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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • 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
• • 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

• AML acute myelogenous leukemia
• ALL Acute Lymphocytic Leukemia
• CML Chronic Myelogenous Leukemia
• CLL Chronic Lymphocytic Leukemia
• AML symptoms result from insufficient production of healthy blood cells.
• an AML patient's bone marrow makes too many blast cells (immature white blood cells), and those leukemic blast cells do not lead to the normal production of granulocytes.
• the AML patient's bone marrow produces insufficient normal red blood cells, white blood cells and platelets.
• AML patients often receive two or more stages of treatment.
• the first stage referred to as “induction therapy” involves treatment with powerful chemotherapy drugs such as an antimetabolite like cytarabine (ara-C) and an anthracycline drug such as daunorubicin, doxorubicin or idarubicin (Daunomycin, Adriamycin, Idamycin) to induce remission by killing leukemia cells and restoring normal blood production.
• chemotherapy drugs such as an antimetabolite like cytarabine (ara-C) and an anthracycline drug such as daunorubicin, doxorubicin or idarubicin (Daunomycin, Adriamycin, Idamycin) to induce remission by killing leukemia cells and restoring normal blood production.
• other drugs are also used such as 6-thioguanine, gentuzumab ozogamicin (Mylotarg) and/or a colony stimulating factor such as G-CSF or GM
• chemotherapeutic agents used for induction therapy also kill normal cells, often leading to serious side effects and hospitalization.
• "consolidation" treatment may be initiated with additional chemotherapy (e.g., several courses of high-dose ara-C) or an allogeneic or autologous blood stem cell transplant (involving transplantation of bone marrow, peripheral blood or umbilical cord blood cells).
• additional chemotherapy e.g., several courses of high-dose ara-C
• an allogeneic or autologous blood stem cell transplant involving transplantation of bone marrow, peripheral blood or umbilical cord blood cells.
• Such transplants are usually preceded by pre-transplant chemotherapy and/or radiation therapy to destroy the patient's leukemia cells and immune system.
• the blood stem cell transplantation if successful, restores the patient's immune system and blood cell production.
• the additional chemotherapy and/or radiation can have serious side effects.
• - l - transplantation can have significant shortcomings, including among others, relapse in the case of autologous transplants, and graft-versus-host disease, in the case of the more common allogeneic transplants.
• "maintenance" therapy has been introduced as a third stage of therapy involving continued lower doses of chemotherapy for three or more years after the induction and consolidation courses of treatment.
• an mTOR inhibitor can indeed be useful for the treatment of AML, including relapsed AML and cases which are refractory to one or more other drugs or other therapeutic regimens. Also included are cases which have evolved from myelodysplastic syndrome (MDS) and cases of leukemia with a trisomy 8 chromosomal abnormality.
• MDS myelodysplastic syndrome
• This invention thus provides a method for treating AML in a patient in need thereof which comprises administering a treatment effective amount of an mTOR inhibitor to the patient. Also covered is the use of an mTOR inhibitor for preparing a pharmaceutical composition for treating a patient with AML.
• the mTOR inhibitor may be rapamycin or any of its derivatives which retain substantial mTOR inhibitory activity, i.e., which retain at least 10% of the mTOR inhibitory activity of rapamycin in any scientifically valid assay.
• rapamycin and its derivatives such as AP23573 (WO 03/064383, example 9), temsirolimus (CCI779), everolimus (RAD001), ABT-578, and other such rapamycin derivatives in which the hydroxyl group on rapamycin's cyclohexyl ring is replaced by a different functional group.
• AP23573 contains a dimethylphosphine oxide group
• temsirolimus contains an ester group
• everolimus contains an ether group at that position.
• Many other rapamycin derivatives modified at that same position and/or at one or more other positions are known which have the requisite mTOR inhibitory activity for use in practicing this invention.
• certain other O-substituted rapamycins are disclosed in WO 94/02136, U.S. Pat. No. 5.258.389 and WO 94/09010 (O-aryl and O-alkyl rapamycins); see also WO 92/05179 (carboxylic acid esters), U.S. Pat. No.
• rapamycin and derivatives methylene rapamycin and derivatives
• WO 94/02136 methoxy derivatives
• WO 94/02385 alkenyl derivatives
• Certain dihydro or substituted rapamycin derivatives are described, e.g., Tn U.S. Pat. No. 5,256,790 See also US6710053.
• Further rapamycin derivatives are described in PCT application number EP96/02441 , for example 32-deoxorapamycin as described in Example 1 , and
• the mTOR inhibitor may be administered at any stage of treatment of the patient, including the induction, post-induction (or consolidation) and maintenance stages of treatment, either as a monotherapy, or more preferably, in combination with other induction, consolidation and/or maintenance therapies, including surgery, radiation or chemotherapies such as are noted above (e.g., antimetabolites like cytarabine (ara- C); anthracyclines such as daunorubicin, doxorubicin or idarubicin; and other drugs such as 6-thioguanine, gentuzumab ozogamicin (Mylotarg) and/or a colony stimulating factors such as G-CSF or GM-CSF).
