(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`(43) International Publication Date
`23 May 2002 (23.05.2002)
`
`PCT
`
`(10) International Publication Number
`WO 02/40000 A2
`
`(51) International Patent Classification7:
`
`A61K 31/00
`
`(21) International Application Number: PCT/USOl/47324
`
`(22) International Filing Date:
`13 November2001 (13.11.2001)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/249,077
`
`15 November 2000 (15.11.2000) US
`
`(71) Applicant: WYETH [US/US]; Five Giralda Farms, Madi(cid:173)
`son, NJ 07940-0874 (US).
`
`(72) Inventors: DUKART, Gary; 1714 Benjamin Drive, Am(cid:173)
`bler, PA 19002 (US). GIBBONS, James, Joseph, Jr.; 33
`Terrace Drive, Westwood, NJ 07675 (US). SPEICHER,
`Lisa, Anne; 509 Covington Road, Havertown, PA 19083
`(US). FROST, Philip; 4 Emerson Court, Morris Township,
`NJ 07960 (US). DISCAFANI-MARRO, Carolyn, Mary;
`8 Brookside Avenue, Cortlandt Manor, NY 10567 (US).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`GM, HR, ffiJ, TD, TL, TN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG,
`SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU,
`ZA, ZW.
`
`(84) Designated States (regional): ARlPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE,
`IT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
`CG, Cl, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD,
`TG).
`
`Declarations under Rule 4.17:
`as to applicant's entitlement to apply for and be granted a
`patent (Rule 4.17(ii)) for all designations
`as to the applicant's entitlement to claim the priority of the
`earlier application (Rule 4.17(iii)) for all designations
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`(74) Agents: MILOWSKY, Arnold, S.; Wyeth, Patent Law
`Department, Five Giralda Farms, Madison, NJ 07940-0874
`eta!. (US).
`
`For two-letter codes and other abbreviations. refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`-==
`iiiiiiiiiiii -
`
`iiiiiiiiiiii
`iiiiiiiiiiii
`
`--
`
`iiiiiiiiiiii
`
`iiiiiiiiiiii ----
`
`0
`0
`0
`0
`~
`N
`o (54) Title: USE OF CCI-779 AS AN ANTINEOPLASTIC AGENT
`0----------------------------------------------------------------------
`~ (57) Abstract: This invention provides the use of CCI -779 in the treatment of neoplasms.
`
`ARGENTUM
`Exhibit 1054
`
`000001
`
`

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`PCT/USOl/47324
`
`USE OF CCI-779 AS AN ANTINEOPLASTIC AGENT
`
`This invention relates to the use of rapamycin 42-ester with 3-hydroxy-2-
`
`(hydroxymethyl)-2-methylpropionic acid (CCI-779) as an antineoplastic agent.
`
`5
`
`Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces
`
`hygroscopicus, which was found to have antifungal activity, particularly against
`
`Candida albicans, both in vitro and in vivo [C. Vezina et al., J. Antibiot. 28, 721
`(1975); S.N. Sehgal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot.
`
`10
`
`31, 539 (1978); U.S. Patent 3,929,992; and U.S. Patent 3,993,749]. Additionally,
`
`rapamycin alone (U.S. Patent 4,885,171) or in combination with picibanil (U.S.
`
`Patent 4,401,653) has been shown to have antitumor activity.
`
`The immunosuppressive effects of rapamycin have been disclosed in F ASEB
`
`3, 3411 (1989). Cyc1osporin A and FK-506, other macrocyclic molecules, also have
`
`15
`
`been shown to be effective as immunosuppressive agents, therefore useful in
`
`preventing transplant rejection [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); R.
`
`Y. Caine et al., Lancet 1183 (1978); and U.S. Patent 5,100,899]. R. Martel et al. [Can.
`
`J. Physiol. Pharmacol. 55, 48 (1977)] disclosed that rapamycin is effective in the
`
`experimental allergic encephalomyelitis model, a model for multiple sclerosis; in the
`
`20
`
`adjuvant arthritis model, a model for rheumatoid arthritis; and effectively inhibited
`
`the formation oflgE-like antibodies.
`
`Rapamycin
`
`is also useful
`
`in preventing or treating systemic
`
`lupus
`
`erythematosus [U.S. Patent 5,078,999], pulmonary inflammation [U.S. Patent
`
`5,080,899], insulin dependent diabetes mellitus [U.S. Patent 5,321,009], skin
`
`25
`
`disorders, such as psoriasis [U.S. Patent 5,286,730], bowel disorders [U.S. Patent
`
`5,286,731], smooth muscle cell proliferation and intimal thickening following
`vascular injury tu.s. Patents 5,288,711 and 5,516,781], adult T-cell leukemia/(cid:173)
`lymphoma [European Patent Application 525,960 A1], ocular inflammation [U.S.
