(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`<19>Worw llllllllllllllHIIIHIIIIII||l|||||||H|||H|||||||||||||||||||||||||||||||||||||||||||||||||||
`International Bureau
`'5
`
`(43) International Publication Date
`5May 2011 (05.05.2011)
`
`P
`
`F
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`(10) International Publication Number
`W0 2011/051394 A1
`
`International Patent Classification:
`A6IK 31/164 (2006.01)
`A61K 45/06 (2006.01)
`A6IK 31/56 (2006.01)
`A61P 35/00 (2006.01)
`_
`_
`_
`,
`International Application l\umber:
`
`International Filing Date:
`
`Filing Languagei
`Publication Language:
`
`PCMBZOIO/054866
`
`27 October 2010 (27.10.2010)
`.
`Fflghsh
`English
`
`(81) Designated States (unless otherwise indicated, fir every
`kind ofnaiional protection available): AE, AG, AL, AM,
`A0, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ EC EE EG ES FI GB GD GE GH GM GT
`HN! HR HU lJ_),JL iN is Ji’ Kb,’ Rd KIVI KN’ KP,
`KR, KZ, LA, LC, 1-K, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, Pia, PG, PH, PL, PT, RO, RS, RU, sc, si),
`SE, so, SK, sL, SM, sT, sv, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`P1.i01.ityDam,
`61‘/256,160
`61/293,903
`61‘/355,834
`61/355,888
`61/369,929
`61/383,933
`61/389,969
`
`29 October 2009 (29.10.2009)
`11 January 2010 (11.01.2010)
`17111116 2010
`17 June 2010 (17.06.2010)
`2 August 2010 (02.08.2010)
`17 September 2010 (17.09.2010)
`5 October 2010 (05.10.2010)
`
`Designated States (t,tnles.v otherwise indicated, for ever);
`kind ofregional pl"0[€’Cll0I’Z available): ARIPO (BW, GH,
`GM» KF» LR» LS» MW» MZ» NA» SD» SL» SZ» TZ» UG»
`ZM, ZW), llurasian (Al)/l, AZ, BY, KCI, KZ, MD, RU, TJ,
`TM)» European (AL» AT» BE» BG» CH» CY» CZ» DE» DK»
`FF» F5» F1» FR» GB» GR» HR» HU» TF» 15» TT» LT» LU»
`LV» MC» MK» MT» NL» N0» PL» PT» R0» R3» SF» 51» SK»
`SM» TR)» OAFT (BF» BJ» CF» CG» CT» CM» GA» GN» GQ»
`GW, ML, MR, NE, SN, TD, TG).
`_
`Applicant (for all designated States except US): AVEN-
`Tis PI-IARMA s.A. [FR/FR]; 20 avenue Raymond Aron, De°'a”“10“S under Rule 4-173
`392160 Antony (FR)~
`— ofim/entorship (Rule 4.1 7(ii2))
`Inventor: and
`Published:
`1‘ only): GUPTA, Sunil
`(for
`Inventor/Applicant
`[US/US]; c/o Sanofi—AVentis US.
`Inc.,
`1041 Routes
`202-206 Mail Code: D-303A, Bridgewater, New Jersey — bejbre the expiration of the time limit for amending the
`08807 (US).
`claims and to be republished in the event of receipt of
`Agent: GASLONDE Aude c/o Sanofi—AVentis Patent
`‘””“”d’”“”” (Rule 48'2”’))
`Department, 174 avenue de France, F-75013 Paris (FR).
`
`Us
`US
`
`US
`Us
`Us
`Us
`
`— with international Search report (Art. 21
`
`(54) Title: NOVEL ANTITUMORAL USE OF CABAZITAXEL
`
`(57) Abstract: The invention relates to a compound of Formula (I): which may be in base form or in the form of a hydrate or a
`solvate, in conibination with prednisone or preduisolone, for its use as a inedicainent in the treatment of prostate cancer, particu-
`larly metastatic prostate cancer, especially for patients who are 11ot catered for by a taxane-based treatment.
`
`V-1
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`AVENTIS EXHIBIT 2230
`Mylan v. Aventis IPR2016-00712
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`WO 2011/051894
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`PCT/IB2010/054866
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`NOVEL ANTITUMORAL USE OF CABAZITAXEL
`
`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.
