WO2013135766A1 - Novel combinations for treating acute myeloid leukaemia or chronic myeloid leukaemia - Google Patents
Novel combinations for treating acute myeloid leukaemia or chronic myeloid leukaemia Download PDFInfo
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- WO2013135766A1 WO2013135766A1 PCT/EP2013/055137 EP2013055137W WO2013135766A1 WO 2013135766 A1 WO2013135766 A1 WO 2013135766A1 EP 2013055137 W EP2013055137 W EP 2013055137W WO 2013135766 A1 WO2013135766 A1 WO 2013135766A1
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- combination
- cytarabine
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- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to the treatment of leukaemias, in particular myeloid leukaemias.
- Leukaemia is a cancerous disease of the bone marrow and the blood.
- Four types of leukaemia can be distinguished: chronic myeloid leukaemia, acute myeloid leukaemia, chronic lymphoid leukaemia and acute lymphoid leukaemia.
- Myeloid leukaemias of the acute type with a rapid progression are called AML or acute myeloid leukaemia.
- Myeloid leukaemias of the chronic type with a gradual, less aggressive progression are called CML or chronic myeloid leukaemia.
- CML chronic myeloid leukaemia.
- WO2008/102075 discloses in vivo anti-tumour activity of the compound N-[2- (2,1 ,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'- (1 ,1 -dimethylethyl)-urea in animals bearing human leukaemias.
- Cytarabine is an anti metabolite drug, mainly used to treat acute leukaemias and non Hodgkin's lymphoma (NHL).
- the present invention concerns the combination of the compound N-[2-(2,1 ,3- benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1 ,1 - dimethylethyl)-urea (A) with cytarabine (B).
- Compound (A) as used herein refers to the compound N-[2-(2,1 ,3-benzothiadiazol- 5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1 ,1 -dimethylethyl)-urea or a hydrate, a pharmaceutically acceptable salt or a solvate thereof.
- Compound (B) as used therein refers to cytarabine.
- the present invention concerns the use of said combination for treating acute myeloid leukaemia (AML). According to an object, the present invention concerns the use of said combination for treating chronic myeloid leukaemia (CML).
- AML acute myeloid leukaemia
- CML chronic myeloid leukaemia
- the combinations of the invention are synergistic.
- the synergy is herein defined as an effect greater that the added effect of each ingredient.
- Said synergy is in particular achieved by the combinations of the invention in inhibiting AML or CML progression, or alleviating AML or CML, more particularly in inhibiting tumor volume and/or tumor weight increase or in reducing tumor volume and/or tumor weight.
- the compounds of formula (A) and (B) are in amounts that produce a synergistic effect.
- the object of the present invention relates to the uses cited above and below for the treatment of mammals, in particular human.
- the combinations of the inventions are such that both active ingredients may be administered simultaneously, separately or sequentially.
- both active ingredients may be administered according to the same administration route or by distinct administration route.
- both active may be administered in the same dosage form or with separate dosage forms.
- Cytarabine is generally administered by the intravenous route (iv) or by intraperitoneal route (ip).
- N-[2-(2,1 ,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d] pyrimidin-7-yl]-N'-(1 ,1 -dimethylethyl)-urea can be administered by the oral route, the intravenous route, the intraperitoneal route, or by two or more routes such as by the intravenous route followed by an intraperitoneal route or by the intravenous route followed by an oral route.
- a conventional administration route is the intravenous route and/or the oral route.
- a particular administration route of (A) is the intravenous route followed by the oral route.
- the combination of the invention is for use for treating acute myeloid leukaemia wherein compound (A) is administered by the intravenous route and cytarabine (B) is administered by the intravenous route.
- the combination of the invention is for use for treating acute myeloid leukaemia wherein compound (A) is administered by the oral route and cytarabine (B) is administered by the intravenous route.
