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`
`the
`
`International application number: PCT/IB2010/054866
`
`International filing date:
`
`27 October 2010 (27.10.2010)
`
`Document type:
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`Certified copy of priority document
`
`Document details:
`
`Country/Office: US
`61/355,834
`Number:
`17 June 2010 (17.06.2010)
`Filing date:
`
`Date of receipt at the International Bureau: 17 November 2010 (17.11.2010)
`
`Remark: Priority document submitted or transmitted to the International Bureau in
`compliance with Rule 17.1(a),(b) or (b-bis)
`
`HIPO
`RMM
`
`World Intellectual Property Organization (WIPO) - Geneva, Switzerland
`Organisation Mondiale de la Propriete Intellectuelle (OMPI) - Geneve, Suisse
`
`00001
`
`MYLAN - EXHIBIT 1007
`
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`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`
`I
`1
`
`August 27, 2010
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
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`USC
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`
`APPLICATION NUMBER: 61/355,834
`FILING DATE: June 17, 2010
`
`PRIORITY
`YOUR
`ABROAD
`UNDER
`
`,',M E
`• :,\y i
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`i
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`i'.vi; Sa?
`
`the
`By Authority of
`for
`Under Secretary of Commerce
`and Director of
`the United States
`
`Intellectual
`Patent
`and
`
`Property
`Trademark
`
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`I THE COUNTRY CODE AND NUMBER OF
`w Wi
`APPLICATION, TO BE USED
`FOR FILING
`IS'
`CONVENTION, IS US61/355,834
`i i
`i V T *
`1! g
`
`• mfa
`
`.'MONTGO
`Certifying Officer
`
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`00002
`
`

`
`Electronic Acknowledgement Receipt
`
`EFS ID:
`
`Application Number:
`
`7836696
`
`61355834
`
`International Application Number:
`
`Confirmation Number:
`
`6302
`
`Title of Invention:
`
`NOVEL ANTITUMORAL USE OF CABAZITAXEL
`
`First Named Inventor/Applicant Name:
`
`Sunil GUPTA
`
`Customer Number:
`
`05487
`
`Filer:
`
`Kelly L Bender/Linda Remer
`
`Filer Authorized By:
`
`Kelly L. Bender
`
`Attorney Docket Number:
`
`FR2009/121 U5PSP2
`
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`
`Provisional
`
`yes
`
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`
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`
`3310
`
`181982
`
`Authorized User
`The Director of the USPTO is hereby authorized to charge indicated fees and credit any overpayment as follows:
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`Charge any Additional Fees required under 37 C.F.R. Section 1.21 (Miscellaneous fees and charges)
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`100616
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`43120bbe756c60c12lde24e878f2l627322
`72d41
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`no
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`Application Data Sheet
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`26
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`29480
`
`4
`
`Fee Worksheet (PTO-875)
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`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`sanofi-aventis Docket No. FR2009/121 US PSP2
`
`In re Application of:
`GUPTA
`
`Application No.:
`Not Yet Assigned
`
`Filed:
`Concurrently Herewith
`
`Examiner:
`Not Applicable
`
`Art Unit:
`Not Applicable
`
`Conf. No.:
`Not Yet Assigned
`
`Title
`
`
`NOVEL ANTITUMORAL USE OF CABAZITAXEL
`
`CERTIFICATE OF EFS-WF.B TRANSMISSION
`
`
`is I hereby certify that the correspondence below being transmitted via the
`USPTO's electronic filing system in accordance with 1.6(aX4),
`on
`
`17 June 2010
`Date of Deposit
`
`Signature"
`
`/I.inda J. Remer/
`
`TO: Commissioner for Patents
`P. O. Box 1450
`Alexandria, VA 22313-1450
`
`Attached are the following documents:
`
`Application Data Sheet
`
`Drawings
`
`1449
`
`M
`• Declaration
`• Extension of Time
`• Information Disclosure Statement and Form
`• Response to
`•
`
`Specification, Claims and Abstract
`
`Number of Pages
`4
`
`2
`
`Specification
`Claims
`Abstract
`
`• Transmittal Letter:
`121
`• Other (specify):
`• Other (specify):
`
`Other (specify):
`
`Provisional Application
`
`26
`
`sanofi-aventis U.S. Inc., Route 202-206, P.O. Box
`
`6800,
`
`Bridgewater, New
`
`
`
`Jersey 08807, www.sanofi-avenlis.com U.S.A.
