MXPA06010245A - Antineoplastic combinations of cci-779 and rituximab - Google Patents

Abstract

This invention provides the use of a combination of CCI-779 and rituximab in the treatment of non-Hodgkin’s lymphoma.

Description

COMBINATIONS ANTINEOPLASTICS OF 42-ESTER OF RAPAMYCIN WITH 3-HYDROXY-2- (HYDROXlMETHYL) -2-METLLPROPIONIC AND R1TUXIMAB ACID BACKGROUND OF THE INVENTION This invention relates to the use of combinations of CCI-779 and rituximab for the treatment of non-Hodgkin's lymphoma. CCI-779, is a 42-ester of rapamycin with 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid, an ester of rapamycin which has demonstrated significant inhibitory effects on tumor growth in in vitro and in vivo models. This compound is now generically known under the name temsirolimus. The preparation and use of rapamycin hydroxyesters, including CCI-779, are described in the U.S. Patents. 5,362,718 and 6,277,983. CCI-779 presents cytostatic properties, unlike cytotoxic properties, and may delay the time for tumor progression or the time for tumor recurrence. It is considered that CCI-779 has a mechanism of action that is similar to that of sirolimus. CCI-779 binds and forms a complex with the cytoplasmic protein FKBP, which has an enzyme, mTOR (target of rapamycin in mammals, also known as a protein associated with FKBP12-rapamycin [FRAP]). Inhibition of mTOR kinase activity inhibits a variety of signal transduction pathways, including cytokine-stimulated cell proliferation, mRNA translation for several key proteins that regulate the G1 phase of the cell cycle, and transcription induced by IL-2, which leads to the inhibition of cell cycle progression from G1 to S. The mechanism of action of CCI-779 which results in the G1-S phase block is novel for an anticancer drug. CCI-779 has been described as a single agent in relation to the treatment of mantle cell lymphoma. Rituximab, a mclonal anti-CD20 antibody is approved in the United States for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin lymphoma. In Europe, it is also approved for This indication, as well as for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for the most common diffuse diffuse large non-Hodgkin's lymphoma. However, rituximab is associated with serious side effects that include acute renal failure, severe mucocutaneous reactions and cardiovascular distension. What is needed is an improved therapy for CD20 + and mantle cell lymphoma and for another non-Hodgkin's lymphoma.

DETAILED DESCRIPTION OF THE INVENTION This invention provides for the use of combinations of CCI-779 and rituximab in the treatment of non-Hodgkin's lymphoma.

