Anticancer combinations of cci-779 and rituximab

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, and can be used in treating the patients with Non Hodgkin Lymphoma. That is ensured by administration of a combination containing an effective amount of CCI-779 and rituximab in the form of a dosage form with one or more neutral components added. The combination is introduced simultaneously, separately or consistently with the other agents.

EFFECT: method allows improving clinical effectiveness for the given pathology, including in the patients resistant to rituximab due to synergetic interactions of these preparations.

5 cl


Description of the invention

The present invention relates to the use of combinations of CCI-779 and rituximab for the treatment of Non-Hodgkin's lymphoma.

CCI-779 is a complex 42-ester of rapamycin and 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, which demonstrates a significant inhibitory effect on tumor growth in models in vitro and in vivo. This connection is known now under the name of temsirolimus. Preparation and application of complex hydroxyamino rapamycin, including CCI-779, described in U.S. patent 5362718 and 6277983.

CCI-779 exhibits cytostatic and not cytotoxic properties and may delay the time of tumor development or re-occurrence of the tumor. Believe that CCI-779 has a similar mechanism of action the mechanism of action of sirolimus. CCI-779 binds and forms a complex with the cytoplasmic protein FKBP, which inhibits the enzyme mTOR (target of rapamycin in mammals, which is known as FKBP12 - rapamycin binding protein [FRAP]). Inhibition of mTOR kinase activity inhibits various ways of transmitting signals, including cytokine-stimulated cell proliferation, translation of mRNA molecules for several key proteins that regulate the G1 phase of the cell cycle and IL-2-induced transcription, which leads to inhibition of the transition of the cell cycle from the G1 phase to the phase of S. IU is aNISM actions CCI-779, which leads to G1-S stop is new for anti-cancer drug. CCI-779 has been described as the only active agent in the treatment of lymphoma cells of the cerebral cortex.

Rituximab, which is against the CD20 monoclonal antibody, is permitted in the United States for the treatment of patients with relapsed or resistant to treatment, substandard or follicular, D20-positive, b-cell Non-Hodgkin lymphoma. In Europe, this drug is also approved for use for this purpose and for use in combination with CDIT (CHOP) (cyclophosphamide, doxorubicin, vincristine, prednisone) for the most well-known aggressive both diffuse Non-Hodgkin's lymphoma. However rituximab associated with serious side effects, including acute renal failure, severe candidiasis and cardiovascular disorders.

Thus, the need to improved therapy for CD+ and cell lymphoma of the cerebral cortex and to other Non-Hodgkin's lymphoma.

Detailed description of the invention

The present invention relates to the use of combinations of CCI-779 and rituximab in the treatment of Non-Hodgkin's lymphoma.

The present invention also relates to the use of other combinations of mTOR inhibitors such as rapamycin and 42-O-(2-hydroxy)ethyl rapamycin and rituximab in the treatment of the AI Non-Hodgkin lymphoma. Preparation of 42-O-(2-hydroxy)ethyl rapamycin are described in U.S. Patent 5665772, referenced.

In accordance with the present invention the term "treatment" means the treatment of a mammal having Nahodkinskuju lymphoma, the introduction of this mammal an effective amount of a combination of CCI-779 and rituximab in order to inhibit such mammal growth of Non-Hodgkin lymphoma, suppression of Non-Hodgkin lymphoma or temporary relief of disease in a mammal.