`
`
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
`
`00006
`
`

`
`FR2009/121 US PSP2
`
`NOVEL ANTITUMORAL USE OF CABAZITAXEL
`
`I
`
`5
`
`invention relates to a novel antitumoral use of cabazitaxel in the treatment of prostate
`The present
`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.
`
`1 0
`
`15
`
`2 0
`
`25
`
`30
`
`35
`
`[Technical problem]
`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 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
`
`
`
`The State of Hormonal Therapy Current for Prostate Cancer
`surgical excision of
`the
`testicles
`CA Cancer J. Clin., May 2002; 52: 154-179, or by radiotherapy treatment External beam
`radiation therapy
`for prostate
`cancer
`CA Clin., Nov. 2000; 50: Cancer J.
`
`
`
`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
`in
`role
`its
`routine treatment, whereas
`
`symptoms and reducing the levels of PSA (prostate-specific 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 addition to
`they are generally
`suffering
`
`from health problems and have a limited reserve related
`
`their tumour,
`of bone marrow.
`
`alleviating
`
`Until recently, the chemotherapies used were limited to cyclophosphamide, anthracyclines
`(doxorubicin or mitoxantrone) and
`estramustine,
`
`and these treatmients are the effects relatively
`
`
`
`mediocre. Palliative effects were observed in patients following the administration of corticoids
`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
`combination
`hormone-resistant prostate cancer. More recently,
`treatments with
`docetaxel
`in
`estramustine or prednisone have made
`it
`
`
`to possible treat cancers that are resistant to
`hormone
`deprivation Advances In Prostate Cancer Chemotherapy: A New Era Begins CA Cancer J.
`
`Clin., Sep. 2005; 55: 300-318, the survival was improved by 2.4 months.
`
`of
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
`
`00007
`
`

`
`FR2009/121 US PSP2
`
`It is generally accepted that the responses in advanced prostate cancers are difficult to evaluate
`on account of
`the
`heterogeneity
`the of disease and the
`
`
`lack of
`consensus
`regarding
`response criteria. Many patients with metastatic prostate
`
`
`cancer no measurable disease, but have
`
`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.
`
`the
`
`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, 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 prostate 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
`
`
`under (sold 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 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 surgery) or as a first-(i.e.
`
`
`line treatment. The response levels were 14.6% as adjuvant and 9.5% as second-line treatment.
`
`after
`
`[Brief description of the invention]
`The invention relates to a novel antitumoral pharmaceutical therapeutic use comprising
`cabazitaxel of formula
`
`10
`
`15
`
`2 0
`
`25
`
`30
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
`
`00008
`
`

`
`FR2009/121 US PSP2
`
`H3C
`
`H3C
`
`CHg
`
`o
`
`O
`
`HN
`
`H
`
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`
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`
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`
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`5
`
`1 0
`
`15
`
`2 0
`
`25
`
`The invention also relates to methods of treating patients with prostate cancer comprising
`
`administering an effective amount of the antitumorai agent cabazitaxel to said patient.
`
`This antitumorai agent may
`solvate, for
`
`a
`or
`in anhydrous base, a hydrate the form of
`
`
`
`
`be
`treating prostate 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
`cancer. Cabazitaxel is preferably administered in combination with a corticoid chosen especially
`from prednisone and prednisolone. This corticoid is preferably administered at a daily dose of 10
`mg orally.
`
`patient
`
`intended
`
`In some aspects of the invention, cabazitaxel is administered at a dose (defined 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.
`
`In some aspects of the invention, cabazitaxel may be administered by intravenous infusion at a
`dose of between 20 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.
`
`In some embodiments, the effective amount of cabazitaxel produces at least one therapeutic
`effect selected from the group consisting of increase in overall survival, partial response,
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
`
`00009
`
`

`
`FR2009/121 US PSP2
`
`reduction in tumor size, reduction in metastasis, complete remission, partial remission, stable
`disease, or complete
`response.
`
`invention also relates
`The present
`prostate cancer
`comprising a
`
`that
`composition
`pharmaceutical
`to a
`
`
`safe clinically proven effective amount of cabazitaxel. and
`
`
`5
`
`treats
`
`patients
`
`Further embodiments of the invention comprise methods or using, treating, promoting, and
`providing cabazitaxel.
