Drug Design, Development and Therapy
`
`Open Access Full Text Article
`
`Preclinical profile of cabazitaxel
`
`Dovepress
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`open access to scientific and medical research
`
`R e v i e w
`
`Patricia vrignaud 1
`Dorothée Semiond2
`veronique Benning2
`eric Beys 2
`Hervé Bouchard3
`Sunil Gupta4
`1Sanofi Oncology, Vitry-sur-Seine,
`France; 2Sanofi DSAR, Alfortville,
`France; 3Sanofi LGCR, Vitry-sur-
`Seine, France; 4Sanofi Oncology,
`Cambridge, MA, USA
`
`Correspondence: Patricia Vrignaud
`Sanofi Oncology, 13 quai Jules Guesde,
`Vitry-sur-Seine, 94403 Cedex, France
`Tel +33 1 58 93 36 29
`Fax +33 1 58 93 34 71
`email patricia.vrignaud77@gmail.com
`
`Abstract: First-generation taxanes have changed the treatment paradigm for a wide variety
`of cancers, but innate or acquired resistance frequently limits their use. Cabazitaxel is a novel
`second-generation taxane developed to overcome such resistance. In vitro, cabazitaxel showed
`similar antiproliferative activity to docetaxel in taxane-sensitive cell lines and markedly greater
`activity in cell lines resistant to taxanes. In vivo, cabazitaxel demonstrated excellent antitumor
`activity in a broad spectrum of docetaxel-sensitive tumor xenografts, including a castration-
`resistant prostate tumor xenograft, HID28, where cabazitaxel exhibited greater efficacy than
`docetaxel. Importantly, cabazitaxel was also active against tumors with innate or acquired
`resistance to docetaxel, suggesting therapeutic potential for patients progressing following
`taxane treatment and those with docetaxel-refractory tumors. In patients with tumors of the
`central nervous system (CNS), and in patients with pediatric tumors, therapeutic success with
`first-generation taxanes has been limited. Cabazitaxel demonstrated greater antitumor activity
`than docetaxel in xenograft models of CNS disease and pediatric tumors, suggesting potential
`clinical utility in these special patient populations. Based on therapeutic synergism observed
`in an in vivo tumor model, cabazitaxel is also being investigated clinically in combination
`with cisplatin. Nonclinical evaluation of the safety of cabazitaxel in a range of animal species
`showed largely reversible changes in the bone marrow, lymphoid system, gastrointestinal tract,
`and male reproductive system. Preclinical safety signals of cabazitaxel were consistent with
`the previously reported safety profiles of paclitaxel and docetaxel. Clinical observations with
`cabazitaxel were consistent with preclinical results, and cabazitaxel is indicated, in combination
`with prednisone, for the treatment of patients with hormone-refractory metastatic prostate cancer
`previously treated with docetaxel. In conclusion, the demonstrated activity of cabazitaxel in
`tumors with innate or acquired resistance to docetaxel, CNS tumors, and pediatric tumors made
`this agent a candidate for further clinical evaluation in a broader range of patient populations
`compared with first-generation taxanes.
`Keywords: XRP6258, CNS tumors, mCRPC, pediatric tumor, taxane resistance, xenograft
`
`Introduction
`Since the initial approval of paclitaxel (Taxol®; Bristol-Myers Squibb, New York City,
`NY, USA) in 1992,1,2 the first-generation taxanes paclitaxel and docetaxel (Taxotere®;
`Sanofi, Paris, France) have altered the treatment paradigm for a wide variety of solid
`tumors, including breast, lung, prostate, gastric, and ovarian cancers.3,4 Despite dem-
`onstrating significant antitumor activity as monotherapy or in combination regimens,
`clinical use of first-generation taxanes is frequently limited by innate or acquired
`resistance.5–7 In prostate cancer, the majority of patients will eventually acquire resis-
`tance to docetaxel therapy.8
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`Cabazitaxel (Jevtana®, Sanofi) is a novel second-
`generation semisynthetic taxane that was identif ied
`through a preclinical screen of 450 molecules derived
`from 10- deacetylbaccatin-III, with the aim of identifying
`a compound with activity in both taxane-sensitive and
`taxane-resistant tumors.9 In the pivotal Phase III TROPIC
`study (NCT00417079), cabazitaxel combined with predni-
`sone significantly extended overall survival compared with
`mitoxantrone plus prednisone in patients with metastatic
`castration-resistant prostate cancer (mCRPC) previously
`treated with a docetaxel-containing regimen.10 This led to
`cabazitaxel’s approval in 2010, in combination with predni-
`sone, for the treatment of patients with hormone-refractory
`metastatic prostate cancer who have previously received
`docetaxel-based therapy.11,12
`This review article presents an overview of the preclinical
`properties of cabazitaxel, including its development, mecha-
`nism of action, antitumor activity in a range of in vitro and
`in vivo tumor models, pharmacokinetics (PK), and metabolic
`and toxicity profiles, as well as a summary of its clinical
`development.
