HK1142538A - Anti-tumor activity of temsirolimus in papillary renal cell cancer - Google Patents

Description

Anti-tumor activity of temsirolimus against papillary renal cell carcinoma

Background

CCI-779 is rapamycin 42-ester with 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid, a rapamycin ester that has shown significant inhibition of tumor growth in both in vivo and in vitro models. This compound is now generally referred to as temsirolimus (temsirolimus). The use of CCI-779 has been described [ see, e.g., U.S. Pat. No. 7,189,735] alone or in combination with other active agents [ see, e.g., U.S. published patent application No. 2004-0258662A 1 ].

Renal Cell Carcinoma (RCC) is the most common primary renal malignancy in adults, accounting for over 85% of the total malignancy, and 2% of the total adult malignancy. Most renal malignancies arise from tubular epithelial cells and are classified into several distinct subtypes according to the morphological characteristics defined by the WHO international histological classification of renal tumors.

The most common subtype, clear cell renal cell carcinoma (cRCC), accounts for approximately 70-75% of the total RCCs. Papillary renal cell carcinoma (pRCC) is the second most common subtype in about 15% of cases, followed by chromophobe carcinoma (about 5%), large eosinophilic adenoma (about 3%) and collecting vessel carcinoma (about 2%).

PRCC is characterized histologically by the arrangement of the fibrovascular nucleus in a papillary conformation with the tumor cells. Most PRCC tumors show painless behavior and limited risk of development and mortality, but individual subtypes show highly aggressive behavior [ x.j.yang et al, Cancer res.65, 5628(2005) ]. Treatment of PRCC remains problematic. Currently, there is no effective treatment available for advanced pRCC patients, which are usually excluded by clinical trials often designed for the more common clear cell renal cell carcinoma.

Multi-kinase inhibitor, sorafenib (Nexavar)^TM) And sunitinib (Sutent)^TM) FDA approval has been given for the treatment of patients with advanced renal cell carcinoma and metastatic renal cancer. Both inhibitors are VEGF, PDGFR and other small molecule multi-receptor kinase inhibitors that have shown improved progression-free survival with a reduced toxicity profile compared to certain conventional cytokine treatments. However, these clinical trials only contained clear cytopathology patients and excluded non-clear cytopathology patients.

What is needed is an effective method for treating non-clear cell renal cell carcinoma.

Summary of The Invention

The present invention provides methods for treating non-clear cell renal cell carcinoma, such as papillary renal cell carcinoma, using an mTOR inhibitor, such as CCI-779 (temsirolimus).

The invention also provides the use of an mTOR inhibitor, e.g., CCI-779 (temsirolimus), in the treatment or manufacture of a medicament for the treatment of non-clear cell renal cell carcinoma, e.g., papillary renal cell carcinoma.

In one aspect, the invention provides a method of treating papillary renal cell carcinoma in a patient in need thereof by administering an effective amount of a CCI-779 as the sole antineoplastic agent. In one embodiment, the subject has not previously been treated with any systemic antineoplastic agents.

In another aspect, the invention provides the use of CCI-779 in the treatment of hereditary papillary renal cell carcinoma of type I. In yet another aspect, the invention provides the use of CCI-779 in the treatment of hereditary papillary renal cell carcinoma type II. In yet another aspect, the invention provides the use of CCI-779 in the treatment of sporadic papillary renal cell carcinoma.

Other aspects and advantages of the invention will become apparent from the following detailed description of the invention.

Detailed Description

The present invention provides the use of a rapamycin derivative, CCI-779, in the treatment, or manufacture of a medicament for treating papillary renal cell carcinoma in a patient, e.g., treating hereditary type I pRCC, hereditary type II pRCC, including sporadic pRCC, and including previously untreated, refractory, or advanced pRCC.

As used in accordance with this invention, the term "treatment" refers to the treatment of a mammal having a papillary renal cell neoplasm by administering to said mammal an effective amount of CCI-779 for the purpose of reducing or eradicating the neoplasm and/or prolonging the survival of the mammal and/or alleviating the suffering of the mammal.