`
`10
`
`The present
`
`invention also relates
`
`to packages
`
`and
`
`
`
`articles manufacture. of
`
`
`
`[Brief Description
`Figure 1 displays
`
`of the Drawings]
`
`
`
`the Kaplan-Meier curves of the overall survival in a cabazitaxel study.
`
`15
`
`
`
`Figure 2 displays the Kaplan-Meier curves of progression-free survival in a cabazitaxel study.
`
`such as
`
`[Description of the invention]
`Definitions
`• Effective amount, as used herein, means an amount of a pharmaceutical compound,
`cabazitaxel, that produces
`an
`
`effect on the cancer
`
`to be treated.
`• Clinically proven, as
`
`used herein, means
`clinical efficacy results that
`FDA approval standards.
`• Castration resistant prostate cancer, as used herein, is synonymous with hormone-refractory
`prostate cancer.
`• "Patient," as
`used herein, includes both human and animals. In one embodiment, a patient is
`a human.
`
`2 0
`
`25
`
`are
`
`sufficient
`
`to
`
`Cabazitaxel belongs
`
`to
`
`the
`
`taxoid family and
`
`has
`
`the
`
`formula:
`
`Copy provided by USPTO from the
`
`IFW Image Database
`
`on
`
`08/24/2010
`
`00010
`
`

`
`FR2009/121 US PSP2
`
`~ 5 ~
`
`H3C
`
`H3C
`
`CH.
`
`O
`
`O
`
`H N ^
`
`H
`
`O
`
`"30
`
`Oil""
`
`o'
`HO
`
`H
`
`CH3
`
`CH
`
`HO
`o
`
`o
`
`CH
`I
`o
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`•
`o
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`CH3
`
`H ^ o y
`
`o
`
`5
`
`10
`
`15
`
`2 0
`
`25
`
`The chemical name
`4a-acetoxy-2a-benzoyloxy-50,2O-epoxy-10-hydroxy-7p,1O3-
`is
`of cabazitaxel
`dimethoxy-9-oxo-11-taxen-13a-yl
`(2R,3S)-3-te/t-butoxycarbonylamino-2-hydroxy-3-
`phenylpropionate. Cabazitaxel is synonymously known as
`(2a,5|3,7|3,10|3,13a)-4-acetoxy-13-
`({(2R,3S)-3-[(tertbutoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1 -hydroxy-7,10-
`dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate.
`
`779
`
`B1
`
`817
`in WO 96/30355, EP 0
`This compound and a preparative method thereof is described
`and US 5 847 170. 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
`incorporation of the crystallization solvent into the crystal of the molecule of the active principle
`(see in this respect page 1276 of J. 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
`of value 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:
`
`940 ml of purified water are added at 20±5oC (room temperature)
`to a solution of 207 g of 4a-
`acetoxy-2a-benzoyloxy-50,2O-epoxy-1 P-hydroxy-7P,10P-dimethoxy-9-oxo-11-taxen-13a-yl
`(2R,3S)-3-fert-butoxycarbonylamino-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-2a-
`benzoyloxy-5p,20-epoxy-13-hydroxy-7p,10P-dimethoxy-9-oxo-11-taxen-13a-yl
`(2R,3S)-3-fert-
`butoxycarbonylamino-2-hydroxy-3-phenylpropionate isolated from acetone/water in a mixture of
`
`Copy provided by USPTO from the
`
`IFW Image Database
`
`on 08/24/2010
`
`00011
`
`

`
`FR2009/121 US PSP2
`
`J
`to 22 hours, and
`resulting mixture is stirred for about 10
`20 ml of water and 20 ml of acetone. The
`
`over hours. This mixture is stirred 4 to 5
`
`
`
`for 60
`to 90
`1.5 litres of purified water are
`added
`and the suspension
`
`is then filtered under reduced pressure. The cake is washed on the filter with
`a solution prepared from 450 ml of acetone and 550 ml of purified water, and then oven-dried at
`-55CC under reduced pressure (0.7 kPa) for 4 hours. 197 g of 4a-acetoxy-2a-benzoyloxy-5p,20-
`epoxy-1 p-hydroxy-7p, 10|3-dimethoxy-9-oxo-11 -taxen-13a-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 solvate) are obtained.
`
`minutes,
`
`
`
`A galenical
`
`administration.
