WO2010022277A2 - Association de 10-propargyl-10-déazaaminoptérine et de bortézomib pour le traitement de cancers - Google Patents

Association de 10-propargyl-10-déazaaminoptérine et de bortézomib pour le traitement de cancers Download PDF

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WO2010022277A2
WO2010022277A2 PCT/US2009/054526 US2009054526W WO2010022277A2 WO 2010022277 A2 WO2010022277 A2 WO 2010022277A2 US 2009054526 W US2009054526 W US 2009054526W WO 2010022277 A2 WO2010022277 A2 WO 2010022277A2
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pdx
bortezomib
deazaaminopterin
propargyl
cell
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PCT/US2009/054526
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WO2010022277A3 (fr
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Owen A. O'connor
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O'connor Owen A
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to methods to treat cancers, such as T-cell leukemias, with combinations of drugs including 10-propargyl-lO-deazaaminopterin.
  • 10-dAM is a member of a large class of compounds which have been tested and in some cases found useful in the treatment of cancer.
  • This compound was disclosed by DeGraw et al., "Synthesis and Antitumor Activity of 10-Propargyl-l O-deazaaminopterin," J. Med. Chem. 36: 2228- 2231 (1993) and shown to act as an inhibitor of the enzyme dihydrofolate reductase (“DHFR”) and as an inhibitor of growth in the murine L 1210 cell line.
  • DHFR dihydrofolate reductase
  • some results were presented for the antitumor properties of the compound using the E0771 murine mammary tumor model.
  • the boron atom in bortezomib binds the catalytic site of the 26S proteasome with high affinity and specificity.
  • the proteasome regulates protein expression and function by degradation of ubiquitinylated proteins, and also cleanses the cell of abnormal or misfolded proteins.
  • Clinical and preclinical data support a role in maintaining the immortal phenotype of myeloma cells, and cell-culture and xenograft data support a similar function in solid tumor cancers. While multiple mechanisms are likely to be involved, proteasome inhibition may prevent degradation of pro-apoptotic factors, permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways.
  • Figures l(a) and (b) show cytotoxicity curves for PDX at 48 hours and 72 hours of incubation in T acute lymphoblastic leukemia lines.
  • Figures 2(a) and (b) show cytotoxicity curves for PDX and bortezomib after 24-
  • Figure 2(c) shows a normalized isobologram for PDX and bortezomib for data shown in Figures 2(a) and (b).
  • Figures 3(a) and (b) show cytotoxicity curves for PDX and bortezomib after 48 hours of incubation in P 12 cells.
  • Figure 3(c) shows a normalized isobologram for PDX and bortezomib for data shown in Figures 3 (a) and (b).
  • Figures 4(a) and (b) show cytotoxicity curves for PDX and bortezomib after 48 hours of incubation in PF 382 cells.
  • Figure 4(c) shows a normalized isobologram for PDX and bortezomib for data shown in Figures 4(a) and (b).
  • Figure 5 shows PDX and bortezomib synergistically inducing apoptosis in CTCL
  • Figures 6(a) and (b) show PDX and bortezomib inducing Caspase 8 and 9 activation in CTCL (H9) from Figures 2(a) and (b) after 24 hours of exposure.
  • Figures 7(a) and (b) show PDX and bortezomib synergistically inducing apoptosis in T-ALL (P12 cells) of Figure 2(a) and PF382 of Figure 4(b) after 48 hours of exposure.
  • Pralatrexate (10-propargyl-lO-deazaaminopterin, or 10-propargyl-lO-dAM, or
  • PDX is a novel antifolate with greater affinity for the reduced folate carrier (RFC-I) and foly- polyglutamyl synthase (FPGS).
  • ROC-I reduced folate carrier
  • FPGS foly- polyglutamyl synthase
  • PDX is emerging as a promising drug for the treatment of chemotherapy resistant T-cell lymphomas and leukemias.
