-71 bearing SCID mice: Comparison of the agents at the same dose.

Day

Cabazitaxel 3.5 mg/kg

Docetaxel 3.5 mg/kg

P valu·

Cabazitaxel 5.8 mg/kg

Docetaxel 5.6 mg/kg

P value

Cabazitaxel 9 mg/kg

Docetaxel 9 mg/kg

P value

Cabazitaxel 14.5 mg/kg

Docetaxel 14.5 mg/kg

P value

14

78 (43) n*7

101 (26 7) n*7

01681

88(29.7) o=7

118(4 4) n»7

0.2209

54(43) n»7

108(19 3) n«7

0 0755

36(53 4) n*7

96(86) n*7

0.3339

16

194(32 6) n-7

320(904) n*7

<.000t

150(80.1) η·7

268(17 8) n=7

0 0096

52(91.9) n*7

222(29 7) n-7

0.0006

32 (47.4) o=7

154(140 8) n*7

0 0404

1«

355(112.7) o»7

629 (200 2) o*7

0 0031

-18(46) n*7

371 (150 5) n=6

<.0001

-105(267) n-7

139(151.2) n=7

<0001

-140 (44.5) n-7

-72(1156) o«7

0.1164

21

369 (93 4) n=7

1044(243.1) n=7

<.0001

-81 (28,2) n*7

416(148 8) n=6

<0001

-166 (57.8) n=7

-36(118 6) n*7

0 0019

-166 (32 6) o=7

-130(112.7) n-7

0 2719

26

-182(652) n*7

1022.5(493) n=6

<.0001

-196(51 9) n*7

158(173 5) n=7

<0001

-184 (43) o=7

-130(80-1) o*7

0.1633

26

-196(50.4) n*7

243 (244 6) 0*7

<.0001

-194(47.4) n*7

-144(56.3) 0-7

0 0608

30

-196(50.4) n=7

406 (252) 0=7

<.0001

-198 (53 4) n*7

-126(801) n*7

00112

34

-196(72.8) n=7

867(209) 0=5

<.0001

-198 (53 4) n=7

-49 (260 9) n*7

0 0048

36

-180(53 4) n=7

75 (330.6) n-7

0.0055

40

-180(53 4) 0=7

763 (775 4) o*7

0 0259

p-value: obtained with a contrast analysis to compare the compounds et the same tested dose after 2-way Anova-Type on tumor volume changes from baseline on the two corresponding groups

Upon comparison between cabazitaxel and docetaxel at équivalent doses, a significant différence was observed with regards to improved antitumor activity for cabazitaxel.

· At 14.5 mg/kg per injection, a significant différence was observed between cabazitaxel and docetaxel on day 16, and from day 30 to day 40.

• At 9.0 mg/kg per Injection, a significant différence was observed from day 16 to 34.

• At 5.6 mg/kg per injection, a significant différence was observed from day 16 to 26.

• At 3.5 mg/kg per injection, a significant différence was observed from days 16 to 21 io (Table 6; p<0.05).

Tumor régressions and TFS were observed at the 2 highest doses of cabazitaxel, 14.5mg/kg per injection (7/7 CR, 6/7 TFS) and 9 mg/kg per injection (6/7 CR, 7/7 PR, 6/7 TFS), 6/7 PR being achieved at 5.6 mg/kg per injection.

In comparison, CR and TFS were only obtained at the highest dose of docetaxel, 14.5 mg/kg per injection (2/7 CR, 6/7 PR, 1/7 TFS), 5/7 PR being observed at 9 mg/kg per injection (Table 4 and Figure 4).

In conclusion, cabazitaxel is also more active than docetaxel against this second human pédiatrie tumor, Ewing’s sarcoma TC-71.

Cabazitaxel achieves 6/7 TFS at 2 dose Ievels, 6/7 PR being also observed at the third dose level. In comparison, docetaxel only induces CR at the highest dose 25 tested.

Example 3: ANTITUMOR ACTIVITY OF CABAZITAXEL AND DOCETAXEL AGAINST HUMAN EWING’S SARCOMA SK-ES-1 IN SCID FEMALE MICE.

In this example, the better antitumor activity of cabazitaxel as compared to docetaxel for tumor growth inhibition was demonstrated in vivo.

The selected tumor model was a human Ewing’s sarcoma SK-ES-1, xenografted in SCID mice [Fogh J. New York: Plénum Press, 1975].

Cabazitaxel and docetaxel were weighed for each treatment and dissolved in éthanol. Treatment solutions were prepared first by mixing 1 volume of ethanolic stock solution and 1 volume of polysorbate 80, then by adding 18 volumes of glucose 5% in water.

î Cabazitaxel and docetaxel were administered intravenously on days 15 and after tumor implantation.

The results of the experiments are reported in Tables 7, 8 & 9 and in Figures 5 & 6.

The Td in days was estimated from the plot of the log linear growth of the control group tumors in exponential growth (100 to 1,000 mm³ range) and the number of tumor régressions observed after therapy.

Tumor doubling time was 6.1 days.

The following end points hâve been used:

- Toxicity was declared at dosages inducing £ 20% body weight loss or 10 % drug death;

- Relative tumor growth inhibition was determined on day 22 post tumor implantation when the médian tumor size in the control group was 456 mm³;

-Tumor régressions (as explained above);

- Statistical analysis performed (as explained above).

I

Table 7 Evaluation of the efficacy of cabazitaxel and docetaxel in SCID female mice bearing a model of human Ewing's sarcoma SK-ES-1.

Agent	Route/ Dosage In mL/kgper injection	Dosage in mg/kg per injection (total dose)	SdncMa in days	Drug death	Average body weight change in % per mouse at nadir (day of nadir)	ΔΤ/Δ0 ln% (day 22)	Regimbe	Tuncrtee auiAm et day120	Pwtue (Day22T	Btfcgfcai Hvpotofcn
Partial	Complété
		14.5(29)		017	-7.1 (20)	<0	7/7	on	zn	p<ocœi	H^AAe
		9 0(18)	15;19	0/7	-6 3. (16)	<0	7/7	on	on	p<ocœi	Hÿ^AAe
CABAZITAXEL	IV (16)							H^fyAAe
	5 6(11.2)		0/7	-4 2(16)	<0	7/7	on	on	ρΌΌΟΟΙ
		3.5(7 0)		On	-4 4 (16)	22	on	on	on	p=Q0422	Adhe
		14 5(29)		on	-105(27)	<0	7/7	zn	on	ρΌΌΟΟΙ	Hÿ^AAe
		90(18)	15; 19	on	-6 8(23)	<0	on	on	on	ρΟΌΟΟΙ	Hÿ^AAe
DOCETAXEL	IV (16)
	5 6(11.2)		on	-5 4(16)	<0	1/7	on	on	p=ooooi	Hj^AAe
		3.5 (7 0)		on	-2.1 (16)	72	on	on	on	p=C.0J78	hacfive
Control	-	-	•	0/10	-14(16)	-	0/10	0/10	0/10

Tumor doubling time * β 1 days. Tumor size at start of therapy was 126-384mm*, with a médian tumor burden per group of 221-245mm*.

