(19)
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`(12)
`
`(cid:6)(cid:27)&(cid:11)(cid:11)(cid:12)(cid:17)(cid:19) (cid:12)(cid:14)(cid:12)(cid:24)(cid:12)(cid:6)
`EP 1 682 131 B1
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`
`EUROPEAN PATENT SPECIFICATION
`(51) Int Cl.:(cid:3)
`A61K31/4353(2006.01) A61P35/00(2006.01)
`
`(45) Date of publication and mention
`of the grant of the patent:
`19.09.2007 Bulletin 2007/38
`
`(21) Application number: 04796697.3
`
`(86) International application number:
`PCT/US2004/035900
`
`(22) Date of filing: 28.10.2004
`
`(87) International publication number:
`WO 2005/046681 (26.05.2005 Gazette 2005/21)(cid:3)
`(54) CCI-(cid:3)779 FOR TREATING MANTLE CELL LYMPHOMA
`CCI-(cid:3)779 ZUR BEHANDLUNG VON MANTELZELLLYMPHOM
`CCI-(cid:3)779 POUR TRAITER DES LYMPHOMES A CELLULES DU MANTEAU
`
`• HUANG S ET AL: "INHIBITORS OF MAMMALIAN
`TARGET OF RAPAMYCIN AS NOVEL
`ANTITUMOR AGENTS: FROM BENCH TO
`CLINIC" CURRENT OPINION IN
`INVESTIGATIONAL DRUGS, CURRENT DRUGS,
`LONDON, GB, vol. 3, no. 2, 2002, pages 295-304,
`XP001094491 ISSN: 0967-8298
`• ELIT L: "CCI-(cid:3)779 WYETH" CURRENT OPINION IN
`INVESTIGATIONAL DRUGS, PHARMAPRESS,
`US, vol. 3, no. 8, August 2002 (2002-08), pages
`1249-1253, XP008037562 ISSN: 1472-4472
`• ALEXANDRE J ET AL: "LA RAPAMYCINE ET LE
`CCI-(cid:3)779 RAPAMYCIN AND CCI-(cid:3)779" CANCER
`BULLETIN, MEDICAL ARTS PUB, HOUSTON, US,
`vol. 86, no. 10, October 1999 (1999-10), pages
`808-811, XP001078856 ISSN: 0008-5448
`• HIDALGO M ET AL: "THE RAPAMYCIN-(cid:3)
`SENSITIVE SIGNAL TRANSDUCTION PATHWAY
`AS A TARGET FOR CANCER THERAPY"
`ONCOGENE, BASINGSTOKE, HANTS, GB, vol.
`19, no. 56, December 2000 (2000-12), pages
`6680-6686, XP009002368 ISSN: 0950-9232
`• FAYAD L E ET AL: "Mantle cell lymphoma: A
`review" HEMATOLOGIA - CITOCINAS,
`INMUNOTERAPIA Y TERAPIA CELULAR 2003
`SPAIN, vol. 6, no. 2, 2003, pages 100-112,
`XP008043746 ISSN: 1138-6029
`
`(84) Designated Contracting States:
`AT BE BG CH CY CZ DE DK EE ES FI FR GB GR
`HU IE IT LI LU MC NL PL PT RO SE SI SK TR
`
`(30) Priority: 04.11.2003 US 517329 P
`
`(43) Date of publication of application:
`26.07.2006 Bulletin 2006/30
`
`(73) Proprietor: MAYO FOUNDATION FOR MEDICAL
`EDUCATION AND RESEARCH
`Rochester, MN 55905 (US)(cid:3)
`
`(72) Inventors:
`• WITZIG, Thomas, E.(cid:3)
`Rochester, MN 55902 (US)(cid:3)
`• KAUFMANN, Scott, H.(cid:3)
`Rochester, MN 55901 (US)(cid:3)
`
`(74) Representative: Dörries, Hans Ulrich
`df-(cid:3)mp
`Fünf Höfe
`Theatinerstrasse 16
`80333 München (DE)(cid:3)
`
`(56) References cited:
`WO-(cid:3)A-(cid:3)03/020266
`
`• WITZIG THOMAS E ET AL: "A phase II trial of the
`rapamycin analog CCI-(cid:3)779 in previously treated
`mantle cell non-(cid:3)Hodgkin’s lymphoma: Interim
`analysis of 18 patients." BLOOD, vol. 102, no. 11,
`16 November 2003 (2003-11-16), page 643a,
`XP008043754 & 45TH ANNUAL MEETING OF THE
`AMERICAN SOCIETY OF HEMATOLOGY; SAN
`DIEGO, CA, USA; DECEMBER 06-09, 2003 ISSN:
`0006-4971
`
`Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give
`notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in
`a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art.