  • Bortezomib (B) is a modified dipeptidyl boronic acid that induces apoptosis by inhibiting the 26S proteasome in a variety of hematologic malignancies, including multiple myeloma and non-Hodgkin's lymphoma.
  • the present invention provides a pharmaceutical composition comprising a peptide boronic acid compound and PDX in a pharmaceutically acceptable carrier.
  • the peptide boronic acid compound is bortezomib, as discussed in more detail hereinbelow.
  • the composition comprises "highly purified"
  • compositions which are "highly purified" contain PDX substantially free of other folic acid derivatives, particularly 10-deazaaminopterin, which can interfere with the antitumor activity of PDX.
  • a composition within the scope of the invention may include carriers or excipients for formulating the PDX into a suitable dosage unit form for therapeutic use, as well as additional, non- folate therapeutic agents.
  • PDX can be synthesized using the method disclosed in the DeGraw paper, supra or in Example 7 of DeGraw et al, U.S. Pat. No. 5,354,751, issued October 11, 1994, which is incorporated herein by reference. PDX may also be synthesized by methods presented in U.S. Patent No. 6,028,071, especially in Example 1. Such methods are incorporated by reference herein in their entireties.
  • PDX is advantageously formulated as part of a pharmaceutical preparation.
  • the specific dosage form will depend on the method of administration, but may include tablets, capsules, oral liquids, and injectable solutions for intravenous, intramuscular or intraperitoneal administration.
  • One suitable dosing schedule involves the administration of 150 mg/m 2 every two weeks. Alternatively, dosing may be expressed as mg/kg body weight by any manner acceptable to one skilled in the art.
  • One method for obtaining an equivalent dosing in mg/kg body weight involves applying the conversion factor 0.025 mg/kg, for an average human, as approximately equivalent to 1 mg/m 2 . According to this calculation, dosing of 150 mg/m 2 is approximately equivalent to about 3.75 mg/kg.
  • Lower doses may of course be indicated depending on the tolerance of an individual patient, or if more frequent administration were adopted. For example, doses on the order of 40 to 120 mg/m 2 of body surface area/day (about 1 to 3 mg/kg body weight per day) are appropriate. Dosages of 30 mg/m 2 (about 0.75 mg/kg) weekly for 3 weeks followed by a one week rest, 30 mg/m 2 (about 0.75 mg/kg) weekly x 6 weeks followed by a one week rest, or gradually increasing doses of PDX on the weekly x 6 week schedule are also suitable. Higher doses could be utilized if less frequent administration were used.
  • dosages of 30 to 275 mg/m 2 are suitably used with various dosing schedules, for example 135 to 275 mg/m 2 (about 3.4 to about 6.87 mg/kg) for biweekly dosages, and 30 to 150 mg/m 2 (about 0.75 to about 3.75 mg/kg) for weekly dosages.
  • dosing schedules for example 135 to 275 mg/m 2 (about 3.4 to about 6.87 mg/kg) for biweekly dosages, and 30 to 150 mg/m 2 (about 0.75 to about 3.75 mg/kg) for weekly dosages.
  • the 10-propargyl-lO-deazaaminopterin is administered in an amount of from about 30 to about 275 mg/m 2 (about 0.75 to about 6.87 mg/kg) per dose.
  • Methods of the present invention also include administration of 10-propargyl- 10-deazaaminopterin weekly; administration of 10-propargyl-lO-deazaaminopterin in a dose of about 30 mg/m 2 (0.75 mg/kg); administration of 10-propargyl-lO-deazaaminopterin in an amount of from about 30 to about 150 mg/m 2 (about 0.75 to about 3.75 mg/kg) per dose; administration of 10-propargyl-lO-deazaaminopterin biweekly; and/or administering 10-propargyl- 10- deazaaminopterin in a dosage amount of about 135 to about 275 mg/m 2 (about 3.4 to about 6.9 mg/kg).
