MXPA06004707A - Cci-779 for treating mantle cell lymphoma - Google Patents

Abstract

This invention provides the use of rapamycin 42-ester with 3-hydroxy-2- (hydroxymethyl)-2-methylpropionic acid (CCI-779) in the treatment or inhibition of mantle cell lymphoma.

Description

CCI-779 TO TREAT LUNG CELL LYMPHOMA BACKGROUND OF THE INVENTION This invention relates to the use of the rapamycin 42 ester with 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid (CCI-779) in the treatment or inhibition of mantle cell lymphoma. The rapamycin ester 42 with 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid (CCI-779) is an ester of rapamycin. Rapamycin, also known as sirolimus, is a macrocyclic trieno antibiotic produced by Streptomyces hygroscopicus. The preparation and use of rapamycin hydroxyesters, including CCI-779, are described in U.S. Patent Nos. 5,362,718 and 6,277,983. ICC-779 has been described as having in vitro and in vivo activity against a number of tumor cell types. It is hypothesized that CCI-779 delays the time to tumor progression or the time to tumor recurrence. This mechanism of action is more typical of cytostatic agents rather than cytotoxic and similar to sirolimus. CCI-779 binds to and forms a complex with the cytoplasmic protein FKBP, which inhibits an enzyme, mTOR (mammalian target of rapamycin, also known as Ref. 172467 protein associated with FKBP12 -rapamycin [FRAP]). Inhibition of TOR kinase activity inhibits a variety of signal transduction pathways, including cytokine-stimulated cell proliferation, mRNA translation for several key proteins that regulate the Gl phase of the cell cycle, and transcription induced by IL-2 , leading to the inhibition of the cell cycle progress from Gl to S. Mantle cell lymphoma, cancer of B lymphocytes housed in mantle regions of lymph nodes, is a unique subtype of non-Hodgkin lymphoma (NHL) characterized by a specific chromosomal translocation of the bc-1 gene (t (11; 14) (ql3: q32)) and the subsequent overproduction of the gene product in cyclin DI. The proto-oncogene bcl-1 (which means lympho / B-cell leukemia) is one of five genes in the section of chromosome 11 that translocates into MCL, but is the only one expressed in MCL. The unique nature of the lymphocytes and, in particular, the bcl-1 site it occupies on chromosome 14 contributes to at least some of the bizarre behavior of MCL cells. MCLs represent approximately 10% of all NHL. The average age of onset is approximately 60 years and there is a higher incidence in men [Decaudin, D., et al. , Leuk Lymphoma 37: 181-4 (2000)]. Patients typically present at an advanced stage and extranodal sites are often indicated. For example, some patients present with prominent lymphocytosis and may be confused with chronic lymphocytic leukemia [Wong, K.F. et al. , Cancer 86: 850-7 (1999)]. Others present with multiple polyps in the colon that can cause gastrointestinal hemorrhage [Hashimoto, Y., et al. , Hum Pathol, 30: 581-7 (1999)]. Another unusual presentation is that of massive splenomegaly and minimal lymphadenopathy [Molina, T.J., et al. , Virchows Arch 437: 591-8 (2000)]. Patients with MCL have shown that they have a significantly worse prognosis than those with other histologies with an average survival of 3-4 years [Weisenburger, D.D. et al. , Am J Hematol 64: 190-6 (2000); Hiddemann, W., et al. , Journal of Clinical Oncology 16: 1922-30 (1998); Samaha, H., et al. , Leukemia 12: 1281-7, (1998); Callea, V., et al. , Haematologica 83: 993-7 (1998)]. The treatment of MCL has remained problematic despite the availability of purine nucleoside analogs, non-differentiated cell transplantation, and monoclonal antibody therapy with rituximab. Each of these modalities can produce tumor responses in the MCI but the disease typically resorts to and requires additional therapy. There is no treatment regimen that can be considered the treatment of choice for patients with MCL not treated new. Most patients are treated with cnations of rituximab and chemotherapy - usually R-CHOP or a nucleoside analog of purine and rituximab. Patients who are eligible with high-dose therapy supported by undifferentiated cells are usually transplanted into the first remission. Less than 50% of patients with MCL achieve a complete remission (CR) with current therapy and a few patients achieve durable remissions. The typical scenario is that the patient will respond to chemotherapy, but the answers are usually partial and the progress time is short [Oinonen, R., et al. , European Journal of Cancer 34: 329-36 (1998)]. Mantle cell lymphoma