`99(1) European Patent Convention).
`
`Printed by Jouve, 75001 PARIS (FR)
`
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`Description
`
`BACKGROUND OF THE INVENTION
`(cid:3)[0001] This invention relates to the use of rapamycin
`42-(cid:3)ester with 3-(cid:3)hydroxy-(cid:3)2-(hydroacymethyl)-(cid:3)2-(cid:3)methyl-
`propionic acid (CCI-(cid:3)779) in the treatment or inhibition of
`mantle cell lymphoma.
`(cid:3)[0002] Rapamycin 42-(cid:3)ester with 3-(cid:3)hydroxy-(cid:3)2-(hy-
`droxymethyl)-(cid:3)2-(cid:3)methylpropionic acid (CCI-(cid:3)779) is an es-
`ter of rapamycin. Rapamycin, also termed sirolimus, is a
`macrocyclic triene antibiotic produced by Streptomyces
`hygroscopicus. The preparation and use of hydrox-
`yesters of rapamycin, including CCI-(cid:3)779, are described
`in U.S. Patents 5,362,718 and 6,277,983.
`(cid:3)[0003] CCI-(cid:3)779 has been described as having in vitro
`and in vivo activity against a number of tumor cell types.
`It is hypothesized that CCI-(cid:3)779 delays the time to pro-
`gression of tumors or time to tumor recurrence. This
`mechanism of action is more typical of cytostatic rather
`than cytotoxic agents and is similar to that of sirolimus.
`(cid:3)[0004] CCI-(cid:3)779 binds to and forms a complex with the
`cytoplasmic protein FKBP, which inhibits an enzyme,
`mTOR (mammalian target of rapamycin, also known as
`FKBP12-(cid:3)rapamycin associated protein [FRAP]). Inhibi-
`tion of mTOR’s kinase activity inhibits a variety of signal
`transduction pathways, including cytokine-(cid:3)stimulated
`cell proliferation, translation of mRNAs for several key
`proteins that regulate the G1 phase of the cell cycle, and
`IL-(cid:3)2-(cid:3)induced transcription, leading to inhibition of pro-
`gression of the cell cycle from G1 to S.
`(cid:3)[0005] Mantle cell lymphoma (MCL) a cancer of the B-
`lymphocytes housed in the mantle regions of the lymph
`nodes, is a unique subtype of non-(cid:3)Hodgkin’s lymphoma
`(NHL) which is characterized by a specific chromosomal
`translocation of the bcl-(cid:3)1 gene (t(cid:3)(11;(cid:3)14)(cid:3)(q13,q32)) and
`subsequent over-(cid:3)production of the gene product cyclin
`D1. The proto-(cid:3)oncogene bel-(cid:3)1 (which stands for B-(cid:3)cell
`lymphoma/(cid:3)leukemia) is one offive genes on the section
`of chromosome 11 which are translocated in MCL, but it
`is the only one expressed in MCL. The unique nature of
`lymphocytes and, in particular, the site bcl-(cid:3)1 occupies on
`chromosome 14 account for at least some of the bizarre
`behavior of MCL cells.
`(cid:3)[0006] MCL represents approximately 10% of all NHL.
`The median age of onset is approximately 60 years and
`there is a higher incidence in males [Decaudin, D., et al,
`Leuk Lymphoma 37: 181-4(cid:3)(2000)(cid:3)]. Patients typically
`present in advanced stage and extranodal sites are often
`involved. For example, some patients present with prom-
`inent lymphocytosis and may be mistaken for chronic
`lymphocytic leukemia. [Wong, K. F., et al., Cancer 86:
`850-7 (1999)(cid:3)], Others present with multiple polyps in the
`colon that can produce gastrointestinal bleeding [Hash-
`imoto, Y., et al, Hum Pathol 30:(cid:3)581-7 (1999)(cid:3)]. Anoater-
`aamuaIpiMentationiB&atofBMasive splenomegaly and
`minimal lymphadenopathy [Molina, T. J., et al, Virchows
`Arch 437:(cid:3)591-8(cid:3)(2000)(cid:3)]. Patients with MCL have been
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`demonstrated to have a significantly worse prognosis
`than those with other low-(cid:3)grade histologies with a median
`survival of 3-4 years [Weisenburger, D. D., et al., Am J
`Hematol 64:(cid:3)190-6 (2000)(cid:3); Hiddemann, W., et al., Journal
`of Clinical Oncology 16: 1922-30 (1998)(cid:3) ; Samaha, H.,
`et al., Leukemia 12: 1281-7, (1998)(cid:3); Callea, V., et al.,
`Haematologica 83 : 993-7(cid:3)(1998)(cid:3)].
