(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2012/0301425 A1
`GUPTA
`(43) Pub. Date:
`NOV. 29, 2012
`
`US 20l2030l425Al
`
`(54) NOVEL ANTITUMORAL USE OF
`CABAZITAXEL
`
`(75) Inventor:
`
`Sunil GUPTA, Chester Springs, PA
`(US)
`
`(73) Assignee:
`
`AVENTIS PHARMA S.A., Antony
`FR
`(
`)
`
`Publication Classi?cation
`
`(51) Int Cl
`(2006.01)
`C07D 305/14
`(200601)
`A61 K 38/19
`(2006.01)
`A61P 35/00
`(2006.01)
`A61K 31/573
`(52) US. Cl. ....................... .. 424/851; 514/171; 549/510
`(57)
`ABSTRACT
`
`The invention relates to a compound of formula:
`
`(21) Appl. No.:
`
`13/456,720
`
`.
`(22) F1led:
`
`Apr. 26 2012
`
`’
`Related U.S. Application Data
`
`(63) Continuation of application No. PCT/lB20l0/ 054866,
`?led on Oct. 27, 2010.
`
`(60) Provisional application No. 6l/389,969, ?led on Oct.
`5, 2010, provisional application No. 6l/383,933, ?led
`on Sep. 17, 2010, provisional application No. 61/369,
`929, ?led onAug. 2, 2010, provisional application No.
`6l/355,888, ?led on Jun. 17, 2010, provisional appli
`cation No. 6l/355,834, ?led on Jun. 17, 2010, provi
`sional application No. 6l/293,903, ?led on Jan. 11,
`2010, provisional application No. 6l/256,l60, ?led on
`Oct. 29, 2009.
`
`CH3 0
`
`H C
`3
`
`H3C>|\O)]\HNI
`
`Which may be in base form or in the form of a hydrate or a
`solvate, in combination With prednisone or prednisolone, for
`its use as a medicament in the treatment of prostate cancer,
`particularly metastatic prostate cancer, especially for patients
`Who are not catered for by a taXane-based treatment.
`
`002010002039
`
`AVENTIS EXHIBIT 2039
`Mylan v. Aventis, IPR2016-00712
`
`

`
`Patent Application Publication
`
`Nov. 29, 2012 Sheet 1 of 7
`
`US 2012/0301425 A1
`
`Symbo|s=Censors
`m MTX+PRED
`6-9-9 CBZ+PRED
`
`100
`90-.
`80
`
`70
`
`60
`
`12
`18
`Time (Months%
`188
`7
`231
`90
`
`300
`321
`
`1
`11
`4
`28
`(23OCT2009-1 6:27)
`
`FIG. 1
`
`
`
`Proportion of Overall Survival
`
`50-.
`40-.
`30
`20:
`10
`0.‘
`0
`Number at Risk
`MTX+PRED 377
`CBZ+PRED 378
`
`

`
`Patent Application Publication
`
`Nov. 29, 2012 Sheet 2 0f 7
`
`US 2012/0301425 A1
`
`100
`
`90
`
`80
`
`70
`so:
`50-.
`40
`
`Proportion of PFS
`
`30
`ml
`10-
`0Q
`0
`Number at Risk
`MTX+PRED 377
`CBZ+PRED 378
`
`Symbo|s=Censors
`m MTX+PRED
`9-9-9 CBZ+PRED
`
`6
`
`52
`90
`
`12
`'
`9
`Time (Months)
`27
`9
`52
`15
`
`168
`
`'
`
`15
`
`'
`
`18
`
`21
`
`6
`4
`
`2
`4
`0
`o
`2009-1354
`
`FIG. 2
`
`

`
`Patent Application Publication
`
`Nov. 29, 2012 Sheet 3 0f 7
`
`US 2012/0301425 A1
`
`Factor
`All randomized patients
`ECOG status: 0,1
`ECOC status: 2
`Measurable disease: No
`Measurable disease: Yes
`No. of prior chematherapies: 1
`No. of prior chemotherapies: 22
`Age: <65 years
`Age: 265 years
`Rising PSA at baseline: No
`Rising PSA at baseline: Yes
`Total docetaxel dose: <225 mg/m2
`Total docetaxel dose: 2225 to 450 mg/m2
`Total docetaxel dose: 2450 to 675 mg/m2