remains a difficult disease to treat once it has relapsed and patients are typically treated with multiple regimens with a short time until progress between treatments. SUMMARY OF THE INVENTION The invention is provided for the use of a CCI-779 in the preparation of a medicament for treating or inhibiting mantle cell lymphoma in a subject. In one aspect, the invention provides a pharmaceutical composition for treating or inhibiting mantle cell lymphoma, which comprises a CCI-779 in unit dosage form in association with a pharmaceutically acceptable carrier or excipient. In another aspect, the invention provides a pharmaceutical package containing a course of treatment of mantle cell lymphomas for an individual mammal, comprising a container comprising a CCI-779 in unit dosage form. Other aspects and advantages of the invention will be apparent from the following detailed description of the invention. DETAILED DESCRIPTION OF THE INVENTION In this way, the invention provides a method and equipment useful in the treatment or inhibition of mantle cell lymphoma. As used in accordance with this invention, the term "treatment" means treating a mammal having mantle cell lymphoma by providing the mammal with an effective amount of a CCI-779 for the purpose of inhibiting the growth of the lymphoma in that mammal, eradication of lymphoma, or palliation of lymphoma. As used, according to this invention, the term "inhibition" means to inhibit the onset or progression of mantle cell lymphoma in a mammal having or is susceptible to developing that disease by providing the mammal with an effective amount of CCI-779.

As used in accordance with this invention, the term "provide" means directly administering CCI-779 or administering a prodrug, derivative, pharmaceutical salt or analog of CCI-779 that will form an effective amount of CCI-779 in the body. Through this specification and the claims, the term "a CCI-779" encompasses CCI-779, and prodrugs, derivatives, pharmaceutical salts or the like thereof, which provides an effective amount of CCI-779 to the subject. The preparation of the CCI-779 is described in U.S. Patent 5,362,718, which is hereby incorporated by reference. A regiospecific synthesis of CCI-779 is described in US Pat. No. 6,277,983, which is hereby incorporated by reference. Another, more regiospecific method for the synthesis of CCI-779 is described in US Patent Application No. 10 / 903,062, filed July 30, 2004, and its counterpart, International Patent Application PCT / US2004 / 22860, filed July 15, 2004. Although the invention illustrates the use of CCI-779, it was anticipated that they may be used other rapamycins in the invention in place of CCI-779. The term "a rapamycin" defines a class of immunosuppressive compounds which contain the basic nucleus of rapamycin. The rapamycins of this invention include compounds which can be chemically or biologically modified as derivatives of the rapamycin nucleus, although they still retain their immunosuppressive properties. Accordingly, the term "a rapamycin" includes esters, ethers, oximes, hydrazones and hydroxylamines of rapamycin, as well as rapamycins in which the functional groups on the rapamycin nucleus have been modified, for example through reduction or oxidation. The term "a rapamycin" also includes pharmaceutically acceptable salts of rapamycins, which are capable of forming those salts, either by virtue of containing an acidic or basic portion. It is preferred that the rapamycin compound be selected from rapamycin [Rapamune ™ brand of sirolimus, Wyeth, Madison, NJ], or 42-0- (2-hydroxy) ethyl rapamycin. Other suitable rapamycins include, for example, Ap23573 [Ariad], FK-506, RAD001 (everolimus) and TAFA-93, a prodrug of rapamycin [Isotechnika Inc.]. The ability of a CCI-779 to treat or inhibit mantle cell lymphoma was evaluated in a clinical trial. Briefly, 18 patients (average age of 72 years, range of 38-89 years) with an intravenous dose of 250 of CCI-779 were treated on days 1, 8, 15 and 22 of a 4-week treatment cycle. , up to a maximum of 12 cycles. Of these patients, 15 were in stage IV, 2 were in stage III and 1 was in stage II. The percentage of total response was 44.4% (95% CI, 24% -68%) and thus satisfied the criteria of initial evidence of efficacy in this group of patients. 