  • 10-propargyl- 10-deazaaminopterin is administered in an amount of between about 1 mg/kg and about 4 mg/kg; between about 1.25 mg/kg and about 3 mg/kg; in an amount between about 1.5 mg/kg and about 2.5 mg/kg; in an amount of about 2 mg/kg (or an equivalent amount in body surface area (BSA)).
  • BSA body surface area
  • PDX and peptide boronic acid compounds such as bortezomib may be concurrently administered or utilized in combination as part of a common treatment regimen, in which the PDX and the other agent(s) are administered at different times.
  • the other agent may be administered before, immediately afterward or after a period of time (for example
  • administering refers generally to concurrent administration or to sequential administration of the drugs and in either order in a parallel treatment regimen with or without a separation in time between the drugs unless otherwise specified.
  • 10-propargyl- 10-deazaaminopterin is administered at 2 mg/kg QD for five days, or two cycles of five days each, starting at the beginning of the treatment regimen.
  • PDX is suitably used in combination with folic acid and vitamin B 12 supplementation to reduce the side effects of the treatment.
  • patients may be treated with folic acid (1 mg/m 2 daily starting 1 week prior to treatment with PDX, or alternatively 1 mg perioral (p.o.) daily not based on BSA); and B12 (1 mg/m 2 monthly, or alternatively given intramuscularly (LM.) every 8-10 weeks as 1 mg (not based on BSA), or alternatively p.o. daily
  • the invention provides compositions and methods useful for treatment of cancers of any of a wide variety of types, including solid tumors and leukemias.
  • Types of cancer that may be treated include (but are not limited to): adenocarcinoma of the breast, prostate, and colon; all forms of bronchogenic carcinoma of the lung; myeloid; melanoma; hepatoma; neuroblastoma; papilloma; apudoma; choristoma; branchioma; malignant carcinoid syndrome; carcinoid heart disease; carcinoma (e.g., Walker, basal cell, basosquamous, Brown-Pearce, ductal, Ehrlich tumor, in situ, Krebs 2, merkel cell, mucinous, non-small cell lung, oat cell, papillary, scirrhous, bronchiolar, bronchogenic, squamous cell, and transitional cell), histiocytic disorders; leukemia (e.g., B
  • a cancer type to treat is a T-cell lymphoma.
  • T-cell lymphomas are lymphomas in which the T cells of the patient are determined to be cancerous.
  • T cell lymphomas encompass a variety of conditions including without limitation: (a) lymphoblastic lymphomas in which the malignancy occurs in primitive lymphoid progenitors from the thymus; (b) mature or peripheral T cell neoplasms, including T cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, cutaneous T cell lymphoma (Mycosis fungoides/Sezary syndrome), anaplastic large cell lymphoma, T cell type, enteropathy-type T cell lymphoma, Adult T-cell leukemia/lymphoma including those associated with HTLV-I, and angioimmunoblastic T cell lymphoma, and subcutaneous panniculitic T cell lymphoma; and (
  • bortezomib and other amino acid or peptidyl boronic ester and acid compounds are useful in the present invention.
  • Such compounds are disclosed in for example, U.S. Patent No. 5,780,454, which is incorporated herein by reference in its entirety.
  • the peptide boronic acid compound can be a mono- peptide, di- peptide, tri-peptide, or a higher order peptide compound.
  • Peptide boronic acid compounds are also described in U.S. Patent Nos. 6,083,903, 6,297,217, 6,617,317, for example, all of which are incorporated by reference herein in their entireties.
  • the peptide boronic acid compound is bortezomib
  • the drug is a tripeptide and can be written as Pyz-Phe-boroLeu, which stands for pyrazinoic acid, phenylalanine and Leucine with boric acid instead of a carboxylic acid.
  • Peptides are written N-terminus to C-terminus, but as peptide synthesis proceeds C-terminus to N-terminus, peptide drugs are illustrated C to N, as in this case.