Mœe average weight Due to body weight heterogeneity (range: DOCETAXEL» 19 09 · 26 69g; CAZABITAXEL »19.13 - 25.19g) dosages were adjusted to individual body weight

Abbreviatfons used ΔΤ/Δ0» ratio of médian tumor volume changes from baseline between treated and control groups.

a) Statlstical analysis' p-value obtained with a cootrast analysis versus control with Bonferroni-Holm adjustment for muftiplicity after Anova-Type on tumor volume changes from baseline.

f/ <

The médian tumor burden at start of therapy was 221 to 245 mm³. Cabazitaxel and docetaxel were administered as single agents by IV tail vein injection on day 15 and day 19 post tumor at the following doses, 14.5, 9.0, 5.6 and 3.5 mg/kg per injection (Table 7).

Cabazitaxel and docetaxel were well tolerated with a maximum 7.1% bwl on day 20 for cabazitaxel and 10.5% bwl on day 27 for docetaxel (Table 7 and Figure

5).

io Cabazitaxel and docetaxel were both highly active at 14.5, 9.0 and 5.6 mg/kg per injection, ΔΤ/AC < 0% on day 22 (p<0.0001 for ail doses).

Cabazitaxel at 3.5mg/kg per injection was considered active (AT/AC =22 % on day 22, p=0.0422), while docetaxel at 3.5 mg/kg per injection was inactive, AT/AC > 40 % on day 22, NS (Table 7).

Table 8 Antitumor activity of cabazitaxel and docetaxel against human Ewlng’s sarcoma SK-ES-1 bearlng SCID mice: Comparison of each agent versus control group.

Tumor volume changes from baseline:

Group	Global	19	Day 22	25	28
Control	-	32(81.5) n=10	188.5 (149) n*10	341.5 (123.1) n*10	648.5 (196.4) n®10
Cabazitaxel 14.5 mg/kg	•	•108(91 9) n»7	-203 (87.5) n=7	-221 (81.5) η·7	•221 (81.5) n*7
	p<.0001	p=0.0053	p<.0001	p«.0001	p<.0001
Cabazitaxel fl mg/kg	-	25(37.1) n=7	-137 (50 8) n®7	-227 (100 8) n»7	-227 (100 8) n«7
	p<0001	p=1.0000	p< 0001	p< 0001	p< 0001
Cabazitaxel 5.5 mg/kg	-	-31 (87.5) η·7	•126 (86) n«7	-157 (81.5) n»7	-157(81-5) η·7
	p<0001	p-07871	p<0001	p<0001	p<0001
Cabazitaxel 3.5 mg/kg	•	32 (207.6) n“7	41 (1082) n“7	180(100.8) n«7	499 (324.7) n^a7
	p=0 6074	pM 0000	p-0.0422	p>0 5810	p*0 9384
Docetaxel 14.5 mg/kg	•	-18(77.1) n*7	-156 (56.3) η·7	-173(69 7) η·7	-164 (56 3) n»7
	p<0001	pO 5639	p< 0001	p<.0001	p<,0001
Docetaxel 9 mg/kg	-	0(37.1) n=7	•101 (62.3) n»7	-126 (32 6) n*7	-126(46) n*7
	p<.0001	p-1.0000	p<.0001	p<0001	p<0001
Docetaxel 5.6 mg/kg	•	0(106 7) n=7	-36 (60.8) n=7	168(80.1) n»7	342 (89) n«7
	p-0 0194	pal 0000	p=0 0001	paO 0359	p»0.1047
Docetaxel 3.5 mg/kg	-	52(89) n=7	136(266.9) n»7	712(29 7) n=*7	900(373 6) n»7
	p-0,7742	p-1 0000	p=O 0978	p-0 5810	p-0.9384

p-value: obtained with a contrast analysis versus control with Bonferroni-Holm adjustment for multipllcity after Anova-Type on tumor volume changes from baseline

The effect of cabazitaxel was significant in comparison with control from days 19 to 28 at 14.5 mg/kg per injection, on days 22 to 28 at 9.0 and 5.6 mg/kg per injection. Global p values were p<0.0001 for each dose.

A significant effect was also seen on day 22 only for cabazitaxel at 3.5mg/kg per injection (p=0.0422) (Table 8 and Figure 6).

In this study, docetaxel had a significant effect in comparison with control on io days 22 to 28 at 14.5 and 9 mg/kg per injection and on day 22 and 25 at 5.6 mg/kg per injection. Global p values were p<0.0001, p<0.001 & p=0.0194 respective for each dose (Table 8 and Figure 6).

Docetaxel at 3.5 mg/kg per injection had no significant effect on tumor volume changes as compared to the control group.

is

Table 9 Antltumor activlty of cabazitaxel and docetaxel against human Ewlng’s sarcoma SK-ES-1 bearing SCID mlceî Comparison of the agents at the same dose.

Tumor volume changes from baseline:

Médian (nMad) and Anova-Type foilowed by a contrast analysis on tumor volume changes from baseline

Day

Cabazitaxel 3.5 mg/kg

Docetaxel 3.5 mg/kg

P value

Cabazitaxel 5.6 mg/kg

Docetaxel 5-8 mg/kg

P value

Cabazitaxel 9 mg/kg

Docetaxel 9 mg/kg

P value

Cabazitaxel 14.5 mg/kg

Docetaxel 14.5 mg/kg

P value

19

32 (207,6) n»7

52 (89) n-7

0 7323

-31 (87 5) n’7

0(106.7) n-7

0 3683

25 (37.1) n-7

0 (37.1) n-7

0 5214

-108(91 9) n-7

-18 (77.1) n-7

04035

22

41 (108.2) n-7

136(266 9) n«7

0.3594

-126 (86) n’7

-36 (60 8) n»7

0 0466

-137(80 8) n»7

-101 (62.3) n’7

0.1647

-203 (87.5) n-7

-156(563) n«7

02939

25

180 (100 8) n«7

712 (29 η n*7

0 0057

-157 (81.5) n*7

168 (80.1) n»7

<.0001

-227(100 8) n»7

-126 (32.6) n=7

00031

-221 (81.5) n»7

-173(69.7) n-7

0 6869

28

499 (324,7) η·7

900 (373 6) n«7

0.1065

-157(81.5) n-7

342 (89) n-7

<.0001

-227 (100 8) n-7

-126 (46) n-7

00005

-221 (81.5) n-7

-164(563) n-7

06382

32

-128 (112 η n»7

480 (204 6) n-7

<.0001

-231 (78 6) n’7

-49 (100.8) n=7

<.0001

-221 (87,5) n«7

-162 (60 8) n-7

0.25

35

-157 (1127) n»7

2005 (1055 6) n-7

<.0001

-231 (78 6) n-7

201 (256 5) n=7

<0001

-221 (87.5) n»7

-162 (60 8) n-7

0.257

39

-221 (108.2) n-7

290 (468 5) n»7

00002

41

-221 (140 8) π·7

274 (299 5) n-6

0 0011

43

-221 (140 8) n-7

427.5 (428 5) n=6

0.0002

45

-144 (222 4) n-7

574(566 4) n-5

0 0014

p-value: obtained with a contrast analysis to compare the compounds at the same tested dose after 2-way Anova-Type on tumor volume changes from baseline on the two corresponding groupa

s · At 14.5 mg/kg per injection, a significant différence was observed between docetaxel and cabazitaxel from day 39 to day 45.