As used herein, papillary renal cell carcinoma can be further divided into subtypes 1 and 2, and can occur as a mixture of these subtypes. Type 1 is characterized by papillary and tubular structures covered by small cells with light-colored bleb plasma, small oval nuclei with insignificant nucleoli, frequent glomerular (glomeriloid) papillae, papillary edema, foamy macrophages and arenomasomes in the papillary nucleus. Type 2 is characterized by consisting of large cells covered by a large volume of eosinophilic plasma and pseudolamella (pseudolamella). PRCC may also occur in sporadic (non-hereditary) and hereditary forms.

As used in accordance with this invention, the term "providing" in relation to providing CCI-779 means either directly administering CCI-779 or administering a prodrug, derivative or analog which will form an effective amount of CCI-779 in vivo.

As used in accordance with the present invention, the term "previously untreated" refers to a tumor of a patient that has not yet been approved by standard, systemic, chemotherapy, or other experimental treatment or adaptation to a given tumor.

As used in accordance with the present invention, the term "refractory" refers to a tumor of a patient that typically develops after standard chemotherapy appropriate for a given tumor.

As used herein, the term CCI-779 refers to rapamycin 42-ester with 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid (temsirolimus) and encompasses prodrugs, derivatives, pharmaceutically acceptable salts, or analogs thereof. Throughout this specification, the terms "CCI-779" and "temsirolimus" are used interchangeably.

The preparation of temsirolimus is described in U.S. Pat. No. 5,362,718. Regiospecific synthesis of temsirolimus is described in U.S. Pat. No. 6,277,983, which is incorporated herein by reference. Yet another method for regiospecific synthesis of temsirolimus is described in U.S. patent application No. 10/903,062 filed at 30.7.2004 [ disclosed at 10.2.2005 as U.S. patent publication No. 2005-0033046-A1 ] and its counterpart, International patent publication No. WO 2005/016935 (published at 7.4.2005).

In one embodiment, the temsirolimus provided treats hereditary type I papillary renal cell carcinoma. In another embodiment, temsirolimus is provided for treating hereditary type II papillary renal cell carcinoma. In yet another embodiment, temsirolimus is provided for treating sporadic papillary renal cell carcinoma. In yet another embodiment, the papillary renal cell carcinoma has not been previously treated. In another embodiment, the papillary renal cell carcinoma is advanced.

Papillary renal cell carcinoma, on the other hand, is implicated as a prognostic factor associated with poor risk characteristics, i.e., shortened patient survival. In other embodiments, the poor risk profile includes: elevated serum lactate dehydrogenase levels; decreased hemoglobin levels; elevated blood calcium; the time from initial diagnosis to random sampling is less than one year; a Karnofsky score of 70 or less; and transferred to multiple organ sites.

In one embodiment, the temsirolimus is administered as the sole active agent, e.g., excluding chemotherapeutic agents, such as alkylating agents; hormonal agents (i.e., estramustine, tamoxifen, toremifene, anastrozole, or letrozole); antibiotics (i.e., plicamycin, bleomycin, mitoxantrone, idarubicin, actinomycin D, mitomycin, or daunorubicin); antimitotic drugs (i.e., vinblastine, vincristine, teniposide, or vinorelbine); topoisomerase inhibitors (i.e., topotecan, irinotecan, etoposide, or doxorubin); and other drugs (i.e., hydroxyurea, trastuzumab, altretamine, rituximab, paclitaxel, docetaxel, L-asparaginase, or gemumab ozogamicin); biochemical modulators, imatinib (imatinib), EGFR inhibitors, such as EKB or other multi-kinase inhibitors, e.g., those targeting serine/threonine and receptor tyrosine kinases in tumor cells and tumor vessels, or immunomodulators (i.e., interferons, IL-2 or BCG). Examples of interferons include interferon alpha (interferon alpha), interferon beta, interferon gamma and mixtures thereof.

In another embodiment, the CCI-779 is a separate antineoplastic agent. In yet another embodiment, CCI-779 is provided with other active agents, provided that the other active agent is not an interferon, e.g., interferon alpha.