`Total docetaxel dose: 2675 to 900 mg/m2
`Total docetaxel dose: 2900 mg/m2
`Progression during docetaxel treatment
`Progression <3 months after docetaxel
`Progression 23 months after docetaxel
`
`Patient
`number
`755
`594
`61
`350
`405
`528
`227
`295
`460
`159
`583
`59
`206
`217
`131
`134
`219
`339
`192
`
`Favors Mitoxantroneq
`
`Hazard ratio
`“Favors Cobazitaxel
`(95% Cl)
`+
`0.70 (0.59-0.83)
`+
`0.58 (11.57-11.82)
`—.——
`0.81 (0.48-1.38)
`—.—
`0.72 (055-093)
`—0—
`0.68 (0.54-0.85)
`—'—
`0.67 (055-083)
`—.—
`0.75 (0.55-1.02)
`—¢—
`0.81 (0.61-1.08)
`+
`0.62 (0.50-0.78)
`—0——
`0.88 (0.61-1.26)
`+
`0.65 (0.53-0.80)
`0.96 (0.49-1.86) —0i—
`0.60 (0.43-0.84)
`—O—
`0.83 (0.60-1.16)
`—0——
`0.73 (0.48-1.10)
`—.——
`0.53 (0.47-0.90)
`—¢—
`0.68 (0.57-0.82)
`—0—
`0.70 (0.55-0.91)
`—.—
`0.75 (0.51-1.11)
`—¢——
`2
`1:5
`015
`1
`0
`Hazard ratio and 95% con?dence interval
`
`FIG. 3
`
`

`
`Patent Application Publication
`
`Nov. 29, 2012 Sheet 4 0f 7
`
`US 2012/0301425 A1
`
`
`
`Percent of ECOG change from baseline
`
`
`
`
`
`80.0% -
`
`70.0% -
`
`60.0% -
`
`50.0% -
`
`40.0% -
`
`30.0% -
`
`20,073-
`
`10.0%
`
`0.0%
`
`19.0% 19.3%
`
`Hz 2.2%
`Improve
`(n=12)
`
`Stable
`(n=567)
`
`Worse
`(n=142)
`
`Treatment
`-CBZ+PRED 4
`IIIMTX+PRED 8
`
`ECOG Categories
`
`283
`283
`
`70
`72
`
`FIG. 4
`
`

`
`Patent Application Publication
`
`Nov. 29, 2012 Sheet 5 0f 7
`
`US 2012/0301425 A1
`
`40.7%
`46.2%
`
`32.4% 321%
`
`_
`500%
`
`(D .g
`3 40.0%
`.8
`E
`2 30.0%
`%
`5
`5 20.0%-
`"6
`‘E
`g 10.0%
`i
`
`21.3%
`18.2%
`
`0'07"‘
`
`Improve
`(n=130)
`
`Stable
`(n=315)
`
`Worse
`(n=212)
`
`Treatment
`-CBZ+PRED 4
`|:|MTX+PRED 8
`
`PPI Categories
`
`283
`283
`
`70
`72
`
`FIG. 5
`
`

`
`Patent Application Publication
`
`Nov. 29, 2012 Sheet 6 0f 7
`
`US 2012/0301425 A1
`
`100-5
`150-;
`140-;
`130-;
`120-;
`110-;
`100-;
`90-;
`80-;
`70-;
`60-;
`50-;
`40-;
`30-;
`20-;
`10-;
`
`
`
`Average AUC of Personal Pain Index
`
`
`
`
`
`

`
`Patent Application Publication
`
`Nov. 29, 2012 Sheet 7 0f 7
`
`US 2012/0301425 A1
`
`
`
`
`
`Average AUC of Analgesic Score
`
`2400
`
`2100
`
`1800
`
`1500
`
`1200
`
`900
`
`600
`
`300
`
`

`
`US 2012/0301425 A1
`
`Nov. 29, 2012
`
`NOVEL ANTITUMORAL USE OF
`CABAZITAXEL
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application is a continuation of International
`Application No. PCT/IB2010/054866, ?led Oct. 27, 2010,
`Which claims the bene?t of priority of US. Provisional Appli
`cation No. 61/256,160, ?led Oct. 29, 2009, US. Provisional
`Application No. 61/293,903, ?led Jan. 11, 2010, US. Provi
`sional Application No. 61/355,834, ?led Jun. 17, 2010, US.
`Provisional Application No. 61/355,888, ?led Jun. 17, 2010,
`US. Provisional Application No. 61/369,929, ?led Aug. 2,
`2010, US. Provisional Application No. 61/383,933, ?led
`Sep. 17, 2010, and US. Provisional Application No. 61/389,
`969, ?led Oct. 5, 2010, all of Which are incorporated herein by
`reference.