- the combination of the invention is for use for treating acute myeloid leukaemia wherein compound (A) is administered by the intravenous route followed by the oral route and cytarabine (B) is administered by the intravenous route.
- the combination of the invention is for use for treating chronic myeloid leukaemia wherein compound (A) is administered by the intravenous route and cytarabine (B) is administered by the intravenous route.
- the combination of the invention is for use for treating chronic myeloid leukaemia wherein compound (A) is administered by the oral route and cytarabine (B) is administered by the intravenous route.
- the combination of the invention is for use for treating chronic myeloid leukaemia wherein compound (A) is administered by the intravenous route followed by the oral route and cytarabine (B) is administered by the intravenous route.
- the combination of the invention is for use for treating chronic myeloid leukaemia wherein compound (A) is administered by the intraperitoneal route followed by the oral route and cytarabine (B) is administered by the intraperitoneal route.
- the present invention provides for the combination for use for the treatment of AML or CML in patients resistant to standard chemotherapy.
- the present invention provides for the combination for use for the treatment of AML or CML in high-risk cytogenetic patients.
- high-risk cytogenetic patients refer to AML or CML patients which display significantly lower rate of response, high-risk of relapse and/or poor survival.
- combination is administered according to a dosage scheme which enables the treatment of AML or CML.
- the dosage scheme varies depending on the administration route and depending on the physical characteristics of the patient.
- the dosage schemes suitable for this purpose include those which display therapeutic efficacy for the treatment of AML or CML.
- the combination of the invention can be administered as often as is necessary to obtain the therapeutic effect sought.
- the present invention also relates to a kit comprising:
- the present invention also provides for methods of treatment of AML or CML comprising administration of a combination of the invention to a patient in the need thereof.
- anti-cancer active principle(s) in particular antitumour compounds such as:
- alkylating agents such as the alkylsulphonates (busulfan), dacarbazine, procarbazine, cloretazine, the nitrogen mustards (chlormethine, melphalan, chlorambucil, cyclophosphamide, ifosfamide), the nitrosoureas such as carmustine, lomustine, semustine, streptozocine and altretamine;
- antineoplastic alkaloids such as vincristine, vinblastine, vinorelbine and vindesine;
- taxanes such as paclitaxel or taxotere
- - antineoplastic antibiotics such as actinomycin and bleomycin
- - antineoplastic antimetabolites folate antagonists, methotrexate; inhibitors of purine synthesis; purine analogues such as mercaptopurine and 6-thioguanine; inhibitors of pyrimidine synthesis, aromatase inhibitors, capecitabine, pyrimidine analogues such as fluorouracil, gemcitabine, cytarabine and cytosine arabinoside; brequinar and nelarabine;
- topoisomerase inhibitors such as irinotecan, exatecan, topotecan, teniposide, camptothecin or etoposide;
- - anticancer hormone agonists and antagonists including tamoxifen
- - kinase inhibitors such as imatinib, nilotinib and dasatinib, midaustorin, sorafenib, lestaurtinib and tandutinib;
- - growth factor inhibitors such as pentosan polysulphate, corticosteroids, prednisone and dexamethasone;
- anthracyclines such as daunorubicin, epirubicin, pirarubicin, idarubicin, zorubicin, aclarubicin, annamycin, doxorubicin, mitomycin and methramycin;
- DNA methyl transferase inhibitors such as MG98
- combinations of the invention may also be administered in combination with one or more other active principles useful in one of the pathologies mentioned above, for example an anti-emetic, analgesic, anti-inflammatory or anti-cachexia agent.
- These treatments can be administered simultaneously, separately, sequentially.
- the treatment will be adapted by the doctor depending on the patient to be treated.
- a “pharmaceutically acceptable salt” of the compound refers to a salt that is pharmaceutically acceptable and that retains pharmacological activity. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, or S. M. Berge, et al., "Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1 -19, both of which are incorporated herein by reference.
- Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, as well as those salts formed with organic acids, such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic
- Simultaneous administration typically means that both compounds enter the patient at precisely the same time. However, simultaneous administration also includes the possibility that the compounds enter the patient at different times, but the difference in time is sufficiently miniscule that the first administered compound is not provided the time to take effect on the patient before entry of the second administered compound. Such delayed times typically correspond to less than 1 minute, and more typically, less than 30 seconds.
- simultaneous administration can be achieved by administering a solution containing the combination of compounds.
- simultaneous administration of separate solutions, one of which contains the compound (A) and the other of which contains cytarabine (B) can be employed.
- simultaneous administration can be achieved by administering a composition containing the combination of compounds.
- the compounds are not simultaneously administered.
- the first administered compound is provided time to take effect on the patient before the second administered compound is administered.
- the difference in time does not extend beyond the time for the first administered compound to complete its effect in the patient, or beyond the time the first administered compound is completely or substantially eliminated or deactivated in the patient.
- the compound (A) is administered before cytarabine (B).
- cytarabine (B) is administered before the compound (A).
- the time difference in non- simultaneous administrations is typically greater than 1 minute, and can be, for example, precisely, at least, up to, or less than 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, two hours, three hours, six hours, nine hours, 12 hours, 24 hours, 36 hours, or 48 hours, or more than 48 hours.
- one or both of compounds are administered in a therapeutically effective (i.e., therapeutic) amount or dosage.
- a "therapeutically effective amount” is an amount of the active ingredient that, when administered to a patient by itself, effectively achieves at least partially the treatment of AML or CML (for example, inhibits tumor growth, stops tumor growth, or causes tumor regression).
- the amount of the compound that corresponds to a therapeutically effective amount is strongly dependent on the type and stage of AML/CML, the age of the patient being treated, and other facts. In general, therapeutically effective amounts of these compounds are well-known in the art, such as provided in the supporting references cited above.
- one or both of the active ingredients are administered in a sub-therapeutically effective amount or dosage.
- a sub-therapeutically effective amount is an amount that, when administered to a patient by itself, does not completely inhibit over time the biological activity of the intended target.
- a sub-therapeutic amount of compound (A) can be an effective amount if, when combined with cytarabine (B), the combination is effective in the treatment of AML or CML.
- the combination of compounds exhibits a synergistic effect (i.e., greater than additive effect) in treating AML or CML, particularly in reducing a tumor volume and/or weight in the patient.
- the combination can either inhibit tumor growth and/or weight, achieve tumor stasis, or even achieve substantial or complete tumor regression.
- Compound (A) can be administered at a dosage of about 5 mg/kg to 150 mg/kg daily in mice, in particular 10 to 50 mg/kg daily, more particularly 20 mg/kg.
- Cytarabine meanwhile, can be administered in mice at a dosage of about 1 mg/kg to 250 mg/kg daily, more particularly about 31 ,5 mg/kg.
- Corresponding doses in human can be obtained accordingly.
- a typical dosage of cytarabine (B) in human is 2 to 6 mg/kg/day as a continuous IV infusion over 24 hours or in divided doses by rapid injection for 5 to 10 days.
- Compound (A) may be administered in human at doses comprised between 0.01 mg/g and 1000 mg/kg daily, typically between 50-200 mg/m 2 . There may be special cases where higher or lower dosages are appropriate; such dosages do not fall outside the scope of the invention. According to the normal practice, the dosage appropriate for each patient is determined by the doctor depending on the mode of administration, and the weight and/or response of the said patient. The dosage regimen of each active ingredient may be one, two, three or four administration a day or a continuous infusion over time.
- the term "about” generally indicates a possible variation of no more than 10%, 5%, or 1 % of a value.
- “about 25 mg/kg” will generally indicate, in its broadest sense, a value of 22.5-27.5 mg/kg, i.e., 25 ⁇ 2.5 mg/kg.
- the amounts, when combined, are preferably not excessively toxic to the patient (i.e., the amounts are preferably within toxicity limits as established by medical guidelines).
