USOO8927592B2
`
`(12) United States Patent
`Gupta
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,927,592 B2
`Jan. 6, 2015
`
`(54) ANTITUMORAL USE OF CABAZITAXEL
`
`(75) Inventor: Sunil Gupta, Chester Springs, PA (US)
`
`(73) Assignee: Aventis Pharma SA, Antony (FR)
`
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 13/456,720
`
`2008/0279923 A1 11/2008 Bradke et al.
`2010.0311825 A1 12/2010 Rortalis et al.
`2011/O105598 A1
`5/2011 Gurjar et al.
`2011/O144362 A1
`6, 2011 Billot et al.
`2011 0160159 A1
`6/2011 Ryan
`2011/0177970 A1
`7, 2011 Chauchereau et al.
`2011/0237540 Al
`9, 2011 Crawford et al.
`2012fOO77845 A1
`3, 2012 Dalton et al.
`2012/0115806 A1
`5/2012 Magherini
`
`EP
`EP
`
`FOREIGN PATENT DOCUMENTS
`O817779
`1, 2000
`217763O
`4/2010
`
`(65)
`
`Prior Publication Data
`
`US 2012/O3O1425A1
`
`Nov. 29, 2012
`
`Related U.S. Application Data
`(63) Continuation of application No. PCT/IB2010/054866,
`filed on Oct. 27, 2010.
`(60) Provisional application No. 61/389,969, filed on Oct.
`5, 2010, provisional application No. 61/383,933, filed
`on Sep. 17, 2010, provisional application No.
`61/369,929, filed on Aug. 2, 2010, provisional
`application No. 61/355,888, filed on Jun. 17, 2010,
`provisional application No. 61/355,834, filed on Jun.
`17, 2010, provisional application No. 61/293.903,
`filed on Jan. 11, 2010, provisional application No.
`61/256,160, filed on Oct. 29, 2009.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A6 IK3I/337
`A 6LX3/573
`A6 IK3I/64
`A6 IK3I/56
`A6 IK 45/06
`(52) U.S. Cl.
`CPC ............. A6 IK3I/337 (2013.01); A61 K3I/I64
`(2013.01); A61 K3I/56 (2013.01); A61 K
`3 1/573 (2013.01); A61K 45/06 (2013.01)
`USPC .......................................................... 514/449
`(58) Field of Classification Search
`CPC ........................... A61K31/337; A61K31/573
`See application file for complete search history.
`
`(56)
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`
`Primary Examiner — James D Anderson
`(74) Attorney, Agent, or Firm — Kelly L. Bender
`
`(57)
`ABSTRACT
`The invention relates to a compound of formula:
`
`
`
`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.
`
`30 Claims, 7 Drawing Sheets
`
`NEPTUNE GENERICS EX. 1048 00001
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`US 8,927,592 B2
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`TAX 327 Study, Journal of Clinical Oncology, vol. 26, No. 2, (2008)
`pp. 242-245.
`
`Merck Index 14th 2006, No. 190, p. 36, Agomelatine.
`Tan, Novel Agents in the Treatment of Hormone-Independent Meta
`static Prostate Cancer, Actas Urol Esp., (2007), vol. 31, No. 6, pp.
`660-685 (followed by non-verified English translation).
`El Docetaxel Asociado a la Prednisona Mejora et Cancer de Prostate,
`Retrieved from the internet on Oct. 26, 2012 Retrieved from http://
`www.rnedicinageriatrica.com.ar/viewnews.
`php?id=EEpVVFZVppsBCOavi.
`Dres, et al., Treatment alternatives for advanced prostate cancer,
`Retrieved from the internet on Jul. 29, 2014 Retrieved from http://
`www.intramed.net/contenidover.asp?contenidoID=37957 (followed
`by non-verified English translation).
`Taxotere (Docetaxel) Mejora Significativamente la Supervivencia de
`los Pacientes con Cancer de Prostate Avanzado, PMFARMA Espana,
`(2007).
`Docetexel Reduce el Riesgo de Muerte en Pacientes con Cancer de
`Prostate Metastatico Androgeno Independiente, Retrieved from the
`internet on Jul. 29, 2014). Retrieved from http://www.intramed.net/
`contenidover.asp?contenidolD=31823 (followed by non-verified
`English translation).
`Cancer de Prostata Diseminado, Quimioterapia. Retrieved from the
`internet on Jul. 29, 2014. Retrieved from http://www.guiasalud.es/
`egpc/cancer prostata resumidal apartado06/otros02.html, pp. 1-9.
`Revision Sistematica y Modelo Economico de Efectividad Clinicay
`Coste-Efectividad de Docetaxel en Combinacion con Prednisonal
`Prednisolona para el Tratamiento de Cancer de Prostata Metastasico
`Refractario a Hormonas, Retrieved from the internet on Jul. 29,
`2014.
`Retrieved
`from
`http://www.sefh.es/sefnboletin/
`vernoticiaboletin.php?id=2663.
`Figg et al., Cabazitaxel Filling One of the Gaps in the Treatment of
`prostate Cancer. Cancer Biology & Therapy, vol. 10. No. 12, pp.
`1233-1234, (2010).
`Mirtsching, Prostate Cancer Clinical Trials in Dallas; Texas Area.
`Retrieved from the Internet on Aug. 19, 2014). Retrieved from
`http://www.healthcentral.com/prostate/c/5618/14589/dallas-texas
`area, pp. 3-4.
`* cited by examiner
`
`NEPTUNE GENERICS EX. 1048 00004
`
`