`[0002] The present invention relates to a novel antitumoral
`use of cabaZitaxel in the treatment of prostate cancer, Which
`may be metastatic, especially for patients Who are not catered
`for by a taxane-based treatment. In particular, the present
`invention relates to the use of cabaZitaxel in the treatment of
`patients With castration resistant metastatic prostate cancer,
`Who have been previously treated With a docetaxel based
`regimen, an unmet medical need.
`
`BACKGROUND
`
`[0003] Prostate cancer affects a large proportion of the male
`population WorldWide: 680 000 cases WorldWide in 2002; it is
`predicted that there Will be 900 000 neW cases per year up to
`2010 (CA Cancer]. Clin., 2005, 55, 74-108). It is the most
`frequently occurring cancer in men after lung cancer.
`[0004] Prostate cancer is generally treated at the start by
`depriving the androgenic hormones, i.e. by surgical excision
`of the testicles The Current State of Hormonal Therapy for
`Prostate Cancer CA Cancer J. Clin., May 2002; 52: 154-179,
`or by radiotherapy treatment External beam radiation therapy
`for prostate cancer CA Cancer J. Clin., November 2000; 50:
`349-375. Treatments With antiandrogens or hormone
`manipulations are associated With responses of short duration
`and Without any improvement in the survival time.
`[0005] The use of cytotoxic chemotherapy is not a routine
`treatment, Whereas its role in alleviating the symptoms and
`reducing the levels of PSA (prostate-speci?c antigen) is
`established. No monotherapy has obtained a degree of
`response of greater than 30%; combinations With an effect on
`PSA levels Were tested. No effect on the survival time Was
`seen and, What is more, the toxicity of these treatments,
`particularly on elderly patients, is problematic since, in addi
`tion to their tumour, they are generally suffering from related
`health problems and have a limited reserve of bone marroW.
`[0006] Until recently, the chemotherapies used Were lim
`ited to cyclophosphamide, anthracyclines (doxorubicin or
`mitoxantrone) and estramustine, and the effects of these treat
`ments are relatively mediocre. Palliative effects Were
`observed in patients folloWing the administration of corti
`coids alone or of mitoxantrone With either prednisone or
`hydrocortisone. FolloWing Phase II trials, the combination of
`mitoxantrone With corticoids Was recogniZed as the reference
`treatment for hormone-resistant prostate cancer. More
`recently, treatments With docetaxel in combination With estra
`mustine or prednisone have made it possible to treat cancers
`that are resistant to hormone deprivationAdvances in Pro state
`
`Cancer Chemotherapy: A NeW Era Begins CA Cancer J .
`Clin., September 2005; 55: 300-318, the survival Was
`improved by 2.4 months.
`[0007] It is generally accepted that the responses in
`advanced prostate cancers are dif?cult to evaluate on account
`of the heterogeneity of the disease and the lack of consensus
`regarding the treatment response criteria. Many patients With
`metastatic prostate cancer have no measurable disease, but
`have symptoms dominated by bone metastases. Measurement
`of the PSA level has been found to be a means for evaluating
`novel candidates and also the measurement of the tumour
`When this is possible, the measurement of bone tumours, the
`quality of life and the measurement of the pain.
`[0008] Furthermore, cancer may become resistant to the
`agents used, in particular to taxanes, Which limits the possible
`treatment options. Several taxane resistance mechanisms
`have been described (expression of P-glycoprotein P-gp,
`mdr-1 gene, modi?ed metabolism of taxane, mutation of the
`tubulin gene, etc.): see Drug Resistance Updates 2001, 4(1),
`3-8; J. Clin. Onc. 1999, 17(3), 1061-1070.
`[0009] The technical problem that the invention intends to
`solve is that of providing a novel therapeutic option for treat
`ing prostate cancer, especially for patients Who are not catered
`for by a taxane-based treatment, such as patients With castra
`tion resistant metastatic prostate cancer Who have been pre
`viously treated With docetaxel (sold under the brand name
`Taxotere®) based regimen, an unmet medical need.
`[0010] Four clinical trials on cabaZitaxel are knoWn since
`April 2006. Three monotherapy tests have made it possible to
`determine the maximum tolerated dose and the toxicities at
`the limit doses: these tests Were performed on breast, sarcoma
`and prostate tumours. Doses of 10-30 mg/m2 every three
`hours Were used. A phase II trial Was performed on patients
`With a breast cancer, Who had previously received taxanes and
`anthracyclines as adjuvant (i.e. after a surgery) or as a ?rst
`line treatment. The response levels Were 14.6% as adjuvant
`and 9.5% as second-line treatment.
