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`US008927592B2
`
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`
`(12) United States Patent
`Gupta
`
`US 8,927,592 B2
`(io) Patent No.:
`(45) Date of Patent:
`Jan. 6, 2015
`
`(54) ANTITUMORAL USE OF CABAZITAXEL
`
`(75)
`
`Inventor: Sunil Gupta, Chester Springs, PA (US)
`
`(73) Assignee: Aventis Pharma SA, Antony (FR)
`
`( * ) Notice:
`
`term
`the
`Subject to any disclaimer,
`patent is extended or adjusted under 35
`days.
`U.S.C. 154(b) by 0
`
`of
`
`2008/0279923 A1
`2010/0311825 A1
`2011/0105598 A1
`2011/0144362 A1
`2011/0160159 A1
`2011/0177970 A1
`2011/0237540 A1
`this
`2012/0077845 A1
`2012/0115806 A1
`
`11/2008 Bradke et al.
`12/2010 Rortaisetal.
`5/2011 Gurjar et al.
`6/2011 Billot etal.
`6/2011 Ryan
`7/2011 Chauchereau et
`9/2011 Crawford et al.
`3/2012 Daltonetal.
`5/2012 Magherini
`
`al.
`
`FOREIGN PATENT DOCUMENTS
`
`(21) Appl.No.: 13/456,720
`
`(22) Filed:
`
`Apr. 26, 2012
`
`(65)
`
`Prior Publication Data
`US 2012/0301425 Al 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,
`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.
`
`EP
`EP
`FR
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`filed
`WO
`
`0817779
`2177630
`2732340
`WO 94/18164
`WO 96/30355
`WO 96/30356
`WO 00/10547
`WO 2005/028462
`WO 2006/062811
`WO 2010/117668
`WO 2010/128258
`WO 2011/051894
`WO 2011/063421
`WO 2011/124669
`WO 2011/130317
`WO 2011/130566
`
`1/2000
`4/2010
`10/1996
`8/1994
`10/1996
`10/1996
`3/2000
`3/2005
`6/2006
`10/2010
`11/2010
`5/2011
`5/2011
`10/2011
`10/2011
`10/2011
`OTHER PUBLICATIONS
`
`Mita et al. Clinical Cancer
`2009,
`Research,
`
`
`2004, Med., vol. 351, pp. 1502-1512.*
`J.
`Tannock et al. N. Engl.
`
`Opinions in Supportive and
`Palliative
`Beardsley et al. Current
`Sep. 2008, vol. 2, pp.
`161-166*
`(Continued)
`
`vol.
`
`15,
`
`Care,
`
`(51) Int. CI.
`A6IK 31/337
`A61K 31/573
`A61K 31/164
`A6IK 31/56
`A6 IK 45/06
`(52) U.S. CI.
`CPC
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Primary Examiner — James D Anderson
`(74) Attorney, Agent, or Firm — Kelly L. Bender
`
`ABSTRACT
`(57)
`The invention relates to a compound of
`
`formula:
`
`(2013.01); A61K31/164
`.... A61K31/337
`(2013.01); A61K31/56
`(2013.01); A61K
`31/573 (2013.01); A61K45/06
`(2013.01)
`514/449
`
`USPC
`(58) Field of Classification Search
`CPC
`A61K 31/337; A61K 31/573
`search history.
`See application file for complete
`
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`V
`
`(56)
`
`References Cited
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`
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`5,847,170 A
`5,889,043 A
`5,962,705 A
`6,160,135 A
`6,331,635 B1
`6,346,543 B1
`6,372,780 B2
`6,387,946 B1
`6,403,634 B1
`7,241,907 B2
`7,772,274 B1
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`2004/0126379 Al
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`2005/0070496 Al
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`
`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.
`
`514/173
`
`30 Claims, 7 Drawing Sheets
`
`MYLAN - EXHIBIT 1001
`
`