`
`Patent 5,387,589], malignant carcinomas
`
`[U.S. Patent 5,206,018], cardiac
`
`30
`
`inflammatory disease [U.S. Patent 5,496,832], and anemia [U.S. Patent 5,561,138].
`
`000002
`
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`
`The preparation and use of hydroxyesters of rapamycin, including CCI-779,
`
`are disclosed in U.S. Patent 5,362,718.
`
`DESCRIPTION OF THE INVENTION
`
`5
`
`This invention provides the use of CCI-779 as an antineoplastic agent, and
`
`particularly for neoplasms which are refractory to standard therapy, or for whom
`
`standard therapy is not appropriate. In particular CCI-779 is useful in the treatment of
`
`renal cancer, soft tissue cancer, breast cancer, neuroendocrine tumor of the lung,
`
`cervical cancer, uterine cancer, head and neck cancer, glioblastoma, non-small lung
`
`10
`
`cell cancer, prostate cancer, pancreatic cancer, lymphoma, melanoma, small cell lung
`
`cancer, ovarian cancer, colon cancer.
`
`As used in accordance with this invention, the term "treatment" means treating
`
`a mammal having a neoplastic disease by providing said mammal an effective amount
`
`15
`
`ofCCI-779 with the purpose of inhibiting growth of the neoplasm in such mammal,
`
`eradication of the neoplasm, or palliation of the neoplasm.
`
`As used in accordance with this invention, the term "providing," with respect
`
`to providing CCI-779, means either directly administering CCI-779, or administering
`
`20
`
`a prodrug, deqvative, or analog which will form an effective amount of CCI-779
`
`within the body.
`
`As used in accordance with this invention, the term "refractory neoplasm"
`
`refers to neoplasms in patients which typically had progressed following treatment
`
`25 with standard chemotherapy that was appropriate for that given neoplasm.
`
`The preparation of CCI-779 is described in U.S. Patent 5,362,718, which is
`
`hereby incorporated by reference.
`
`30
`
`The antineoplastic activity of CCI-779 was confirmed in a preclinical in vitro
`
`and in vivo standard pharmacological test procedure which measured the ability of
`
`-2-
`
`000003
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`CCI-779 to treat human renal cell cancer (a rapidly progressive disease with very
`
`limited treatment options), as well as in two Phase I human clinical trials. The
`
`procedures used and results obtained are briefly described below.
`
`5
`
`Preclinical Test Procedures
`
`In vitro test procedure: Renal tumor lines HTB-44 and CRL-1161 were
`
`obtained from the American Tissue Culture Collection (ATCC), Bethesda, 1\ID.
`
`SN12-C line was obtained from Dr. J. Fidler, M.D. Anderson Hospital, Houston, TX.
`
`Cells were plated in MEM (Gibco) supplemented with 2 mM glutamine, 1 mM
`
`10
`
`sodium pyruvate, 5 ml penicillin-streptomycin solution, 1 mM non-essential amino
`
`
`acid solution, 10% fetal bovine solution. Cells (5 x 103) were plated in 96 well plates
`
`with a final volume of 200 ml and incubated for 24 hours at 37°C. Log dilutions of
`
`CCI-779 beginning at 100 flg/ml were then added to the cultures for 48 hours. Over
`the last 5 hours, cells were pulsed with 1 ~-tci 3H-thymidine (New England Nuclear,
`6.7 ci/m Mol). Cells were then harvested and the degree of thymidine uptake
`
`15
`
`determined by liquid scintillation spectrometry. The IC50 was determined as the
`concentration that produced 50% of the maximum uptake of thymidine in control
`
`untreated cells.
`
`20
`
`In vivo test procedure: Female Balb/c nu/nu mice were obtained from Charles
`
`River Labs, Wilmington, DE, at 6-8 weeks of age. Mice (n=10/group) were injected
`sc with 5 x 106 cells resuspended in a 50% solution ofMatrigel (BD Biosciences) and
`tumors allowed to develop. When tumor size reached 100 mg, mice were treated
`
`orally with CCI-779 at 25 mg/kg. CCI-779 was dosed for 5 consecutive days with
`
`25
`
`repeated 14 day cycles throughout the duration of the experiment. The formulation
`
`used for CCI-779 was a 50% ethanol, 49% phosal, 1% tween 80 vehicle for
`
`resuspending CCI-779, where the stock was resuspended into a 1:10 dilution of the
`
`vehicle prior to dosing. Tumor growth was evaluated using a vernier caliper and
`
`volume (1 x w x h) was converted to mass using the formula: 1 x w2 I 2.