`
`[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).
`cancer.
`
`It is the most frequently occurring cancer in men after lung
`
`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., Nov. 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 treatment, whereas its role in alleviating the
`
`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,
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`is problematic since,
`
`in addition to
`
`their tumour, they are generally suffering from related health problems and have a limited reserve
`
`of bone marrow.
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`Until
`
`recently,
`
`the chemotherapies used were limited to cyclophosphamide, anthracyclines
`
`(doxorubicin or mitoxantrone) and estramustine, and the effects of these treatments are relatively
`
`mediocre. Palliative effects were observed in patients following the administration of corticoids
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`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
`
`estramustine or prednisone have made it possible to 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.
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`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 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.
`
`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. Onc.
`
`1999, 17(3), 1061-1070.
`
`10
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`15
`
`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 (sold under the brand name Taxotere®) based regimen, an
`
`20
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`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 (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.
`
`[Brief description of the invention]
`
`The invention relates to a novel antitumoral pharmaceutical
`
`therapeutic use comprising
`
`cabazitaxel of formula
`
`25
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`PCT/IB2010/054866
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`
`
`The invention also relates to methods of treating patients with prostate cancer comprising
`
`administering an effective amount of the antitumoral agent cabazitaxel to said patient.
`
`This antitumoral agent may be in the form of anhydrous base, a hydrate or a solvate, intended for
`
`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 patient with castration resistant prostate
`
`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.
`
`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-refractory prostate cancer who
`
`have been previously treated with docetaxel based regimen.
`
`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 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.
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`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,
`
`reduction in tumor size, reduction in metastasis, complete remission, partial remission, stable
`
`disease, or complete response.
`
`The present invention also relates to a pharmaceutical composition that treats patients with
`
`prostate cancer comprising a clinically proven safe and effective amount of cabazitaxel.
`
`Further embodiments of the invention comprise methods or using,
`
`treating, promoting, and
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`10
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`providing cabazitaxel.
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`20
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`25
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`The present invention also relates to packages and articles of manufacture.
`
`[Brief Description of the Drawings]
`
`Figure 1 displays the Kaplan-Meier curves of the overall survival in a cabazitaxel study.
`
`Figure 2 displays the Kaplan-Meier curves of progression-free survival in a cabazitaxel study.
`
`Figure 3 shows an intention-to-treat analysis of overall survival in subgroups of patients defined
`
`by baseline characteristics. Hazard ratios <1 favor the cabazitaxel group, while those >1 favor the
`
`mitoxantrone group. Cl denotes confidence intervals.
`
`Figure 4 graphically depicts the proportion of patients with changes in ECOG performance status
`
`from baseline during treatment (safety population).
`
`Figure 5 graphically depicts the proportion of patients with changes from baseline in the Present
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`Pain Intensity score during treatment (ITT).
`
`Figure 6 graphically presents the mean area under the curve for PPI and analgesic scores by
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`3O
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`treatment cycle.
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`Figure 7 graphically presents the mean AUC analgesic score.
`
`[Description of the invention]
`
`35
`
`Definitions
`
`0
`
`Effective amount, as used herein, means an amount of a pharmaceutical compound, such as
`
`cabazitaxel, that produces an effect on the cancer to be treated.
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`PCT/IB2010/054866
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`0
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`Clinically proven, as used herein, means clinical efficacy results that are sufficient to meet
`
`FDA approval standards.
`
`0 Castration resistant prostate cancer, as used herein, is synonymous with hormone-refractory
`
`prostate cancer.
`
`0
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`"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 formula:
`
`CH3
`
`10
`
`15
`
`20
`
`25
`
`The chemical name of cabazitaxel is 4o-acetoxy-2o-benzoyloxy-58,20-epoxy-1B-hydroxy-78,1OB-
`
`dimethoxy-9-oxo-1 1-taxen-13o-y| (2 R,3S)-3-tert-butoxycarbonylamino-2-hyd roxy-3-
`
`phenylpropionate. Cabazitaxel is synonymously known as (2o,5B,7B,10B,13o)-4-acetoxy-13-
`
`({(2R,3S)-3-[(tertbutoxycarbony|)amino]-2-hydroxy-3-phenylpropanoy|}oxy)-1-hydroxy-7,10-
`
`dimethoxy-9-oxo-5,20-epoxytax-1 1-en-2-yl benzoate.