Non-Hodgkin lymphomas are cancers of the lymphatic tissue (lymph nodes, spleen and other organs of the immune system. To Nehodgkinski lymphomas are slow-growing lymphoma and subtypes of b-cell or T-cell lymphocytic leukaemia, such as lymphoma B-cell chronic lymphocytic leukemia b-cells (b-CLL)/small lymphocytic lymphoma (MLL), lymphoplasmacytoid lymphoma, centrallibrary lymphoma, follicular lymphoma of the small split (FMR) cells and follicular sesenna lymphoma (FS) of the mixed cell, b-cell lymphoma marginal zone, something called hairy cell leukemia, plasmacytoma/myeloma and T-cell lymphomas, including leukemia, large granular lymphocytes, Mature T-cell leukemia/lymphoma (ZTL/L), fungal mycoses/syndrome Cesari. Also include the reasonable price is an aggressive lymphoma and lymphocytic leukemia of B-cell precursor, for example In cell prolymphocyte leukemia (B-PLL), lymphoma cells of the cerebral cortex, centrallibrary lymphoma, follicular lymphoma of the small split (FMR) cells, centrallibrary lymphoma (large follicular cell) or T-cell precursor T-cell chronic lymphocytic leukemia/prolymphocyte leukemia (T-CLL/PLL), Mature T-cell leukemia/lymphoma (ZTL/L) [chronic], angiocentricity lymphoma, angioimmunoblastic lymphoma, and aggressive lymphomas, including b-cell both lymphoma, peripheral T-cell lymphoma, intestinal T-cell lymphoma, anaplastic both lymphoma aggressive lymphoma and lymphoid leukemias, including B-lymphoblastic leukemia/lymphoma (B-VPL/L) cell precursor, lymphoma of Berkata, b-cell lymphoma, high grade, Berket-like lymphoma and T-lymphoblastic leukemia/lymphoma cell precursor (T-LBL/L), Mature T-cell leukemia/lymphoma (ZTL/L) [acute and lymphomatous]and slow-growing (with depressed growth (slow-growing (Low Grade) lymphoma b-cell types, such as small lymphocytic/prolymphocytes lymphoma (MLL), follicular lymphoma (a few large cells), lymphoplasmacytoid lymphoma, lymphoma of the marginal zone and slow-growing if the Thomas T-cell subtypes, for example, large granular lymphocytic leukemia, Mature T-cell leukemia/lymphoma (ZTL/L) and fungal mycoses/syndrome Cesare.

Used in this invention, the term "introduction" in relation to the introduction of CCI-779 and rituximab means or directly assigning CCI-779 or the appointment of a prodrug, derivative, or analog which will form an effective amount of CCI-779 inside the body, directly along with rituximab, or the appointment of a prodrug, derivative, or analog which will form an effective amount rituximab in the body. The use of a combination of CCI-779 and rituximab also provides the use of combinations of each of the agents, in which one or both of these agents are used in subtherapeutic effective amounts.

Subtherapeutic effective dose can be easily determined by one of the special methods, whereas this description. In the further description of subtherapeutic effective dose is a dose that is effective at low dosages, when it is used in combination with a mode of the present invention, compared to the dose that is effective for single use.

Preparation of CCI-779 described in U.S. patent 5362718 that there is a link. Regiospecific synthesis of CCI-779 described in U.S. patent 277983, which is denoted by the reference. However, other regiospecific synthesis of CCI-779 is described in Patent Publication U.S. No. 10/903062 registered on July 30, 2004 and complement international Patent Publication PCT/US 2004/22860 registered 15 July 2004 Rituximab is commercially available in the form of Rituxan® (Rituximab).

Combinations of this invention can be in the form of patent sets. Therefore, this invention includes a product containing an inhibitor of mTOR and rituximab in the form of a combined preparation for simultaneous, separate or continuous use in the treatment of Non-Hodgkin lymphoma in a mammal in need of treatment. In one example, the product contains CCI-779 and rituximab as a combined medication for simultaneous, separate or sequential use in the treatment of Non-Hodgkin lymphoma in a mammal in need of treatment.

The invention also includes a pharmaceutical pack containing a course of treatment for Non-Hodgkin lymphoma for one individual mammal, which contains doses of mTOR inhibitor in the form of a single dose and dose rituximab as a single dose.