  • the present invention accordingly, provides a method for the treatment of a cancer
  • the cancer is T-cell lymphoma, in a patient in need thereof, comprising administering to a patient either simultaneously or sequentially a therapeutically effective amount of a combination comprising a peptide boronic acid compound and 10- propargyl-10-deazaminopterin.
  • a peptide boronic acid compound and/or the 10-propargyl-lO-deazaminopterin is administered in an amount that provides for a synergistic anti-tumor effect.
  • the peptide boronic acid compound is bortezomib.
  • the amount of peptide boronic acid compound administered and the timing of peptide boronic acid compound administration will depend on the type (species, gender, age, weight, etc.) and condition of the patient being treated, the severity of the disease or condition being treated, and on the route of administration.
  • small molecule peptide boronic acid compounds can be administered to a patient in doses ranging from 0.001 to 100 mg/kg of body weight per day or per week in single or divided doses, or by continuous infusion (see for example, International Patent Publication No. WO 01/34574).
  • Appropriate doses for administration in conjunction with PDX can be determined by one of skill in the art.
  • bortezomib is given by injection (1.3 mg/mVdose administered) into the bloodstream twice a week for 2 weeks, followed by a 10-day rest period. This is called a treatment cycle.
  • a treatment cycle Typically, a total of eight cycles of bortezomib therapy are administered. Doses are typically given on Monday and Thursday or Tuesday and Friday. For more than eight cycles, bortezomib may be given on this same schedule as mentioned above or on a maintenance schedule.
  • the length of treatment with bortezomib may be different from patient to patient and is based on how well the drug is working and if the side effects are manageable.
  • co-administration of and "coadministering" PDX with a peptide boronic acid compound refer to any administration of the two active agents, either separately or together, where the two active agents are administered as part of an appropriate dose regimen designed to obtain the benefit of the combination therapy.
  • the two active agents can be administered either as part of the same pharmaceutical composition or in separate pharmaceutical compositions.
  • PDX can be administered prior to, at the same time as, or subsequent to administration of the peptide boronic acid compound, or in some combination thereof.
  • PDX can be administered prior to, at the same time as, or subsequent to, each administration of the peptide boronic acid compound, or some combination thereof, or at different intervals in relation to the peptide boronic acid compound treatment, or in a single dose prior to, at any time during, or subsequent to the course of treatment with the peptide boronic acid compound.
  • the peptide boronic acid compound and/or PDX will typically be administered to the patient in a dose regimen that provides for the most effective treatment of the cancer (from both efficacy and safety perspectives) for which the patient is being treated, as known in the art, and as disclosed, e.g. in International Patent Publication No. WO 01/34574.
  • the peptide boronic acid compound and/or PDX can be administered in any effective manner known in the art, such as by oral, topical, intravenous, intra-peritoneal, intramuscular, intra-articular, subcutaneous, intranasal, intra-ocular, vaginal, rectal, or intradermal routes, depending upon the type of cancer being treated, the type of peptide boronic acid compound being used (e.g., small molecule, antibody, RNAi or antisense construct), and the medical judgment of the prescribing physician as based, e.g., on the results of published clinical studies.
  • the type of peptide boronic acid compound being used e.g., small molecule, antibody, RNAi or antisense construct
  • the medical judgment of the prescribing physician as based, e.g., on the results of published clinical studies.
  • the peptide boronic acid compound and PDX can be administered either separately or together by the same or different routes, and in a wide variety of different dosage forms.
  • the peptide boronic acid compound is preferably administered by injection into the blood stream, and PDX is preferably administered orally or parenterally.
  • the peptide boronic acid compound is administered by injection into the blood stream, and may be administered via the LV. route.
  • PDX is administered parenterally, and may be administered via LV. route.
  • solutions in either sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions comprising the active agent or a corresponding water-soluble salt thereof.
  • sterile aqueous solutions are preferably suitably buffered, and are also preferably rendered isotonic, e.g., with sufficient saline or glucose.