`(cid:3)[0007] The treatment of MCL has remained problem-
`atic despite the availability of purine nucleoside ana-
`logues, stern cell transplantation, and monoclonal anti-
`body therapy with rituximab. Each of these modalities
`can produce tumor responses in MCL, but the disease
`typically recurs and requires additional therapy. There is
`no one treatment regimen that can be considered the
`treatment of choice for patients with new, untreated MCL.
`Most patients are treated with combinations of rituximab
`and chemotherapy-(cid:3)usually R-(cid:3)CHOP or a purine nucleo-
`side analogue and rituximab. patients who are eligible
`for high-(cid:3)dose therapy with stern cell support are usually
`transplanted in first remission.
`(cid:3)[0008]
`Less than 50% of MCL patients achieve a com-
`plete remission (CR) with current therapy and few pa-
`tients achieve durable remissions. The typical scenario
`is that the patient will respond to chemotherapy, but the
`responses are usually partial and the time to progression
`short [Oinonen, R., et al., European Journal of Cancer
`34: 329-36(cid:3)(1998)(cid:3)].
`(cid:3)[0009] Huang and Houghton (Current Opinion In In-
`vestigational Drugs, 2002, voL 3, no. 2,295-304; ISSN:
`0967-8298) describe rapamycin generally and its activity
`as an immunosuppressant and antitumor agent. Huang
`and Houghton teach rapamycin exerts antitumor proper-
`ties against different B-(cid:3)cell lymphoma cell lines. Huang
`and Houghton describe CCI-(cid:3)779 is an analogue of ra-
`pamycin with some similar cellular effects as those of
`rapamycin. However, Huang and Houghton do not teach
`or suggest CCI-(cid:3)779 for treating or inhibiting mantle cell
`lymphoma, which is a unique subtype of non-(cid:3)Hodgkin’s
`lymphoma.
`(cid:3)[0010] Elit (Current Opinion in Investigational Drugs,
`2002, voL 3, no. 8,1249-1253; ISSN: 1472-4472) teaches
`CCI-(cid:3)779 is an ester of rapamycin and has antitumor prop-
`erties. Elit teaches CCI-(cid:3)779 is being studied in various
`clinical studies. Blit further teaches that CCI-(cid:3)779 has
`been shown to stabilize non-(cid:3)Hodkin’s lymphoma. How-
`ever, Elit does not teach or suggest CCI-(cid:3)779 for treating
`or inhibiting mantle cell lymphoma, which is a unique sub-
`type of non-(cid:3)Hodgkin’s lymphoma.
`(cid:3)[0011] Alexandre and Armand (Cancer Bulletin, 1999,
`vol. 86, no. 10, 808-811; ISSN: 0008-5448) teach that
`rapamycin has immunosuppressant and antitumor prop-
`erties. Alexandre and Armand further teach that CCI-(cid:3)779
`is an analogue of rapamycin with the advantage of being
`administrable by a parenteral route, e.g., intravenous.
`Alexandre and Armand do not teach or suggest CCI-(cid:3)779
`for treating or inhibiting mantle cell lymphoma, which is
`a unique subtype of non-(cid:3)Hodgkin’s lymphoma.
`(cid:3)[0012] Hidalgo and Rowinsky (Oncogene, 2000, vol.
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`19, no. 56, 6680-6686; ISSN: 0950-9232) teach that CCI-
`779 is an ester of rapamycin that inhibits the cell cycle,
`i.e., has antitumor properties. In particular, the article by
`Hidalgo and Rowinsky is directed to a study and conclu-
`sions evaluating the feasibility, pharmacokinetics, and
`biological effects of escalating doses of CCI-(cid:3)779. Hidalgo
`and Rowinsky do not teach or suggest CCI-(cid:3)779 for treat-
`ing or inhibiting mantle cell lymphoma, which is a unique
`subtype of non-(cid:3)Hodgkin’s lymphoma.
`(cid:3)[0013] WO 03/020266 is drawn to antitumor combina-
`tions comprising CCI-(cid:3)779 and another antitumor agent,
`EKB-(cid:3)569. Generally, WO 03/020266 teaches that ra-
`pamycin is useful for treating, inter alia adult T-(cid:3)cell leuke-
`mia/(cid:3)lymphoma and that CCI-(cid:3)779 is an analogue of ra-
`pamycin. WO 03/020266 further teaches that CCI-(cid:3)779
`has been shown to inhibit the growth of various tumour
`cells. However, WO 03/020266 does not teach or sug-
`gest CCI-(cid:3)779 for treating or inhibiting mantle cell lympho-
`ma, which is a unique subtype of non-(cid:3)Hodgkin’s lympho-
`ma.