This invention also provides for the use of combinations of other mTOR inhibitors such as rapamycin and 42-0- (2-hydroxy) ethyl rapamycin and rituximab in the treatment of non-Hodgkin's lymphoma. The preparation of 42-0- (2-hydroxy) ethyl rapamycin is described in the patent of E.U.A. 5,665,772, which is incorporated herein by reference. As used in accordance with this invention, the term "treatment" means treating a mammal having a non-Hodgkin's lymphoma by providing said mammal with an effective amount of a combination of CCI-779 and rituximab for the purpose of inhibiting growth. of non-Hodgkin's lymphoma in said mammal, eradication of non-Hodgkin's lymphoma, or relief of the mammal. Non-Hodgkin's lymphomas are cancers of lymphoid tissue (lymph nodes, spleen, and other organs of the immune system). Non-Hodgkin's lymphoma includes slow-growing lymphomas and lymphoid leukemias of B-cell or T-cell subtypes, such as B-cell lymphomas, such as B-cell chronic lymphocytic leukemia (B-CLL) / small lymphocytic pathology (SLL), lymphoplasmacytic lymphoma, follicle center lymphoma, small follicular split cell (FSC), mixed follicular cell (FM), marginal zone B-cell lymphoma, hairy cell leukemia, plasmacytoma / myeloma, and T-cell lymphomas, which include granular lymphocytic leukemia of large cells, leukemia / T-cell lymphoma in adults (ATL / L), mycosis fungoides / Sézary syndrome. Moderately aggressive lymphomas and original B cell lymphoid leukemias are also included, for example, B-cell prolymphocytic leukemia (B-PLL), mantle cell lymphoma, follicle center lymphoma, small follicular split cell (FSC), lymphoma follicle center (follicular large cell) or original T cells, chronic lymphocytic T-cell leukemia / prolymphocytic leukemia (T-CLL / PLL), leukemia / T-cell lymphoma in adults (ATL / L) [chronic], angiocentric lymphoma, Angioimmunoblastic lymphoma, aggressive lymphomas including, large B-cell lymphoma, peripheral T-cell lymphomas, intestinal T-cell lymphoma, anaplastic large-cell lymphoma, highly aggressive lymphomas, and lymphoid leukemias, including leukemia / precursor B-lymphoblastic lymphoma (PB -LBL / L), Burkitt's lymphoma, high-grade B-cell lymphoma, leukemia / precursor T-lymphoblastic lymphoma and Burkitt type (T-LBL / L), leukemia / lymphoma of T cells in adults (ATLL) [acute and lymphomatous], slow-growing (low-grade) lymphomas of B cell types, for example, small lymphocytic / prolifoncitic lymphoma (SLL), follicular lymphoma (few large cells), lymphoplasmacytic lymphoma, marginal zone lymphoma, and slow-growing lymphomas of T-cell subtypes, eg, granulosa lymphocytic leukemia of large cells, leukemia / T-cell lymphoma in adults (ATL / L), and mycosis fungoides / Sézary syndrome . As used in accordance with this invention, the term "providing", with respect to providing CCI-779 and rituximab, means either directly administering CCI-779, or administering a prodrug, derivative or analogue which will form an effective amount of CCI-779 within the body, together with rituximab directly, or administer a prodrug, derivative or analog that will form an effective amount of rituximab in the body. The use of a combination of CCI-779 and rituximab also provides for the use of combinations of each of the agents in which one or both agents are used in sub-therapeutically effective dosages. The subtherapeutically effective dosages can easily be determined by one skilled in the art, in view of the teachings herein. In one embodiment, the subtherapeutically effective dosage is a dosage which is effective at a lower dose when used in the combination regimen of the invention, as compared to the dosage that is effective when used alone. The preparation of CCI-779 is described in U.S. Patent 5,362,718, which is incorporated herein by reference. A regiospecific synthesis of CCI-779 is described in the patent of E.U.A. 6,277,983, which is incorporated herein by reference. Even another specific regio method for synthesis of CCI-779 is described in the patent application of E.U.A. No. 10 / 903,062, filed July 30, 2004, and its counterpart, international patent application PCT / US2004 / 22860 filed July 15, 2004. Rituximab is commercially available as Rituxan® rituximab. The combinations of the invention may be in the form of a team of parts. The invention, therefore, includes a product containing an mTOR inhibitor and rituximab as a combined preparation for simultaneous, separate or sequential use for the treatment of non-Hodgkin's lymphoma in a mammal in need thereof. In one embodiment, a product contains CCI-779 and rituximab as a combined preparation for simultaneous, separate or sequential use for the treatment of non-Hodgkin's lymphoma in a mammal in need thereof. The invention also includes a pharmaceutical package containing a course of treatment of non-Hodgkin's lymphoma for an individual mammal, wherein the package contains units of an mTOR inhibitor in a unit dosage form and units of rituximab in a unit dosage form. . In a modality, a pharmaceutical package contains a non-Hodgkin lymphoma treatment course for an individual mammal wherein the package contains units of CCI-779 in a unit dosage form and units of rituximab in a unit dosage form. Although the components of the invention can be delivered through the same route, a product or package according to the invention can contain an mTOR inhibitor, such as CCI-779, for delivery through a different route than that of rituximab, for example, one component may be administered orally, while the other is administered intravenously. In one modality, CCI-779 is prepared for oral delivery and rituximab is prepared for intravenous delivery. Other variations will be apparent to one skilled in the art and are contemplated within the scope of the invention. As is typical with chemotherapy, dosing regimens are closely monitored by the treating physician, based on numerous factors including the severity of the disease, the response to the disease, any treatment-related toxicity, the patient's age and health . Based on the results obtained with CCI-779, it is projected that the initial infusion dosages i.v. they will be between approximately 25 and 175 mg when administered over a weekly dosing regimen. Other regimens and dosage variations are envisaged, and will be determined through the doctor's instructions. It is preferred that CCI-779 be administered by i.v. infusion. or orally, preferably in the form of tablets or capsules. Other routes of administration, such as by means of implants, are also feasible parenterally (in addition to i.v., such as intraperitoneal and subcutaneous injections), rectally, intranasally, vaginally and transdermally. For rituximab, single doses and multiple doses are contemplated. In one embodiment, single doses are provided intravenously at concentrations of 10 to 500 mg / m2, 50 to 500 mg / m2, 100 to 500 mg / m2, or 250 to 500 mg / m2. In another embodiment, the initial dosages are projected to be from about 350 to about 400 mg / m2 / week intravenously of 4-8 weeks, or 4, 6, or 8 weeks, or 375 mg / m2 / weeks in a manner intravenous 4-8 weeks, or 4, 6, or 8 weeks, with a readministration potential every 3 to 6 months.