Because the components of the invention can be obtained in the same way, the product or packaging in accordance with the invention may contain an inhibitor of mTOR, such as CC-779, for delivery which can be used a method other than the method of delivery rituximab, for example, one component may be delivered orally, while the other is administered intravenously. In one example, CCI-779 is prepared for oral delivery, and rituximab is prepared for intravenous delivery. Other options would be obvious patent data and considered within the scope of this invention.

Typical chemotherapy is that the doctor carefully monitors measuring mode, based on numerous factors, taking into account the seriousness of the disease, the response of the disease, the toxicity of the drug, the age and health of the patient. Based on the results of the CCI-779, assume that the initial dosage of intravenous infusion estimated to be between 25 and 175 mg, in case of appointment of a weekly dosing regimen. Other modes and options dosing predictable and will be determined under the guidance of a physician. Preferably, CCI-779 administered for intravenous infusion or oral use, preferably in the form of tablets or capsules. Possible other ways of purposes, for example by means of implants, parenteral (in addition to intravenous injection, for example, intraperitoneal and subcutaneous injections), rectally, intranasally, in the original, and transdermal.

For rituximab considered single and multiple doses. In one case, a single dose administered intravenously at a concentration of from 10 to 500 mg/m2from 50 to 500 mg/m2from 10 to 500 mg/m2from 100 to 500 mg/m2from 250 to 500 mg/m2. In another case, it is planned that the initial dose will be administered in amounts of from about 350 to 400 mg/m2per week intravenously, from 4 to 8 weeks, or 4, 6 or 8 weeks with the possibility of one renewal every 3-6 months. Other modes and ways of dosing are predictable and will be determined under the guidance of a physician. Preferably, rituximab was administered subcutaneously.

As already mentioned, subtherapeutic effective amount rituximab and CCI-779 can be used to achieve a therapeutic effect, in the case when they are combined. For example rituximab can enter in doses that 5-50%, 10-25% or 15-20% less, when it is simultaneously injected with CCI-779. The result is a dose rituximab in the number 315-380 mg/m2per week intravenously or about 350 mg/m2per week or less. The use of subtherapeutic effective amount rituximab is expected to reduce the side effects of its impact.

Suggest that dosing regimens vary in accordance with the method of using the drug. For example, the R, doses for oral administration are often five to ten times more than for intravenous administration, that is, from 125 mg to 1000 mg per week for CCI-779. It is expected that the combination of CCI-779 with rituximab may be appointed as the sole active chemotherapeutic effect, or may be part of a chemotherapy regime that contains other antineoplastic agents. When using concomitant chemotherapeutic agents often whereas the lower doses of each individual agent, thus increasing the safe limit of individual agents. Because the combination of this invention contain at least two active antitumor agent, the use of such combinations also provides for the combination of each agent, in which one or both agents used in subtherapeutic effective doses. For example, CCI-779 may be appointed by the dose, which is 5-50%, 10-25%, 15-20% lower than when delivered as a separate agent.

According to the present invention the combination mode may be simultaneous or phased acceptance, in which CCI-779 and rituximab give at different times during the course of chemotherapy. The temporary difference can be several minutes, hours, days, weeks or more between these two agents. Therefore, the term combination (or conjunction is Amy) does not necessarily mean the assignment at the same time or naznachenie as a single dose, and the fact that each of the components is prescribed for the desired period of treatment.