`(cid:3)[0014] Mantle cell lymphoma remains a difficult dis-
`ease to treat once it has relapsed and patients are typi-
`cally treated with multiple regimens with a short time to
`progression between treatments.
`
`SUMMARY OF THE INVENTION
`(cid:3)[0015] The invention provides for the use of a CCI-(cid:3)779
`in preparing a medicament for treating or inhibiting man-
`tle cell lymphoma in a subject.
`(cid:3)[0016] Also described is a pharmaceutical composition
`for treating or inhibiting mantle cell lymphoma which com-
`prises a CCI-(cid:3)779 in unit dosage form in association with
`a pharmaceutically acceptable carrier.
`(cid:3)[0017] Also described is a pharmaceutical pack con-
`taining a course of treatment of mantle cell lymphoma
`for one individual mammal, comprising a container hav-
`ing a CCI-(cid:3)779 in unit dosage form.
`(cid:3)[0018] Also described is a method and kits useful in
`the treatment or inhibition of mantle cell lymphoma. Other
`aspects and advantages of the invention will be apparent
`from the following detailed description of the invention.
`
`DETAILED DESCRIPTION OF THE INVENTION
`(cid:3)[0019] As used in accordance with this invention, the
`term "treatment" means treating a mammal having man-
`tle Cell lymphoma by providing said mammal with an ef-
`fective amount of a CCI-(cid:3)779 with the purpose of inhibiting
`growth of the lymphoma in such mammal, eradication of
`the lymphoma, or palliation of the lymphoma.
`(cid:3)[0020] As used in accordance with this invention, this
`term "inhibition" means inhibiting the onset or progres-
`sion of mantle cell lymphoma in a mammal having or
`susceptible to developing such disease by providing said
`mammal an effective amount of CCI-(cid:3)779.
`(cid:3)[0021] As used in accordance with this invention, the
`term "providing" means either directly administering CCI-
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`EP 1 682 131 B1
`4
`779 or administering a pharmaceutical salt of CCI-(cid:3)779
`which will form an effective amount of CCI-(cid:3)779 in the
`body. Throughout this specification and claims, the term
`"a CCI-(cid:3)779" encompasses CCI-(cid:3)779, an such pharma-
`ceutical salts wich provide an effective amount of CCI-
`779 to the subject.
`(cid:3)[0022] The preparation of CCI-(cid:3)779 is described in U.S.
`Patent 5,362,718 . A regiospecific synthesis of CCI-(cid:3)779
`is described in US Patent 6,277,983. Still another re-
`giospecific method for synthesis of CCI-(cid:3)779 is described
`in US Patent Application No. 10/903,062, filed July 30,
`3004, and its counterpart. International Patent Applica-
`tion PCT/US2004/22860, filed July 15, 2004.
`(cid:3)[0023] The ability of CCI-(cid:3)779 to treat or inhibit mantle
`cell lymphoma was evaluated in a clinical trial. Briefly, 18
`patients (mean age 72 years, range 38-89 years) were
`treated with an intravenous dose of 250 mg CCI-(cid:3)779 on
`days 1, 8, 15, and 22 of a 4 week treatment cycle, for up
`to a maximum of 12 cycles. Of these patients, 15 were
`stage IV, 2 were stage III, and 1 was stage II. The overall
`response rate was 44.4% (95% CI; 24%-(cid:3)68%) and thus
`satisfied the criteria as early evidence of efficacy in this
`patient group. One patient had a complete response
`(CR), and 7 patients had a partial response (PR). Only
`3 patients progressed before the end of the cycle. Based
`on the results obtained in this clinical trial, CCI-(cid:3)779 is
`useful in the treatment or inhibition of mantle cell lym-
`phoma.
`(cid:3)[0024] When CCI-(cid:3)779 is used in the treatment or inhi-
`bition of mantle cell lymphoma, it is projected that a sub-
`ject will be provided with a weekly dosage of 10 to 250
`mg of CCI-(cid:3)779 per week. Treatment typically consists of
`a monthly cycle composed of weekly dosage administra-
`tions, although weekly or bi-(cid:3)weekly cycles may be se-
`lected. A subject may undergo from one to twelve con-
`tinuous monthly cycles. Alternatively, a subject may un-
`dergo one cycle, cease treatment, and then undergo an-
`other cycle.