`
`Taxanes’ mechanism of action
`and resistance mechanisms
`Mechanism of action
`Taxanes are microtubule inhibitors that induce cellular
`apoptosis through the stabilization of microtubules.7 Micro-
`tubules are major components of the cytoskeleton, with
`critical roles in a variety of cellular processes including
`maintenance of cell shape, intracellular transport, cell signal-
`ing, and cell division.7,13–15 It is this pivotal role in mitosis
`that makes microtubules a key cellular target for anticancer
`therapeutics.7
`Microtubules are highly dynamic polymers of tubulin,
`continually undergoing assembly and disassembly within the
`cell. Taxanes inhibit microtubule function by binding to tubu-
`lin molecules, promoting their polymerization, and stabilizing
`microtubules. Suppression of microtubule dynamics leads to
`a block in mitosis and, ultimately, tumor cell death.7,13,14
`
`Resistance mechanisms
`Innate or acquired resistance to first-generation taxanes is
`frequently observed in different tumor types, resulting in
`treatment failure. Multiple potential mechanisms of taxane
`resistance have been identified in preclinical studies, and
`it is likely that several of these contribute to a resistant
`phenotype.6,7,16–19
`Two mechanisms in particular have frequently been
`associated with the development of resistance to taxanes;
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`however, it is worth noting that these are yet to be validated
`in patient samples, and their clinical relevance is not fully
`understood.6,7 In preclinical studies, resistance commonly
`results from overexpression of members of the ATP-binding
`cassette family of transporters, of which P-glycoprotein,
`encoded by the multidrug resistance gene (ATP-binding
`cassette, sub-family B [MDR/TAP], member 1; ABCB1), is
`the best known.20 Docetaxel and paclitaxel are substrates of
`P-glycoprotein, which acts as a drug efflux pump, decreas-
`ing intracellular drug levels and limiting cytotoxicity.6,7,21,22
`Resistance may also arise from spontaneously acquired
`mutations in tubulin, the cellular target of taxanes, resulting
`in changes to the tubulin binding site or altered microtubule
`dynamics.6,7,23
`Clinical data suggest that additional mechanisms may
`contribute to taxane resistance in patients, including the
`altered expression of specific tubulin isotypes,17 and expres-
`sion or binding of microtubule-regulatory proteins,18 loss of
`functional p53,16 dysfunctional regulation of apoptotic and
`intracellular signaling (eg, HER2 overexpression),19 and
`decreased tumor cell permeability.24
`A number of potential predictive markers for taxane
` resistance have been identified, including the mitotic
`spindle checkpoint proteins Aurora A, BUBR1, MAD2, and
`synuclein-γ, and cell cycle proteins such as BRCA1;18 however,
`conflicting results have been reported clinically.24
`The development of alternative therapies able to over-
`come taxane resistance has been the focus of considerable
`attention.
`
`Cabazitaxel development
`Paclitaxel and docetaxel are semisynthetic derivatives of
`10-deacetylbaccatin-III,25,26 a natural paclitaxel precursor
`molecule that can be extracted easily and sustainably from
`the needles of the European yew tree (Figure 1).26 In light
`of the clinical limitations that result from taxane resistance,
`a large-scale preclinical screening process was undertaken
`that aimed to identify a taxane derivative with equivalent
`efficacy to docetaxel in docetaxel-sensitive tumors, but
`greater activity than docetaxel in tumors that are docetaxel-
`resistant.9
`In total, 450 candidate molecules were designed and
`generated for preclinical assessment, based on preclinical
`comparative structure–activity relationships of paclitaxel
`and docetaxel. Structural modifications initially focused on
`the side chain, as this was considered critical for potency,
`with subsequent modifications to other functional groups
`within the baccatin moiety.9 The antitumor potential of the
`taxane derivatives was assessed over three stages: in vitro
`
`Drug Design, Development and Therapy 2014:8
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`Preclinical profile of cabazitaxel
`
`A
`
`B
`
`C
`
`Side chain
`attachment
`at C-13
`
`HO
`
`13
`
`HO
`
`O
`
`O
`
`NH
`
`O
`
`O
`
`OH
`
`HO
`
`HO
`
`O
`
`OH
`
`10
`
`H
`
`O
`
`OCOCH3
`OCOC6H5
`
`HO
`
`O
`
`OH
`
`H
`
`O
`
`OCOCH3
`OCOC6H5
`
`Baccatin moiety
`
`Side chain
`
`O
`
`O
`
`NH
`
`O
`
`10
`
`H3C
`
`O
`
`O
`
`CH3
`
`O
`
`7
`
`O
`
`OH
`
`HO
`
`H
`
`O
`
`OCOCH3
`OCOC6H5
`
`Figure 1 Chemical structure of 10-deacetylbaccatin III, docetaxel, and cabazitaxel.