`
`SUMMARY
`
`[0011] The invention relates to a novel antitumoral phar
`maceutical therapeutic use comprising cabaZitaxel of formula
`
`The invention also relates to methods of treating
`[0012]
`patients With prostate cancer comprising administering an
`effective amount of the antitumoral agent cabaZitaxel to said
`patient.
`
`

`
`US 2012/0301425 A1
`
`Nov. 29, 2012
`
`[0013] This antitumoral agent may be in the form of anhy
`drous base, a hydrate or a solvate, intended for treating pros
`tate cancer, in particular for treating patients Who are not
`catered for by a taXane-based treatment, such as patients Who
`have been previously treated With a docetaXel-based regimen.
`This compound is preferably administered to a patient With
`advanced metastatic disease. In particular, the compound is
`administered to a patient With castration resistant prostate
`cancer. CabaZitaXel is preferably administered in combina
`tion With a corticoid chosen especially from prednisone and
`prednisolone. This corticoid is preferably administered at a
`daily dose of 10 mg orally.
`[0014] In some aspects of the invention, cabaZitaxel is
`administered in combination With prednisone for its use as a
`medicament in the treatment of patients With hormone-refrac
`tory prostate cancer Who have been previously treated With
`docetaxel based regimen.
`[0015] In some aspects of the invention, cabaZitaxel is
`administered at a dose (de?ned for each administration) of
`betWeen 20 and 25 mg/m2. CabaZitaXel may be in the form of
`an acetone solvate. More particularly, the acetone solvate of
`cabaZitaXel contains betWeen 5% and 8% and preferably
`betWeen 5% and 7% by Weight of acetone.
`[0016] In some aspects of the invention, cabaZitaXel may be
`administered by intravenous infusion at a dose of betWeen 15
`and 25 mg/m2, this administration cycle of the antitumour
`agent being repeated at an interval of 3 Weeks betWeen each
`cabaZitaXel administration, Which interval may be prolonged
`by 1 to 2 Weeks depending on the tolerance to the preceding
`cabaZitaXel administration.
`[0017] In some embodiments, the effective amount of caba
`Zitaxel produces at least one therapeutic effect selected from
`the group consisting of increase in overall survival, partial
`response, reduction in tumor siZe, reduction in metastasis,
`complete remission, partial remission, stable disease, or com
`plete response.
`[0018] The present invention also relates to a pharmaceu
`tical composition that treats patients With prostate cancer
`comprising a clinically proven safe and effective amount of
`cabaZitaXel.
`[0019] Further embodiments of the invention comprise
`methods or using, treating, promoting, and providing cabaZi
`taxel.
`[0020] The present invention also relates to packages and
`articles of manufacture.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0021] FIG. 1 displays the Kaplan-Meier curves of the
`overall survival in a cabaZitaxel study.
`[0022] FIG. 2 displays the Kaplan-Meier curves of progres
`sion-free survival in a cabaZitaxel study.
`[0023] FIG. 3 shoWs an intention-to-treat analysis of over
`all survival in subgroups of patients de?ned by baseline char
`acteristics. HaZard ratios<1 favor the cabaZitaxel group,
`While those >1 favor the mitoxantrone group. CI denotes
`con?dence intervals.
`[0024] FIG. 4 graphically depicts the proportion of patients
`With changes in ECOG performance status from baseline
`during treatment (safety population).
`[0025] FIG. 5 graphically depicts the proportion of patients
`With changes from baseline in the Present Pain Intensity score
`during treatment (ITT).
`[0026] FIG. 6 graphically presents the mean area under the
`curve for PPI and analgesic scores by treatment cycle.
`
`[0027] FIG. 7 graphically presents the meanAUC analgesic
`score.
`
`DETAILED DESCRIPTION
`
`De?nitions
`
`[0028] Effective amount, as used herein, means an
`amount of a pharmaceutical compound, such as cabaZi
`taxel, that produces an effect on the cancer to be treated.
`[0029] Clinically proven, as used herein, means clinical
`ef?cacy results that are suf?cient to meet FDA approval
`standards.
`[0030] Castration resistant prostate cancer, as used
`herein, is synonymous With hormone-refractory pro state
`cancer.
`[0031] “Patient,” as used herein, includes both human
`and animals. In one embodiment, a patient is a human.