`
`30
`
`-3-
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`Results:
`
`PCT/USOl/47324
`
`Human renal cell tumors were cultured in vitro in the presence or absence of
`CCI-779 for 3 days and the effect on growth determined by 3H-thymidine
`incorporation of control versus treated cells. Table 1 shows that IC50 (50% growth
`inhibitory concentration) for all 3 lines tested was in the low nM range.
`
`5
`
`Table 1 The effect of CCI-779 on the growth of human renal tumor cells in vitro
`
`Renal Tumor Line
`
`CCI-779 ICso CnM)
`
`HTB-44
`CRL-1161
`SN12-C
`
`5.0
`2.0
`5.5
`
`10
`
`The effect of CCI-779 in two human renal lines (HTB-44 and CRL-1161)
`
`were was evaluated in vivo by engrafting tumor cells on the flanks of nude mice. Once
`
`tumors were established at a size of about 100 mg, mice were treated with CCI-779 or
`
`a vehicle control. Treatment with CCI-779 at 25 mg/kg resulted in significant
`
`15
`
`inhibition of tumor cell growth in the mice (Table 2).
`
`Table 2 Effect of CCI-779 on the growth of human renal tumor cells in nude mouse
`xenografts
`
`HTB-44
`
`Drug
`
`Control
`CCI
`%TIC
`
`288±21
`290±15
`101
`
`219±18
`156±13*
`71
`
`273±18
`355±36
`272±14 219±16*
`100
`62
`
`CRL-1161 Control
`CCI
`%TIC
`* p value-< .05
`%TIC- Treated/Control x 100
`
`20
`
`25
`
`616±55
`252±48*
`41
`
`413±60
`226±17*
`60
`
`1095±44
`453±85*
`41
`
`2033±247 2412±342
`1050±183*
`980±155*
`48
`44
`
`480±127
`200±21*
`42
`
`546±170
`229±28*
`42
`
`507±156
`268±30
`53
`
`-4-
`
`000005
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`Clinical Trial:
`
`Two single agent (CCI-779) Phase I clinical trials have been conducted. In the
`
`first study, CCI-779 was administered as a 30 minute i.v. infusion daily for 5 days,
`
`every two to three weeks. In the second study, CCI-779 was administered as a 30
`
`5 minute i.v. infusion, once weekly. Both trials were open label, ascending dose,
`
`single-arm, multicenter studies. Patients were allowed to continue treatment as long
`
`as the CCI-779 was tolerated and there was no evidence of obvious disease
`
`progression. The following eligibility criteria were used:
`
`Inclusion Criteria
`1. Patients with a histologic diagnosis of advanced cancer (solid tumors and, in
`
`10
`
`the first study, lymphomas) who are refractory to standard therapy or for
`
`whom standard therapy is not appropriate.
`
`2. Measurable or evaluable disease.
`
`3. At least 3 weeks since prior chemotherapy and/or radiation therapy (6 weeks
`
`15
`
`since nitrosoureas or mitomycin C).
`
`4. At least 4 weeks since any other investigational agent.
`
`5. Age at least 18 years old.
`
`6. Adequate bone marrow, renal, and hepatic function.
`
`7. Serum cholesterol:::;; 350 mg/dL and triglycerides:::;; 300 mg/dL.
`
`20
`
`8. ECOG performance status 0-2.
`
`9. Life expectancy of at least 3 months.
`
`10. Signed, dated, witnessed written informed consent.
`
`25
`
`A total of 63 patients and 24 patients were enrolled in first and second studies,
`respectively. Dose levels ranged from 0.75-24 mg/m2 and 7.5-220 mg/m2
`daily x 5 every 2 weeks and weekly schedules, respectively.
`
`, with the
`
`The following summarizes the results that were obtained:
`
`In patients having renal cancer on the weekly schedule, 1 partial response (:2::
`
`30
`
`50% reduction in tumor size) and 2 minor responses (:2:: 25% but< 50% reduction in
`
`000006
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`
`tumor size) were observed. fu renal cancer patients on the daily x 5 schedule, 1 minor
`response, 1 unconfirmed minor response, and 1 stable disease ( < 25% increase to <
`
`25% reduction in tumor size) lasting approximately 5 months were observed.
`
`fu
`
`5
`
`patients having soft tissue sarcoma on the daily x 5 dosage schedule, 1 possible partial
`response, 2 minor responses, and 1 stable disease lasting approximately 5Yz months
`fu patients with breast cancer on the weekly dosage schedule, one
`were observed.