• At 9.0 mg/kg per injection, a significant différence was observed from day 25 to 35.

• At 5.6 mg/kg per injection, a significant différence was observed from day 22 to 35.

• At 3.5 mg/kg per injection, a significant différence was observed on day 25 only io (Table 9; p<0.05).

CR and TFS were observed at the highest dose of cabazitaxel, 14.5 mg/kg per injection (6/7 CR, 7/7 PR, 3/7 TFS), 100 % PR being achieved at 9 and 5.6 mg/kg per injection.

In comparison only 3/7 mice displayed CR at 14.5 mg/kg per injection of docetaxel, with 7/7 PR and no TFS on day 120. At 9 and 5.6 mg/kg per injection, docetaxel induced 6/7 and 1/7 PR, respecttvely (Table 7 and Figure 6).

In conclusion, cabazitaxel is more also active than docetaxel against this third 2o human pédiatrie tumor, Ewing’s sarcoma SK-ES-1.

Cabazitaxel achieves 100% PR at a 3 dose levels, with 6/7 CR leading to 3/7 TFS at the highest doses tested. In comparison, docetaxel induced 3/7 CR at the highest dose tested and no TFS.

Example 4: ANTITUMOR ACTMTY OF CABAZITAXEL AND DOCETAXEL AGAINST HUMAN OSTEOSARCOMA DM77 IN NUDE FEMALE MICE.

The selected tumor model, DM77, was a low passage patient-derived tumor xenograft derived from an osteosarcoma taken from the lung of a 19 year old male patient.

io The results of the experiments are reported below in Tables 10, 11 & 12 and in Figure 7.

The tumor doubling time (in days; Td) was 6.6 days.

is The following end points were used:

- Toxicity was declared at dosages inducing 2 20% body weight loss or 2 10 % drug death;

- Antitumor efficacy was determined by calculating the AT/AC value in percent on day 21 post treatment initiation, according to the above mentioned formula;

- Individual tumor volume changes from baseline were analyzed by a non-parametric two-way ANOVA-TYPE (with factors: group and repeated day from 3 to 21) followed by a post-hoc contraste analysis, with Bonferroni-Holm adjustment for multiplicity, comparing ail treated groups to the control group on day 21.

Additionally, a non parametric two-way ANOVA-TYPE (with factors: treated group 25 and repeated day from 3 to 56) was performed and followed by a contrast analysis, with Bonferroni-Holm adjustment for multiplicity, to compare at each day the effects of docetaxel and cabazitaxel when administered at the same dose or at equi-toxic doses.

- At study completion, tumor growth delay (T-C) in days is calculated using the médian time to endpoint (MTTE) value for each treatment (T) group versus control (C). The volume endpoint for T-C calculations was chosen to be 1400 mm³. A Log Rank multiple comparison test with Bonferroni-Holm adjustment for multiplicity was applied on individual TTE to compare the treated groups to the control group.

- Tumor régressions (as explained above).

“ 17078

Résulte:

Cabazitaxel and docetaxel demonstrate anti-tumor effects compared to the control (Figure 7 and Table 11). At day 21, a ΔΤ/AC of 14.1% or 18.5% was s reported for animais treated with 5.8 mg/kg of cabazitaxel or docetaxel, respectively and 0% or 9.6% ΔΤ/AC was reported for animais treated with 9.3 mg/kg of cabazitaxel or docetaxel, respectively. Animais dosed with 15 or 24.2 mg/kg had a ΔΤ/AC lower than 0% for both test agents.

Comparison of tumor volume changes demonstrated that cabazitaxel at 9.3 io mg/kg was more effîcacious than docetaxel from day 25 to day 56 (Table 12).

Similar results are observed when comparing the numbers of PR between treatment groups at 9.3 mg/kg (2/9 versus 0/9 PR, respectively) (Table 11).

Using weight loss as a gross indicator of toxicity, docetaxel appears to more toxic than cabazitaxel (Table 10). Docetaxel at 24.2 mg/kg was inducing an is excessive body weight loss of 17% on day 14. At 15 mg/kg, docetaxel is inducing

14% body weight loss on day 11, which is comparable to the 15% body weight loss observed for cabazitaxel at 24.2 mg/kg on day 14. Alternative analysis, adjusting for the higher level of toxicity was performed (Table 12). The tumor volume changes from baseline for docetaxel at 5.8, 9.3, or 15 mg/kg were compared along time to 2o cabazitaxel at 9.3, 15, or 24.2 mg/kg, respectively. Docetaxel was significantly different from cabazitaxel: 5.8 mg/kg docetaxel to 9.3 mg/kg cabazitaxel (from day 18) and 9.3 mg/kg docetaxel to 15 mg/kg cabazitaxel (from day 11). The comparison of tumor volume changes did not show any significant différences at the highest dosages, the study being terminated before the regrowth ofthe tumors.

2S

Table 10 - Cabazltaxel and docetaxel toxicity In nude mice bearing DM77 ostéosarcome

Treatment	Dose (mg/kg)	Route/Schedule	Weight Change at Nadir	Drug Deaths
%	Day	Total	Day (#)
Control	—	i.v./ q4dx3	—	—	—	—
Cabazitaxe!	5.8	i.v./ q4dx3	-5%	11	0	—
	9.3	i.v./q4dx3	-8%	11	0	—
	15	i.v./ q4dx3	-9%	11	0	—
	24.2	i.v./ q4dx3	-15%	14	0	—
Docetaxel	5.8	i.v,/ q4dx3	-6%	11	0	—
	9.3	i.v./ q4dx3	-7%	14	0	—
	15	i.v./ q4dx3	-14%	11	0	—
	24.2	i.v./ q4dx3	-17%	14	0	—

Ta_ble_11 - Cabazitaxel and docetaxel antitumor activity in nude mice bearlng DM77 osteosarcoma