`

`U.S. Patent
`
`Jan. 6, 2015
`
`Sheet 1 of 7
`
`US 8,927,592 B2
`
`Symbols=Censors
`-o-o-o-MTX-PRED
`e-e-e CBZ--PRED
`
`
`
`
`
`5 O
`
`40
`
`30
`
`20
`
`10
`
`O
`
`O
`Number at Risk
`MTX+PRED 377
`CBZ--PRED 378
`
`6
`
`300
`321
`
`18
`12
`Time (Months
`7
`188
`231
`90
`
`24
`
`30
`
`1
`11
`4.
`28
`(230CT2009–16:27)
`
`FIG. 1
`
`NEPTUNE GENERICS EX. 1048 00005
`
`

`

`U.S. Patent
`
`Jan. 6, 2015
`
`Sheet 2 of 7
`
`US 8,927,592 B2
`
`Symbols=Censors
`-o-o-o-MTX-PRED
`e-ee-CBZ--PRED
`
`100
`
`90
`
`
`
`i
`
`O
`Number at Risk
`MTX-PRED 377
`CBZ--PRED 378
`
`3
`
`105
`168
`
`6
`
`52
`90
`
`12
`9
`Time (Months)
`27
`9
`52
`15
`
`15
`
`6
`4.
`
`18
`
`21
`
`2
`4
`O
`O
`2009-13:54
`
`FIG. 2
`
`NEPTUNE GENERICS EX. 1048 00006
`
`

`

`U.S. Patent
`
`Jan. 6, 2015
`
`Sheet 3 of 7
`
`US 8,927,592 B2
`
`Factor
`All rondomized potients
`ECOG status; 0,1
`ECOG status: 2
`Measurable disease: No
`Measurable disease: Yes
`No. of prior chemotherapies: 1
`No. of prior chemotherapies: 22
`Age: {65 years
`Age: 265 years
`Rising PSA at baseline: No
`Rising PSA otbOSeline: Yes
`Total docetoxel dose: K225 mg/m2
`Total docetoxel dose: x225 to 450 mg/m2
`Total docetoxel dose: X450 to 675 mg/m2
`Total docetoxel dose: X675 to 900 mg/m2
`Total docetoxel dose: 2900 mg/m2
`Progression during docetaxel treatment
`Progression <5 months after docetoxel
`Progression 25 months after docetoxel
`
`Potient
`number
`755
`694
`61
`350
`405
`528
`227
`295
`460
`159
`585
`59
`206
`217
`131
`134
`219
`539
`192
`
`HOZOrd ratio
`Favors Cobozitoxel | Fovors Mitoxontrone)
`(95% CI)
`-H
`070 (0.59–0.83)
`-H
`0.68 (057-082)
`0.81 (0.48-138) -H
`072 (0.55–0.93)
`--
`0.68 (054–0.85)
`-H
`0.67 (0.55-083)
`-OH
`O75 (0.55-1.02)
`-OH
`0.81 (0.61-1.08)
`---
`062 (050-078)
`-H
`0.88 (0.61-126)
`-H
`0.65 (0.53–0.80)
`--
`0.96 (O49–186) -OH
`0.60 (0.43-084)
`-H
`0.83 (0.60–1,16)
`-H
`O75 (0.48-110)
`-OH
`0.53 (0.47–0.90)
`-H
`O.68 (057-082)
`-H
`O.70 (0.55-091)
`-H
`O75 (0.51-1.11)
`-H
`2
`0.5
`1
`15
`O
`Hozard ratio and 95% confidence interval
`
`FIG 3
`
`NEPTUNE GENERICS EX. 1048 00007
`
`

`

`U.S. Patent
`
`Jan. 6, 2015
`
`Sheet 4 of 7
`
`US 8,927,592 B2
`
`80.0%
`
`70.0%
`
`60.0%
`
`50.0%
`
`40.0%
`
`30.0%
`
`
`
`20.0%
`
`10.0%
`
`0.0%
`
`79.5%. 78.0%
`
`19.0%. 19.3%
`
`Improve
`(n=12)
`
`Stable
`(n=567)
`
`Worse
`(n=142)
`
`Treatment
`4
`CBZ--PRED
`OMTX-PRED 8
`
`EC00 Categories
`
`283
`283
`
`70
`72
`
`FIG. 4
`
`NEPTUNE GENERICS EX. 1048 00008
`
`