• chemotherapies such as are noted above (e.g., antimetabolites like cytarabine (ara- C); anthracyclines such as daunorubicin, doxorubicin or idarubicin; and other drugs such as 6-thioguanine, gentu
• the mTOR inhibitor is administered in a dose of 0.1 to 50 mg, one or more times per week.
• Administration may be once or multiple times daily, weekly (or at some other multiple-day interval) or on an intermittent schedule.
• it may be administered one or more times per day on a weekly basis (e.g. every Monday) for a period of weeks, e.g. 4 - 10 weeks.
• it may be administered daily for a period of days (e.g. 2 - 10 days) followed by a period of days (e.g. 1 - 30 days) without administration of the drug, with that cycle repeated a given number of times, e.g. 4 - 10 cycles.
• an mTOR inhibitor may be administered daily for 5 days, then discontinued for 9 days, then administered daily for another 5 day period, then discontinued for 9 days, and so on, repeating the cycle a total of 4 - 10 times, or indefinitely.
• an mTOR inhibitor will vary depending upon the particular compound used, the mode of administration, the severity of the disease, as well as the various physical factors related to the individual being treated, as determined by the attending physician. In many cases, satisfactory results may be obtained when the mTOR inhibitor is administered in a daily dosage of from about 0.01 mg/kg-100 mg/kg, preferably between 0.01-25 mg/kg, and more preferably between 0.01-5 mg/kg.
• the projected daily dosages are expected to vary with route of administration.
• parenteral dosing will often be at levels significantly lower than oral dosing levels, in some cases roughly 10% to 20% of oral dosing levels.
• a typical i.v. dose e.g. for administration one or more times per week, will contain between 2 and 50 mg, e.g., between 5 and 30 mg, of an mTOR inhibitor.
• a corresponding typical oral dose will often contain 2 to 5 times as much mTOR inhibitor.
• dosages of each of the components of the combination are administered during a desired treatment period.
• the components of the combination may administered at the same time; either as a unitary dosage form containing both components, or as separate dosage units; the components of the combination can also be administered at different times during a treatment period, or one may be administered as a pretreatment for the other.
• any of the various materials and methods for formulating drugs may be adapted for use in practicing this invention.
• any of the various liquid formulations for rapamycin, temsirolimus, everolimus or AP23573 may be used, especially for parenteral administration, but also for oral administration.
• Solid dosage forms are often preferred for oral administration and include among others conventional admixtures, solid dispersions and nanoparticles, typically in tablet, capsule, caplet, gel cap or other conventional solid or partially solid form.
• Such formulations may optionally contain an enteric coating. Numerous materials and methods for such oral formulations are well known, including oral formulations specifically developed for sirolimus, temsirolimus and everolimus.
• the AP23573 may be prepared as described in Example 9 of WO 03/064383. Using routine methods, purified material may then be formulated as a pharmaceutical composition for intravenous administration to human beings.
• pharmaceutical compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary or desirable, the composition may also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection.
• the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
• composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
• an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
• a solution of AP23573 for injection may contain 0.1 to 10 mg/ml, e.g. 1 -3 mg/ml, of drug in a diluant solution containing Phosal 50 PG (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids and ascorbyl ' palmitate) and polysorbate 80, containing 0.5 - 4% ethanol, e.g. 1.5% - 2.5% ethanol.
• the diluant may contain 2-8%, e.g. 5 - 6%, each of propylene glycol USP and polysorbate 80 in water for injection. We have found that 5.2% of each works well in some cases.
• a solution is processed using conventional methods and materials, including e.g. one or more rounds of sterile filteration.
• Progressive Disease One of the following: a 50% or greater decrement from maximum response levels in graunulocytes or platelets, a reduction in hemoglobin concentration by at least 2 g/dL, or transfusion dependence
• the QDX5 administration was found to have an acceptable side-effect profile, with few Grade 3 or Grade 4 adverse drug reactions.

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• 2005
  • 2005-09-30 CA CA000000004A patent/CA2581372A1/en not_active Abandoned
  • 2005-09-30 AU AU2005292033A patent/AU2005292033A1/en not_active Abandoned
  • 2005-09-30 EP EP05799834A patent/EP1809276A4/en not_active Withdrawn
  • 2005-09-30 MX MX2007003790A patent/MX2007003790A/es unknown
  • 2005-09-30 JP JP2007534765A patent/JP2008514721A/ja active Pending
  • 2005-09-30 US US11/663,940 patent/US20080081053A1/en not_active Abandoned
  • 2005-09-30 WO PCT/US2005/035047 patent/WO2006039414A2/en not_active Ceased

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