`Notes: (A) 10-deacetylbaccatin III. (B) Docetaxel. (C) Cabazitaxel.
`
`activity against microtubules; in vitro activity in resistant
`cell lines; and in vivo activity in a tumor model.24 The in
`vivo assessments included evaluation in a B16/TXT mela-
`noma resistance model, which was developed through repeat
`exposure to docetaxel in mice bearing the docetaxel-sensitive
`
`B16 tumor, to allow evaluation of the taxane derivatives in
`a clinically relevant setting. This model mimics the clinical
`development of docetaxel resistance, where tumors initially
`respond to treatment, but develop resistance progressively
`over time.24
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`Initial attempts to modify the C-3′N–Boc and C-3′ phenyl
`groups within the side chain of docetaxel resulted in derivatives
`demonstrating either reduced in vitro potency or failure to
`improve activity in docetaxel-resistant cell lines (Figure S1).9,27
`Alterations to the C-2/C-4 and oxetane ring regions of the bac-
`catin moiety were also evaluated, but failed to increase activity
`in the in vitro and/or in vivo resistance models.9
`Cabazitaxel is a dimethyl derivative of docetaxel, bear-
`ing methoxy groups in place of hydroxyl groups at posi-
`tions C-7 and C-10 (Figure 1).9 In both docetaxel-sensitive
`and docetaxel-resistant cell lines, these structural altera-
`tions resulted in the greatest increase in in vitro potency,
`without significantly increasing toxicity at the maximum
`tolerated dose, in contrast to other C-7/C-10 modifications
`(Figure S1).9 These modifications confer two advantages
`on cabazitaxel over docetaxel. Firstly, cabazitaxel, which is
`a P-glycoprotein substrate, has a higher lipophilicity than
`docetaxel (logP 3.9 versus 3.2),9,28 resulting from the con-
`version of two secondary alcohols to more lipophilic ethers.
`This may result in increased cell penetration through passive
`influx, consequently leading to better activity in resistant cell
`lines where permeability of the plasma membrane may be
`altered.24,28–30 This hypothesis was recently confirmed in an
`experiment in which drug uptake into MCF7 breast adeno-
`carcinoma cells, which do not overexpress P-glycoprotein,
`was faster for cabazitaxel than for docetaxel.31 Secondly,
`cabazitaxel has an improved ability to cross the blood–brain
`barrier (BBB) compared with docetaxel, offering potential
`benefit in patients with tumors of the central nervous system
`(CNS).9,29,32,33
`Accordingly, during the screening of taxane derivatives
`and subsequent preclinical evaluation, cabazitaxel has
`demonstrated equivalent efficacy to docetaxel for stabiliz-
`ing microtubules in vitro, greater potency than docetaxel in
`cell lines resistant to taxanes and other chemotherapeutics,
`activity superior to docetaxel in in vivo CNS disease models,
`broad-spectrum antitumor activity against a range of murine
`and human tumors, and in vivo activity in tumor models that
`are not sensitive, or are poorly sensitive, to docetaxel.9,24,33
`
`In vitro activity
`Microtubule stabilization
`Cabazitaxel has shown equivalent potency to docetaxel for
`stabilization of microtubules in vitro. Both cabazitaxel and
`docetaxel induced a similar reduction in lag time for tubulin
`assembly (lag time to 50% aggregation 0–0.1 µmol/L) and stabi-
`lization of microtubules against cold-induced depolymerization
`(concentration producing 50% cell killing 0.1–0.25 µmol/L),
`
`indicating that cabazitaxel has a cytotoxic mechanism of action
`similar to that of docetaxel.24
`
`Antiproliferative activity
`In cell lines sensitive to chemotherapy, cabazitaxel had similar
`antiproliferative activity to docetaxel, achieving comparable
`50% inhibitory concentration (IC50) values across a range of
`murine and human cell types (0.004–0.041 µmol/L for cabazi-
`taxel versus 0.008–0.079 µmol/L for docetaxel) (Table 1).24
`In a panel of cell lines bearing acquired resistance to
`taxanes or to the chemotherapeutic agents doxorubicin, vin-
`cristine, or vinblastine, cabazitaxel showed markedly greater
`antiproliferative activity than docetaxel (IC50 ranged from
`0.016–0.414 µmol/L for cabazitaxel versus 0.17–4.01 µmol/L
`for docetaxel).24 Resistance factors, an indication of the dif-
`ference in drug concentrations needed to inhibit resistant
`versus sensitive/parental cell lines, ranged from 2–10 for
`cabazitaxel and 5–59 for docetaxel in these P-glycoprotein-
`expressing cell lines (Table 1).24
`In murine and human cell lines with resistance mecha-
`nisms other than P-glycoprotein overexpression, no cross-
`resistance to cabazitaxel was observed.24
`
`In vivo activity
`Plasma pharmacokinetics
`The PK profile of cabazitaxel was evaluated in healthy and
`tumor-bearing mice, and healthy rats and dogs (Table 2 )
`(Sanofi, data on file, 2010).