`
`US 8,927,592 B2
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`Advanced Solid Cancer, Web Site, (Jul. 22, 2009), pp. 1-7 [retrieved
`on Jan. 6, 2014].
`Sanofi-Aventis Press Release: Sanofi-Aventis Delivers 2008 Results
`Above Guidance, (2009), Feb. 11, pp. 1-27.
`Numata, et al., The Preliminary Results of Docetaxel-Prednisolone
`Combination Therapy for the Japanese Pateients With Hormone-
`Refractory Prostate Cancer, Acta Urol. Jpn., vol. 53, pp. 93-97,
`(2007).
`Miura, et al., A Case of Hormone-Refractory Prostate Cancer
`(HRPC) With Tumor Fever Responding to Docetaxel Plus
`Prednisolone Therapy, Jpn J Cancer Chemother, vol. 33, No. 6, pp.
`841-844, (2006).
`Shimazui, et al., Three-Weekly Docetaxel With Prednisone is Fea­
`sible for Japanese Patients With Hormone-Refractory Prostate Can­
`cer: A Retrospective Comparative Study With Weekly Docetaxel
`Alone, Jpn J Clin Oncol, (2007), vol. 37, No. 8, pp. 603-808.
`Kola, et al., Can the Pharmaceutical Industry Reduce Attrition
`Rates?, Nature Reviews Drug Discovery, vol. 3, (2004), pp. 711-715.
`Dimasi, et al., Trends in Risks Associated With New Drug Develop­
`ment: Success Rates for Investigational Drugs, Nature, vol. 87, No. 3,
`pp. 272-277,(2010).
`Bertold, et al., Docetaxel Plus Prednisone or Mitoxantrone Plus
`Prednisone for Advanced Prostate Cancer: Updated Survival in the
`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=EEpVVFZVppsBCjOavj.
`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).
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`Prostate Metastatico Androgeno Independiente, [Retrieved from the
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`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/resumida/apartado06/otros02.html, pp. 1-9.
`Revision Sistematica y Modelo Economico de Efectividad Clinica y
`Coste-Efectividad de Docetaxel en Combinacion con Prednisona/
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`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).
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`[Retrieved from the Internet on Aug. 19, 2014]. Retrieved from
`http://www.healthcentral.eom/prostate/c/5618/14589/dallas-texas-
`area, pp. 3-4.
`• cited by examiner
`
`

`
`U.S. Patent
`
`Jan. 6, 2015
`
`Sheet 1 of 7
`
`US 8,927,592 B2
`
`Symbols=Censors
`MTX+PRED
`O O o CBZ+PRED
`
`10(H
`
`90-
`
`80-
`
`O
`^ 70-
`3
`CO
`
`60-
`
`<u
`o 50-
`
`40-
`
`C o
`"g 30-
`Q_
`O
`Q- 20-
`
`10-
`
`0 -
`
`0
`Number at Risk
`MTX+PRED
`377
`CBZ+PRED
`378
`
`6
`
`300
`321
`
`12
`Time
`188
`231
`
`18
`(Months^
`7
`90
`
`24
`
`30
`
`1
`1 1
`28
`4
`(230CT2009-16:27)
`
`FIG. 1
`
`

`
`U.S. Patent
`
`Jan. 6, 2015
`
`Sheet 2 of 7
`
`US 8,927,592 B2
`
`10(H
`
`90-
`
`80- ^
`
`70-
`
`CO
`Li_
`B- 60-
`O
`«= 50-
`O
`-c
`e 40-
`Q_
`O
`^ 30-
`
`20-
`
`10-
`o-
`
`0
`Number at Risk
`MTX+PRED
`377
`CBZ+PRED
`378
`
`Symbols=Censors
`MTX+PRED
`O O o CBZ+PRED
`
`3
`
`105
`168
`
`6
`
`52
`90
`
`12
`9
`Time (Months)
`27
`9
`52
`15
`
`•ec
`
`15
`
`6
`4
`
`1 8
`
`21
`
`4
`0
`2009-13:54
`
`2
`0
`
`FIG. 2
`
`

`
`U.S. Patent
`
`Jan. 6, 2015
`
`Sheet 3 of 7
`
`US 8,927,592 B2
`
`Factor
`All randomized patients
`ECOG status: 0,1
`ECOG status: 2
`Measurable disease: No
`Measurable disease: Yes
`No. of prior chemotherapies: 1
`No. of prior chemotherapies: ^2
`Age: <65 years
`Age: ^65 years
`Rising PSA at baseline: No
`Rising PSA at baseline: Yes
`Total docetaxel dose: <225 mg/m^
`Total docetaxel dose: ^225 to 450 mg/m?
`Total docetaxel dose: ^450 to 675 mg/m^
`Total docetaxel dose: ^675 to 900 mg/m^
`Total docetaxel dose: ^900 mg/m^
`Progression during docetaxel treatment
`Progression <3 months after docetaxel
`Progression ^3 months after docetaxel
`
`Patient
`number
`755
`694
`61
`350
`405
`528
`227
`295
`460
`159
`583
`59
`206
`217
`131
`134
`219
`339
`192
`
`Hazard ratio
`(95% CI)
`0.70 (0.59-0.83)
`0.68 (0.57-0.82)
`0.81 (0.48-1.38)
`0.72 (0.55-0.93)
`0.68 (0.54-0.85)
`0.67 (0.55-0.83)
`0.75 (0.55-1.02)
`0.81 (0.61-1.08)
`0.62 (0.50-0.78)
`0.88 (0.61-1.26)
`0.65 (0.53-0.80)
`0.96 (0.49-1.86)
`0.60 (0.43-0.84)
`0.83 (0.60-1.16)
`0.73 (0.48-1.10)
`0.53 (0.47-0.90)
`0.68 (0.57-0.82)
`0.70 (0.55-0.91)
`0.75 (0.51-1.11)
`
`^Favors Cabazitaxel
`
`Favors Mitoxantrone^
`
`•­
`—•—
`
`-•—
`—•­
`—•­
`
`•
`
`—•­
`
`-•
`—•­
`—•­
`
`—•—
`
`—•-
`1
`2
`1.5
`0.5
`O
`Hazard ratio and 95% confidence interval
`
`FIG. 3
`
`