Other regimens and dosage variations are envisaged, and will be determined through the doctor's instructions. It is preferred that rituximab be administered subcutaneously. As described herein, subtherapeutically effective amounts of rituximab and CCI-779 can be used to obtain a therapeutic effect when administered in combination. For example, rituximab can be provided in dosages of 5 to 50% lower, 10 to 25% lower, or 15 to 20% lower, when provided in conjunction with CCI-779. For example, a resulting dosage of rituximab may be approximately 315 to 380 mg / m2 / week intravenously, or approximately 350 mg / m2 / week, or less. The use of subtherapeutically effective amounts of rituximab is expected to reduce the side effects of rituximab treatment. It is expected that dosing regimens vary according to the route of administration. For example, dosages for oral administration are often up to 5 to 10 times higher than for i.v. administration. that is 125 mg to 1000 mg / week for CCI-779. It is anticipated that the combination of CCI-779 plus rituximab may be administered as the only active chemotherapeutic agents, or may be part of a chemotherapeutic regimen containing other antineoplastic agents. The use of concomitant chemotherapeutic agents often allows the dosage reduction of each particular agent, thereby increasing the safety margin of the particular agents. Inasmuch as the combinations of this invention contain at least two active antineoplastic agents, the use of such combinations also provides for the use of combinations of each of the agents in which one or both of the agents are used at subtherapeutic dosages. effective. For example, CCI-779 can be administered at a dosage of 5 to 50% lower, 10 to 25% lower, or 15 to 20% lower than when supplied as a single agent. As used in this invention, the combination regimen may be given simultaneously or may be given in an alternating regime, giving CCI-779 at a time in the course of chemotherapy other than that of rituximab. This time differential can range from several minutes, hours, days, weeks or more between administration of the two agents. Therefore, the term combination (or combination) does not necessarily mean administered at the same time or as a unit dose, but rather that each of the components are administered during a desired treatment period. Agents can also be administered through different routes. Oral formulations containing the active compounds of this invention may comprise any oral form conventionally used, including tablets, capsules, mouth, troches, lozenges and liquids, suspensions or oral solutions. The capsules can contain mixtures of the active compound or compounds with inert fillers and / or diluents such as pharmaceutically acceptable starches (eg corn starch, potato or tapioca), sugars, artificial sweetening agents, powdered celluloses, such as crystalline celluloses and microcrystalline, flours, jellies, gums, etc. Useful tablet formulations can be made through conventional methods of compression, wet granulation or dry granulation and use diluents, bonding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents pharmaceutically acceptable, including, but not limited to, magnesium stearate, stearic acid, talc, sodium laurisulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitoi, 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 herein may utilize standard delayed or time-release formulations to alter the absorption of the active compound or compounds. The oral formulation may also consist of the administration of the active ingredient in water or a fruit juice, which contains appropriate solubilizers or emulsifiers as needed. Preferred oral formulations for rapamycin 42-ester with 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid are described in the patent publication of E.U.A. No. 2004/0077677 A1, published April 22, 2004, which is incorporated herein by reference. In some cases, it may be advisable to administer the compounds directly to the respiratory tract in the form of an aerosol. The compounds can also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds can be prepared as a free base or pharmacologically acceptable salt in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions in glycerol, liquid polyethylene glycols and mixtures thereof in oils can also be prepared. 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 point where there is easy injectability. It must be stable under the conditions of manufacture and storage and must be protected against 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. Preferred injectable formulations for rapamycin 42-ester with 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid are described in U.S. Patent Publication No. 2004/0167152 A1, published August 26, 2004, which is incorporated herein by reference. For purposes of this description, transdermal administrations are understood to include all administrations through the body surface and the internal coatings of body passages including epithelial and mucosal tissues. Such 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 accomplished through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, that is not toxic to the skin, and that allows the delivery of the agent for systemic absorption into the stream blood through the skin. The carrier can have any number of forms such as creams and ointments, pastes, gels and occlusion devices. The creams and ointments can be liquid or semi-solid viscous emulsions of any of the types of oil in water or water in oil. Also suitable are pastes made up of absorption powders dispersed in petroleum or hydrophilic oil containing the active ingredient. A variety of occlusion devices can be used to release the active ingredient into the bloodstream such as a semi-permeable membrane that covers a reservoir containing the active ingredient with or without a carrier., or a matrix that contains the active ingredient. In the literature, other occlusion devices are known. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository melting point, and glycerin. It is also possible to use water-soluble suppository bases, such as polyethylene glycols of various molecular weights. All patents, patent publications, articles, and other documents referred to herein are incorporated by reference. It will be clear to one skilled in the art that modifications can be made to the specific embodiments described herein without departing from the scope of the invention.