`
`Absorption
`Exposure to cabazitaxel increased with dose after single or
`repeated intravenous (IV) administration in all species. The
`increase in exposure was approximately dose-proportional
`in mice and more than dose-proportional in rats and dogs.
`No plasma accumulation was observed in mice, rats, or dogs
`after administration every 5 days, weekly, or every 3 weeks.
`No sex effect was observed in rats and dogs (Sanofi, data
`on file, 2010).
`
`Distribution
`Plasma protein binding of cabazitaxel was very high in mice
`(99.3%) and high in rats (95.5%), rabbits (91.4%), dogs
`(97.1%), and humans (91.9%) (Sanofi, data on file, 2010).
`Following a single IV administration, cabazitaxel exhibited
`a very large volume of distribution at steady state in both
`healthy (2.5–3.7 L/kg) and tumor-bearing mice (8.8 L/kg),
`in rats (22.7 L/kg), and in dogs (3.3–14.5 L/kg) (Sanofi, data
`on file, 2010).
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`Preclinical profile of cabazitaxel
`
`Table 1 In vitro antiproliferative effects of cabazitaxel and docetaxel against sensitive and P-glycoprotein-expressing resistant cell
`lines
`
`Cell line
`
`ABCB1
`mRNA levelb
`
`Mean IC50, μmol/L ± SD
`Resistance factora
`Cabazitaxel
`Docetaxel
`Docetaxel
`Cabazitaxel
`-
`-
`-
`0.079±0.004
`0.041±0.017
`P388 murine leukemia
`+++
` 4.01±0.280
`0.414±0.036
`10
`51
`P388/DOX
`-
`-
`-
`0.039±0.012
`0.013±0.005
`P388 murine leukemia
`++
`0.188±0.022
`0.024±0.015
`2
`5
`P388/TXT
`-
`-
`-
`0.039±0.012
`0.013±0.005
`P388 murine leukemia
`++
`0.227±0.038
`0.024±0.003
`2
`6
`P388/VCR
`-
`-
`-
`0.031±0.004
`0.022±0.010
`HL60 human leukemia
`++
`0.250±0.110
`0.060±0.029
`3
`8
`HL60/TAX
`-
`-
`-
`0.008±0.002
`0.004±0.002
`Calc18 human breast adenocarcinoma
`++
`0.170±0.040
`0.016±0.004
`4
`21
`Calc18/TXT
`-
`-
`-
`0.042±0.021
`0.035±0.026
`KB human epidermoid carcinoma
`++++
`2.480±0.120
`0.270±0.013
`8
`59
`KBv1
`Notes: Cells were incubated for 96 hours at 37°C in liquid medium with drugs at different concentrations. Viability was assessed by neutral red, with the mean of at least
`three results obtained. aResistance factor = IC50 (resistant)/IC50 (parental) from the same experiment; brelative expression obtained from Northern blot experiments using
`the human ABCB1 gene as probe. Reprinted by permission from the American Association for Cancer Research: Vrignaud P, Sémiond D, Lejeune P, et al. Preclinical antitumor
`activity of cabazitaxel, a semi-synthetic taxane active in taxane-resistant tumors. Clin Cancer Res. 2013;19:2973–2983, doi: 10.1158/1078-0432.CCR-12-3146.24
`Abbreviations: ABCB1, ATP-binding cassette, sub-family B, member 1; Calc18/TXT, Calc18 human breast adenocarcinoma resistant to docetaxel; HL60/TAX, HL60 human
`leukemia resistant to paclitaxel; IC50, 50% inhibitory concentration; KBV1, KB human epidermoid carcinoma resistant to vinblastine; P388/DOX, P388 murine leukemia
`resistant to doxorubicin; P388/TXT, P388 murine leukemia resistant to docetaxel; P388/VCR, P388 murine leukemia resistant to vincristine; SD, standard deviation.