`

`U.S. Patent
`
`Jan.
`6, 2015
`
`Sheet 5 Of 7
`
`US 8,927,592 B2
`
`50.0%
`
`40.0%
`
`
`
`30.0%
`
`20.0%
`
`10.0%
`
`0.0%
`
`40.7%
`
`J2.4%. 32.1%
`
`Improve
`(n=130)
`
`Stable
`(n=315)
`
`Worse
`(n=212)
`
`Treatment
`CBZ--PRED
`DMTX-PRED
`
`4.
`8
`
`PPI Categories
`
`283
`285
`
`70
`72
`
`FIG. 5
`
`NEPTUNE GENERICS EX. 1048 00009
`
`

`

`U.S. Patent
`
`Jan. 6, 2015
`
`Sheet 6 of 7
`
`US 8,927,592 B2
`
`se-le-sk MTX-PRED
`-o-o-e CBZ--PRED
`
`
`
`160
`150
`140
`130
`120
`110
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`
`NEPTUNE GENERICS EX. 1048 00010
`
`

`

`U.S. Patent
`
`Jan. 6, 2015
`
`Sheet 7 Of 7
`
`US 8,927,592 B2
`
`se-le-sk MTX-PRED
`-o-o-e CBZ--PRED
`
`
`
`3000
`2700
`
`2400
`2100
`1800
`1500
`1200
`900
`600
`300
`
`NEPTUNE GENERICS EX. 1048 00011
`
`

`

`US 8,927,592 B2
`
`1.
`ANTITUMIORALUSE OF CABAZTAXEL
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of International Appli
`cation No. PCT/IB2010/054866, filed Oct. 27, 2010, which
`claims the benefit of priority of U.S. Provisional Application
`No. 61/256,160, filed Oct. 29, 2009, U.S. Provisional Appli
`cation No. 61/293,903, filed Jan. 11, 2010, U.S. Provisional
`Application No. 61/355,834, filed Jun. 17, 2010, U.S. Provi
`sional Application No. 61/355,888, filed Jun. 17, 2010, U.S.
`Provisional Application No. 61/369,929, filed Aug. 2, 2010,
`U.S. Provisional Application No. 61/383,933, filed Sep. 17,
`2010, and U.S. Provisional Application No. 61/389,969, filed
`Oct. 5, 2010, all of which are incorporated herein by refer
`CCC.
`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.
`
`10
`
`15
`
`25
`
`BACKGROUND
`
`2
`It is generally accepted that the responses in advanced
`prostate cancers are difficult to evaluate on account of the
`heterogeneity of the disease and the lack of consensus regard
`ing the treatment response criteria. Many patients with meta
`static 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.
`Furthermore, cancer may become resistant to the agents
`used, in particular to taxanes, which limits the possible treat
`ment options. Several taxane resistance mechanisms have
`been described (expression of P-glycoprotein P-gp, mdr-1
`gene, modified 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.
`The technical problem that the invention intends to solve is
`that of providing a novel therapeutic option for treating pros
`tate cancer, especially for patients who are not catered for by
`a taxane-based treatment, Such as patients with castration
`resistant metastatic prostate cancer who have been previously
`treated with docetaxel (sold under the brand name TaxotereR)
`based regimen, an unmet medical need.
`Four clinical trials on cabazitaxel are known since April
`2006. Three monotherapy tests have made it possible to deter
`mine 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/m 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 first
`line treatment. The response levels were 14.6% as adjuvant
`and 9.5% as second-line treatment.
`
`SUMMARY
`
`The invention relates to a novel antitumoral pharmaceuti
`cal therapeutic use comprising cabazitaxel of formula
`
`
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Prostate cancer affects a large proportion of the male popu
`lation 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 J. Clin., 2005, 55, 74-108). It is the most
`frequently occurring cancer in men after lung cancer.
`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.
`The use of cytotoxic chemotherapy is not a routine treat
`ment, whereas its role in alleviating the symptoms and reduc
`ing the levels of PSA (prostate-specific antigen) is estab
`lished. 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 eld
`erly patients, is problematic since, in addition to their tumour,
`they are generally suffering from related health problems and
`have a limited reserve of bone marrow.
`Until recently, the chemotherapies used were limited to
`cyclophosphamide, anthracyclines (doxorubicin or mitox
`antrone) and estramustine, and the effects of these treatments
`are relatively mediocre. Palliative effects were observed in
`patients following the administration of corticoids alone or of
`mitoxantrone with either prednisone or hydrocortisone. Fol
`lowing Phase II trials, the combination of mitoxantrone with
`corticoids was recognized as the reference treatment for hor
`mone-resistant prostate cancer. More recently, treatments
`with docetaxel in combination with estramustine or pred
`nisone have made it possible to treat cancers that are resistant
`to hormone deprivation Advances in Prostate Cancer Chemo
`therapy: A New Era Begins CA Cancer J. Clin. September
`2005:55:300-318, the survival was improved by 2.4 months.
`
`60
`
`65
`
`The invention also relates to methods of treating patients
`with prostate cancer comprising administering