Treatment	Dose (mg/kg)	Route/Schedule	Tumor Volume Data (Day 21)	~ MTTE (days)	pvalue*·	T-C (days)	n	#PR/CR/TFS
Médian (mm³)	ΔΤ/AC %	pvalue*
Controî	—	i.v./ q4dx3	1102.5			25	-	—	10	-
Cabazitaxel	58	I.v./ q4dx3	333	14.1	p=0.0006	49	p=0.0132	24	9	0/0/0
	9.3	I.v./ q4dx3	131	0	p<0.0001	>60	p<.0001	>35	9	2/0/0
	15	i.v./ q4dx3	78	-9.3	p<0.0001	>60	p<0001	>35	9	6/0/0
	24.2	i.v./ q4dx3	101.5	-6.9	p<0.0001	>60	p<.0001	>35	10	5/1/1
Docetaxel	5.8	i.v./ q4dx3	300	18.5	p=0.0056	53	p=0.0023	28	9	0/0/0
	9.3	i.v./ q4dx3	266	96	p<0.0001	>60	p=0.0014	>35	9	0/0/0
	15	Lv./q4dx3	78	-5.9	p<0.0001	>60	p<.0001	>35	9	3/0/0
	24.2	i.v./ q4dx3	71.5	-6.1	p<0.0001	>60	p<.0001	>35	10	6/1/1

·: Contraste analysis versus control with Bonferroni-Holm adjustment for multiplicity following a non parametric two-way Anova-Type on tumor volume changes from baseline ·*: Log-Rank multiple compensons test versus controi on individuals time to event

«i

Table 12 - Comparison of the tumor volumes of the groups treated with cabazitaxel and docetaxel at the same dose and at equl-toxic doses ln nude mice bearlng DM77 osteosarcoma

Médian ♦/· nMAO (number of subject) and pvalue*
	Cabazitaxel 3.8 mg/kg	Cabazitaxel 9 J mg/kg	Cabazitaxel IB mg/kg	Cabazitaxel 24.2 mg/kg	Docetaxel 5.B mg/kg	Docetaxel 9 J mg/kg	Docetaxel 15 mg/kg	Docetaxel 24.2 mg/kg
DAY 4	47 +/- 47 (n-9)	54+/-54 (n-9)	0 +/- 0 (n-9)	22+/-22 (n-10)	47+/-47 (n-9)	57+/-40 (n-9)	66+/-66 (n=9)	0+/-0 (n-10)
Comparison versus	Docetaxel SB mg/kg	Docetaxel B 3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p-1 0000	p-1 0000	p-1 0000	p-1 0000	p-1 0000	p-1 0000	p-1 0000
DAY 7	121 +/-80 (n-9)	73 ♦/- 73 (n-9)	0 */- 25 (n-9)	0+/-9 5 (n-10)	73+/-23 (n-9)	87+/-42 (n-9)	73+/-73 (n-9)	0+/-0 (n-10)
Comparison versus	Docetaxel 5 B mg/kg	Docetaxel 91 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p-1 0000	p-1 0000	p-1 0000	p-1 0000	p-1 0000	p-0 5271	p-1 0000
DAY 11	102 */-89 (n-9)	19+/-35 (n-9)	-53 *A 19 (n-9)	-26 5 +/26 5 (n-10)	122+/-56 (n-9)	96+/-77 (n-9)	-41 +/-41 (n-9)	-50 +/- 24 (n-10)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 9 3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p=1 0000	p-1 0000	p-1 0000	p-1 0000	p=1 0000	p-0.0008	p-1 0000
DAY 14	182 ♦/- 97 (0=9)	19+/-35 (n-9)	-53+/-27 (n-9)	-29 5 ♦/- 29 5 (n-10)	129+/-83 (n-9)	96 */- 89 (n-9)	-41 +/-41 (n-9)	-55 5 +/- 20 (n-10)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 9 3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p=1 0000	p-1 0000	p-1 0000	p-1 0000	p=1 0000	p<0.0001	p=1 0000
DAY IB	195 +/-122 (n-9)	0 */- 33 (n-9)	-73 +/- 20 (n-9)	•81 5 */- 27 (n-10)	189 */-118 (n-9)	96 +/- 89 (n-9)	-53 +/-17 (n-9)	-55 5 ♦/· 20 (n-10)
Comparison versus	Docetaxel 5 B mg/kg	Docetaxel 93 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p=1 0000	P-01171	p=t 0000	p=1 0000	p-0.8302	pcQ.0001	p-1 0000
DAY 31	129*/-129 (n-9)	0+/-34 (n-9)	-85 *A 13 (n-9)	-63+/-25 5 (n-10)	189+/-103 (n-9)	86+/-74 (n-9)	-54 +/-12 (n-9)	-55 5 tins (n-10)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 9 3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p-1 0000	p-01509	p-1 0000	p-1 0000	p-0.0175	P<0.0001	p-1 0000
DAY 23	96+/-115 (n-9)	-19 ♦/- 26 (n-9)	-85+/-13 (n-9)	-69 5 */· 24 5 (n-10)	217 ♦/-151 (n=9)	124+/-93 (n=9)	-66+/-17 (n-9)	-55 5 tins (n-10)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 0 3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p-1 0000	p-0.0028	p-1 0000	p-1 0000	p-0.0002	P<0.0001	p-1 0000
DAY 28	96+/-115 (n-9)	-45 +/- 26 (n-9)	65 ♦/-13 (n-9)	-60 +/- 28 5 (n-10)	290 +/-198 (n-9)	124 +/-171 (n-9)	·« ♦/-17 (n-9)	-53 5+/-13 (n-10)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 9 3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p-1 0000	p-0 0002	p-1 0000	p-1 0000	P<0.0061	p«0.0001	p-1 0000
DAY 12	96+/-109 (n-9)	-45 */- 26 (n-9)	•65 */-19 (n-9)	-60 */- 28 5 (n-10)	332 +/- 268 (n-9)	154+/-201 (n-9)	-66 +/-17 (n-9)	-53 5 ♦/- 33 (n-10)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 9 3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p=1 0000	pO.0001	p-1 0000	p-1 0000	pcQ.0001	p«0.0001	p-1 0000
DAY 13	t69+/-182 (n-9)	•68+A7 (n-9)	-85+/-19 (n-9)	-60+/-35 (n-10)	342 */- 250 (n-9)	169 +/- 235 (n-9)	-66 */-13 (n-9)	-57 5 ♦/- 45 5(n-10)
Comparison versus	Docetaxel 3 8 mg/kg	Docetaxel 9 3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p=1 0000	pO.0001	p=1 0000	p-1 0000	pcO.OOOl	P<O.OOO1	p-1 0000

Médian ♦/- nMAD (number of subject) and pvalue'

Cabazitaxel Cabazitaxel Cabazitaxel Cabazitaxel Docetaxel Docetaxel Docetaxel Docetaxel