`CabaZitaXel belongs to the taxoid family and has the
`[0032]
`formula:
`
`[0033] The chemical name of cabaZitaXel is 40t-acetoxy
`20t-benZoyloXy-5[3,20-epoXy-1[3-hydroXy-7[3,10[3
`dimethoxy-9-oXo-1 1-taXen-130t-yl (2R,3S)-3 -tert-butoxy
`carbonyl-amino-2-hydroXy-3-phenylpropionate.
`CabaZitaXel is synonymously knoWn as (2(X,5[3,7[3,10[3,13(X)
`4-acetoXy-13-({(2R,3S)-3 -[(tertbutoxycarbonyl)amino] -2
`hydroXy-3 -phenylpropanoyl}oxy)-1-hydroXy-7,10
`dimethoXy-9-oXo-5 ,20-epoxytaX-1 1-en-2 -yl benZoate.
`[0034] This compound and a preparative method thereof is
`described in WO 96/30355, EP 0 817 779 B1 and US. Pat.
`No. 5,847,170, Which are hereby incorporated herein by ref
`erence.
`[0035] CabaZitaXel may be administered in base form (cf.
`above formula), or in the form of a hydrate. It may also be a
`solvate, i.e. a molecular complex characterized by the incor
`poration of the crystallization solvent into the crystal of the
`molecule of the active principle (see in this respect page 1276
`of.]. Pharm. Sci. 1975, 64(8), 1269-1288). In particular, it
`may be an acetone solvate, and, more particularly, may be the
`solvate described in WO 2005/02846. It may be an acetone
`solvate of cabaZitaXel containing betWeen 5% and 8% and
`preferably betWeen 5% and 7% by Weight of acetone (%
`means content of acetone/content of acetone+cabaZitaXel><
`100). An average value of the acetone content is 7%, Which
`approximately represents the acetone stoichiometry, Which is
`6.5% for a solvate containing one molecule of acetone. The
`procedure described beloW alloWs the preparation of an
`acetone solvate of cabaZitaxel:
`
`

`
`US 2012/0301425 A1
`
`Nov. 29, 2012
`
`[0036] 940 ml of puri?ed Water are added at 20150 C.
`(room temperature) to a solution of 207 g of 40t-acetoxy-20t
`benZoyloxy-5 [3 ,20-epoxy-1 [3-hydroxy-7[3,10[3-dimethoxy
`9-oxo-1 1-taxen-130t-yl
`(2R,3S)-3 -tert-butoxycarbony
`lamino-2-hydroxy-3-phenylpropionate at about 92% by
`Weight in about 2 litres of acetone, followed by seeding With
`a suspension of 2 g of 4a-acetoxy-20t-benZoyloxy-5[3,20
`epoxy-1 [3-hydroxy-7[3,10[3-dimethoxy-9-oxo-1 1-taxen
`130t-yl (2R,3S)-3 -tert-butoxycarbonylamino -2 -hydroxy-3 -
`phenylpropionate 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 puri?ed Water
`are added over 4 to 5 hours. This mixture is stirred for 60 to 90
`minutes, and the suspension is then ?ltered under reduced
`pressure. The cake is Washed on the ?lter With a solution
`prepared from 450 ml of acetone and 550 ml of puri?ed Water,
`and then oven-dried at 55° C. under reduced pressure (0.7
`kPa) for 4 hours. 197 g of 4a-acetoxy-20t-benZoyloxy-5[3,20
`epoxy-1 [3-hydroxy-7[3,10[3-dimethoxy-9-oxo-1 1-taxen
`130t-yl (2R,3S)-3 -tert-butoxycarbonylamino -2 -hydroxy-3 -
`phenylpropionate acetone containing 0.1% Water and 7.2%
`acetone (theoretical amount: 6.5% for a stoichiometric sol
`vate) are obtained.
`[0037] CabaZitaxel may be administered parenterally, such
`as via intravenous administration. A galenical form of caba
`Zitaxel suitable for administration by intravenous infusion is
`that in Which the cabaZitaxel is dissolved in Water in the
`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 sterile vial (80 mg of
`cabaZitaxel+2 ml of solvent+Polysorbate 80) With a sterile
`vial containing a solution of 6 ml of Water and ethanol (13%
`by Weight of 95% ethanol) in order to 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 appro
`priate amount of this ready-to-redilute solution into the per
`fusion bag containing Water and glucose (about 5%) or
`sodium chloride (about 0.9%).
`[0038] CabaZitaxel may be administered in combination
`With a corticoid, such as prednisone or prednisolone, as tWo
`distinct pharmaceutical preparations.