- the amounts considered herein for example are per day; however, half-day and two-day or three-day cycles also are considered herein.
- a daily dosage such as any of the exemplary dosages described above, is administered once, twice, three times, or four times a day for at least three, four, five, six, seven, eight, nine, or ten days.
- a shorter treatment time e.g., up to five days
- a longer treatment time e.g., ten or more days, or weeks, or a month, or longer
- a once- or twice-daily dosage is administered every other day.
- each dosage contains both the compound (A) and cytarabine (B), while in other embodiments, each dosage contains either the compound (A) or cytarabine (B). In yet other embodiments, some of the dosages contain both compound (A) and cytarabine (B), while other dosages contain only compound (A) or cytarabine (B).
- the patient considered herein is typically a human. However, the patient can be any mammal for which AML or CML treatment is desired. Thus, the methods described herein can be applied to both human and veterinary applications.
- treating indicates that the method has, at the least, mitigated abnormal cellular proliferation.
- the method can reduce the rate of tumor growth in a patient, or prevent the continued growth of a tumor, or even reduce the size and/or weight of a tumor.
- methods for preventing AML or CML in a patient are provided.
- prevention denotes causing the clinical symptoms of the disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease.
- the methods comprise administering to the patient a combination as described herein.
- the methods comprise administering to the patient in need thereof a combination, as described herein.
- Compounds (A) and (B), or their pharmaceutically acceptable salts or solvate forms, in pure form or in an appropriate pharmaceutical composition, can be administered via any of the accepted modes of administration or agents known in the art.
- the compounds can be administered, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermal ⁇ , intravaginally, intravesical ⁇ , intracistemally, or rectally.
- the dosage form can be, for example, a solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, pills, soft elastic or hard gelatin capsules, powders, solutions, suspensions, suppositories, aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
- a particular route of administration is oral, particularly one in which a convenient daily dosage regimen can be adjusted according to the degree of severity of the disease to be treated.
- the active ingredients or the combination thereof may be in the form of a solid (e.g., a powder or tablet) or a liquid dosage form.
- the compositions may include optionally, one or more auxiliary (e.g., adjuvant) and/or one or more pharmaceutically acceptable carriers (i.e., vehicles or excipients) known in the art.
- auxiliary and adjuvant agents may include, for example, preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents.
- antibacterial and antifungal agents such as, parabens, chlorobutanol, phenol, sorbic acid, and the like.
- Isotonic agents such as sugars, sodium chloride, and the like, may also be included.
- Prolonged absorption of an injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
- the auxiliary agents also can include wetting agents, emulsifying agents, pH buffering agents, and antioxidants, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, and the like.
- Dosage forms suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
- Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
- Solid dosage forms for oral administration include soft or hard capsules, tablets, pills, powders, and granules.
- the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
- fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
- binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
- humectants as for example, glycerol
- disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
- solution retarders as for example paraffin
- absorption accelerators as for example,
- Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They can contain pacifying agents and can be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds also can be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., an active ingredient described herein, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3- butyleneglycol, dimethyl formamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneg
- Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
- suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
- compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds described herein with, for example, suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
- suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
- Dosage forms for topical administration may include, for example, ointments, powders, sprays, and inhalants.
- the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.
- Ophthalmic formulations, eye ointments, powders, and solutions also can be employed.
- the pharmaceutically acceptable compositions will contain about 1 % to about 99% by weight of the compounds described herein, or a pharmaceutically acceptable salt thereof, and 99% to 1 % by weight of a pharmaceutically acceptable excipient.
- the composition will be between about 5% and about 75% by weight of a compounds described herein, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
- a PEG400 22% / Solutol 5% / G5 73% formulation may be used for the administration by intravenous route of compound (A).
- a Labrasol 21 % / Solutol 5% / HCI 0.001 N 74% formulation may be used for the administration by the oral route of compound (A).