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-779 is useful in the treatment or inhibition of mantle cell lymphoma. When a CCI-779 was used in the treatment or inhibition of mantle cell lymphoma, it was projected that a subject will be given a weekly dose of 10 to 250 mg of CCI-779 per week. The treatment typically consists of a monthly cycle composed of weekly dose administrations, although weekly or biweekly cycles can be selected. A subject can be subjected to one to twelve continuous monthly cycles. Alternatively, the subject may be subjected to a cycle, cease treatment, and then be subjected to another cycle. Oral or intravenous infusion are the preferred routes of administration, with intravenous being the most preferred. The initial intravenous doses were typically projected to be ten times smaller than the oral doses. For example, intravenous doses may be in the range of 10 mg / week to 175 mg / week, or 20 mg / week to 150 mg / week, or more desirably, 25 mg / week to 75 mg / week; while, oral doses may be in the range of 100 mg / week to 250 mg / week, 125 mg / week to 225 mg / week, or 150 mg / week to 200 mg / week. The precise doses for oral, parenteral, nasal or intrabronchial administration were determined by the managing physician based on the experience with the individual subject treated. Treatment will usually start with small doses less than the optimal dose of the compound. Subsequently the dose is increased until an optimal effect is reached under the circumstances. Optionally, the dose is then decreased for a week, two weeks or cycle, as desired or necessary. Preferably, the pharmaceutical composition is a unit dose form, for example, as prefilled tablets, capsules, bottles or syringes. In that form, the composition is subdivided into unit doses containing the appropriate amounts of the active ingredient, the unit dosage forms can be packaged compositions, for example, packaged powders, flasks, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form may, for example, a capsule or tablet itself, may be the appropriate number of any of those compositions in the form of a pack.

Oral formulations containing the active compounds of this invention may comprise any conventional used oral forms, including tablets, capsules, buccal forms, troches, lozenges and liquids, suspensions or oral solutions. The capsules may contain mixtures of active compounds with inert fillers and / or diluents such as pharmaceutically acceptable starches (for example corn starch, potato or tapioca), sugars, artificial sweetening agents, artificial celluloses, powdered celluloses, such as crystalline cellulose and microcrystalline celluloses, flours, jellies, gums, etc. Useful tablet formulations can be produced by the conventional wet compression, wet granulation, or dry granulation methods and utilize pharmaceutically acceptable surface-active agents (including surfactants), suspending agents, stabilizers, stabilizers, lubricants, disintegrants, binders, lubricants, lubricants, disintegrants, including but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethyl cellulose, polyvinyl pyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, carbonate calcium, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starches and powdered sugar. Preferred surface modifying agents include nonionic and anionic surface modifying agents. 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 silicon dioxide, phosphates, sodium dodecylisulfate, silicate of magnesium and aluminum, and triethanolamine. Oral formulations here may use delayed-release formulations or with standard time to alter the absorption of the active compounds. The oral formulation may also consist of administering the active ingredient in water or a fruit juice, containing the appropriate solubilizers or emulsifiers as necessary. Preferred oral formulations for the rapamycin ester 42 with 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid are described in published U.S. Patent Application, US 2004-0077677 Al (also USSN 10/663, 506), which is hereby incorporated by reference. In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol. The compounds can also be administered parenterally or intraperitoneally. Solutions or suspensions of those active compounds as free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. The 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. 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 there is an easy flow in a syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The support or excipient may 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. Preferred injectable formulations for the rapamycin ester 42 with 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid are disclosed in US 2004-0167152 (also USSN 10 / 626,943), which is therefore incorporated herein by reference reference.