`
`The PK of cabazitaxel was also evaluated in mice
`bearing advanced-stage ( 400 mm 3) mammar y
`MA16/C adenocarcinomas.24 Cabazitaxel was adminis-
`tered at the highest nontoxic dose (HNTD) of 40 mg/kg.
`Drug uptake into the tumor was both rapid and sustained,
`with maximum drug concentrations in tumor tissue reached
`within 15 minutes, and a 40-fold greater concentration of
`cabazitaxel within the tumor versus plasma after 48 hours
`(Figure 2).24
`In this model, exposure to cabazitaxel was 1.6-times greater
`in the tumor compared with plasma during the 48 hours fol-
`lowing treatment administration, and 2.9-times greater over
`
`the entire experimental period (168 hours). Concentrations
`of cabazitaxel above the cellular antiproliferative IC50 were
`sustained for 24 hours in the plasma and for 96 hours in
`tumor tissue.24
`Brain distribution of cabazitaxel was assessed in mice,
`rats, and dogs. Cabazitaxel penetrated rapidly in the brain,
`with similar relative exposure between brain and blood across
`the different species.33
`
`Metabolism
`Cabazitaxel metabolism has been compared across mul-
`tiple species. In vivo, cabazitaxel was the major circulating
`
`Normal mice
`
`F
`
`Tumor-bearing mouse
`Rat
`Dog
`
`Table 2 Pharmacokinetic parameters of cabazitaxel in normal and tumor-bearing mice, rats, and dogs
`Species
`Sex
`Dose
`Number of
`Infusion
`AUC
`Cmax
`(ng ⋅ h/mL)
`(M/F)
`(mg/kg)
`administrations
`duration
`(ng/mL)
`F
`5
`1
`1 h
`2,728
`4,468
`10
`1
`1 h
`4,805
`11,211
`15
`1
`1 h
`6,072
`13,460
`5
`5a
`1 h
`4,421
`6,881
`10
`5a
`1 h
`6,478
`17,497
`15
`5a
`1 h
`6,504
`13,489
`40
`1
`45 s
`23,784
`24,113
`F
`2.5
`1
`1 h
`477
`522
`M
`0.5
`1
`72–91 m
`65
`95
`M
`0.5
`1
`72–91 m
`97
`101
`F
`1
`1
`72–91 m
`164
`230
`M
`1
`1
`72–91 m
`360
`417
`F
`Notes: aevery 3 weeks. Sanofi, data on file, 2013.
`Abbreviations: AUC, area under the concentration–time curve; CL, clearance; Cmax, maximum plasma concentration; F, female; M, male; t1/2, half-life; Vss, steady-state volume
`of distribution.
`
`CL
`(L/hr/kg)
`1.1
`0.9
`1.1
`0.7
`0.6
`1.1
`1.7
`4.8
`5.3
`5.2
`4.4
`2.5
`
`Vss
`(L/kg)
`2.5
`2.7
`3.7
`2.1
`1.1
`2.8
`8.8
`22.7
`14.5
`12.8
`9.5
`3.3
`
`t1/2
`(hr)
`5.1
`7.4
`7.6
`4.9
`5.5
`7.5
`26.0
`10.1
`4.3
`3.2
`3.8
`3.0
`
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`Plasma
`Tumor
`
`the dose). In contrast, unchanged cabazitaxel was the major
`circulating compound in plasma in all species, including
`humans, accounting for 65% of the total radioactivity area
`under the curve.34
`
`105
`
`104
`
`103
`
`102
`
`101
`
`100
`
`(ng/mL or ng/g)
`
`Cabazitaxel concentration
`
`0
`
`10
`
`20
`
`30
`
`50
`40
`60
`Time (h)
`
`70
`
`80
`
`90 100
`
`Figure 2 Pharmacokinetics of 40 mg/kg cabazitaxel (highest nontoxic dose) in
`plasma and tumor tissues in mice.
`Note: Reprinted by permission from the American Association for Cancer
`Research: Vrignaud P, Sémiond D, Lejeune P, et al. Preclinical antitumor activity of
`cabazitaxel, a semi-synthetic taxane active in taxane-resistant tumors. Clin Cancer
`Res. 2013;19:2973–2983, doi: 10.1158/1078-0432.CCR-12-3146.24
`compound in all species including humans (65% of the
`total radioactivity area under the curve). Cabazitaxel under-
`goes extensive biotransformation, with less than 2.5% of the
`administered dose excreted unchanged in studies of mice,
`rats, dogs, and humans. The two main metabolic pathways,
`accounting for 40%, 54%, and 45% of the dose excreted in
`humans, dogs, and mice, respectively, corresponded to two
`O-demethylations at the C-7 and C-10 positions, one leading
`to 7-O-demethyl-cabazitaxel (pathway B) and the other to
`10-O-demethyl-cabazitaxel (pathway A) (Figure 3; Table 3).