`[0039] Accordingly, one aspect of the invention is a method
`of treating prostate cancer comprising administering to a
`patient in need thereof an effective amount of cabaZitaxel in
`combination With a corticoid, such as prednisone or predniso
`lone.
`[0040] The combination is administered repeatedly accord
`ing to a protocol that depends on the patient to be treated (age,
`Weight, treatment history, etc .), Which can be determined by a
`skilled physician. In one aspect of the invention, cabaZitaxel
`is administered by perfusion to the patient according to an
`intermittent program With an interval betWeen each adminis
`tration of 3 Weeks, Which may be prolonged by 1 to 2 Weeks
`depending on the tolerance to the preceding administration.
`The median number of cycles is 6. The prednisone or pred
`nisolone may be administered daily, for example in the form
`of one dosage intake per day, throughout the duration of the
`treatment. Examples of doses for the tWo antitumoral agents
`are given in the “Example” section. The currently recom
`mended dose is 25 mg/m2 of cabaZitaxel administered as a
`on-hour infusion and 10 mg per day of prednisone or pred
`nisolone administered orally.
`
`[0041] In some aspects of the invention, the patient to be
`treated has pro state cancer that is resistant to hormone therapy
`(i.e., hormone refractory) and has previously been treated
`With docetaxel. In some aspects, the patient has prostate can
`cer that progressed during or after treatment With docetaxel.
`In some aspects, the patient Was previously treated With at
`least 225 mg/m2 cumulative dose of docetaxel. In a particular
`aspect, the patient shoWed progression of their disease in the
`six months folloWing hormone therapy or during docetaxel
`treatment or after docetaxel treatment. In another particular
`aspect, the patient shoWed progression of their disease in the
`three months folloWing hormone therapy or after docetaxel
`treatment.
`[0042] In some aspects of the invention, the patient to be
`treated has a measurable tumour and may shoW progression
`of the disease via a metastatic lesion of the viscera or of a soft
`tissue of at least 1 cm determined by MRI or by an axial
`tomographic scan (CT scan).
`[0043] In some aspects of the invention, the patient to be
`treated has an unmeasurable tumour and may shoW an
`increase in the PSA level With three measurements at a
`1-Week interval or the appearance of neW lesions.
`[0044] In some aspects of the invention, the patient to be
`treated has undergone castration by orchidectomy or With
`LHRH agonists, elimination of the androgens or mono
`therapy With estramustine.
`[0045] In a preferred aspect, the life expectancy of the
`patient to be treated should be at least 2 months.
`[0046] In some aspects, the treatment does not include
`patients Who have previously received mitoxantrone, or Who
`have received less than 225 mg/m2 of docetaxel, or Who have
`undergone a radiotherapy that has eliminated more than 40%
`of the marroW, Who have received a treatment Within the 4
`Weeks preceding the test, Who have a neuropathy or a stoma
`titis, involving the brain or the meninges, Who have shoWn
`severe hypersensitivity to polysorbate or to prednisone,
`Whose blood analysis shoWs an appreciable decrease in neu
`trophils, haemoglobin or platelets, an increase in bilirubin
`and/or liver enZymes and creatinine, or Who have heart prob
`lems or an infection requiring antibiotics.
`[0047] An aspect of the invention comprises increasing the
`survival of a patient With hormone refractory metastatic pros
`tate cancer, comprising administering a clinically proven
`effective amount of cabaZitaxel to the patient in combination
`With prednisone or prednisolone. In a particular aspect, the
`patient has previously been treated With a docetaxel-contain
`ing regimen.
`[0048] CabaZitaxel may be administered in combination
`With a medication to prevent or control nausea and vomiting
`or to prevent or control hypersensitivity to the cabaZitaxel
`treatment. Preferably, a patient is pre-medicated With the
`medication, for example, at least 30 minutes prior to admin
`istering each dose of cabaZitaxel.
`[0049] One aspect of the invention comprises a method of
`reducing the risk of a severe hypersensitivity reaction in a
`patient With prostate cancer being treated With cabaZitaxel,
`comprising administering to the patient a medication to pre
`vent hypersensitivity prior to the administration of cabaZi
`taxel.