`
`This compound and a preparative method thereof is described in WO 96/30355, EP 0 817 779 B1
`
`and US 5 847 170, which are hereby incorporated herein by reference. 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 W0 2005/02846.
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`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+cabazitaxe| X 100). An average value of the
`
`acetone content is 7%, which approximately represents the acetone stoichiometry, which is 6.5%
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`WO 2011/051894
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`PCT/IB2010/054866
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`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 20i5°C (room temperature) to a solution of 207 g of 4d-
`
`acetoxy-2d-benzoyloxy-5B,20-epoxy-1B-hydroxy-7B,1OB-dimethoxy-9-oxo-1 1-taxen-13d-yl
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`(2R,3S)-3-ten‘-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 4d-acetoxy-2d-
`
`benzoyloxy-5B,20-epoxy-1B-hydroxy-7B,1OB-dimethoxy-9-oxo-1 1-taxen-130-yl
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`(2R,3S)-3-tert-
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`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
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`1.5 litres of purified water are added over 4 to 5 hours. This mixture is stirred for 60 to 90 minutes,
`
`and the suspension is then filtered under reduced pressure. The cake is washed on the filter with
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`a solution prepared from 450 ml of acetone and 550 ml of purified water, and then oven-dried at
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`55°C under reduced pressure (0.7 kPa) for 4 hours. 197 g of 4d-acetoxy-2d-benzoyloxy-5B,20-
`
`epoxy-1B-hydroxy-78,1OB-dimethoxy-9-oxo-1 1-taxen-1301-yl
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`(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.
`
`Cabazitaxel may be administered parenterally, such as via intravenous administration. A galenical
`
`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
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`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 appropriate amount of this ready-
`
`to-redilute 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 patient in need thereof an effective amount of cabazitaxel in combination with a
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`corticoid, such as prednisone or prednisolone.
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`The combination is administered repeatedly according to a protocol that depends on the patient to
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`be treated (age, weight, treatment history, etc.), which can be determined by a skilled physician.
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`In one aspect of the invention, cabazitaxel is administered by perfusion to the patient according to
`
`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
`
`median number of cycles is 6. 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
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`currently recommended dose is 25 mg/m2 of cabazitaxel administered as a on-hour infusion and
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`10 mg per day of prednisone or prednisolone administered orally.
`
`In some aspects of the invention, the patient to be treated has prostate 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 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.
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`In another particular aspect, the patient showed progression of their disease
`
`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
`
`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).
`
`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.
`
`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
`
`within the 4 weeks preceding the test, who have a neuropathy or a stomatitis, involving the brain
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`or the meninges, who have shown severe hypersensitivity to 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 increasing the survival of a patient with hormone refractory
`
`metastatic prostate 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-containing regimen.
`
`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.
`
`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 prevent hypersensitivity prior to the administration of cabazitaxel.
`
`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 8 mg) or an
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`equivalent steroid.
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`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
`
`35
`
`hypersensitivity reactions to other drugs formulated with polysorbate 80.
`
`One aspect of the invention comprises an article of manufacture comprising:
`
`a)
`
`a packaging material;
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`b)
`
`c)
`
`cabazitaxel, and
`
`a label or package insert contained within the packaging material
`
`indicating
`
`that severe hypersensitivity reactions can occur.
`
`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 2 3 diarrhea.
`
`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.
`
`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.
`
`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 S 1,500 ce||s/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
`
`patient, and measuring neutrophil
`
`levels.
`
`In one aspect,
`
`the method further comprises
`
`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
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`stimulating factor, (G-CSF).
`
`In a particular aspect of the invention, the neutropenia is complicated
`
`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 5
`
`1,500 cells/mm3; and optionally restarting cabazitaxel treatment when the patient’s neutrophil
`
`counts recover to a level 2 1,500 cells/mm3.
`
`In a particular aspect, primary prophylaxis with G-CSF should be considered in patients with high-
`
`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, 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 cabazitaxel. An example of a
`
`dose modification is described in Example 2.