- Kits according to the invention include package(s) comprising combinations of the invention.
- the phrase "package” means any vessel containing compounds or compositions presented herein.
- the package can be a box or wrapping.
- Packaging materials for use in packaging pharmaceutical products are well- known to those of skill in the art. Examples of pharmaceutical packaging materials include, but are not limited to, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
- the kit also can contain items that are not contained within the package but are attached to the outside of the package, for example, pipettes.
- Kits can contain instructions for administering compounds or compositions of the invention to a patient. Kits also can comprise instructions for approved uses of compounds herein by regulatory agencies, such as the United States Food and Drug Administration. Kits also can contain labeling or product inserts for the inventive compounds. The package(s) and/or any product insert(s) may themselves be approved by regulatory agencies.
- the kits can include compounds in the solid phase or in a liquid phase (such as buffers provided) in a package.
- the kits also can include buffers for preparing solutions for conducting the methods, and pipettes for transferring liquids from one container to another.
- tumor as used therein is understood to refer to solid and/or liquid tumors.
- Figure 1 illustrates the evolution of the median tumor weight (mg) following post tumor implantation in mice implanted with AML KG1 cells and treated with the combinations of the invention.
- Figure 2 illustrates the evolution of the median tumor weight (mg) following post tumor implantation in mice implanted with CML T1 cells and treated with the combinations of the invention. Examples have been set forth below for the purpose of illustration and to describe certain specific embodiments of the invention. However, the scope of the claims is not to be in any way limited by the examples set forth herein.
- compound (A) was dissolved at 10 mM in DMSO and diluted in complete RPMI-1640 medium or in phenol red-free complete RPMI-1640 medium in sterile 96-well polystyrene cell culture plates.
- compound (A) was prepared for intravenous (IV) or intraperitoneal (IP) administration by mixing 22% PEG400 with 5% solutol and 73% glucose in 5% water.
- IV intravenous
- IP intraperitoneal
- compound (A) was prepared in a generally regarded as safe (GRAS) formulation composed of 21 % labrasol with 5% solutol and 74% HCL 0.001 N. Solutions were kept on ice and administered as a bolus within 1 hour after formulation preparation. The volume of injection was 0.2 mL per mouse.
- the assay is as described by Recher and colleagues (Recher C. et al., Blood 2005; 105:2527-2534) with slight modifications. Briefly, cells were washed twice in PBS and suspended at 1 x 10 5 cell/mL in H4230 medium (Stem Cell Technologies) supplemented with 10% 5637-conditioned medium and appropriate dilutions of COMPOUND (A). Cells were then plated on 35 mm petri dishes and incubated at 37°C in 5% C0 2 , fully humidified atmosphere. After 7 days, colonies (more than 20 cells) and clusters (more than 5 cells) were scored using an inverted microscope. Clonogenic assay with human tumor xenografts
- Tumor xenografts were derived from patients' tumors engrafted subcutaneously in nude mice (Oncotest). Details of the clonogenic assay procedure have been described earlier (Fiebig H.H. et al., Eur. J. Cancer 2004, 40: 802-820). Normal myeloid progenitor cell clonogenic assay
- Fresh CD34 + human bone marrow cells were washed twice in Iscove modified Dulbecco medium (IMDM) containing 10% FCS and resuspended in H4230 medium supplemented with 10% 5637-conditioned medium for CFU-GM growth, in H4435 medium for CFU-M growth, and in H4535 medium for BFU-E growth.
- IMDM Iscove modified Dulbecco medium
- H4230, H4435, and H4535 medium were purchased from Stem Cell Technologies.
- the cells were then plated in 35- mm Petri dishes and incubated in a humidified C0 2 incubator (5% C0 2 , 37°C) for 14 days. Colonies (>50 cells) were then scored under an inverted microscope.