`(cid:3)[0025] Oral or intravenous infusion are the preferred
`routes of administration, with intravenous being more
`preferred. Initial intravenous dosages are typically pro-
`jected to be tenfold less than the oral dosages. For ex-
`ample, intraveous dosages may be in the range of 10
`mg/(cid:3)week to 175 mg/(cid:3)week, or from 20 mg/(cid:3)week to 150
`mg/(cid:3)week, or more desirably, from 25 mg/(cid:3)week to 75 mg/
`week; whereas, oral doses maybe in the range of 100
`mg/(cid:3)week to 250 mg/(cid:3)week, 125 mg/(cid:3)week to 225 mg/(cid:3)week,
`or 150 mg/(cid:3)week to 200 mg/(cid:3)week. Precise dosages for
`oral, parenteral, nasal, or intrabronchial administration
`will be determined by the administering physician based
`on experience with the individual subject treated.
`(cid:3)[0026] Treatment will generally be initiated with small
`dosages less than the optimum dose of the compound.
`Thereafter the dosage is increased until the optimum ef-
`fect under the circumstances is reached. Optionally, the
`dosage is then decreased for a week, biweek, or cycle,
`as desired or necessary.
`(cid:3)[0027] Preferably, the pharmaceutical composition is
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`in unit dosage form, e.g. as tablets, capsules, or prefilled
`vials or syringes. In such form, the composition is subdi-
`vided in unit dose containing appropriate quantities of
`the active ingredient; the unit dosage forms can be pack-
`aged compositions, for example, packeted powders, vi-
`als, ampoules, prefilled syringes or sachets containing
`liquids. The unit dosage form can be, for example, a cap-
`sule or tablet itself, or it can be the appropriate number
`of any such compositions in package form.
`(cid:3)[0028] Oral formulations containing the active com-
`pounds of this invention may comprise any convention-
`ally used oral forms, including tablets, capsules, buccal
`forms, troches, lozenges and oral liquids, suspensions
`or solutions. Capsules may contain mixtures of the active
`compound(cid:3)(s) with inert fillers and/or diluents such as the
`pharmaceutically acceptable starches (e.g. corn, potato
`or tapioca starch), sugars, artificial sweetening agents,
`powdered celluloses, such as crystalline and microcrys-
`talline celluloses, flours, gelatins and gums etc. Useful
`tablet formulations may be made by conventional com-
`pression, wet granulation or dry granulation methods and
`utilize pharmaceutically acceptable diluents, binding
`agents, lubricants, disintegrants, surface modifying
`agents (including surfactants), suspending or stabilizing
`agents, including magnesium stearate, stearic acid, talc,
`sodium lauryl sulfate, microcrystalline cellulose, car-
`boxymethylcellulose calcium, polyvinylpyrrolidone, gel-
`atin, alginic acid, acacia gum, xanthan gum, sodium cit-
`rate, complex silicates, calcium carbonate, glycine, dex-
`trin, sucrose, sorbitol, dicalcium phosphate, calcium sul-
`fate, lactose, kaolin, mannitol, sodium chloride, talc, dry
`starches and powdered sugar. Preferred surface modi-
`fying agents include nonionic and anionic surface mod-
`ifying agents. Representative examples of surface mod-
`ifying agents include poloxamer 188, benzalkonium chlo-
`ride, calcium stearate, cetostearyl alcohol, cetomacrogol
`emulsifying wax, sorbitan esters, colloidal silicon dioxide,
`phosphates, sodium dodecylsulfate, magnesium alumi-
`num silicate, and triethanolamine. Oral formulations
`herein may utilize standard delay or time release formu-
`lations to alter the absorption of the active compound(cid:3)(s).
`The oral formulation may also consist of administering
`the active ingredient in water or a fruit juice, containing
`appropriate solubilizers or emulsifiers as needed. Pre-
`ferred oral formulations for rapamycin 42-(cid:3)ester with 3-
`hydroxy-(cid:3)2-(hydroxymethyl)-(cid:3)2-(cid:3)methylpropionic acid are
`disclosed in US Published Patent Application, US
`2004-0077677 A1 (also USSN 10/663,506).
`(cid:3)[0029]
`In some cases it may be desirable to administer
`the compounds directly to the airways in the form of an
`aerosol.
`(cid:3)[0030] The compounds may also be administered
`parenterally or intraperitoneally. Solutions or suspen-
`sions of these active compounds as a free base or phar-
`macologically acceptable salt can be prepared in water
`suitably mixed with a surfactant such as hydroxy-(cid:3)propyl-
`cellulose. Dispersions can also be prepared in glycerol,
`liquid polyethylene glycols and mixtures thereof in oils.