`[0050] Severe hypersensitivity reactions to cabaZitaxel can
`occur and may include generaliZed rash/erythema, hypoten
`sion and bronchospasm. Patients should be observed closely
`for hypersensitivity reactions, especially during the ?rst and
`second infusions. Hypersensitivity reactions may occur
`
`

`
`US 2012/0301425 A1
`
`Nov. 29, 2012
`
`Within a feW minutes following the initiation of the infusion of
`cabaZitaxel, thus facilities and equipment for the treatment of
`hypotension and bronchospasm should be available. If severe
`hypersensitivity reaction occurs, cabaZitaxel infusion should
`be immediately discontinued and appropriate therapy should
`be administered. Examples of medications Which may be
`used to prevent hypersensitivity to the cabaZitaxel treatment
`include antihistamines, such as dexchloropheniramine (for
`example 5 mg), and diphenhydramine (for example 25 mg) or
`equivalent antihistamines; and corticosteroids, such as dex
`amethasone (for example 8 mg) or an equivalent steroid.
`[0051] Nevertheless, cabaZitaxel should not be given to and
`may be contraindicated in patients Who have a history of
`severe hypersensitivity reactions to cabaZitaxel. Depending
`on the formulation administered, cabaZitaxel may also be
`contraindicated in patients Who have a history of hypersensi
`tivity reactions to other drugs formulated With polysorbate
`80.
`[0052] One aspect of the invention comprises an article of
`manufacture comprising:
`[0053] a) a packaging material;
`[0054] b) cabaZitaxel, and
`[0055] c) a label or package insert contained Within the
`packaging material indicating that severe hypersensitiv
`ity reactions can occur.
`[0056] Gastrointestinal symptoms, such as, for example
`nausea, vomiting, and diarrhea, may occur With the treatment
`of cabaZitaxel. Mortality related to diarrhea and electrolyte
`imbalance has been reported. Therefore, patients may also be
`rehydrated and treated With anti-diarrheal or anti-emetic
`medications as needed. Treatment delay or dosage reduction
`may be necessary if patients experience Grade§3 diarrhea.
`[0057] Accordingly, the methods of the invention include
`administering a medication to prevent hypersensitivity or a
`medication to prevent or control nausea and vomiting in com
`bination With cabaZitaxel.
`[0058] Examples of medications Which may be used to
`prevent or control nausea and vomiting include histamine H2
`antagonists and antiemetics, such as ondansetron, granisetron
`and dolesetron.
`[0059] A possible side effect of the treatment With cabaZi
`taxel is neutropenia, Which is characterized by a reduced
`number of neutrophils. Unfortunately, a number of neutrope
`nia deaths have been reported. Therefore, frequent blood
`counts should be obtained or performed to monitor for neu
`tropenia. Ifneutropenia occurs, cabaZitaxel treatment may be
`discontinued, and restarted When neutrophil counts recover to
`a level of >l,500/mm3. CabaZitaxel should not be given to a
`patient With a neutrophil count; 1,500 cells/mm3 .
`[0060] The present invention therefore also relates to a
`method of treating prostate cancer With cabaZitaxel compris
`ing administering cabaZitaxel to the patient, monitoring blood
`counts in the patient, and measuring neutrophil levels. In one
`aspect, the method further comprises discontinuing cabaZi
`taxel treatment if neutropenia occurs, and optionally restart
`ing cabaZitaxel treatment When neutrophil counts recover to a
`level of >1 ,500/mm3 . In one aspect, the monitoring comprises
`taking a blood sample from the patient.
`[0061] Determining neutrophil counts can be performed
`according to procedures Well knoW to those skilled in the art.
`[0062] One aspect of the invention is a method of reducing
`the risk of neutropenia complications comprising administer
`ing cabaZitaxel in combination With an agent useful for treat
`ing neutropenia. Such a neutropenia treatment agent is, for
`
`example, a hematopoietic groWth factor Which regulates the
`production and function of neutrophils such as a human
`granulocyte colony stimulating factor, (G-CSF). In a particu
`lar aspect of the invention, the neutropenia is complicated
`neutropenia. Complicated neutropenia includes febrile neu
`tropenia, prolonged neutropenia, or neutropenic infection. In
`a preferred embodiment, the neutropenia treatment agent is
`administered prior to the administration of cabaZitaxel.
`[0063] A particular aspect of the invention comprises a
`method of reducing the risk of neutropenia complications in a
`patient With prostate cancer being treated With cabaZitaxel,
`comprising monitoring blood counts in the patient at regular
`intervals during treatment of the patient With cabaZitaxel;
`reducing the dose of cabaZitaxel if the patient experiences
`febrile neutropenia or prolonged neutropenia; discontinuing
`cabaZitaxel treatment if the patient’s neutrophil count is
`21,500 cells/mm3; and optionally restarting cabaZitaxel
`treatment When the patient’s neutrophil counts recover to a
`level; 1 ,500 cells/mm3.