  • These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
  • the oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • the present invention further provides a kit comprising a single container comprising both a peptide boronic acid compound and PDX.
  • the present invention further provides a kit comprising a first container comprising a peptide boronic acid compound and a second container comprising PDX.
  • the kit containers may further include a pharmaceutically acceptable carrier.
  • the kit may further include a sterile diluent, which is preferably stored in a separate additional container.
  • the kit may further include a package insert comprising printed instructions directing the use of the combined treatment as a method for treating cancer.
  • the composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a peptide boronic acid compound and PDX (including pharmaceutically acceptable salts of each component thereof).
  • the invention encompasses a pharmaceutical composition for the treatment of disease, the use of which results in the inhibition of growth of neoplastic cells, benign or malignant tumors, or metastases, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a peptide boronic acid compound and PDX (including pharmaceutically acceptable salts of each component thereof).
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (cupric and cuprous), ferric, ferrous, lithium, magnesium, manganese (manganic and manganous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium slats.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylameine, trimethylamine, tripropylamine, tromethamine and the like.
  • ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine
  • a compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • compositions of the present invention comprise a peptide boronic acid compound and PDX (including pharmaceutically acceptable salts of each component thereof) as active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • Other therapeutic agents may include those cytotoxic, chemotherapeutic or anti-cancer agents, or agents which enhance the effects of such agents, as listed above.
  • compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • PDX combination (including pharmaceutically acceptable salts of each component thereof) of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion.
  • a peptide boronic acid compound and PDX combination may also be administered by controlled release means and/or delivery devices.
  • the combination compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredients with the carrier that constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • a pharmaceutical composition can comprise a peptide boronic acid compound and PDX in combination with an anticancer agent, wherein said anti-cancer agent is a member selected from the group consisting of alkylating drugs, antimetabolites, microtubule inhibitors, podophyllotoxins, antibiotics, nitrosoureas, hormone therapies, kinase inhibitors, activators of tumor cell apoptosis, and antiangiogenic agents.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • compositions for oral dosage form any convenient pharmaceutical media may be employed.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, micro crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing a composition of this invention which may include PDX may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient and each cachet or capsule preferably containing from about 0.05 mg to about 5 g of the active ingredient.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved 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 (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a peptide boronic acid compound and PDX combination (including pharmaceutically acceptable salts of each component thereof) of this invention, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds. [0053] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • compositions containing a peptide boronic acid compound and PDX combination may also be prepared in powder or liquid concentrate form.
  • Dosage levels for the compounds of the combination of this invention will be approximately as described herein, or as described in the art for these compounds. It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. [0055] Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.
  • T cell lymphoma and leukemia cell lines including CTCL (H9), T- acute lymphoblastic leukemia (T-ALL) lines resistant or sensitive to gamma- secretase inhibitors (GSI) (P 12, PF 382 and CEM are GSI resistant while KOKPT-I, DND-41 and HPB-ALL are GSI sensitive lines).
  • GSI gamma- secretase inhibitors
  • CI combination index
  • RRR relative risk ratios
  • Apoptosis was assessed by staining with Yo-Pro-1 and propidium iodine followed by FACSCalibur acquisition.
  • Caspase 8 and 9 activation was evaluated using Active Caspase 8 and 9 staining kits (Biovision) followed by FACSCalibur acquisition.
  • the IC50S for PDX alone at 48 and 72 hours were generally in the low nanomolar range: H9: 1. InM - 2.5nM; P12: 1.7nM - 2.4nM; CEM: 3.2nM - 4.2nM; PF 382: 5.47nM - 2.72nM; KOPT-Kl : InM - 1.69nM; DND 41 : 97.37nM - 1.2InM; HPB-ALL: 247.78nM - 0.77nM.
  • the IC 50 S for bortezomib alone at 48 and 72 hours were: H9: 5.99nM - 5.27nM; P12: 4.7InM; PF 382: 2.22nM.