- All tumor cell lines were obtained from DSMZ GmbH. Initially, cell lines were cultured in RPMI 1640 containing 10% FCS and antibiotics, and implanted subcutaneously in SCID mice (10 7 cells/mouse). When the tumor reached approximately 1000 mg, it was removed from the donor mouse, cut into fragments (2-3 mm diameter), placed in a phosphate buffer saline, and implanted bilaterally with a 12-gauge trocar. Tumor fragments were propagated until stable growth behavior occurred (a stable doubling time), before using in experiments. Distribution was performed using body weight and tumor weight criteria with the "Newlab oncology" software (Newlab).
- TMS tumor-free survivors
- the anti-proliferative activity of COMPOUND (A) was evaluated in 5 granulomonocytic and erythroblastic normal myeloid progenitors.
- COMPOUND (A) The anti-proliferative effect of COMPOUND (A) was also evaluated on the myeloid progenitors (CFU-L) of 29 AML patient samples using a clonogenic test (see Table 1 below). COMPOUND (A) potently inhibited colony formation in the majority of the tested samples, with IC 50 values ranging from 3.8 to >1000 nM.
- the high-risk cytogenetic group i.e., patients 4, 1 1 , 14, 19, 21 , 23, 25, 27, 28 and 29
- Only 3 AML cell samples displayed resistance to treatment with COMPOUND (A) (patients 27, 28, 29).
- patient sample 1 1 harbouring a complex karyotype, was highly sensitive to treatment with COMPOUND (A).
- Table 1 Evaluation of Compound (A) on the leukemia progenitors (CFU-L) of 30 AML patient samples using an ex vivo clonogenic test.
- mice bearing KG1 a cells were treated with IV COMPOUND (A) 10 or 17 mg/kg daily from day 5 to day 13, and with IP COMPOUND (A) on days 15, 16, 18-20, 22, 24-26, 29 and 31 .
- a 16.2% body weight loss was seen at nadir (day 22) with COMPOUND (A) 17 mg/kg, which was reversible after treatment was stopped.
- COMPOUND (A) was highly active: AT/AC evaluated on day 32 was negative at both dosages (-4.99 [range: -6.46, -3.66] and -4.70 [range: -6.90, -3.91 ], respectively).
- mice bearing KG1 cells were treated daily with IV COMPOUND (A) from day 19 to day 38 post-tumor inoculations at 10 and 25 mg/kg/day.
- the DT/DC was inferior to -14.27 (range: -29.81 , -7.12).
- Body weight loss amounting to 18.2% was observed on day 29 at the end of the treatment period.
- Weight loss was reversible, indicating that 25mg/kg was the MTD.
- a total of 6 out of 6 animals experienced complete regressions (CR) and cures at MTD.
- AT/AC was 17.45 (range: -0.52, 52.10), and one of six animals experienced CR. This indicated that COMPOUND (A) was active at 10 mg/kg, and highly active at 25 mg/kg.
- Statistical analysis confirmed the anti- tumor activity of COMPOUND (A) at these two dosages.
- the anti-tumor activity of COMPOUND (A) was also evaluated in mice bearing KG1 cells when given by oral route.
- AT/AC was -3.80 (range: -5.21 , -2.93).
- a maximum body weight loss of 14.4% was detected on day 28, which was rapidly reversible. None of the animals were cured but 7 animals out of 10 experienced a CR.
- the DT/DC was 7.61 (range: 4.72, 12.88) or 19.72 (range: 15.81 , 29.35) suggesting efficacy.
- a AT/AC of 41 .99 range: 32.19, 59.33
- One aim was to generate an inhibitor of AML cells, which could be administered by
- COMPOUND (A) when dosed as a single agent, at a clinically relevant induction/consolidation regimen, was evaluated in very advanced KG1 bearing mice (1000 mg tumor size at the onset of treatment).