`
`U.S. Patent
`
`Jan. 6, 2015
`
`Sheet 4 of 7
`
`US 8,927,592 B2
`
`80.0% i
`
`CD
`% 70.0%-
`D
`-Q
`E 60.0%-
`o
`OJ 50.0%-
`-I 40.0%-
`o
`o 30.0%-
`o
`LU
`'S 20.0%-
`a
`8 10.0%-
`(U
`D_
`
`0.0%
`
`79-3% 78.0%
`
`19.0% 19.3%
`
`1.1% 2.2%
`I
`1
`Improve
`(n=12)
`
`Stable
`(n=567)
`
`Worse
`(n=142)
`
`Treatment
`CBZ+PRED
`l=l MTX+PRED
`
`4
`8
`
`EC0G Categories
`
`283
`283
`
`70
`72
`
`FIG. 4
`
`

`
`U.S. Patent
`
`Jan. 6, 2015
`
`Sheet 5 of 7
`
`US 8,927,592 B2
`
`50.0% i
`
`CD
`% 40.0%-
`o -Q
`E
`vt 30.0%-
`<D cr> c.
`o
`o 20.0%-
`o
`c:
`8 10.0%-
`<u
`Q_
`
`0.0%
`
`40.7%
`
`46.2%
`
`32.4% 32.1%
`
`21.3%
`
`18.2%
`
`Improve
`(n=130)
`
`Stable
`(n=315)
`
`Worse
`(n=212)
`
`Treatment
`CBZ+PRED
`• MTX+PRED
`
`4
`8
`
`PPI Categories
`
`283
`283
`
`70
`72
`
`FIG. 5
`
`

`
`U.S. Patent
`
`Jan. 6, 2015
`
`Sheet 6 of 7
`
`US 8,927,592 B2
`
`160-d
`x 150
`-§ 140
`£ 130
`•1 120
`^ 110
`1 100
`S 90
`£ 80
`_ 70
`0 60
`o
`=> 50
`<
`1 40
`^ 30
`£ 20
`£ 10
`0^
`
`MTX+PRED
`CBZ+PRED
`
`X
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`Cycle
`
`6
`
`7
`
`8
`
`9
`
` 1
`
`0
`
`
`
`FIG. 6
`
`

`
`U.S. Patent
`
`Jan. 6, 2015
`
`Sheet 7 of 7
`
`US 8,927,592 B2
`
`MTX+PRED
`CBZ+PRED
`
`j I
`
`<
`
`3000­
`
`2700­
`
`0)
`8 2400-
`CO
`2100-
`-I 1800-
`Z 1500-
`
`o
`o 1200-
`=>
`<
`a> cn
`o
`a>
`
`900-
`
`600-
`
`300-
`o-i
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`Cycle
`
`6
`
`7
`
`8
`
`9
`
` 1
`
`0
`
`
`
`FIG. 7
`
`

`
`US 8,927,592 B2
`
`1
`ANTITUMORAL USE OF CABAZITAXEL
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`10
`
`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-
`ence.
`The present invention relates to a novel antitumoral use of
`cabazitaxel in the treatment of prostate cancer, which may be 20
`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 25
`unmet medical need.
`
`15
`
`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-
`5 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. One. 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 Taxotere®)
`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/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 first-
`line treatment. The response levels were 14.6% as adjuvant
`and 9.5% as second-line treatment.
`
`The invention relates to a novel antitumoral pharmaceuti­
`cal therapeutic use comprising cabazitaxel of formula
`
`Prostate cancer affects a large proportion of the male popu- 30
`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 35
`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: 40
`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- 45
`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- 50
`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- 55
`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
`The invention also relates to methods of treating patients
`mitoxantrone with either prednisone or hydrocortisone. Fol­
`with prostate cancer comprising administering an effective
`lowing Phase II trials, the combination of mitoxantrone with 60 amount of the antitumoral agent cabazitaxel to said patient,
`corticoids was recognized as the reference treatment for hor­
`This antitumoral agent may be in the form of anhydrous
`mon