	64 mg/kg	9 J mg/kg	18 mg/kg	24.2 mg/kg	6.8 mg/kg	14 mg/kg	16 mg/kg	24.2 mg/kg
DAY 39	239+/- 172 5 (n-8)	-88+/-7 (n=9)	-85+/-38 (n=9)	-80+/-35 (n-10)	342 ♦/-121 (n-9)	202 *A 268 (n=9)	-86 ♦/-13 (n=9)	-57 5+/- 45 5(n=10)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 9 3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p-1 0000	p<0.0001	p-1 0000	p-1 0000	p<0.0001	p<O.M01	p-1 0000
DAY 42	240 +/- 182 (n-8)	-68+/-7 (n>9)	-85+/-38 (n>9)	-71 +/-46 5 (n-10)	401 */1β9 5(η-β)	309 */- 375 (n-9)	-66+/- 13 (n-9)	-57.5 ♦/45 5 (n-10)
Comparison venus	Docetaxel 5 8 mg/kg	Docetaxel 9 3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p-1 0000	p<0.0001	p-1 0000	p-0 9613	p<0.0001	p<0.0001	p-1 0000
DAY 44	384 5*1- 220 (n-a)	-86+/-7 (n-9)	-85 +/- 38 (n-9)	-71 +/-48 5 (n-10)	548+/- 185 5(n-8)	309 +/- 375 (n«9)	-58+/· 11 (n-9)	-57 5 ♦/45 5 (n-10)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 9 3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p-1 0000	P<0.0001	p-1 0000	p-07558	p<0.0001	p<0.0001	p-1 0000
DAY 49	402 +/- 254 (η-β)	-66+A7 (n-9)	-85 ♦/· 38 (n-9)	•71 ♦/- 43 (n-10)	512+/· 142 (n-7)	424 5 */· 394 5 (n-8)	-58+A11 (n-9)	-46 */-45 5 (n-10)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 9 3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	P-0W89	p<0.0001	p-0 9989	p-04781	p<0.0001	p<0.0001	p-0 9989
DAY 53	706+A 518 (η-β)	-47+/-25 (n-9)	-85+/-38 (n-9)	-64 5+/- 45 5 (n-10)	657 5 ♦/- 211 5(n-8)	542+A 447 5(n-8)	-58+A11 (n-9)	-46+/-69 5 (n-10)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 9 3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p-0 7526	p<0.0001	p=0 752fl	p-0 4742	p<0.0001	p<0.0001	p-07526
DAY 5«	878 ♦/6025(n-8)	-47 +/-28 (n-9)	-85 ♦/- 38 (n-9)	-64 5*/- 46 5 (n-10)	875 5 +/- 358 5 (n-8)	493 */- 236 (n-7)	-58+/-11 (n-9)	-48 */- 89 5 (n-10)
Comparison venus	Docetaxel 5 8 mg/kg	Docetaxel 9 3 mg/kg	Docetaxel 18 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 9 3 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24 2 mg/kg
	p-0 7397	P<0.0001	p-0 7397	p-0 8100	p<0.0001	p<0.0001	p-0 7397

·. Contrasts analysis with Bonferroni-Holm adjustment for multiplictty following a two-way ANOVA-TYPE on tumor volume changes from baseline to compare, et each day. the groups treated with Cabazitaxel or Docetaxel at the same dose or at equitoxlc doses

Conclusion: Cabazitaxel and docetaxel demonstrated robust dose-dependent anti-tumor activity. Overall, dosing with 15 mg/kg and 9.3 mg/ kg of cabazitaxel Induces higher antitumor activity than docetaxel at an équivalent dose or a toxicity adjusted dose. Overall cabazitaxel is more efficacious than docetaxel at both mid doses, on a dose équivalent basis.

Example 5: ANTITUMOR ACTIVITY OF CABAZITAXEL AND DOCETAXEL AGAINST HUMAN OSTEOSARCOMA DM113 IN NUDE FEMALE MICE.

In this second example, the better antitumor activity of cabazitaxel as $ compared to docetaxel for tumor growth inhibition was demonstrated in vivo.

The selected tumor model, DM113, was a low passage patient-derived tumor xenograft derived from an osteosarcoma taken from the lung of a 3 year old female patient.

îo The results of the experiments are reported below in Tables 13, 14 & 15 and in Figure 8.

The tumor doubling time (in days; Td) was 7.9 days.

The following end points were used:

is - Toxicity was declared at dosages inducing s 20% body weight loss or £ 10 % drug death;

- Antitumor efficacy was determined by calculating the ΔΤ/ΔΟ value in percent on day 28 post treatment initiation, according to the above mentioned formula;

- Individual tumor volume changes from baseline were analyzed by a non- parametric two-way ANOVA-TYPE (with factors: group and repeated day from 3 to

28) followed by a post-hoc contrasts analysis, with Bonferroni-Holm adjustment for multiplicity, comparing ail treated groups to the control group on day 28. Additionally, a non parametric two-way ANOVA-TYPE (with factors: treated group and repeated day from 3 to 46) was performed and followed by a contrast analysis, with 25 Bonferroni-Holm adjustment for multiplicity, to compare at each day the effects of docetaxel and cabazitaxel when administered at the same doses.

- At study completion, tumor growth delay (T-C) in days is calculated using the médian time to endpoint (MTTE) value for each treatment (T) group versus control (C). The volume endpoint for T-C calculations was chosen to be 1600 mm³. A Log

3o Rank multiple comparison test with Bonferroni-Holm adjustment for multiplicity was applied on individual TTE to compare the treated groups to the control group.

- Tumor régressions (as explained above).

3«

Résulte:

Treatment with cabazitaxel and docetaxel had minor impacts for the health status of the animais though weight losses were noted at the higher doses of 24.2 (11% versus 13 %, respectively) and 15 mg/kg (9% and 8 %, respectively) (Table s 13).

Both Cabazitaxel and docetaxel demonstrate anti-tumor effects compared to the control via either tumor volume changes from baseline or T-C analysis (p<0.05 for both end-points), except at the 5.8 mg/kg dose level of docetaxel (AT/AC = 42.9%, p = 0.3938; T-C = 9 days, p = 0.1771) (Figure 8 and Table 14).

ίο As shown in Table 15, comparison of tumor volume changes from baseline at équivalent dose levels demonstrated significantly greater actîvity for cabazitaxel compared to docetaxel at 9.3 mg/kg (on days 14 to 38), 15 mg/kg (on days 11 to 46), and 24.2 mg/kg (on days 11, 24 and 31 to46).

Additionally, as reported in Table 14, when comparing the numbers of PR is between treatment groups, a greater actîvity of cabazitaxel compared to docetaxel has been observed at 15 mg/kg (4/10 PR versus 0/10 PR, respectively) and at 24.2 mg/kg (5/10 PR versus 1/10 PR, respectively).