`
`Under ordinary conditions of storage and use, these
`preparations contain a preservative to prevent the growth
`of microorganisms.
`(cid:3)[0031] The pharmaceutical forms suitable for injecta-
`ble use include sterile aqueous solutions or dispersions
`and sterile powders for the extemporaneous preparation
`of sterile injectable solutions or dispersions. In all cases,
`the form must be sterile and must be fluid to the extent
`that easy syringability exists. It must be stable under the
`conditions of manufacture and storage and must be pre-
`served against the contaminating action of microorgan-
`isms such as bacteria and fungi. The carrier can be a
`solvent or dispersion medium containing, for example,
`water, ethanol, polyol (e.g., glycerol, propylene glycol
`and liquid polyethylene glycol), suitable mixtures thereof,
`and vegetable oils. Preferred injectable formulations for
`rapamycin 42-(cid:3)ester with 3-(cid:3)hydroxy-(cid:3)2-(hydroxymethyl)-(cid:3)2-
`methylpropionic acid are disclosed in US 2004-0167152
`(also USSN 10/626,943).
`(cid:3)[0032]
`In this embodiment, the injectable formulation
`useful in the invention provides a CCI-(cid:3)779 cosolvent con-
`centrate containing a parenterally acceptable solvent
`and an antioxidant as described above and a parenteral
`formulation containing a CCI-(cid:3)779, composed of CCI-(cid:3)779,
`a parenterally acceptable cosolvent, an antioxidant, a
`diluent solvent, and a surfactant. Any given formulation
`useful in this invention may contain multiple ingredients
`of each class of component. For example, a parenterally
`acceptable solvent can include a non-(cid:3)alcoholic solvent,
`an alcoholic solvent, or mixtures thereof. Examples of
`suitable non-(cid:3)alcoholic solvents include, e.g., dimethyla-
`cetamide, dimethylsulfoxide or acetonitrile, or mixtures
`thereof. "An alcoholic solvent," may contain one or more
`alcohols as the alcoholic solvent component of the for-
`mulation. Examples of solvents useful in the formulations
`invention include ethanol, propylene glycol, polyethylene
`glycol 300, polyethylene glycol 400, polyethylene glycol
`600, polyethylene glycol 1000, or mixtures thereof. These
`cosolvents are particularly desirable because degrada-
`tion via oxidation and lactone cleavage occurs to a lower
`extent for these cosolvents. Further, ethanol and propyl-
`ene glycol can be combined to produce a less flammable
`product, but larger amounts of ethanol in the mixture gen-
`erally result in better chemical stability. A concentration
`of 30 to 100%v/v of ethanol in the mixture is preferred.
`(cid:3)[0033]
`In this embodiment, the stability of CCI-(cid:3)779 in
`parenterally acceptable alcoholic cosolvents is en-
`hanced by addition of an antioxidant to the formulation.
`Acceptable antioxidants include citric acid, d,(cid:3)1-(cid:3)a -(cid:3)toco-
`pherol, BHA, BHT, monothioglycerol, ascorbic acid, pro-
`pyl gallate, and mixtures thereof. Generally, the parenter-
`al formulations useful in this embodiment of the invention
`will contain an antioxidant component(cid:3)(s) in a concentra-
`tion ranging from 0.001% to 1% w/v, or 0.01% to 0.5%
`w/v, of the cosolvent concentrate, although lower or high-
`er concentrations may be desired. Of the antioxidants,
`d,(cid:3)1-(cid:3)a -(cid:3)tocopherol is particularly desirable and is used at
`a concentration of 0.01 to 0.1% w/v with a preferred con-
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`centration of 0.075% w/v of the cosolvent concentrate.
`(cid:3)[0034]
`In certain embodiments, the antioxidant com-
`ponent of the formulation of the invention also exhibits
`chelating activity. Examples of such chelating agents in-
`clude, e.g., citric acid, acetic acid, and ascorbic acid
`(which may function as both a classic antioxidant and a
`chelating agent in the present formulations). Other
`chelating agents include such materials as are capable
`of binding metal ions in solution, such as ethylene di-
`amine tetra acetic acid (EDTA), its salts, or amino acids
`such as glycine are capable of enhancing the stability of
`CCI-(cid:3)779. In some embodiments, components with
`chelating activity are included in the formulations of the
`invention as the sole "antioxidant component". Typically,
`such metal-(cid:3)binding components, when acting as chelat-
`ing agents are used in the lower end of the range of con-
`centrations for the antioxidant component provided here-
`in. In one example, citric acid enhanced the stability of
`CCI-(cid:3)779 when used at a concentration of less than 0.01%
`w/v. Higher concentrations are less stable solutions and
`thus, less desirable for products to be subject to long-
`term storage in liquid form. Additionally, such chelating
`agents may be used in combination with other antioxi-
`dants as part of the antioxidant component of the inven-
`tion. For example, an acceptable formulation may contain
`both citric acid and d,(cid:3)1-(cid:3)a -(cid:3)tocopherol. Optimal concentra-
`tions for the selected antioxidant(cid:3)(s) can be readily deter-
`mined by one of skill in the art, based upon the information
`provided herein.