- COMPOUND (A) was first administered daily at 25 mg/kg IV from day 22 until day 30 post-tumor inoculation. Then the treatment was switched to daily oral dosing at 50 mg/kg or 2 x 40mg/kg as previously tested from day 31 to day 95.
- COMPOUND (A) dosed at 25 mg/kg was highly active and induced strong tumor regressions.
- mice were treated daily with oral dosages of COMPOUND (A) at either 2 x 40 mg/kg or 1 x 50 mg/kg. While an immediate re-growth of tumors was observed in the vehicle group, in mice treated with COMPOUND (A) at 1 x 50 mg/kg, tumors re-grew slowly, and at the 2 x 40 mg/kg oral dosage, complete disappearance of tumors was noted. This experiment suggests that following an IV induction phase; COMPOUND (A) could be successfully given orally to mimic a consolidation phase in the clinic as a single agent. Combination of cytarabine and compound (A) was evaluated in mice bearing KG1 cells ( Figure 1 ).
- Compound (A) 20 mg/kg was administered on days 16 to 20 by IV route and Cytarabine 31 .5 mg/kg was administered by IP route on days 16 to 22.
- Single agent cytarabine showed log cell kill-gross (LCK-g) of 1 .6 with no CR, PR or cure.
- Compound (A) showed LCK-g of 2.4 with 83% CR and no cure.
- Combination of the two products elicited significant synergy: LCK-g of 5.9 with 100% CR and 66% cures (see figure 1 ).
- Combination of cytarabine and compound (A) also showed synergistic antitumor activity in mice implanted with Kasumi-1 and CML-T1 tumor cells.
- EXAMPLE 2 Activity on CML
- the sterility of the room is checked once a month and the cages were sterilized at 121 °C for30 minutes before use and changed twice a week.
- Room temperature was maintained at 22 °C, and relative humidity at 60 ⁇ 10%.
- the animals were kept under a natural daylight cycle.
- the animals were fed with R03 irradiated at 10 kGy, purchased from UAR (91360 Epinay/Orge, France), and water sterilized at 121 °C for 30 minutes. Water consumption was visually monitored daily and the bottles were changed twice a week. Food and water were given ad libitum.
- the animal bedding was produced by UAR and sterilized at 121 °C for 30 minutes and renewed twice a week.
- Compound (A) was prepared by mixing 5% DMSO with 10% Tween-80 and 85%
- Cytarabine (B) was prepared in water for injectable preparation (Aracytine®, also referred to as Ara-C).
- IP intraperitoneal
- CML-T1 is a human T cell leukemia established from the peripheral blood of a 36- year-old woman with CML in blast crisis in 1987. Cells were described to express T cell surface markers and to have a Bcr-abl translocation (producing the p210 Bcr-abl protein) (Kuriyama et al Blood. 1989;74(4):1381 -7).
- the immunology of the tumor is the following: CD2 -, smCD3 (+), cyCD3 +, CD4 +, CD5 +, CD6 +, CD7 +, CD8 +, CD13 -, CD19 -, CD34-, TCRalpha/beta -, TCRgamma/delta.
- this cell line was cultured in RPMI 1640 containing 10% foetal calf serum (FCS) and antibiotics, and implanted subcutaneously in SCID mice (10 7 cells/mouse).
- FCS foetal calf serum
- SCID mice 10 7 cells/mouse.
- the tumor reached approximately 1000 mg, it was removed from the donor mice, cutted into fragments (2-3 mm diameter), placed in a phosphate buffer saline, and implanted bilaterally with a 12 gauge trocar. Tumor fragments were propagated until stable growth behavior occurred a stable doubling time (td), before using in experiments.