Typical oncological treatments are: the dosage regimen is closely monitored by the treating physician, depending on a number of factors, including the severity of the disease, the response to the disease, any treatment-related toxicities, the age and health of the patient. It is expected that the initial intravenous infusion dose of temsirolimus will be from about 1 to 250mg, about 5 to about 175mg, or about 5 to about 25mg when administered as a once weekly dose. In one embodiment, the dose is 1-250mg per week. In another embodiment, the dose is 25mg per week. Other dosage regimens and variations are predictable and will be determined by the physician's directions. Temsirolimus is preferably administered by intravenous infusion or preferably orally in the form of a tablet or capsule. In one embodiment, the administration is weekly for 1-24 months. However, other treatment cycles are also suitable and within the skill of the art.

The dosage regimen is expected to vary depending upon the route of administration. It is contemplated that the oral dose of temsirolimus for use in the present invention will be from 10 mg/week to 250 mg/week, from about 20 mg/week to about 150 mg/week, from about 25 mg/week to about 100 mg/week, or from about 30 mg/week to about 75 mg/week. For rapamycin, the planned oral dose will be between 0.1 mg/day and 25 mg/day. The exact dosage will be determined by the physician administering the drug based on experience with the particular subject being treated.

Oral formulations containing temsirolimus for use in the present invention may include any conventionally employed oral form, including tablets, capsules, buccal forms (buccal forms), lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound with inert fillers and/or diluents, such as the pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweeteners, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, and the like. Useful tablets may be prepared by conventional extrusion, wet or dry granulation methods using pharmaceutically acceptable diluents, binders, 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, gum arabic, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starch and powdered sugar. Preferred surface modifiers include nonionic and anionic surface modifiers. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silica, phosphates, sodium lauryl sulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein may employ standard delayed or timed release formulations to modify the absorption of the active compound. Oral formulations may also consist of the active ingredient treated in water or fruit juice, if desired containing suitable solubilizers or emulsifiers. A preferred oral formulation of rapamycin 42-ester with 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid is described in U.S. patent publication No. 2004/0077677A 1, published 4.4.22.2004.

In some cases, it is desirable to administer the composition of temsirolimus directly to the airways in the form of an aerosol.

The temsirolimus composition may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as the free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersants may 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.

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 protected from the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. A preferred injection of rapamycin 42-ester with 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid is disclosed in U.S. patent publication No. 2004/0167152A 1, published on 8/26/2004.

For purposes of this disclosure, transdermal administration is understood to include all administrations across the surface of the body and the lining of body passageways including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present invention or pharmaceutically acceptable salts thereof in the form of lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal).

Transdermal administration can be carried out by employing a transdermal patch containing the active compound and a carrier that is inert to the active compound, non-toxic to the skin, and delivers the drug transdermally for systemic absorption into the bloodstream. The carrier may be in any form, such as creams and ointments, pastes, gels, and occlusive devices. Creams and ointments may be viscous or semisolid emulsions of the oil-in-water or water-in-oil type. Pastes comprised of absorbent powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. Various occlusive devices, for example, including a semipermeable membrane covering a reservoir containing an active ingredient with or without a carrier or matrix containing the active ingredient, may be used to release the active ingredient into the bloodstream. Other occlusion devices are also known in the literature.

Suppositories can be prepared from conventional materials including cocoa butter and glycerin, with or without waxes to adjust the suppository's melting point. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be employed.

In one embodiment, temsirolimus in the method or in the composition for use in the method of the present invention may be replaced with another mTOR inhibitor. As used herein, the term mTOR inhibitor refers to a compound, or a ligand or pharmaceutically acceptable salt thereof, that inhibits cell replication by blocking the cell cycle from G1 to S. The term includes the neutral tricyclic compound rapamycin (sirolimus) and other rapamycin compounds, including, for example, rapamycin derivatives, rapamycin analogs, other macrolide compounds that inhibit mTOR activity, and all compounds encompassed within the following definition of the term "rapamycin". These include compounds having a structure analogous to "rapamycin", e.g., compounds having a structure analogous to a macrocyclic ring, which has been modified to enhance therapeutic benefit. FK-506 can also be used in the method of the present invention.