Table 13 - Cabazitaxel and docetaxel toxlcity In nude mice bearing 20 DM113 osteosarcoma

Treatment	Dose (mg/kg)	Route/Schedule	Weight Nadir	Drug Deaths
%	Day	Total	Day (#)
Control	—	i.v./ q4dx3	-1%	3	—	—
Cabazitaxel	5.8	i.v./ q4dx3	—	—	0	—
	9.3	I.v./q4dx3	-3%	3	0	—
	15	i.v./ q4dx3	-9%	14	0	—
	24.2	i.v./ q4dx3	-11%	11	0	-
Docetaxel	5.8	i.v./ q4dx3	-2%	3	0	-
	9.3	I.v./q4dx3	-3%	17	0*	—
	15	I.v./ q4dx3	-8%	17	0	—
	24.2	i.v./ q4dx3	-13%	17	0	-

*one animal died on day 35 with no known cause of death following necropsy

Table 14 - Cabazitaxel and docetaxel antitumor activity In nude mice bearfng DM113 osteosarcoma

Treatment	Dose (mg/kg)	Tumor Volume Data	pvalue	T-C (days)	n	#PR/CR/TFS
Route/ Schedule	Médian (mm³)	(Day 28) ΔΤ/Δ0 %	pvalue*	MTTE (days)
Control	-	i.v./ q4dx3	1258			31	—	-	10	—
Cabazitaxel	5.8	i.v./ q4dx3	512.5	29.4	p=0.0442	47	p=0.0206	16	10	0/0/0
	9.3	I.v./ q4dx3	204	1.8	p<.0001	>59	p=0 0003	>28	10	0/0/0
	15	I.v./ q4dx3	131	-4.4	p<.0001	>59	p<.0001	>28	10	4/0/0
	24.2	I.v./ q4dx3	112	-3.6	p<.0001	>59	p<-0001	>28	10	5/0/0
Docetaxel	5.8	I.v./ q4dx3	598	42.9	p=0.3938	41	p=0.1771	9	10	0/0/0
	9.3	I.v./ q4dx3	442	27.4	p=0.0235	49	p=0.0206	17	9	1/0/0
	15	I.v./ q4dx3	178	3.2	p<.0001	>59	p<.0001	>28	10	0/0/0
	24.2	I.v./ q4dx3	131	0	p<.0001	>59	p<0001	>28	10	1/0/0

*: Contrasta analysis versus control with Bonferroni-Holm adjustment for muttiplicity following a non paramètre two-way Anova-Type on tumor volume changes from baseline *: Log-Rank multiple comparisons test versus control on Individuels time to averti

Table 15 · Comparison of the tumor volumes of the groups treated with cabazitaxel and docetaxel at the same equi-toxic doses In nude mlce bearlng DM113 osteosarcoma

Médian /- MAO (number of subject) and pvafue
	Cabazitaxel 8.8 mg/kg	Docetaxel 6.8 mg/kg	Cabazitaxel Docetaxel 9.3 mg/kg 9.3 mg/kg	Cabazitaxel 15 mg/kg	Docetaxel 15 mg/kg	Cabazitaxel 24.2 mg/kg	Docetaxel 24.2 mg/kg
DAY 3	58 */-21 5 (n-10)	22 5+/-22 5 (n-10)	29 5+/-27 56 5*7-26 5 (n-10) (n-10)	13 */-13 (n-10)	26+/-26 (n-10)	9 5*7-9 5 (n-10)	295*7-13 5 (n-10)
comparison	p-1 0000	p-1 0000	p-1 0000	p-1 0000
DAY 8	63 5+7-37 (n-10)	95 */- 22 5 (n-10)	29 5 */- 29 5 85 5 ♦/- 27 (n-10) (n-10)	0*7-0 (n-10)	26*7-26 (n-10)	0*7-265 (n-10)	22 5*7-22 5 (n-10)
comparison	p-0 5005	p-0 3795	p-0 5005	p-0 1597
DAY 11	«3 5 ♦/- 21 5 (n-10)	117.5*/· 45 (n-10)	29 57-29 5 737-42 5 (n-10) (n-10)	•23 5*/- 23 5 (n-10)	13 */-16 5 (n-10)	-40 5 */- 34 (n-10)	0*7-22 (n-10)
comparison	p-0 3121	p-0 3121	p-0.0058	p-0.0240
DAY 14	05 */-41 5 (n-10)	189 */-60 5 (n-10)	9 */- 9 85 5 ♦/· 34 5 (n-10) (n-10)	-40 5 *7- 30 (n-10)	13 */-18 5 (n-10)	-43 5 */· 28 5 (n-10)	-9 5 *7- 35 (n-10)
comparison	p-0 1492	p-0.0253	p-0 0011	p-0 1105
DAY 17	95 +7-59 (n-10)	242 5 ♦/- 110 (n-10)	07-0 117 57- (n-10) 51 5 (n-10)	-40 5 */- 30 (n-10)	13 */-16 5 (n-10)	-40 5 ♦/- 24 5 (n-10)	-9 5*7-26 (n-10)
comparison	p-01028	p-0.0057	p-0.0011	p-01028
DAY 21	158 5 */-39 5 (n-10)	278 5*7- 142(n-10)	07-9 140 57-52 (n-10) (n-10)	-40 5 */- 30 (n-10)	0*7-19 (n-10)	-40 5 ♦/- 24 5 (n-10)	-9 5 ♦/- 26 (n-10)
comparison	p-0 1026	p-0.0005	p-0.0129	p-01028
DAY 24	234 ♦/- 63 5 (n-10)	435*7-159 (n-10)	O /- 31 239 /- 94 5 (n-10) (n-10)	-50*7-38 5 (n-10)	22 5 ♦/- 23 5 (n-10)	-40 5 */- 40 5 (n-10)	0*7-0 (n-10)
comparison	pO.1050	p-0.0001	p-0.0018	p-0.0282
DAY 28	334 5 */- 96 (n-10)	487*7- 231 5 (n-10)	207-39 5 3117-75 5 (n-10) (n=lCf)	-50 */-38 5 (n-10)	36 5*7-355 (n-10)	-40 5 */- 40 5 (n-10)	0 *7- 9 5 (n-10)
comparison	p-0 1591	p-0.0002	p-0.0008	p-0 0704
DAY 31	459 5*/-123 (n-10)	598 */- 204 (n«9)	697-69 390 /-90 5 (n-10) (n-10)	-53 *7- 36 5 (n-10)	425 */- 29 5 (n-10)	-40 5 ♦/· 34 (n-10)	0 *7- 9 5 (n-10)
comparison	p-0 2301	p-0.0011	p-0.0004	p-0.0332
DAY 35	579 5 */-228 (n—10)	813 */-367 (n-9)	67 5 /-70 5 5457-52 (n-10) (n«9)	-59 5*7-29 (n-10)	81 *7-61 (n-10)	-51 *7-41 5 (n-10)	0*7-95 (n-10)
comparison	p-0 2378	p-0.0132	p<0.0001	p-0.0118
DAY 38	834 5 */-245 (n-10)	960 */- 388 (n-8)	1627- 6777-118 155 5 (n-10) (n=9)	-59 5 *7- 39 5(n-10)	61 *7-81 (n-10)	-51 *7-41 5 (n-10)	0 */- 9 5 (n-10)
comparison	p-0 3251	p-0.0401	p<0.0001	p-0 0089
DAY 42	1097 */-248 (n-10)	1032 */-328 (n-7)	311 7-248 627 57- (n—10) 293 5 (n-8)	-59 5 */39 5 (n-10)	107*7-90 (n-10)	-51 */- 41 5 (n-10)	0 */- 9 5 (n-10)
comparison	p-0 4213	p-0 2684	p<0.0001	p-0.0057
DAY 48	1548 5 *7- 438 5 (n-10)	1340 */- 384 (n-6)	676 ♦/- 1167 */- 317 5 (n-10) 347 5(n-8)	-59 5 ♦/- 42 5 (n-10)	155*7- 153 (n-10)	-51 *7- 41 5 (n-10)	50 5*7-47 5 (n-10)
comparison	p-0 8530	p-0 8530	[K0.0001	p<0.0001

*: Contraste analysis with Bonferroni-Holm adjustment for multiplicity following a two-way ANOVA-TYPE on tumor volume changes from baseline to compare, at each day, the groups treated with Cabazitaxel or Docetaxel at the eame dose or at equWoxic doses

4»

Conclusion: These results demonstrate that both cabazitaxel and docetaxel demonstrate robust anti-tumor activity in this model. Furthermore, cabazitaxel demonstrates higher efficacy than docetaxel at the 9.3, 15, and 24.2 mg/kg dose s levels.