- Tumors fragments were frozen with 80% medium, 10% foetal calf serum (FCS), 10% DMSO at 6-10 fragments/vial. Grouping identification and randomization of animals
- mice were within a 19-20 g weight range. Animals with a body weight inferior to 18 g were excluded of the study. On day 8, tumor bearing animals were stratified into several groups. Only animals with 2 appropriate tumor volumes were selected and randomly distributed to treatment and control groups. The average tumor weight at start of therapy was 63-77 mg. Distribution was performed using body weight and tumor weight criteria with the "Newlab oncology" software (Newlab, 23 bd Europe, 54500 Vandoeuvre les Nancy, France). Each group consisted of 6-7 mice. At the beginning of the study, each cage was labelled with a record card, indicating the date of tumor implantation, tumor type, test compound and route of administration.
- Chemotherapy was started on the day of grouping (8 days after tumor implantation). Mice were checked daily and adverse clinical reactions noted. Each parameter was measured and results recorded using the "Newlab oncology" software.
- mice with complete regression consist in tumor regression below limit of palpation ( ⁇ 63 mg).
- TFS tumor free survivors
- Td tumor doubling time
- T is the median time (in days) required for the treatment group tumors to reach a predetermined size (eg, 1000 mg), and C is the median time tumors to reach the same size (in days) for the vehicle group of each schedule. Tumor-free survivors are excluded from these calculations (cures are tabulated separately).
- T-C is the tumor growth delay and Td is the tumor doubling time in days.
- the conversion of the T-C values to LCK-g is possible because the Td of tumors regrowing post treatment approximates the Td values of the tumors in untreated control mice. LCK-g values can be translated into an activity rating, according to the Southern Research Institute (SRI) criteria:
- the second endpoint used to assess antitumor activity was the evaluation of the
- T/C The T/C value in percent is an indication of antitumor effectiveness.
- the treatment and control groups are measured when the control group tumors reach approximately 700 to 1200 mg in size.
- a T/C equal to or less than 42% is considered significant antitumor activity by the Drug Evaluation Branch of the Division of Cancer Treatment of the National Cancer Institute.
- a body weight loss nadir (mean of group) of greater than 20% or 10% drug deaths are considered to indicate an excessively toxic dosage.
- Antitumor activity evaluation was done at the highest non toxic dose (HNTD).
- COMPOUND (A) The activity of COMPOUND (A) was determined in CML-T1 bearing mice.
- a control group (no treatment) and a vehicle-treated group are included in the study. These are made up of mice carrying tumors either untreated or treated with the vehicle.
- the control group serves to study the effect of the vehicle and the vehicle-treated group serves as reference to the different treatments.
- Cytarabine was administered by IP route on days 8, 12 and 16 at 5 dosages (50, 100, 150, 200, 250 mg/kg).
- COMPOUND (A) was administered by IP route on days 8, 9, 1 1 to 17 and 19 at 4 dosages (10, 17, 25 or 30 mg/kg/administration).
- COMPOUND (A) and Cytarabine were administered by IP route respectively on days 8, 9, 1 1 to 17 and 19 for COMPOUND (A) and on days 8, 12 and 16 for Cytarabine.
- LCK-g 1 .9 with 1 out of 7 animals considered as cured on day 141 at the end of the study.
- Cytarabine at 200 mg/kg produced only a 0.9 LCK-g and COMPOUND (A) at 10 mg/kg produced a 0.1 LCK-g. This indicated that this combination is active, producing a higher LCK-g than the isolated compounds at their respective doses.
- Synergism has been evaluated on log tumoral weight at fixed day for a combination of dose of the 2 products by comparison of the sum of the effect of each product alone at these doses and the effect of this combination of the 2 products, compared with the vehicle Cytarabine + vehicle Compound (A) group. There is a significant synergism on day 20 between COMPOUND (A) at 10 mg/kg and Cytarabine at 200 mg/kg. The synergism becomes significant between all Cytarabine doses and COMPOUND (A) at 17 mg/kg on day 26.
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US14/484,948 US20150005253A1 (en) | 2012-03-14 | 2014-09-12 | Novel combinations for treating acute myeloid leukaemia or chronic myeloid leukaemia |
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EA201491682A1 (en) | 2015-01-30 |
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