As used herein, the term rapamycin refers to a class of immunosuppressive compounds that contain the basic rapamycin nucleus as represented below.

The rapamycins of the present invention include compounds that are chemically or biologically modified to have derivatives of the rapamycin nucleus, while still retaining immunosuppressive properties. Thus, the term rapamycin includes rapamycin and esters, ethers, carbamates, oximes, hydrazones, and hydroxylamines of rapamycin, as well as rapamycin that has been modified at the rapamycin nucleus, for example, by reduction or oxidation. Also included in the term rapamycin are pharmaceutically acceptable salts of rapamycin.

The term rapamycin also includes 42-and/or 31-esters and ethers of rapamycin as described in the following patents, which are incorporated herein by reference in their entirety: alkyl esters (U.S. Pat. No. 4,316,885); aminoalkyl esters (U.S. Pat. No. 4,650,803); fluoro esters (U.S. Pat. No. 5,100,883); amide esters (U.S. patent No. 5,118,677); carbamates (U.S. patent No. 5,118,678); silyl esters (U.S. Pat. No. 5,120,842); aminodiesters (U.S. Pat. No. 5,162,333); sulfonates and sulfates (U.S. Pat. No. 5,177,203); esters (U.S. patent No. 5,221,670); alkoxy esters (U.S. patent No. 5,233,036); o-aryl, -alkyl, -alkenyl, and-alkynyl ethers (U.S. patent No. 5,258,389); carbonates (U.S. patent No. 5,260,300); arylcarbonyl and alkoxycarbonyl carbamates (U.S. patent No. 5,262,423); carbamates (U.S. patent No. 5,302,584); hydroxy esters (U.S. Pat. No. 5,362,718); hindered esters (hindered esters) (U.S. Pat. No. 5,385,908); heterocyclic esters (U.S. Pat. No. 5,385,909); geminally disubstituted esters (U.S. Pat. No. 5,385,910); aminoalkanoic esters (U.S. Pat. No. 5,389,639); phosphoryl carbamates (U.S. Pat. No. 5,391,730); carbamates (U.S. patent No. 5,411,967); carbamates (U.S. patent No. 5,434,260); amidinocarbamates (U.S. patent No. 5,463,048); carbamates (U.S. patent No. 5,480,988); carbamates (U.S. patent No. 5,480,989); carbamates (U.S. patent No. 5,489,680); hindered N-oxide esters (U.S. patent No. 5,491,231); biotin esters (U.S. patent No. 5,504,091); o-alkyl ethers (U.S. Pat. No. 5,665,772); and PEG esters of rapamycin (U.S. patent No. 5,780,462). The preparation of these esters and ethers is disclosed in the patents listed above.

Also included within the definition of the term rapamycin are the 27-esters and ethers of rapamycin, which are disclosed in U.S. patent No. 5,256,790. Also described is C-27 keto rapamycin which is reduced to the corresponding alcohol which in turn is converted to the corresponding ester or ether. The preparation of these esters and ethers is disclosed in the patents listed above. Also included are the oximes, hydrazones, and hydroxylamines of rapamycin disclosed in U.S. Pat. Nos. 5,373,014, 5,378,836, 5,023,264, and 5,563,145. The preparation of these oximes, hydrazones and hydroxylamines is disclosed in the patents listed above. The preparation of 42-oxorapamycin is disclosed in 5,023,263.

Examples of rapamycins include, for example, as disclosed in U.S. Pat. No. 5,362,718, rapamycin, 32-deoxorapamycin, 16-pent-2-ynyloxy-32 (S) -dihydro-rapamycin, 16-pent-2-ynyloxy-32 (S) -dihydro-O-40-O- (2-hydroxyethyl) -rapamycin, rapamycin 42-ester with 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid (CCI-779), 40- [ 3-hydroxy-2- (hydroxymethyl) -2-methyl propionate.]Rapamycin or a pharmaceutically acceptable salt thereof, for example ABT578 or 40- (tetrazolyl) -rapamycin, 40-epi- (tetrazolyl) -rapamycin as disclosed in international patent publication No. WO 99/15530, or a rapamycin analogue as disclosed in international patent publication nos. WO98/02441 and WO 01/14387, for example AP 23573. In another embodiment, the compound is Certican^TM(everolimus, 2-O- (2-hydroxy) ethyl rapamycin, Novartis, U.S. Pat. No. 5,665,772).