`via intravenous
`Cabazitaxel may be administered parenterally, such as
`form of cabazitaxel 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
`
`(13% by weight of 95% ethanol)
`in order
`to
`
`obtain 8 of a solution ready to be ml
`
`water and ethanol
`rediiuted in a perfusion bag. The concentration of cabazitaxel in this ready-to-redilute solution is
`
`perfusion is then prepared by injecting the appropriate amount of this ready-
`about 10 mg/ml. The
`toredilute solution into the perfusion bag containing water and glucose (about 5%) or sodium
`chloride (about 0.9%).
`
`Cabazitaxel may be administered in combination with a corticoid, such as prednisone or
`prednisolone, as
`
`two distinct pharmaceutical preparations.
`
`Accordingly, one aspect of the invention is a method of treating prostate cancer comprising
`administering to a
`
`in patient need thereof an effective amount of cabazitaxel in combination with a
`
`corticoid, such as
`
`prednisone or prednisolone.
`
`depends protocol that on the patient to
`
`
`to a
`administered repeatedly according
`
`The combination is
`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
`an intermittent program with an interval between each administration of 3 weeks, which may be
`prolonged by 1 to 2 weeks depending on the tolerance to the preceding administration. The
`prednisone or prednisolone 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 recommended dose is 25
`
`mg/m2 of cabazitaxel administered as a on-hour infusion and 10 mg per day of prednisone or
`prednisolone administered orally.
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`to
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`of the invention, the patient to be treated has prostate cancer that is resistant to
`In some aspects
`hormone therapy (i.e, hormone refractory) and has previously been treated with docetaxel.
`In
`some aspects, the patient has prostate cancer 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 progression of their disease showed
`
`in the three months
`following hormone therapy or after
`docetaxel
`treatment.
`
`In some aspects of the invention, the patient to be treated has a measurable tumour and may
`
`
`lesion show progression of the disease via a metastatic of the viscera or of a
`soft
`tissue
`1 cm determined by MRI or by an axial tomographic scan
`(CT scan).
`
`of at
`
`least
`
`tumour and may
`invention, the patient to be treated has an unmeasurable
`
`of the
`In some aspects
`show an increase in the PSA level with three measurements at a
`1-week interval or the
`appearance of new
`lesions.
`
`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 monotherapy with
`estramustine.
`
`In a preferred aspect, the
`
`life expectancy
`
`of the patient to be
`
`treated
`
`
`
`should be at least 2 months.
`
`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
`test, who have a neuropathy or a stomatitis, involving the brain
`within the 4 weeks preceding the
`or the meninges, who have shown severe
`
`to hypersensitivity polysorbate or
`
`to prednisone, whose
`blood analysis shows an appreciable decrease in neutrophils, haemoglobin or platelets, an
`increase in bilirubin and/or liver enzymes and creatinine, or who have heart problems or an
`infection requiring antibiotics.
`
`An aspect of the invention comprises
`of survival a patient with hormone refractory
`
`
`the
`increasing
`
`a proven effective amount of clinically
`
`metastatic prostate cancer,
`comprising
`administering
`
`cabazitaxel to the patient in combination with prednisone or prednisolone. In a particular aspect,
`the patient has previously been treated with a docetaxel-containing regimen.
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`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
`administering each
`dose
`of cabazitaxel.
`
`invention comprises a method of reducing the risk of a severe hypersensitivity
`
`One aspect of the
`reaction in a patient with prostate cancer being
`treated
`with cabazitaxel, comprising administering
`
`to the patient a
`medication
`to
`prevent
`hypersensitivity
`prior to
`the
`
`administration
`
`Severe hypersensitivity reactions to cabazitaxel can occur and may include generalized
`rash/erythema, hypotension and bronchospasm.
`Patients should be observed closely for
`hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity
`reactions may occur 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
`dexamethasone
`(for example or an
`
`equivalent steroid.
`
`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
`hypersensitivity reactions
`
`to other drugs formulated with polysorbate 80.
`
`One aspect of the
`invention comprises an
`
`a)
`a packaging material;
`b)
`cabazitaxel, and
`c)
`a label or package insert contained within the packaging material indicating
`that severe
`hypersensitivity
`reactions
`can
`occur.
`
`
`
`article of manufacture comprising:
`
`vomiting, and diarrhea, may occur with
`
`such as, for example nausea,
`Gastrointestinal symptoms,
`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.
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`Accordingly, the methods of the invention include administering a medication to prevent
`hypersensitivity or a medication to prevent or control nausea and vomiting in combination with
`cabazitaxel.