`
`partial response was observed. In patients with neuroendocrine tumor of the lung on
`
`the weekly dosage schedule, one partial response was observed. In patients having
`
`10
`
`cervical cancer on the daily x 5 dosage schedule, one minor response was observed.
`In patients having uterine cancer receiving the daily x 5 dosage schedule, one
`unconfirmed minor response was observed. fu patients having head and neck cancer
`
`receiving the daily x 5 dosage schedule, 1 stable disease for approximately 8Yz months
`
`was observed. fu patients having non-small cell lung cancer receiving the daily x 5
`
`dosage schedule, one partial response was observed. These results are particularly
`
`15
`
`surprising, considering that the patients in these studies had advanced cancers that
`
`were generally refractory to standard treatment, and also considering that these were
`
`Phase I clinical trials, in which efficacy is often limited, as the primary objective of a
`
`Phase I trial is to determine the safety and tolerability of the drug being evaluated.
`
`20
`
`Based on the results of the preclinical and clinical test procedures, CCI-779 is
`
`useful in treating neoplasms, in particular, refractory neoplasms. More particularly,
`
`CCI-779 is useful in treating treatment of renal carcinoma, soft tissue carcinoma,
`
`breast cancer, neuroendocrine tumor of the lung, cervical cancer, uterine cancer, head
`
`and neck cancer, glioblastoma, non-small cell lung cancer, prostate cancer, pancreatic
`
`25
`
`cancer, lymphoma, melanoma, small cell lung cancer, ovarian cancer, and colon
`
`cancer.
`
`As typical with chemotherapy, dosage regimens are closely monitored by the
`
`treating physician, based on numerous factors including the severity of the disease,
`
`30
`
`response to the disease, any treatment related toxicities, age, and health of the patient.
`
`-6-
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`Based on the results obtained with CCI-779, it is projected that initial i.v. infusion
`
`dosages will be between about 0.1 and 100 mg/m2 when administered on a daily
`
`dosage regimen, and between about 1 and 1000 mgfm2 when administered on a
`
`weekly dosage regimen. Other dosage regimens and variations are foreseeable, and
`
`5 will be determined through physician guidance.
`
`It is preferred that CCI-779 is
`
`administered by i.v. infusion or orally, preferably in the form of tablets or capsules.
`
`Other routes of administration are also feasible, such as via implants, parenterally
`
`(besides
`
`i.v., such as
`
`intraperitoneal and subcutaneous
`
`injections), rectally,
`
`intranasally, vaginally, and transdermally.
`
`10
`
`Dosage regimens are expected to vary according to the route of administration.
`
`For exan1ple, dosages for oral administration are often up to tenfold greater than for
`
`i.v. administration. It is anticipated that CCI-779 may be administered as the sole
`
`active chemotherapeutic agent, or may be part of a chemotherapeutic regimen
`
`containing more
`
`than one antineoplastic agent.
`
`The use of concomitant
`
`15
`
`chemotherapeutic agents often allows for dosage reduction of each particular agent,
`
`thereby increasing the safety margin of the particular agents.
`
`Oral formulations containing the active compounds of this invention may
`
`comprise any conventionally used oral forms, including tablets, capsules, buccal
`
`forms,
`
`troches, lozenges and oral liquids, suspensions or solutions. Capsules may
`
`20
`
`contain mixtures of the active compound(s) with inert fillers and/or diluents such as
`
`the pharmaceutically acceptable starches (e.g. com, potato or tapioca starch), sugars,
`
`artificial sweetening agents, powdered celluloses, such as crystalline and
`
`microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations
`
`may be made by conventional compression, wet granulation or dry granulation
`
`25 methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants,
`
`disintegrants, surface modifYing agents (including surfactants), suspending or
`
`stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc,
`
`sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium,
`
`polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate,
`
`30
`
`complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium
`
`-7-
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`phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry
`
`starches and powdered sugar. Preferred surface modifying agents include nonionic
`
`and anionic surface modifying agents. Representative exan1ples of surface modifying
`
`agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium
`
`5
`
`stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidol
`
`silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate,
`
`and triethanolamine. Oral formulations herein may utilize standard delay or time
`
`release formulations to alter the absorption of the active compound(s). The oral
`
`formulation may also consist of administering the active ingredient in water or a fruit
`
`10
`
`juice, containing appropriate solubilizers or emulsifiers as needed.
`
`In some cases it may be desirable to administer the compounds directly to the
`
`airways in the form of an aerosol.