In this embodiment, the injectable formulation useful in the invention provides a concentrated CCI-779 cosolvent containing a parenterally acceptable solvent and an antioxidant as described above and a parenteral formulation containing a CCI_779, composed of a CCI-779, a cosolvent parenterally acceptable, an antioxidant, a diluent solvent and a surfactant. Any given formulation useful in this invention may contain multiple ingredients of each component class. For example, a parenterally acceptable solvent may include a non-alcoholic solvent, an alcohol solvent or mixtures thereof. Examples of suitable non-alcoholic solvents include, for example, dimethylacetamide, dimethylsulfoxide or acetonitrile, or mixtures thereof. "An alcoholic solvent" may contain one or more alcohols as the alcohol component of the formulation. Examples of solvents useful in the formulations of the invention include, without limitation, ethanol, propylene glycol, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, or mixtures thereof. These cosolvents are particularly desirable because degradation via oxidation and lactone cleavage occurs to a lesser degree by these cosolvents. In addition, ethanol and propylene glycol can be combined to produce a less flammable product, but large amounts of ethanol in the mixture generally result in better chemical stability. A concentration of 30 to 100% v / v of ethanol in the mixture is preferred. In this embodiment, the stability of a CCI-779 in parenterally acceptable alcohol cosolvents is enhanced by the addition of an antioxidant to the formulation. Acceptable antioxidants include but are not limited to citric acid, d, 1, α-tocopherol, BHA, BHT, monothioglycerol, ascorbic acid, propyl gallate and mixtures thereof. Generally, parenterally useful formulations in this embodiment of the invention will contain an antioxidant component in a concentration ranging from 0.01% to 1% w / v, or 0.01% to 0.5% w / v, of the concentrated cosolvent, although they can be desirable lower or higher concentrations. Of the antioxidants, d, 1, α-tocopherol is particularly desirable and is used at a concentration of 0.01 to 0.1% w / v with a preferred concentration of 0.075% w / v of the concentrated cosolvent. In certain embodiments, the antioxidant component of the formulation of the invention also exhibits chelating activity. Examples of such chelating agents include, for example, citric acid, acetic acid and ascorbic acid (which may function as a classical antioxidant and a chelating agent in the formulations herein). Other chelating agents include those materials that are capable of binding metal ions in solution, such as ethylene diamine tetra acetic acid (EDTA), its salts, or amino acids such as glycine are able to improve the stability of a CCI_779. In some embodiments, components with chelating activity are included in the formulations of the invention, as the sole "antioxidant component". Typically, those metal binding components, when acting as chelating agents are used at the lower end of the concentration range for the antioxidant component provided herein. In one example, citric acid improves the stability of CCI-779 when used at a concentration less than 0.01% w / v. Higher concentrations are less stable solutions and thus less desirable for products to be subjected to long-term storage in liquid form. Additionally, those chelating agents can be used in combinations with other antioxidants as part of the antioxidant component of the invention. For example, an acceptable formulation may contain citric acid, d, 1, α-tocopherol. The optimum concentrations for the selected antioxidant can be readily determined by one skilled in the art on the basis of the information provided herein. Advantageously, in certain embodiments of the parenteral formulations useful in the invention, the precipitation of a CCI-779 after dilution with aqueous infusion solutions or blood is avoided through the use of a surfactant contained in the diluent solution. The most important component of the diluent is a parenterally acceptable surfactant. A particularly desirable surfactant is polysorbate 20 or polysorbate 80. However, one skilled in the art can easily select other suitable surfactants from salts of bile acids (taurocholate, glycocholate, cholate, deoxycholate, etc.) which are optionally combined with lecithin. Alternatively, ethoxylated vegetable oils, such as pegylated castor oil (for example, such as PEG-35 castor oil which is sold, for example, under the name Cremophor EL, BASF), vitamin succinate, may be used. E tocopherol propylene glycol (Vitamin E TGPS), and polyoxyethylene-polyoxypropylene block copolymers in diluent as the surfactant, as well as other members of the polysorbate family, such as polysorbate 20 or 60. Other diluent components may include water, ethanol , polyethylene glycol 300, polyethylene 400, polyethylene 600, polyethylene 1000, or mixtures containing one or more of those polyethylene glycols, propylene glycol and other cosolvents or parenterally acceptable agents to adjust the