  • H9 bortezomib alone: 26% - 53%, PDX: 22% - 58%, bortezomib +PDX: 69% - 89%, RRR for the combination ⁇ 0.9;
  • P12 bortezomib alone: 40% - 57%, PDX alone: 24% - 49%, bortezomib +PDX: 64% - 87%; RRR ⁇ 0.9; PF382 bortezomib alone 72%, PDX alone 65%, bortezomib +PDX 94%; RRR ⁇ 0.65.
  • the combination of PDX and bortezomib also revealed an increase in caspase 8 and 9 activation compared to the single drugs in H9 (relative risk ⁇ 0.81 and ⁇ 0.74 respectively).
  • the percentage of cells with activated caspase 8 or 9 was approximately double in the combination groups compared to the single treatments.
  • H9 a cutaneous T-cell lymphoma; P12, PF382 and CEM are T acute
  • Lymphoblastic leukemia lines resistant to the gamma secretase inhibitors are T acute Lymphoblastic leukemia lines sensitive to the gamma secretase inhibitors.
  • PDX Allos Therapeutics
  • Bortezomib Bortezomib
  • Luminescence was recorded with a Fluoroskan Ascent FL (Thermo Electron Corporation). In the combination experiments all drug concentrations were selected to approximate the EC50 for each drug.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant du bortézomib et de la 10-propargyl-10-déazaaminoptérine, dans un véhicule pharmaceutiquement acceptable. La présente invention concerne également un procédé de traitement du lymphome des lymphocytes T chez un patient, consistant à administrer simultanément ou séquentiellement au dit patient une quantité thérapeutiquement efficace d’une association comprenant du bortézomib et de la 10-propargyl-10-déazaaminoptérine.
PCT/US2009/054526 2008-08-20 2009-08-20 Association de 10-propargyl-10-déazaaminoptérine et de bortézomib pour le traitement de cancers WO2010022277A2 (fr)

Applications Claiming Priority (4)

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US9051308P 2008-08-20 2008-08-20
US61/090,513 2008-08-20
US11787008P 2008-11-25 2008-11-25
US61/117,870 2008-11-25

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WO2010022277A2 true WO2010022277A2 (fr) 2010-02-25
WO2010022277A3 WO2010022277A3 (fr) 2010-06-03

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022204368A1 (fr) * 2021-03-24 2022-09-29 Trustees Of Tufts College Composés d'acide boronique, compositions et méthodes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6323205B1 (en) * 1996-07-17 2001-11-27 Sloan-Kettering Institute For Cancer Research Combinations of 10-propargyl-10-deazaaminopterin and taxols and methods of using same in the treatment of tumors
WO2005117892A1 (fr) * 2004-05-30 2005-12-15 Sloan-Kettering Institute For Cancer Research Traitement du lymphome par la 10-propargyl-10-deazaaminopterine et la gemcitabine
US20060084691A1 (en) * 2004-10-18 2006-04-20 Bilal Piperdi Combined treatment with bortezomib and an epidermal growth factor receptor kinase inhibitor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6323205B1 (en) * 1996-07-17 2001-11-27 Sloan-Kettering Institute For Cancer Research Combinations of 10-propargyl-10-deazaaminopterin and taxols and methods of using same in the treatment of tumors
WO2005117892A1 (fr) * 2004-05-30 2005-12-15 Sloan-Kettering Institute For Cancer Research Traitement du lymphome par la 10-propargyl-10-deazaaminopterine et la gemcitabine
US20060084691A1 (en) * 2004-10-18 2006-04-20 Bilal Piperdi Combined treatment with bortezomib and an epidermal growth factor receptor kinase inhibitor

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022204368A1 (fr) * 2021-03-24 2022-09-29 Trustees Of Tufts College Composés d'acide boronique, compositions et méthodes

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WO2010022277A3 (fr) 2010-06-03

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