`[0064] In a particular aspect, primary prophylaxis With
`G-CSF should be considered in patients With high-risk clini
`cal features (age>65 years, poor performance status, previous
`episodes of febrile neutropenia, extensive prior radiation
`ports, poor nutritional status, or other serious co-morbidities)
`that predispose them to increased complications from pro
`longed neutropenia. Therapeutic use of G-CSF and secondary
`prophylaxis should be considered in all patients considered to
`be at increased risk for neutropenia complications.
`[0065] In another aspect, the monitoring of complete blood
`counts is performed on a Weekly basis during cycle 1 and
`before each treatment cycle thereafter so that the dose can be
`adjusted, if needed. Therefore, another aspect for reducing
`the risk of neutropenia complications comprises, monitoring
`blood counts in the patient and adjusting the dose of cabaZi
`taxel. An example of a dose modi?cation is described in
`Example 2.
`[0066] One aspect of the invention comprises an article of
`manufacture comprising:
`[0067] a) a packaging material;
`[0068] b) cabaZitaxel, and
`[0069] c) a label or package insert contained Within the
`packaging material indicating that cabaZitaxel should
`not be given to patients With neutrophil counts of
`21,500 cells/mm3.
`[0070] Cases of renal failure should be identi?ed and man
`aged aggressively, accordingly to procedures knoWn to those
`skilled in the art. Renal failure may be associated With sepsis,
`dehydration, or obstructive uropathy. Furthermore, impaired
`hepatic function (e.g., total bilirubinZULN, or AST and/or
`ALTZI.5><ULN) may increase cabaZitaxel concentrations,
`and cabaZitaxel should not be given to patients With hepatic
`impairment.
`[0071] CabaZitaxel may cause fetal harm When adminis
`tered to a pregnant Woman.
`[0072] Prednisone or prednisolone administered at 10 mg
`daily does not affect the pharmacokinetics of cabaZitaxel.
`[0073] CabaZitaxel is primarily metaboliZed through
`CYP3A. Concomitant administration of strong CYP3A
`inhibitors
`(for example, ketoconaZole, itraconaZole,
`clarithromycin, ataZanavir, indinavir, nefaZodone, nel?navir,
`ritonavir, saquinavir, telithromycin, voriconaZole) may
`increase cabaZitaxel concentrations. Therefore co-adminis
`tration of cabaZitaxel With strong CYP3A inhibitors should
`be avoided. Caution should be exercised With concomitant
`
`

`
`US 2012/0301425 A1
`
`Nov. 29, 2012
`
`use of moderate CYP3A inhibitors. One aspect of the inven
`tion is a method of treating a patient for prostate cancer
`comprising determining Whether the patient is undergoing
`treatment With a CYP3A inhibitor, discontinuing treatment
`With a CYP3A inhibitor, and then administering cabaZitaxel
`to the patient.
`[0074] Concomitant administration of strong CYP3A
`inducer (e.g., phenyloin, carbamaZepine, rifampin, rifabutin,
`rifapentin, phenobarbital) may decrease cabaZitaxel concen
`trations. Therefore co-administration of cabaZitaxel With
`strong CYP3A inducers should be avoided. Therefore, one
`aspect of the invention is a method of treating a patient for
`pro state cancer comprising determining Whether the patient is
`undergoing treatment With a CYP3A inducer, discontinuing
`treatment With a CYP3A inducer, and administering cabaZi
`taxel to the patient.
`[0075] In addition, patients should also refrain from taking
`St. John’s Wort.
`[0076] In some aspects of the invention, the cabaZitaxel is
`administered in an amount to provide an AUC of about 991
`ng~h/mL (CV 34%).
`[0077] In some aspects of the invention, the cabaZitaxel is
`administered in an amount to provide an Cmax of about 226
`ng~h/mL (CV 107%).
`[0078] In some aspects of the invention, the cabaZitaxel is
`administered in an amount to provide a plasma clearance of
`48.5 L/h (CV 39%).
`[0079] One aspect of the invention is a package comprising
`cabaZitaxel and a label, in a position Which is visible to
`prospective purchasers, comprising a printed statement
`Which informs prospective purchasers that the mean Cmax of
`cabaZitaxel in patients With metastatic prostate cancer Was
`226 ng/mL (CV 107%).
`[0080] Another aspect of the invention is a package com
`prising cabaZitaxel and a label, in a position Which is visible
`to prospective purchasers, comprising a printed statement
`Which informs pro