osmolarity of the solution such as sodium chloride, lactose, mannitol or other sugars, polyols and electrolytes parenterally acceptable The surfactant is expected to comprise 2 to 100% w / v of the diluent solution, from 5 to 80% w / v, from 10 to 75% w / v, from 15 to 60% w / v, and preferably at least 5% w / v, or at least 10% w / v, of the diluent solution. A parenteral formulation useful in the invention can be prepared as a single solution, or it can be prepared, preferably, as a concentrated cosolvent containing a CCI-779, an alcoholic solvent, and an antioxidant, which is then combined with a diluent containing a suitable diluent and surfactant solvent. Before use, the concentrated cosolvent is mixed with a diluent comprising a diluent solvent, and a surfactant. When the CCI-779 is prepared as a concentrated cosolvent according to this invention, the concentrate may contain concentrations of a CCI-779 of 0.05 mg / mL, 2.5 mg / mL, of 5 mg / mL, of 10 mg / mL or from 25 mg / mL to approximately 50 mg / mL. The concentrate can be mixed with the diluent up to about 1 part of the concentrate to 1 part of the diluent, to give parenteral formulations having concentrations of a CCI-779 of 1 mg / mL, of 5 mg / mL, of 10 mg / mL, from 20 mg / mL, to approximately 25 mg / mL. For example, the concentration of CCI-779 in the parenteral formulation can be from about 2.5 to 10 mg / mL. This invention also covers the use of formulations having lower concentrations of a CCI-779 in the concentrated cosolvent and formulations in which a part of the concentrate is mixed with more than one part of the diluent, eg, concentrate: diluent in a ratio from about 1: 1.5, 1: 2, 1: 3, 1: 4 1: 5, or 1: 9 v / v and so on, to parenteral formulations of CCI-779 having concentrations below the lowest levels of detection . Typically, an antioxidant may comprise from about 0.0005 to 0.5% w / v of the formulation. The surfactant may for example comprise from about 0.5% to about 10% w / v of the formulation. The alcohol solvent may comprise, for example, from about 10% to about 90% w / v of the formulation. Parenteral formulations useful in this invention can be used to produce a dosage form that is suitable for administration by direct injection or by addition to sterile infusion fluids for intravenous infusions. For the purposes of this description, it should be understood that transdermal administrations include all administrations through the surface of the body and the internal coatings of the body passages, including the epithelial and mucosal tissues. Those administrations can be carried out using the compounds of the present invention, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal). Transdermal administration can be effected through the use of a transdermal patch containing the active compound and a support which is inert to the active compound, which is not toxic to the skin, and which makes it possible to provide the agent for systemic absorption towards the flow blood through the skin. The support can take any number of forms such as creams and ointments, pastes, gels and occlusive devices. The creams and ointments may be liquid or semisolid viscous emulsions of the oil in water or water in oil type. Pastes comprised of absorbent powders dispersed in petroleum or hydrophilic petroleum containing an active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the bloodstream as a semipermeable membrane that covers a reservoir containing the active ingredient with or without a support, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. Suppository formulations can be produced from traditional materials, including cocoa butter, with or without the addition of waxes to alter the melting point of the suppository and glycerin.

Also, bases for soluble suppositories, such as polyethylene glycol of various molecular weights, can be used. The components of the invention can be in the form of a team of parts. The invention therefore includes a product that contains a CCI-779 for use in the treatment or inhibition of mantle cell lymphoma in a mammalian subject in need thereof. The invention also includes a pharmaceutical package containing a course of the treatment of mantle cell lymphomas for an individual mammalian subject, wherein the package contains units of a CCI-779 or 42-0 (2-hydroxy) ethyl rapamycin in dosage form unitary In one embodiment, the product contains a CCI-779 in ready-for-administration form. Alternatively the product may contain a CCI-779 as a concentrate that can be mixed with a suitable diluent that is optionally provided in the product. In yet another embodiment, the product contains a CCI-779 in solid form and optionally, a separate container with a solvent or support suitable for CCI-779. Further components in the equipment, for example, instructions for dilution, mixing and / or administration of the product, other contents, syringes, needles, etc., will be readily apparent to one skilled in the art. The following examples are illustrative of the present invention but are not a limitation thereof.