Claims (12)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a combination of CCI-779 and rituximab in the preparation of a medicament for treating non-Hodgkin's lymphoma in a mammal in need thereof.

2. The use as claimed in claim 1, wherein either CCI-779 or rituximab, or both, are provided in sub-therapeutically effective amounts.

3. The use of a combination of an inhibitor of mTOR and rituximab in the preparation of a medicament for treating non-Hodgkin's lymphoma in a mammal.

4. The use as claimed in claim 3, wherein either the mTOR inhibitor or rituximab, or both, are provided in subtherapeutically effective amounts.

5. The use as claimed in claim 3 or claim 4, wherein the mTOR inhibitor is rapamycin.

6. The use as claimed in claim 3 or claim 4, wherein the mTOR inhibitor is 42-0- (2-hydroxy) ethyl rapamycin.

7. - A product containing CCI-779 and rituximab as a combined preparation for simultaneous, separate or consecutive use in the treatment of non-Hodgkin's lymphoma in a mammal.

8. A product containing an mTOR inhibitor and rituximab as a combined preparation for simultaneous, separate or consecutive use in the treatment of non-Hodgkin's lymphoma in a mammal.

9. A pharmaceutical package containing a course of treatment of non-Hodgkin's lymphoma for an individual mammal, wherein the package contains (a) at least one unit of CCI-779 and (b) at least one unit of rituximab in a unit dosage form.

10. A pharmaceutical package containing a non-Hodgkin lymphoma treatment course for an individual mammal, wherein the package contains (a) at least one unit of an mTOR inhibitor and (b) at least one unit of rituximab in a unit dosage form.

11. A pharmaceutical composition useful in the treatment of non-Hodgkin's lymphoma in a mammal, the composition comprising (a) at least one unit of CCI-779 and (b) at least one unit of rituximab in a unit dosage form , and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition useful in the treatment of non-Hodgkin's lymphoma in a mammal, the composition comprising (a) at least one unit of an mTOR inhibitor and (b) at least one unit of rituximab in a dosage form unit, and a carrier pharmaceutically acceptable.