`In male and female rats, the main pathway corresponded
`to t-butyl-hydroxylation on the lateral chain (pathway C),
`accounting for 49%–55% of the dose excreted. This pathway
`was also abundant in mice, representing 41% of the dose, and
`was found in humans (21% of the dose). Another pathway
`consisting of the cleavage of the parent drug (pathway D)
`was very minor in all species, including humans (0.3% of
`
`excretion
`The PK of cabazitaxel following a single IV infusion in
`normal mice, tumor-bearing mice, and in dogs is generally
`characterized by a biphasic elimination (Sanofi, data on file,
`2010). Plasma clearance was high in rats (4.8 L/h/kg) and dogs
`(2.5–5.3 L/h/kg) and moderate in normal (0.9–1.1 L/h/kg)
`and tumor-bearing mice (1.7 L/h/kg), compared with respec-
`tive hepatic blood flow. The terminal half-life was moderately
`long in dogs (3.0 to 4.3 hours), long in normal mice (5.1–7.6
`hours) and rats (10 hours), and extremely long in tumor-
`bearing mice (26 hours). It should be noted that a higher
`dose was given to tumor-bearing mice, which was reflected
`in quantifiable levels occurring at later sampling times than
`in normal mice (Sanofi, data on file, 2010).
`Cabazitaxel excretion was nearly complete (91%–95%
`of the administered dose) in mice, rats, and dogs, and radio-
`activity was largely excreted in the feces in all three species
`(87%–91% of the administered dose), with minimal excretion
`via the urinary route (1%–4%). In bile-duct-cannulated male
`rats, radioactivity was mainly excreted via the biliary route,
`accounting for 65% of the administered dose within 48 hours.
`Similarly, in humans the majority of the radioactivity was
`recovered in feces (around 76% of the administered dose),
`with 4% of the dose found in urine.34
`In summary, the disposition of cabazitaxel was assessed
`in a range of animal species, and the distribution, metabolic
`pathways, and elimination processes documented in ani-
`mals are consistent with those observed in humans (Sanofi,
`
`Pathway D cleavage
`
`Pathway A 10-O demethylation
`Pathway B 7-O demethylation
`
`Pathway C hydroxylation
`
`O
`
`H3C
`
`O
`
`O
`
`O
`
`NH
`
`O
`
`10
`
`CH3
`
`O
`
`7
`
`O
`
`OH
`
`HO
`
`Lateral chain
`
`H
`
`O
`OCOCH3
`OCOC6H5
`Taxane ring
`
`Figure 3 Proposed schematic of the principal metabolic pathways of cabazitaxel.
`
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`Preclinical profile of cabazitaxel
`
`Table 3 Relative contribution of different metabolic pathways to
`cabazitaxel metabolism across species
`
`Pathway
`
`% of administered dose
`Dog Human
`Mouse
`Rat
`Rat
`Female Male Female Male Male and
`female
`16.2
`
`9.8
`
`5.7
`
`19.7
`
`16.4
`
`(complete response [CR]) and 83% long-term tumor-free
`survival (TFS).24
`Cabazitaxel was compared with docetaxel and abiraterone
`acetate (a specific inhibitor of CYP17) in a patient-derived
`prostate tumor xenograft with induced resistance to castration
`(HID28). At equivalent dose levels (20 mg/kg), cabazitaxel
`demonstrated greater antitumor efficacy than docetaxel.38
`Cabazitaxel inhibited tumor growth with a percentage tumor
`volume change (calculated as the percentage ratio between
`the mean tumor volume of a treated and a control group)
`of 1.4% at Day 35 compared with 16.7% for docetaxel
`(Figure 4).38 Complete and partial remissions, respectively,
`were achieved in six out of ten and four out of ten mice
`receiving cabazitaxel, and in one out of ten and two out
`of ten mice treated with docetaxel.38 No antitumor activity
`was demonstrated with abiraterone acetate (50 mg/kg orally
`administered daily for 21 days).38 These data provide support
`for the clinical development of cabazitaxel for the first-line
`treatment of mCRPC.