As described herein, the following standard pharmacological test procedures can be used to determine whether a compound is an mTOR inhibitor. Treatment of growth factor-stimulated cells with an mTOR inhibitor, such as rapamycin, completely blocks phosphorylation of serine 389, which itself constitutes a good test for mTOR inhibition, as demonstrated by western blotting. Thus, in the presence of mTOR inhibitors, whole cell lysates from cells stimulated with growth factors in culture (e.g., IGF1) failed to band on polyacrylamide gels that could be specifically labeled with the antibody to serine 389 of p70s 6K.

In one embodiment, a method is provided for treating papillary renal cell carcinoma in a mammal in need thereof, which comprises providing to said mammal an effective amount of CCI-779 without interferon alpha (alpha-interferon or alpha-IFN). Also provided is the use of a CCI-779 in the manufacture of a medicament for a treatment regimen for papillary renal cell carcinoma in a mammal in need thereof, wherein the CCI-779 is the sole active agent in the regimen. In yet another embodiment, there is provided a use of a CCI-779 in a medicament in a treatment regimen for papillary renal cell carcinoma in a mammal in need thereof, wherein the CCI-779 is a combination regimen, wherein the regimen does not include interferon-alpha.

In another aspect, the invention includes a product or pharmaceutical package comprising an anti-tumor course of therapy for one individual mammal comprising one or more containers of temsirolimus in unit dosage form having 1, 1-4, or more units. In another embodiment, a pharmaceutical package containing an anti-tumor treatment course for treating an individual mammal comprises a container having units of temsirolimus in a unit dosage form.

In certain embodiments, the compositions of the present invention are in a package or kit in a form ready for administration. In other embodiments, the compositions of the present invention are in a concentrated form in a package, optionally together with a diluent required to formulate the final solution for administration. In still other embodiments, the product comprises a compound for use in the present invention in solid form and, optionally, a separate container containing a solvent or carrier suitable for use of the compound in the present invention.

In still other embodiments, the above packages/kits include other components, e.g., instructions for dilution, mixing, and/or administration of the product, other containers, syringes, needles, etc. Other such package/kit compositions will be apparent to those skilled in the art.

The following examples are illustrative of the invention and are not to be construed as limiting thereof.

example-CCI-779 as a sole systemically active agent against nontransparent cell renal cell carcinoma

In this phase III study, 626 patients with advanced metastatic renal cell carcinoma from 26 countries received randomized alpha IFN or CCI-779 (temsirolimus) as the first line of treatment. This group is a very poor prognosis patient group with many risk factors for early death. Patients received 3 Million Units (MU) of alpha IFN-alone subcutaneous administration 3 times per week, escalating to 18MU or 25-mg CCI-779 intravenous infusions per week.

The appropriate one for this study needed histologically confirmed advanced (stage IV or recurrent disease) RCC that were not previously systemically treated for the disease. Subjects with central nervous system metastases, previously treated for anti-cancer RCC, and previously received investigational treatments/drugs within 4 weeks of randomized sampling were excluded from the study.

The primary goal of this study was to have a primary endpoint efficacy for overall survival. The secondary goals of the study were safety, healthy outcome and additional efficacy endpoints. The second efficacy endpoint of the study was the evaluation of progression free survival, response rate (full and partial response), clinical benefit rate, duration of full response, treatment failure time, and health outcome measures. In addition, based on screening of tumor expression for proteins involved in the AKT-mTOR pathway, subject responses involving all 3 therapeutic agents were evaluated. Other planned and subsequent analyses were performed to evaluate tumor histology (clear versus opaque cell), age (65 years versus 65 years), and prognostic risk group (medium versus poor comparison) impact.