`(cid:3)[0035] Advantageously, in certain embodiments of the
`parenteral formulations useful in the invention, precipita-
`tion of CCI-(cid:3)779 upon dilution with aqueous infusion so-
`lutions or blood is prevented through the use of a sur-
`factant contained in the diluent solution. The most impor-
`tant component of the diluent is a parenterally acceptable
`surfactant. One particularly desirable surfactant is polys-
`orbate 20 or polysorbate 80. However, one of skill in the
`art may readily select other suitable surfactants from
`among salts of bile acids (taurocholate, glycocholate,
`cholate, deoxycholate, etc.) which are optionally com-
`bined with lecithin. Alternatively, ethoxylated vegetable
`oils, such as a pegylated castor oil [e.g., such as PEG-
`35 castor oil which is sold, e.g., under the name Cremo-
`phor EL, BASF], vitamin E tocopherol propylene glycol
`succinate (Vitamin E TGPS), and polyoxyethylene-(cid:3)poly-
`oxypropylene block copolymers can be used in the dilu-
`ent as a surfactant, as well as other members of the polys-
`orbate family such as polysorbate 20 or 60 Other com-
`ponents of the diluent may include water, ethanol, poly-
`ethylene glycol 300, polyethylene 400, polyethylene 600,
`polyethylene 1000, or blends containing one or more of
`these polyethylene glycols, propylene glycol and other
`parenterally acceptable cosolvents or agents to adjust
`solution osmolarity such as sodium chloride, lactose,
`mannitol or other parenterally acceptable sugars, polyols
`and electrolytes. It is expected that the surfactant will
`comprise 2 to 100% w/v of the diluent solution, 5 to 80%
`w/v, 10 to 75% w/v, 15 to 60 % w/v, and preferably, at
`
`least 5% w/v, or at least 10% w/v, of the diluent solution.
`(cid:3)[0036] A parenteral formulation useful in the invention
`can be prepared as a single solution, or preferably can
`be prepared as a cosolvent concentrate containing CCI-
`779, an alcoholic solvent, and an antioxidant, which is
`subsequently combined with a diluent that contains a
`diluent solvent and suitable surfactant Prior to use, the
`cosolvent concentrate is mixed with a diluent comprising
`a diluent solvent, and a surfactant. When CCI-(cid:3)779 is pre-
`pared as a cosolvent concentrate according to this in-
`vention, the concentrate can contain concentrations of
`CCI-(cid:3)779 from 0.05 mg/mL, from 2.5 mg/mL, from 5
`mg/mL, from 10 mg/mL or from 25 mg/mL up to 50 mg/ml.
`The concentrate can be mixed with the diluent up to ap-
`proximately 1 part concentrate to 1 part diluent, to give
`parenteral formulations having concentrations of CCI-
`779 from 1mg/mL, from 5 mg/mL, from 10 mg/mL, from
`20 mg/mL, up to 25 mg/ml. For example the concentration
`of CCI-(cid:3)779 in the parenteral formulation may be from 2.5
`to 10 mg/mL. This invention also covers the use of for-
`mulations having lesser concentrations of CCI-(cid:3)779 in the
`cosolvent concentrate, and formulations in which one
`part of the concentrate is mixed with greater than 1 part
`of the diluent, e.g., concentrate: diluent in a ratio of 1:(cid:3)1.5,
`1:(cid:3)2, 1:(cid:3)3, 1:(cid:3)4 ,(cid:3)1:(cid:3)5, or 1:(cid:3)9 v/v and so on, to CCI-(cid:3)779
`parenteral formulations having CCI-(cid:3)779 concentration
`down to the lowest levels of detection.
`(cid:3)[0037] Typically the antioxidant may comprise from
`0.0005 to 0.5% w/v of the formulation. The surfactant
`may for example comprise from 0.5% to 10% w/v of the
`formulation. The alcoholic solvent may for example com-
`prise from 10% to 90% w/v of the formulation.