EXAMPLE 1- Antitumor Activity of a single CCI-779 Agent for Recurrent Mantle Cell Lymphoma: a Phase II Trial in the Central North Cancer Treatment Group A mantle cell lymphoma (MCL) is characterized by a t ( 11; 14) which results in overexpression of cyclin DI, a number of the phosphatidylinosital 3 kinase (PI3K) pathway. This study tested whether CCI-779, which inhibits the PI3K pathway at the level of the rapamycin target mammal (mTOR), could produce tumor responses in patients with MCL. A. Patients and Methods This study was conducted through the cooperative group of the Central North Cancer Treatment Group (? CCTG). Patients were eligible for this trial if they had previously received therapy and relapsed. There was no limit on the number of previous therapies. All histologies were confirmed as mantle cell lymphoma by the central pathological review. It was required that cyclin DI positivity by immunohistochemistry t (11; 14) detected by FISH. The patients were required to have measurable disease with a lymphatic node mass or tumor ^ 2 cm or malignant lymphocytosis with an ALC i 5,000; a life expectancy of > 3 months, ECOG performance status of 0, 1 or 2; absolute neutrophil count (ANC) _ > 1,000; platelets _ > 75,000; hemoglobin _ > 8 g / dL; 2x serum creatinine the upper limit of normal (UNL); serum bilirubin < _ 1.5 UNL, serum cholesterol < 350 mg / dL; and triglycerides < 400 mg / dL. Patients should not have central nervous system involvement or known HIV infection. Patients were treated with a 250 mg flat dose of CCI-779 diluted in 250 mL of normal saline and IV was provided for 30 minutes. Patients were pretreated with 25-50 mg diphenhydramine IV. The treatment was weekly and a 4-week cycle was considered. A complete blood count was taken every week and a full dose was given if the platelet count was > 50,000 and the A? C > 1000 and there was no grade 3 non-haematological toxicity (using the version of Common Toxicity Criteria 2 of the IC). Patients who did not meet the criteria for retreatment had to maintain the dose until recovery and then the dose was modified to a flat dose of 175, 125, 75 or 50 mg. Patients did not receive prophylactic white blood cell growth factors to maintain the dose but were able to receive them at the time of neutropenia at the discretion of the physician. It could be used erythropoietin. The patients were reclassified after 1, 3 and 6 cycles and the response evaluated as per the international work criterion. [B. D. Cheson, et al., "Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas," Journal of Clinical Oncology, Vol. 17, Issue 4 (April), 1999: 1244]. Patients who progressed at any time or those patients with stable disease after 6 cycles left the study. Patients who had a complete remission (PR) or partial remission at six months received two cycles after CR or a total of 12 months if there was PR and then they were observed without additional therapy. A phase II, single-stage study was conducted with an interim analysis to assess the proportion of patients with previously treated mantle cell lymphomas who achieved a PR or better after treatment with CCI-779. This trial was designed to test the null hypothesis that the true response percentage was at more than 0.05. The smallest response percentage that would indicate that this regimen was an additional study in this patient population of 0.20. The design was generated based on the parameters and assumptions of a MinMax "11 Simón design of two stages, but where the accumulation of the interim analysis was not suspended." This study design required a maximum of 32 evaluable patients, where the analysis interim was done after 18 patients had accumulated and continued for at least 24 weeks.

Three additional patients were added to this group (for a maximum of 35 patients in total) to consider the possibilities of ineligibility, the withdrawal of the study before the administration of the drug or major violations. However, only the first 32 evaluable patients were used to evaluate decision criteria for this design. At least one response in the first 18 evaluable patients needed to be observed in the interim analysis to continue the accumulation. At the time of the final analysis, a total of four or more responses were required to indicate that this regimen guarantees additional evaluation in this patient population. The response rate was calculated, and the exact binomial confidence interval (CI) of 90% was calculated for the response percentage (with all eligible patients accumulated) assuming that the number of responses was binomially distributed. The duration of the response was defined over time from the documented response date to the progress date. Patients who left treatment due to other reasons (for example, adverse reactions, rejection of additional treatment) were counted at that time. The progress time was defined as the time from registration to the progress date. Patients who died without progression of the disease were counted at the date of their last evaluation. If a patient died without documentation of the progress of the disease, the patient was considered to have progressed at the time of death unless there was sufficient documented evidence to conclude that progress did not occur before death. The time to discontinuation of active treatment was defined over time from the record until the date when the decision was made to withdraw the patient from active treatment. Patients who were receiving treatment at the time of their analysis were counted until the date of their last evaluation. The final survival was defined with time from registration to death resulting from any cause. The distributions of those endpoints at the time of the event were estimated using the Kaplan-Meier method [JM Bland and DG Altman, "Survival probabilities (the Kaplan-Meier method)", BMJ, Zll (7172): 1572 (Dec 5 1998 )]. B. Patient Characteristics A total of 35 patients enrolled in this trial.