`
`One aspect of the invention comprises an article of manufacture comprising:
`
`a)
`
`b)
`
`c)
`
`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.
`
`Cases of renal failure should be indentified and managed 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 bilirubin 2 ULN, or AST
`
`and/or ALT 2 1.5 x ULN) may increase cabazitaxel concentrations, and cabazitaxel should not be
`
`given to patients with hepatic impairment.
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`Cabazitaxel may cause fetal harm when administered to a pregnant woman.
`
`Prednisone or prednisolone administered at 10 mg daily does not affect the pharmacokinetics of
`
`cabazitaxel.
`
`Cabazitaxel
`
`is primarily metabolized through CYP3A. Concomitant administration of strong
`
`CYP3A inhibitors (for example, ketoconazole, itraconazole, clarithromycin, atazanavir,
`
`indinavir,
`
`nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase cabazitaxel
`
`concentrations. Therefore co-administration of cabazitaxel with strong CYP3A inhibitors should be
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`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 treatment with a CYP3A inhibitor, discontinuing
`
`treatment with a CYP3A inhibitor, and then administering cabazitaxel to the patient.
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`Concomitant administration of strong CYP3A inducer (e.g., phenytoin, carbamazepine, rifampin,
`
`rifabutin,
`
`rifapentin, phenobarbital) may decrease cabazitaxel concentrations. 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 prostate cancer comprising
`
`determining whether the patient is undergoing treatment with a CYP3A inducer, discontinuing
`
`treatment with a CYP3A inducer, and administering cabazitaxel to the patient.
`
`In addition, patients should also refrain from taking St. John's Wort.
`
`In some aspects of the invention, the cabazitaxel is administered in an amount to provide an AUC
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`of about 991 ng-h/mL (CV 34%).
`
`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%).
`
`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%).
`
`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%).
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`Another 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 AUC of cabazitaxel in patients with metastatic prostate
`
`cancer was 991 ng-h/mL (CV 34%).
`
`Another 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 cabazitaxel has a plasma clearance of 48.5 L/h (CV 39%).
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`A variety of educational materials may be employed to ensure proper prescribing, dispensing,
`
`and patient compliance according to the methods described herein. For example, a variety of
`
`literature and other materials, such as, for example, prescribing information, package inserts,
`
`medications guides, physician information sheets, healthcare professional
`
`information
`
`sheets, medical journal advertisements, and product websites may describe the risks and
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`benefits of taking cabazitaxel.
`
`The invention also concerns a package comprising cabazitaxel and a label, said label
`
`comprising one or more messages that:
`
`a)
`
`the efficacy and safety of cabazitaxel
`
`in combination with prednisone were
`
`evaluated in patients with hormone refractory metastatic prostate cancer
`
`previously treated with a docetaxel containing regimen; or
`
`b)
`
`a total of 755 patients were randomized to receive either cabazitaxel 25 mg/m3
`
`every 3 weeks for a maximum of 10 cycles with prednisone mg orally daily, or
`
`to receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for a maximum
`
`of 10 cycles with prednisone 10 mg orally daily; or
`
`c)
`
`the median number of cycles was 6 in the cabazitaxel group and 4 in the
`
`mitoxantrone group.
`
`The invention also concerns a package comprising cabazitaxel and a label, said label
`
`comprising one or more messages that:
`
`a)
`
`b)
`
`c)
`
`neutropenic deaths have been reported; or
`
`frequent blood counts should be obtained to monitor for neutropenia; or
`
`cabazitaxel should not be given if neutrophil counts are 5 1,500 cells/mm3.
`
`The invention also concerns a method of promoting the use of cabazitaxel
`
`the method
`
`comprising the step of conveying to a recipient at least one message selected from:
`
`a)
`
`neutropenic deaths have been reported; or
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`b)
`
`c)
`
`d)
`
`e)
`
`frequent blood counts should be obtained to monitor for neutropenia; or
`
`cabazitaxel should not be given if neutrophil counts are 5 1,500 cells/mm3;
`
`severe hypersensitivity can occur; or
`
`severe hypersensitivity can occur and may include generalized rash/erythema,
`
`hypotension and brochospasm; or
`
`f)
`
`g)
`
`discontinue cabazitaxel immediately if severe reaction