Example 6: ANTITUMOR ACTIVITY OF CABAZITAXEL AND DOCETAXEL AGAINST HUMAN EWING’S SARCOMA DM101 IN NUDE FEMALE MICE.

io In this third example, the better antitumor activity of cabazitaxel as compared to docetaxel for tumor growth Inhibition was demonstrated in vivo.

The selected tumor model, DM101, was a low passage patient-derived tumor xenograft derived from an Ewing's sarcoma taken from the bone of a 17 year old male patient.

is The results of the experiments are reported below In Tables 16, 17 & 18 and in Figure 9.

The tumor doubling time (in days; Td) was 4 days.

The following end points were used:

- Toxicity was declared at dosages inducing z 20% body weight loss or z 10 % drug death;

- Antitumor efficacy was determined by calculating the ΔΤ/AC value in percent on day 11 post treatment initiation, according to the above mentioned formula;

2î - Individual tumor volume changes from baseline were analyzed by a nonparametric two-way ANOVA-TYPE (with factors: group and repeated day from 4 to 14) followed by a post-hoc contraste analysis, with Bonferroni-Holm adjustment for multiplicity, comparing ail treated groups to the control group on day 11. Additionally, a non parametric two-way ANOVA-TYPE (with factors: treated group and repeated 30 day from 4 to 32) was performed and followed by a contrast analysis, with

Bonferroni-Holm adjustment for multiplicity, to compare at each day the effects of docetaxel and cabazitaxel when administered at the same doses or at equi-toxic doses.

- At study completion, tumor growth delay (T-C) in days is calculated using the médian time to endpoint (MTTE) value for each T group versus C. The volume endpoint for T-C calculations was chosen to be 2000 mm³. A Log Rank multiple comparison test with Bonferroni-Holm adjustment for muitipiicity was applied on individual TTE to compare the treated groups to the controi group.

• Tumor régressions (as explained above).

s Results:

Both cabazitaxel and docetaxel demonstrate significant anti-tumor effects compared to the contro! via ΔΤ/Δ0 on day 11 (Figure 6 and Table 17).

Using weight loss as a gross Indicator of toxicity (Table 16), docetaxel is more toxic than cabazitaxel at 24.2 mg/kg (17% versus 5 % body weight loss).

io At équivalent dose levels, the comparison of tumor volume changes from baseline shows no significant différence between the groups treated with cabazitaxel or docetaxel at dose 5.8 and 9.3 mg/kg. However, as shown in Table 18, starting from day 7, the groups treated with cabazitaxel at the 15 or 24.2 mg/kg doses were significantly different from the groups treated with docetaxel at the same dose (15 or is 24.2 mg/kg, respectiveiy) or at the equi-toxic dose (9.3 or 15mg/kg, respectiveiy).

In addition, animais treated with 15 or 24.2 mg/kg of cabazitaxel induced more CR and TFS as compared to docetaxel (9/9 CR and 7/9 TFS for cabazitaxel versus 4/9 CR and 1/9 TFS for docetaxel at 15 mg/kg; 9/9 CR and 8/9 TFS for cabazitaxel versus 3/9 CR and 2/9 TFS for docetaxel at 24.2 mg/kg).

Table 16 - Cabazitaxel and docetaxel toxicity In nude mice bearing DM101 Ewlng's sarcome

Treatment	Dose (mg/kg)	Route/Schedule	Weight Nadir	Drug Deaths
%	Day	Total	Day (#)
Control	—	i.v./ q4dx3	-	-	-	-
Cabazitaxel	5.8	i.v./ q4dx3	-	-	0	-
	9.3	I.v./ q4dx3	-2%	7	0	-
	15	I.v./ q4dx3	-3%	7	0	—
	24.2	I.v./ q4dx3	-5%	11	0	—
Docetaxel	5.8	i.v./ q4dx3	-1%	4	0	—
	9.3	i.v./ q4dx3	-4%	7	0	-
	15	I.v./q4dx3	-6%	14	0	-
	24.2	I.v./ q4dx3	-17%	14	0	-

Table 17 - Cabazitaxel and docetaxel antitumor activity In nude mice bearing DM101 Ewlng’s sarcoma

Treatment	Dose (mg/kg)	Route/Schedule	Tumor Volume Data (Day 11) ^{ΔΤ/Δ0% pvalue}’	MTTE (days)	pvalue”	T-C (days)	n	#PR/CR/TFS
Control	—	i.v./ q4dx3	940			16.9	-	—	10	-
Cabazitaxel	5.8	i v./ q4dx3	204	8.9	p=0.0044	34.8	p=0.0576	17.9	9	0/0/0
	9.3	i.v./ q4dx3	255	9.4	p=0.0004	23.9	p=0.1185	7	9	1/1/1
	15	i.v./ q4dx3	0	-16	p<0.0001	>61	p=0.0002	>44.1	9	9/9/7
	24.2	i.v./ q4dx3	0	-18.3	p<0.0001	>61	p<0.0001	>44.1	9	9/9/8
Docetaxel	5.8	i.v./ q4dx3	366	24.7	p=0.0397	35	p=0.1185	18.1	9	0/0/0
	9.3	i.v./ q4dx3	505	36 8	p=0.0004	30.5	p=0.0576	13.6	9	4/4/1
	15	i.v,/q4dx3	204	8.9	p=0.0002	50.9	p=0.0562	34	9	4/4/1
	24.2	I.v./ q4dx3	300	14.9	p=0.0001	32.3	p=0.0576	15.4	9	4/3/2

Contrasts analysis versus control with Bonferroni-Holm adjustment for multiplicity following a non parametric two-way Anova-Type on tumor volume changes from baseline **: Log-Rank multiple comparisons test versus control on individual time to event « *»

Table 18 · Comparison of the tumor volumes of cabazitaxel and docetaxel at the same equi-toxic doses In nude mice bearing DM101 Ewing’s sarcoma