One patient was declared - ineligible after a pathological review indicated although histology was consistent with MCL and cyclin DI staining was negative. Patients tended to be older adults with an average age of 70 years (range: 38-89). The majority of patients (91%) had stage IV disease and were strongly pretreated with an average number of 3 previous therapies (mean, 4, range, 1-11). Most patients had failed rituximab, an alkylating agent such as cyclophosphamide, and an anthracycline such as doxorubicin. All half of the patients had received an analogous purine nucleoside. C. Clinical Results The percentage of total response (ORR) was 38% (13/34, 90% Cl: 24% -54%) with 1 CR and 12 PRs. The tumor responses occurred rapidly, where the mean time for the response was 1 month (range, 1-8). There were eight responses after the first evaluation cycle, three were documented after 3 cycles and one after evaluations of 4 and 8 months each. The average duration of the response for the 13 respondents was 5.7 months (95% CI: 4-13.2 months). At the time of these analyzes, 3 patients were still under treatment. The mean follow-up on the surviving patients was 11 months (range: 6.7- 24.6 months). In total 29 patients had progress of the disease and 22 patients died. The death of patients without progression of the disease has not been documented. The average time for progress was 6.2 months (95% CI: 3.8 - 9.4 months). The average total survival was 12 months (95% CI: 6.7 have not yet been reached). D. Safety and Tolerance The 35 patients were included in the safety and tolerance analysis. During the 30-minute infusion, CCI-779 was well tolerated and did not notice significant toxicities occurring. Thrombocytopenia was the cause of most dose reductions and was rapidly reversible with drug delays that typically are one week. Only three patients required platelet transfusions, and four patients required red blood cell transfusions. Thirteen patients experienced grade 3 infections without concomitant neutropenia; two patients had febrile neutropenia and three had infection (grade 3) with neutropenia. One patient developed facial paralysis of the right lower motor neurons and (Bell's palsy) and changes in mental status and underwent an MRI scan and brain spinal fluid analysis that did not reveal evidence of involvement with the MCL. The conclusion that this was an idiopathic Bell's palsy and was actually solved eventually. A possible relationship with the CCI-779 could not be established or eliminated. The patient who experienced blurred vision was diagnosed with retinitis due to the reactivation of cytomegalovirus (CMV) infection. The patient had a history of CMV retinitis before enrolling in this study but the infection was not evident at the time of entry into the study. The most common adverse events of all grades were thrombocytopenia (100%), hyperglycemia (91%), anemia (66%), neutropenia (77%), increased triglycerides (77%), mucositis (71%), fatigue (66%), infection without concomitant neutropenia (63%), rash (51%), nausea (49%), weight loss (46%), AST elevations (43%), abnormal taste (43%), loss of appetite (40%), hypercholesterolemia (40%), and sensory neuropathy (37%). No grade 5 events (deaths during treatment) were reported. In terms of the tolerance of the treatment regimen, only 4 patients completed the study as designed (1 CR, 2 PR, and one patient with stable disease who completed the 12 cycles). Of the remaining 28 patients who discontinued treatment, one patient was treated with alternative therapy without progress, 7 were withdrawn from treatment due to adverse reactions, 4 rejected additional treatment, one patient was removed due to other medical problems, and 15 progressed during the therapy. It should be noted that those patients who refused additional treatment or who withdrew due to other medical problems discontinued this treatment regimen to a large extent due to low-grade adverse events and a perceived decline in quality of life. The mean time to discontinuation of the treatment was 3.7 months (95% CI: 3 - 6.2 months). Dose reductions were necessary in all but 4 patients. 