`(cid:3)[0038] The parenteral formulations useful in this inven-
`tion can be used to produce a dosage form that is suitable
`for administration by either direct injection or by addition
`to sterile infusion fluids for intravenous infusion.
`(cid:3)[0039] For the purposes of this disclosure, transdermal
`administrations are understood to include all administra-
`tions across the surface of the body and the inner linings
`of bodily passages including epithelial and mucosal tis-
`sues. Such administrations may be carried out using the
`present compounds, or pharmaceutically acceptable
`salts thereof, in lotions, creams, foams, patches, suspen-
`sions, solutions, and suppositories (rectal and vaginal).
`(cid:3)[0040] Transdermal administration may be accom-
`plished through the use of a transdermal patch containing
`the active compound and a carrier that is inert to the
`active compound, is non toxic to the skin, and allows
`delivery of the agent for systemic absorption into the
`blood stream via the skin. The carrier may take any
`number of forms such as creams and ointments, pastes,
`gels, and occlusive devices. The creams and ointments
`may be viscous liquid or semisolid emulsions of either
`the oil-(cid:3)in-(cid:3)water or water-(cid:3)in-(cid:3)oil type. Pastes comprised of
`absorptive powders dispersed in petroleum or hy-
`drophilic petroleum containing the active ingredient may
`also be suitable. A variety of occlusive devices may be
`used to release the active ingredient into the blood stream
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`such as a semi-(cid:3)permeable membrane covering a reser-
`globin ‡ 8 g/(cid:3)dL ; serum creatinine £ 2x the upper limit of
`normal (UNL); serum bilirubin£ 1.5 UNL; serum choles-
`voir containing the active ingredient with or without a car-
`terol £ 350 mg/dL; and triglycerides £ 400 mg/dL. Patients
`rier, or a matrix containing the active ingredient. Other
`occlusive devices are known in the literature.
`could not have known central nervous system involve-
`(cid:3)[0041] Suppository formulations may be made from
`ment or HIV infection.
`(cid:3)[0046] Patients were treated with a flat dose of 250 mg
`traditional materials, including cocoa butter, with or with-
`of CCI-(cid:3)779 diluted in 250 mL of normal saline and deliv-
`out the addition of waxes to alter the suppository’s melting
`point, and glycerin. Water soluble suppository bases,
`ered IV over 30 minutes. Patients were pretreated with
`such as polyethylene glycols of various molecular
`diphenhydramine 25 - 50 mg IV. Treatment was weekly
`weights, may also be used. Also described
`and a cycle was considered 4 weeks. A complete blood
`(cid:3)[0042] The components of the invention may be in the
`count was performed each week and a full dose delivered
`if the platelet count was ‡ 50,000 and the ANC ‡ 1000 and
`form of a kit of parts. Also described therefore is a product
`containing CCI-(cid:3)779 for use in treatment or inhibition of
`there was no grade 3 non-(cid:3)hematologic toxicity (using the
`mantle cell lymphoma in a mammalian subject in need
`NCI Common Toxicity Criteria version 2). Patients who
`thereof. Also described is a pharmaceutical pack con-
`did not meet the retreatment criteria had the dose held
`taining a course of treatment of mantle cell lymphoma
`until recovery and then the dose modified to a flat dose
`for one individual mammalian subject, wherein the pack
`of 175,125, 75, or 50 mg. Patients were not to receive
`contains units of CCI-(cid:3)779 in unit dosage form. The prod-
`prophylactic white blood cell growth factors to maintain
`uct may contain CCI-(cid:3)779 in a form ready for administra-
`dosing but could receive them at time of neutropenia at
`tion. Alternatively, the product may contain CCI-(cid:3)779 as
`physician discretion. Erythropoietin could be used.
`(cid:3)[0047] Patients were restaged after 1, 3, and 6 cycles
`a concentrate which can be mixed with a suitable diluent
`that is optionally provided in the product. The product
`and the response assessed as per the international work-
`may also contain CCI-(cid:3)779 in solid form and, optionally,
`shop criteria.(cid:3)[B. D. Cheson, et al., "Report of an Interna-
`a separate container with a suitable solvent or carrier for
`tional Workshop to Standardize Response Criteria for
`CCI-(cid:3)779. Still other components on the kit, e.g., instruc-
`Non-(cid:3)Hodgkin’s Lymphomas", Journal of Clinical Oncol-
`tions for dilution, mixing and/or administration of the prod-
`ogy, Vol 17, Issue 4 (April), 1999: 1244]. Patients who
`uct, other containers, syringes,