The results obtained are summarized below (table 1):

TABLE 1 Overall survival and progression-free survival in phase III study

The proportion of patients with different histologies was balanced between all study objectives (81% clear cells; 13% indeterminate cells; 6% non-clear cells). Of those with additional subtype data, 75% are papillary RCCs. For patients with clear cell tumors, median survival (OS) and Progression Free Survival (PFS) of CCI-779(TEMSR) were longer than α IFN, with risk ratios (HR) of 0.82 and 0.76, respectively. For patients of other tumor histologies, median OS and PFS of TEMSR were also longer than α IFN, HR 0.49 and 0.38 respectively. Median OS and PFS of TEMSR are longer than alpha IFN in < 65 years of age, with HR of 0.62 and 0.61, respectively. For patients aged 65 years >/, treated with either TEMSR or IFN α, OS or PFS were indistinguishable, but TEMSR had better side effects than IFN α.

TEMSR prolonged PFS by 31% and HR by 0.76 for previously untreated late renal cell carcinoma of clear cell type (advRCC), indicating a 24% reduction in the risk of death or disease progression. TEMSR also increased OS by 22% in previously untreated clear cell advRCC patients compared to IFN α. A risk ratio of 0.82 indicates that the risk of mortality is reduced by 18% in patients receiving TEMSR compared to IFN α.

TEMSR alone extended PFS to 163% and HR to 0.38 in previously untreated non-clear cell advRCC patients, indicating a 62% reduction in the risk of death or disease progression. TEMSR alone also increased OS by 104% in previously untreated non-clear cell advRCC patients compared to IFN α. A risk ratio of 0.49 indicates a 51% reduction in the risk of mortality in patients receiving TEMSR compared to IFN α.

In the < 65 year old patient population, TEMSR extended PFS by 61% in previously untreated advRCC patients. A risk ratio of 0.62 indicates a reduction in the risk of death or disease progression of up to 38%. In a population of patients < 65 years of age, TEMSR increased OS by 64% compared to IFN α in previously untreated advRCC patients. A risk ratio of 0.61 indicates a 39% reduction in the risk of mortality in patients receiving TEMSR compared to IFN α.

All patents, patent applications, articles and other documents cited herein are incorporated by reference. It will be apparent to those skilled in the art that modifications may be made to the specific embodiments described herein without departing from the scope of the invention.

Claims (17)

1. A method of treating papillary renal cell carcinoma in a mammal in need thereof, which comprises providing to said mammal an effective amount of CCI-779.

2. The method according to claim 1, wherein the papillary renal cell carcinoma is hereditary type I papillary renal cell carcinoma.

3. The method according to claim 1, wherein the papillary renal cell carcinoma is hereditary type II papillary renal cell carcinoma.

4. The method according to claim 1, wherein the papillary renal cell carcinoma is sporadic papillary renal cell carcinoma.

5. The method according to any one of claims 1-4, wherein the papillary renal cell carcinoma is a previously untreated papillary renal cell carcinoma.

6. The method according to any one of claims 1-5, wherein the papillary renal cell carcinoma is associated with a poor risk profile.

7. The method according to any one of claims 1-6, wherein the papillary renal cell carcinoma is advanced.

8. The method according to any one of claims 1-7, wherein said CCI-779 is administered intravenously.

9. The method according to any one of claims 1 to 8, wherein said CCI-779 is administered weekly for 1 to 24 months.

10. The method according to any one of claims 1 to 9, wherein the CCI-779 is administered intravenously at a dose of 1 to 250mg per week.

11. The method according to claim 10, wherein said CCI-779 is administered intravenously at a dose of 25mg per week.

12. The method according to any one of claims 1-11, wherein the CCI-779 is the sole antineoplastic agent in the treatment regimen.

13. The method according to any one of claims 1 to 12, wherein the CCI-779 is the sole active agent in the treatment regimen.

14. The method according to any one of claims 1-12, further comprising an additional active agent, with the proviso that the additional active agent is not an interferon.

15. A method of treating papillary renal cell carcinoma in a mammal in need thereof, which comprises administering to said mammal an effective amount of CCI-779 in the absence of interferon alpha.

16. A CCI 779 for treating papillary cell carcinoma as described in any one of claims 1-15.

Use of CCI 779 in the preparation of a medicament for the treatment of papillary renal cell carcinoma as described in any one of claims 1-15.