9 patients were able to receive 250 mg weekly for an average of 2.5 cycles (range, 1-8); the others required dose reductions in the first cycle. Of the 6 patients who received more than one cycle, 2 eventually required a dose reduction. The average dose received per month of study was 175 mg in all patients; 125 mg in the patients who respond; and 175 mg in those who did not respond. Patients who responded and stayed with CCI-779 for prolonged periods experienced an abnormal taste, which resulted in decreased appetite and weight loss. One patient with a partial response had a grade 3 weight loss due to dysge- gemia and was unable to restart the ICC-779. Although mucositis was common, all but two cases were grade 1 or 2. It is known that CCI-779 can cause thrombocytopenia and in fact in this study this was the most common side effect. There were several reasons why thrombocytopenia was very commonly found in this study. First, patients were able to enter the protocol with grade 1 thrombocytopenia (> 75,000) and were able to receive 100% of the dose of CCI-779 if the platelet count was > 50,000 (grade 2). Secondly, the patients enrolled in this study were previously pretreated, and thirdly, most of the patients had bone marrow infiltration with MCL cells which resulted in a poor bone marrow reserve. A single agent, CCI-779 had substantial antitumor activity in the relapsing MCL. This study showed that CCI-779 produces therapeutic benefits. Example 2- Anti-Tumor Activity of the Low Dose of a Single Agent CCI-779 for the Lymphoma of Recurrent Mantle Cells 11 patients were enrolled (4 refractory, 77 repeat offenders, ranging from 55 to 85 years of age) with MCL in a Phase II study of CCI-779 and were treated as described in Example 1 above, with the exception that they received a dose 10 times lower than in the Example 1, that is, 25 mg / week. Eight patients (73%) were in stage 4, two (18%) in stage 3 and 4 (36%) had >2 extranodal sites. Patients received an average of 3 previous therapies (range, 1-7) and 3 were refractory to their last treatment. The percentage of total response was 64% (7/11) with 7 PR (64%).

Example 3 - A dose of CCI-779 as mentioned in Example 1 or Example 2 was packaged in a container to provide a course of treatment for a patient. All documents identified here are incorporated by reference. One skilled in the art will recognize that minor modifications to the conditions and techniques described in the specific embodiments described herein may be varied without departing from the present invention. These modifications and minor variations are within the scope of the invention as defined by the following claims. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (12)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property. A method of treatment or inhibition of mantle cell lymphoma in a mammal in need thereof, characterized in that it comprises providing the mammal with an effective amount of a CCI-779.
2. 2. The method according to claim 1, characterized in that the CCI-779 is administered intravenously.
3. 3. The method according to claim 1, characterized in that the CCI-779 is administered weekly for one to twelve months.
4. 4. The method of compliance with the claim 1, characterized in that the CCI-779 is administered at a dose of 10 to 100 mg per week.
5. 5. The method according to claim 1, characterized in that the CCI-779 is administered intravenously at a dose of 25 mg per week.
6. 6. The method according to claim 1, characterized in that the CCI-779 is administered orally at a dose of 100 mg to 250 mg per week.
7. 7. The use of a CCI-779 in the preparation of a medicament for treating or inhibiting mantle cell lymphoma in a subject.
8. 8. The use according to claim 7, wherein the CCI-779 is formulated for oral administration.
9. 9. The use according to claim 7, wherein the CCI-779 is formulated for intravenous administration.
10. 10. A pharmaceutical composition useful for treating or inhibiting mantle cell lymphoma in a mammal in need thereof, characterized in that it comprises a CCI-779 in a unit dose form in association with a pharmaceutically acceptable carrier or excipient.
11. 11. A pharmaceutical package, characterized in that it contains a course of treatment of mantle cell lymphoma for an individual mammal, the package comprises a container having a CCI-779 unit in a unit dose form.
12. 12. The pharmaceutical package according to claim 11, characterized in that the package contains one to four units of CCI-779.