`
`Docetaxel-sensitive models
`Cabazitaxel demonstrated broad-spectrum activity in murine
`and human xenograft models (Table 4). Excellent antitumor
`activity was observed in murine B16 melanoma, colon adeno-
`carcinoma C51, and mammary adenocarcinoma MA16/C and
`MA17/A tumors.24 In a range of advanced disease models,
`including human colon HCT 116 and HT-29, lung A549 and
`NCI-H460, pancreas MIA PaCa-2, head and neck SR475,
`and kidney Caki-1 xenografts, administration of cabazitaxel
`
`Vehicle (once every 3 weeks)
`Docetaxel 20 mg/kg (once every 3 weeks)
`Cabazitaxel 20 mg/kg (once every 3 weeks)
`Cabazitaxel 15 mg/kg (once every 3 weeks)
`Abiraterone 50 mg/kg (daily for 21 days)
`
`Pathway A
`(10-O-demethylation)
`Pathway B
`(7-O-demethylation)
`Pathway C
`(hydroxylation on
`lateral chain)
`0.1
`Pathway D (cleavage)
`Note: Sanofi, data on file, 2010.
`
`28.4
`
`40.5
`
`15.1
`
`12.7
`
`34.7
`
`24.2
`
`49.3
`
`54.8
`
`12.6
`
`20.9
`
`0.1
`
`0.3
`
`0.3
`
`Trace
`
`data on file, 2010). Thus, the animals studied are likely to
`represent good models for the disposition of cabazitaxel in
`humans. The finding that unchanged cabazitaxel is the main
`circulating compound in plasma indicates that analysis of
`the parent drug is appropriate for PK and pharmacodynam-
`ics studies of cabazitaxel.
`
`Antitumor activity
`Prostate cancer models
`The efficacy of taxanes in prostate cancer, in addition to
`their impact on cell division, may in part relate to inhibitory
`effects on androgen receptor signaling.35–37 In mice bear-
`ing a docetaxel-sensitive cell line-derived castrate-resistant
`prostate cancer xenograft (DU145), cabazitaxel was found to
`be highly active, inducing 100% complete tumor regressions
`
`2,000
`
`1,500
`
`1,000
`
`500
`
`(mean ± SEM)
`
`Tumor volume (mm3)
`
`0
`
`0
`
`7
`
`14
`
`21
`
`28
`Days
`
`35
`
`42
`
`49
`
`Vehicle, cabazitaxel 15 and 20 mg/kg, and docetaxel 20 mg/kg
`treatments (Day 0 and Day 21)
`Abiraterone 50 mg/kg treatments (Day 0 to Day 20)
`
`Figure 4 Antitumor activity of cabazitaxel, docetaxel, and abiraterone in a docetaxel-sensitive hormone-refractory prostate cancer xenograft model.
`Note: Sanofi, data on file, 2012.
`Abbreviation: SEM, standard error of the mean.
`
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`
`vrignaud et al
`
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`
`Table 4 Dose–response antitumor activity of cabazitaxel and docetaxel in mice bearing murine and human docetaxel-sensitive and
`-resistant tumors
`
`Tumor type
`
`Cabazitaxel
`Total HNTD,
`mg/kg
`
`Log
`cell killa
`
`CR
`
`TFS
`
`Docetaxel
`Total HNTD,
`mg/kg
`
`Log
`cell killa
`
`CR
`
`TFS
`
`NA
`NA
`5/5
`NA
`5/5
`NA
`4/5
`NA
`NA
`
`0/5
`0/5
`5/5
`0/5
`4/5
`0/5
`0/5
`0/5
`0/5
`
`60
`60
`60
`45
`ND
`ND
`ND
`ND
`ND
`
`1.7
`0.6
`3.1
`3.1
`ND
`ND
`ND
`ND
`ND
`
`NA
`NA
`0/5
`NA
`ND
`ND
`ND
`ND
`ND
`
`0/5
`0/5
`0/5
`0/5
`ND
`ND
`ND
`ND
`ND
`
`60
`60
`60
`45
`60
`60
`40
`36
`58.5
`
`2.1
`1.3
`–
`2.6
`–
`0.8
`3.7
`3.9
`1.2
`
`Murine tumors
` B16 melanoma
` B16/TXT melanoma
` Colon C38
` Colon C51
` Pancreas P03
` Pancreas P02
` Mammary MA16/C
` Mammary MA17/A
` Lung 3LL
`Human tumors
`ND
`ND
`ND
`ND
`5/6
`6/6
`–
`48.0
` Prostate DU 145
`ND
`ND
`ND
`ND
`2/7
`7/7
`3.4
`36.0
` Colon HCT 116
`0/6
`6/6
`3.4
`96.6b
`0/6
`6/6
`2.0
`22.2
` Colon HT-29
`0/5
`0/5
`0.8
`50b
`0/5
`0/5
`1.9
`28.0
` Colon HCT-8
`6/6
`6/6
`–
`75b
`6/6
`6/6
`–
`48.0
` Pancreas MIA PaCa-2
`ND
`ND
`ND
`ND
`5/8
`NA
`3.4
`61.5
` Breast Calc18
`ND
`ND
`ND
`ND
`0/8
`NA
`0.5
`38.1
` Breast Calc18/TXT
`0/5
`NA
`0.6
`45
`0/5
`NA
`45.0
` Breast UISO BCA-1
`6
`ND
`ND
`ND
`ND
`0/6
`2/6
`2.7
`24.0
` Lung NCI-H460
`0/5
`0/5
`1.9
`96.6b
`0/6
`2/6
`2.2
`36.0
` Lung A549
`1/8
`NA
`4.5
`73.2
`1/8
`NA
`73.2
` Gastric N87
`6
`0/8
`0/8
`0.5
`23.1
`0/8