`
`5
`
`Examples of medications which may be used to prevent or control nausea and vomiting include
`histamine H2
`
`and antagonists antiemetics, such as
`
`ondansetron,
`granisetron
`and
`
`dolesetron.
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`
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`
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`A possible side effect of the treatment with cabazitaxel is neutropenia, which is characterized by
`
`a reduced number of neutrophils. Unfortunately, a number of neutropenia deaths have been
`reported. Therefore, frequent blood counts should be obtained or performed to monitor for
`neutropenia.
`If neutropenia occurs, cabazitaxel treatment may be discontinued, and restarted
`when neutrophil counts recover to a level of >1,500 /mm3. Cabazitaxel should not be given to a
`patient with a neutrophil count < 1,500 cells/mm3.
`
`The present invention therefore also relates to a method of treating prostate cancer with
`cabazitaxel comprising administering cabazitaxel to the patient, monitoring blood counts in the
`In one aspect, the method further comprises
`patient, and measuring neutrophil levels.
`discontinuing cabazitaxel treatment if neutropenia occurs, and optionally restarting 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.
`
`Determining neutrophil counts can be performed according to procedures well know to those
`skilled in the art.
`
`One aspect of the invention is a method of reducing the risk of neutropenia complications
`comprising administering cabazitaxel in combination with an agent useful for treating 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
`
`
`of the invention, the neutropenia is complicated
`stimulating factor, (G-CSF). In a particular aspect
`neutropenia. Complicated neutropenia includes febrile neutropenia, prolonged neutropenia, or
`neutropenic infection.
`In a preferred embodiment, the neutropenia treatment agent is
`administered prior to the administration of cabazitaxel.
`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 s
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`1,500 cells/mm3; and optionally restarting cabazitaxel treatment when the patient's neutrophil
`counts recover to a
`level s 1,500 cells/mm3.
`
`
`considered in patients with high-
`
`primary prophylaxis with G-CSF should be
`In a particular aspect,
`risk clinical 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 prolonged neutropenia.
`Therapeutic use of G-CSF and secondary prophylaxis should be considered in all patients
`considered to be at
`increased
`risk for
`neutropenia
`complications.
`
`In another aspect,
`blood counts is performed on a weekly basis during
`the monitoring of complete
`
`cycle 1 and before each treatment cycle thereafter
`
`so the dose can be adjusted, if needed. that
`
`Therefore, another aspect for reducing the risk of neutropenia complications comprises
`monitoring blood counts in the patient and adjusting the dose of cabazitaxel. An example of a
`dose modification is described
`in Example 2.
`
`One aspect
`a)
`b)
`c)
`
`of article manufacture comprising:
`
`
`
`
`
`invention comprises an
`
`of the
`a packaging material;
`cabazitaxel, and
`a label or package insert contained within the packaging material indicating
`that cabazitaxel should not be given to patients with neutrophil counts of
`£1,500 cells/mm3.
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`
`10
`
`15
`
`2 0
`
`25
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`Cases of renal failure should be indentified and managed aggressively,
`to accordingly procedures
`
`
`know to those skilled in the art. Renal failure may be associated with sepsis, dehydration, or
`obstructive uropathy. Furthermore, impaired hepatic function (e.g., total bilirubin > ULN, or AST
`and/or ALT a 1.5
`x ULN) may increase cabazitaxel
`
`
`and concentrations, cabazitaxel should not be
`given to patients with hepatic
`impairment.
`
`30
`
`Cabazitaxel may cause fetal harm when administered to a pregnant woman.
`
`Cabazitaxel is primarily metabolized through CYP3A.
`Concomitant administration of strong
`CYP3A inhibitors (for example, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin,
`rifapentin, phenobarbital) may increase cabazitaxel
`concentrations.
`Therefore
`co-administration
`cabazitaxel with strong CYP3A inhibitors should be avoided. Caution should be exercised with
`concomitant use of moderate CYP3A inhibitors.
`One aspect of the invention is a method of
`treating a patient for prostate cancer comprising determining whether the patient is undergoing
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`treatment with a CYP3A inhibitor, discontinuing treatment with a CYP3A inhibitor, and then
`administering cabazitaxel
`to
`the
`patient.
`
`Concomitant administration of strong CYP3A inducer (e.g., dexamethasone, phenytoin,
`carbamazepine,
`