Formulations for oral administration containing an active compound of this invention can be applied in any of the commonly used oral form, including tablets, capsules, buccal forms, trosha, cakes and liquids, suspensions or solutions for oral administration. Capsules may contain mixtures of active compounds (active connection) with inert fillers and/or substances such as pharmaceutically acceptable starches (e.g., obtained from corn, potato or tapioca), sugar, artificial sweeteners, powdered cellulose such as crystalline and microcrystalline cellulose, powder, gelatin, glues, etc. Suitable formulations of tablets can be prepared by methods conventional pressing, wet or dry granulation, soderjit pharmaceutically acceptable substances, binding agents, lubricants, disintegrate matter of modifying the surface (including surfactants), suspendresume or stabilizing agents including magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, acacia glue, xanthan glue, sodium citrate,complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, decalcify phosphate, calcium sulfate, lactose, kaolin, lures, sodium chloride, talc, dry starch and powdered sugar. Preferred agents that modify the surface, are non-ionic and anionic agents. Typical examples of agents which modify the surface, are poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol (cetomacrogol) emulsifying wax, complex sorbitane esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium-aluminum silicate, and triethanolamine. To change the absorption of the active compounds/compounds formulations for oral administration of the present invention may use his/their standard delay or gradual liberation. The formulation for oral administration may also be prepared from a solution assigned to the active ingredient in water or fruit juice containing necessary, suitable solvents or emulsifiers. Preferred formulations for oral administration 42-ester of rapamycin with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid described in the patent publication U.S. 2004/0077677 A1, published April 22, 2004

In some cases it may be desirable to use a connection in the form of an aerosol directly through dehat the global path.

The connection can also be assigned parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmaceutically acceptable salts can be prepared in water at an appropriate mixing with such a surface-active agent, as hydroxypropylcellulose. Can also be cooked dispersions in glycerol, liquid polyethylene glycols and their mixtures, as well as in oils. Under normal conditions of preservation and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms for injectable use include sterile aqueous solutions or dispersions and sterile powders for unintended preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it was easy to sprecavati. It must be stable under conditions of manufacture and storage and resistant to contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, high molecular weight alcohol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), and their respective mixtures and vegetable oil. The preferred recipe is ture for injection for 42-ester of rapamycin with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid described in the patent publication U.S. 2004/0167152 A1, published August 26, 2004

In order to reveal the essence of the present invention, it is necessary to clarify that for transdermal drug include all routes of administration of the drug through the body surface and internal pathways, including epithelial and muscle tissue. Such introduction can be carried out using these compounds or their pharmaceutically acceptable salts, in form of lotions, creams, foams, patches, patches, patches, suspensions, solutions and suppositories (rectal and vaginal).

Transdermal appointment can be made through the use of a transdermal patch containing the active compound and a carrier that is inert to the active ingredient that is not toxic to the skin and allows the delivery agent for somatic absorption into the bloodstream through the skin. The media can be, for example, in the form of ointments, pastes, gels and sealed fixtures. Creams and ointments can be viscous liquids or semisolid emulsions of the type oil-in-water or water in oil. Can also apply paste containing absorptive powders dispersed in petroleum or hydrophilic oily active ingredients. As a variety of sealed devices for release of the active ingredient into the bloodstream can be used in esewani such as a semi-permeable membrane covering the container containing the active ingredient with the carrier or without it, or matrix material containing the active ingredient. Other sealed devices known in the literature.

Suppozitornoj recipe can be made with traditional materials, including cocoa butter, with or without adding wax to change the melting point of suppositories, as well as glycerine. Can also be used water-soluble bases suppositories, such as polyethylene glycols of various molecular weights.

All patents, patent publications, articles, and other documents presented here are the links. For professionals, competent in this field, it will be clear that there may be modifications made in separate experiments, described here, without departing from the scope of this invention.

1. A method of treating Non-Hodgkin's lymphoma in a mammal in need of treatment, which includes an introduction to the specified mammal an effective amount of a combination comprising CCI-779 and rituximab in the form of dosage forms with the addition of one or more neutral components.

2. The method according to claim 1, characterized in that CCI-779 and rituximab enter different shipping methods.

3. The method according to claim 1, characterized in that CCI-779 administered orally.

4. the procedure according to claim 1, characterized in that rituximab injected.

5. The method according to claim 1, characterized in that CCI-779 and rituximab presented in the form of the dosage form or the form for simultaneous, separate or sequential use in the treatment of Non-Hodgkin lymphoma in a mammal.


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