`0/8
`1.4
`37.2
` Gastric GXF-209
`0/6
`1/6
`2.5
`45b
`6/6
`6/6
`–
`42.0
` Head and neck SR475
`0/5
`2/5
`1.4
`64.4b
`0/6
`5/6
`1.7
`24.0
` Kidney Caki-1
`Notes: Murine tumors were originally obtained and then maintained in the same syngenic mouse strain for MA17/A (C3H/HeN) and C51 (BALB/c), and in B6D2F1 mice for
`the C57BL/6 syngenic tumors. Human tumors were grafted in immunocompromised mice. aDefinition of antitumor activity (log cell kill = tumor growth delay/3.32 × tumor
`doubling time): log cell kill total 0.7= inactive, 2.8= highly active; bthe dose–response pattern for docetaxel was different from that of cabazitaxel in the following studies:
`HT-29, A549, and Caki-1 studies – 51.9, 32.2, 20, and 12.4 mg/kg per injection; HCT-8, MIA PaCa-2, and SR475 studies – 41.7, 25, and 15 mg/kg per injection. Adapted by
`permission from the American Association for Cancer Research: Vrignaud P, Sémiond D, Lejeune P, et al. Preclinical antitumor activity of cabazitaxel, a semi-synthetic taxane
`active in taxane-resistant tumors. Clin Cancer Res. 2013;19:2973–2983, doi: 10.1158/1078-0432.CCR-12-3146.24
`Abbreviations: CR, complete regression; HNTD, highest nontoxic dose; NA, not available as treatment conducted on early-stage disease; ND, not determined in the same
`study; TFS, long-term tumor-free survivors.
`
`achieved CR. In seven of eleven such models, CR levels were
`100%. In seven models, CR resulted in TFS at study comple-
`tion, with 80 to 100% TFS in five of them.24
`In most cases, the antitumor activity of cabazitaxel was
`similar to that of docetaxel, as assessed by log cell kill values
`derived from measurements of tumor growth (log cell kill =
`tumor growth delay/3.32× tumor doubling time).24 Despite
`this, docetaxel induced CR in just four of seven evaluable
`xenograft models (human colon HCT-29, pancreas MIA
`PaCa-2, head and neck SR475, and kidney Caki-1), and
`TFS at study completion was only observed in mice bearing
`human pancreas MIA PaCa-2 xenografts.
`
`Models resistant or poorly sensitive to docetaxel
`Cabazitaxel was evaluated in the B16/TXT acquired-
` resistance model, which was developed by repeatedly
`exposing mice bearing the docetaxel-sensitive murine B16
`
`melanoma to docetaxel at the HNTD (60 mg/kg per passage),
`with a total of 27 passages over 17 months required to obtain
`a fully docetaxel-resistant tumor. Cabazitaxel demonstrated
`antitumor activity against B16/TXT, which does not over-
`express P-glycoprotein, but was not active against the
`P-glycoprotein-overexpressing tumor Calc18/TXT in which
`docetaxel resistance was induced in vitro.24
`Interestingly, cabazitaxel showed activity against a number of
`murine and human xenograft models bearing innate resistance to
`docetaxel, including the human breast tumor UISO BCA-1. In
`this early-stage model, cabazitaxel achieved a log cell kill value
`of greater than 6, compared with 0.6 with docetaxel. Moreover,
`docetaxel did not delay tumor growth at its HNTD (15 mg/kg
`per injection; log cell kill 0.6, P0.5), whereas cabazitaxel was
`highly active both at its HNTD (15 mg/kg per injection; log cell
`kill 6, P=0.0016) and at the dose level below (9.3 mg/kg per
`injection; log cell kill 4.4, P=0.0016).24
`
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`
`Preclinical profile of cabazitaxel
`
`Taken together, these findings made cabazitaxel a can-
`didate for further clinical evaluation in patients who have
`relapsed following taxane treatment, as well as in those with
`innately docetaxel-refractory tumors.24
`
`Special populations
`CNS tumors
`The activity of first-generation taxanes in patients with
`tumors of the CNS is limited,39–43 due to poor penetration
`of these drugs across the BBB under normal physiologic
`conditions.44,