`
`The compounds of this invention may also be administered parenterally or
`
`intraperitoneally. Solutions or suspensions of these active compounds as a free base
`
`15
`
`or pharmacologically acceptable salt can be prepared in water suitably mixed with a
`
`surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in
`
`glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary
`
`conditions of storage and use, these preparation contain a preservative to prevent the
`
`growth of microorganisms.
`
`20
`
`The pharmaceutical forms suitable for injectable 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 preserved against
`
`the
`
`25
`
`contaminating action of microorganisms 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.
`
`For the purposes of this disclosure,
`
`transdermal administrations are
`
`30
`
`understood to include all administrations across the surface of the body and the inner
`
`-8-
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`linings of bodily passages including epithelial and mucosal tissues.
`
`Such
`
`administrations may be carried out using the present compounds, or pharmaceutically
`
`acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions,
`
`and suppositories (rectal and vaginal).
`
`5
`
`Transdermal administration may be accomplished 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.
`
`10
`
`The crean1s and ointments may be viscous liquid or semisolid emulsions of either the
`
`oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed
`
`in petroleum or hydrophilic 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 such as a semi-permeable membrane covering a reservoir
`
`15
`
`containing the active ingredient with or without a carrier, or a matrix containing the
`
`active ingredient. Other occlusive devices are known in the literature.
`
`Suppository formulations may be made from traditional materials, including
`
`cocoa butter, with or without the addition of waxes to alter the suppository's melting
`
`point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of
`
`20
`
`various molecular weights, may also be used.
`
`-9-
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`CLAIMS
`
`PCT/USOl/47324
`
`5
`
`10
`
`1.
`
`A method of treating a neoplasm in a mammal in need thereof, which
`
`comprises providing to said mammal an effective amount of CCI-779.
`
`2.
`
`A method of treating a refractory neoplasm in a mammal in need
`
`thereof, which comprises providing to said mammal an effective amount of CCI-779.
`
`3.
`
`4.
`
`sarcoma.
`
`The method according to claim 1, wherein the neoplasm is renal cancer.
`
`The method according to claim 1, wherein the neoplasm is soft tissue
`
`5.
`
`The method according to claim 1, wherein the neoplasm is breast
`
`I
`
`15
`
`cancer.
`
`6.
`
`The method according to claim 1, wherein the neoplasm IS a
`
`neuroendocrine tumor of the lung.
`
`20
`
`7.
`cancer.
`
`The method according to claim 1, wherein the neoplasm is cervical
`
`8.
`
`The method according to claim 1, wherein the neoplasm is uterine
`
`cancer.
`
`25
`
`9.
`
`The method according to claim 1, wherein the neoplasm is a head and
`
`neck cancer.
`
`10.
`
`The method according
`
`to claim 1, wherein
`
`the neoplasm
`
`is
`
`30
`
`glioblastoma.
`
`- 10-
`
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`PCT/USOl/47324
`
`11.
`
`The method according to claim 1, wherein the neoplasm is non-small
`
`cell lung cancer.
`
`5
`
`12.
`
`The method according to claim 1, wherein the neoplasm is prostate
`
`cancer.
`
`cancer.
`
`10
`
`13.
`
`The method according to claim 1, wherein the neoplasm is pancreatic
`
`14.
`
`The method according to claim I, wherein the neoplasm is lymphoma.
`
`15.
`
`The method according to claim 1, wherein the neoplasm is melanoma.
`
`15
`
`16.
`
`The method according to claim 1, wherein the neoplasm is small cell
`
`lung cancer.
`
`17.
`
`The method according to claim 1, wherein the neoplasm is ovarian
`
`cancer.
`
`20
`
`cancer.
`
`18.
`
`The method according to claim 1, wherein the neoplasm is colon
`
`19.
`
`Use of rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-
`
`25 methylpropionic acid (CCI-779) in the preparation of a medican1ent for the treatment
`
`of a neoplasm in a mammal.
`
`20.
`
`Use of rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-
`
`methylpropionic acid (CCI-779) in the preparation of a medicament for the treatment
`
`30
`
`of a refractory neoplasm in a mammal.
`
`- 11-
`
`000012
`
`

`

`wo 02/40000
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`PCT/USOl/47324
`
`21.
`
`Use according to claim 19 wherein the neoplasm is renal cancer, soft
`
`tissue sarcoma, breast cancer, neuroendocrine
`
`tumor of the
`
`lung, cervical
`
`cancer,uterine cancer, head and neck cancer, glioblastoma, non-small cell lung cancer,
`
`5
`
`prostate cancer, pancreatic cancer, lymphoma, melanoma, small cell lung cancer,
`
`ovarian cancer or colon cancer.
`
`- 12-
`
`000013
`
`