Médian +/- MAD (number of xubject) and pvafue*
	Cabazitaxel 5Λ mg/kg	Cabazitaxel 93 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 242 mg/kg	Docetaxel 5Λ mg/kg	Docetaxel 93 mg/kg	Docetaxel 15 mg/kg	Docetaxel 242 mg/kg
DAY 4	0+/-0 (n-9)	0+/-33 (n-9)	0+/-0 (n-9)	-19 +/-19 (n-9)	51+/-38 (n^)	25+/-25 (n-9)	26+/-25 (n=9)	26+/-40 (n-9)
Companson versus	Docetaxel 5 8 mg/kg	Docetaxel 93 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 93 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 243 mg/kg
	p-1 0000	p-1 0000	p-1.0000	p-1 0000	p-1 0000	p-I 0000	p-l 0000
DAY 7	34+/-34 (n-9)	I3+/-4I (n-9)	-113+/-32 (n-9)	-150+/-52 (n-9)	98 +/- 79 (n-9)	96+/-172 (n-9)	73+/-109 (n-9)	122+A 184 (n-9)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 93 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 93 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 24.2 mg/kg
	p-1.0000	p-1 0000	p-0.0159	p-0.0042	p-0 6555	p-0.0174	p-0.0043
DAY 11	73+/-73 (n-9)	77+/-118 (n-9)	-131+/-47 (n-9)	-150+/-38 (n-9)	202+/-183 (n-9)	301 +/-223 (n-9)	73+/-186 (n-9)	122+/-184 (n-9)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 9 J mg/kg	Docetaxel 15 mg/kg	Docetaxel 242 mg/kg	Cabazitaxel 93 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 243 mg/kg
	p-1 0000	p-1 0000	p-0.0019	p-0.0019	p-0 5726	p-0.0015	p-0.0019
DAY 14	155+/-136 (n-9)	188+/-241 (n-9)	-131 +/-47 (n-9)	-150+/-38 (n-9)	446+/-393 (n-9)	472 +/- 550 (n-9)	73+/-251 (n-9)	122+/-215 (n-9)
Comparison versus	Docetaxel 5.8 mg/kg	Docetaxel 9.3 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 93 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 243 mg/kg
	p-1.0000	p-1.0000	p-0.0008	Ρ-ΟΛ0Ι2	p-0.4725	p-OJMMU	p-0.0008
DAY 17	306+/-152 (n-9)	498+/-485 (n=9)	-131+/-47 (n-9)	-150+/-38 (n-9)	640+/-621 (n-9)	750+/-828 (n-9)	169+/-347 (n-9)	122+/-234 (n-9)
Comparison versus	Docetaxel 5.8 mg/kg	Docetaxel 93 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 93 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 242 mg/kg
	p-1 0000	p-1.0000	p-0.0002	p-O.OOOJ	p-0 6650	pO.0001	p-0.0002
DAY 20	489+/-199 (n-9)	766+/-713 (n-9)	•131+/-47 (n-9)	-150+/-38 (n-9)	813+/-756 (n-9)	813+/-891 (n-9)	290+/-468 (n-9)	394+/-407 (n-9)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 93 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 93 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 243 mg/kg
	p-1 0000	p-1 0000	pO.0001	(KO.000I	p-O.7250	p<0.000l	pO.OOOl
DAY 25	696.5 +/- 295 5 (n-8)	1095 +/- 1023 (n-9)	•131+/-47 (n-9)	-150+/-38 (n-9)	766+/-478 (n-7)	-78+/-110 (n-7)	-78+/-100 (n-7)	351.5+/- 463.5 (n-8)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 93 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24 2 mg/kg	Cabazitaxel 93 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 242 mg/kg
	p-0 9784	p-0 6388	p-0.0001	(KO.000I	p-0.7289	p<0.000\|	p-0.0001
DAY 28	1097+/I 17(n-8)	182.5 +/· 248(n-6)	-131+/-47 (n-9)	-150+/-38 (n-9)	1140+/- 564 (n-7)	-78 +/- 36 (n-6)	-84 5+/-70 (n-6)	681 +/-793 (n-8)
Comparison versus	Docetaxel 5 8 mg/kg	Docetaxel 93 mg/kg	Docetaxel 15 mg/kg	Docetaxel 24.2 mg/kg	Cabazitaxel 93 mg/kg	Cabazitaxel 15 mg/kg	Cabazitaxel 242 mg/kg
	p-09886	p-0.5325	p-O.OOOJ	pO.0001	p-0.5169	pO.OOOl	p-O.OOOJ

« <» ·

DAY 32	1396+/-	385+/-414	-131+/-40	-150+/-38	1694+/-	-78+/-34	-91+/-40	254+/-366
182.5 (n-8)	(n-6)	(n-9)	(n-9)	281 (n-7)	(n-5)	(n-5)	(n-5)
Comparison versus	Docetaxel	Docetaxel	Docetaxel	Docetaxel	Cahazititxcl	Cabazitaxel	Cabazitaxel
5.8 mg/kg	93 mg/kg	15 mg/kg	24.2 mg/kg	93 mg/kg	15 mg/kg	24.2 mg/kg
	p-0 8900	p-0.5900	p-O.OOIR	p<0.0001	p-0 5900	pO.0001	p-0.0016

*: Coritrasts analysis with Bonferroni-Ilolm adjustment for multiplicity following a two-way ANOVA-TYPE on tumor volume changes from baseline to compare, at each day, the groups treated with Cabazitaxel or Docetaxel al the same dose or al equi-toxic doses.

Conclusion: Both cabazitaxel and docetaxel demonstrate robust anti-tumor activity in this model. Cabazitaxel at the 15 or 24.2 mg/kg doses was significantly more active than docetaxel at the same dose (15 or 24.2 mg/kg, respectively) or at the equi-toxic dose (9.3 or 15 mg/kg, respectively).

Claims

1. The compound of formula (I):

2. The compound for the use of daim 1, for the treatment of pédiatrie solid tumors.

3. The compound for the use of claim 2, wherein the pédiatrie solid tumors are chosen from the group consisting of: anaplastic astrocytomas, glioblastomas, anaplastic oligodendrogliomas, oligoastrocytomas, anaplastic ependymomas, nephroblastoma, medulloblastomas, neuroblastomas, Wilm's tumors, rhabdomyosarcomas, chondrosarcomes, Ewing's sarcomas and osteosarcomas.

4. The compound for the use of any one of daims 1 to 3, for the treatment of rhabdomyosarcoma.

5. The compound for the use of any one of claims 1 to 3, for the treatment of Ewing's tumor.

6. The compound for the use of any one of clalms 1 to 3, for the treatment of osteosarcoma.

7. The compound for the use of claim 1. for the treatment of high grade gliomas.

s

8. The compound for the use of any one of daims 1 to 7. wherein said compound is in the form of an acetone solvaté.

9. The compound for the use of daim 8, wherein the acetone solvaté comprises from 5% to 8% by weight of acetone.

10. The compound for the use of any one of daims 1 to 9, wherein said compound is administered by parentéral route.

11. The compound for the use of daim 10, wherein said compound is is administered by intravenous route.