JP2009501707A - Zoschidar, daunorubicin, and cytarabine for the treatment of cancer - Google Patents

Abstract

The present invention provides a method of treating patients with solid tumors, leukemias, and other malignancies using a combination of zoskidal, daunorubicin and cytarabine. The present invention also relates to pharmaceutical formulations containing zoschidar, daunorubicin, and cytarabine. The formulations of the present invention are particularly effective in treating newly diagnosed acute myeloid leukemia (AML).

Description

Related applications

  This application includes US Provisional Application No. 60 / 696,930 (filed July 6, 2005), US Application No. 11 / 416,832 (filed May 3, 2006), US Application No. 11/416, 829 (filed May 3, 2006), and U.S. Application No. 11 / 416,571 (filed May 3, 2006), which are fully expressly incorporated herein, and Claim priority), which forms part of this specification.

  The present invention relates to methods for treating patients with solid tumors, leukemias, and other malignancies using a combination of zosuquidar, daunorubicin, and cytarabine. The present invention also relates to a pharmaceutical formulation comprising zoskidal, daunorubicin, and cytarabine. The formulation is particularly effective in treating newly diagnosed acute myeloid leukemia (AML).

  The field of oncology is in the process of major development. In the past, cancer treatment was dominated by empirical “one-size-fits-all” treatments based on tumor type and stage. Toxic chemotherapeutic drugs have dominated the treatment landscape despite a very low cure rate, especially for the most common cancers and cancers with known metastatic disease.

  Currently, treatments under development target specific proteins. The targeting is based on a more robust knowledge of the mechanism of cancer, which often crosses over many tumor cells. These treatments typically act on defined subsets of patients, and often in combination with standard chemotherapeutic drugs, based on target protein expression and function rather than tumor type. Designed to. Advances in molecular analysis of cancer will allow the identification of subsets of these patients and the coupling of targeted therapies to new diagnostic methods.

  The future of oncology exists in defining the disease in molecular terms (ie, gene, genome, proteomics) and tailoring treatment according to the nature of individual tumors and normal cells. This new paradigm will pre-determine potential responders, assess responses faster, and adjust treatment based on constant molecular analysis of the tumor.

  Drug resistance is one of the most difficult problems that must be overcome in order to obtain adequate treatment of human tumors with chemotherapeutic drugs. Clinically, the nature of drug-resistant, intrinsically resistant tumors (eg, large intestine, kidney, and pancreas) can become apparent at the start of treatment. Alternatively, acquired drug resistance occurs when the tumor responds initially to therapy but is resistant to subsequent treatment. Once the tumor has acquired resistance to a specific chemotherapeutic drug, it is common to observe para-systemic resistance to other structurally similar drugs. Cellular mechanisms of drug resistance include apoptosis, drug uptake, DMA repair, drug target modification, drug sequestration, detoxification, and efflux pumps (see, eg, Dalton WS Semin., Oncol. 20: 60, 1993) .

  Multidrug resistance (MDR), the ability of cancer cells to become resistant to drugs used energetically and other drugs that are not structurally and functionally related, is a particularly insidious of drug resistance. It is a form. This form of drug resistance is described by Kuzmich et al., “Detoxification Mechanisms and Tumor Cell Resistance to Anticancer Drugs,” especially section VII “The Multidrug-Resistant Phenotype (MDR),” Medical Research Reviews, Vol. 11, No. 2, 185. -217, especially 208-213 (1991); and in Georges et al., “Multi drug resistance and Chemosensitization: Therapeutic Implications for Cancer Chemotherapy,” Advances in Pharmacology, Vol. 21, 185-220 (1990). Are listed.

  Although MDR can be caused by a variety of factors, one of the most prevalent forms of MDR is the type associated with overexpression of P-glycoprotein (P-gp). P-gp is a member of the superfamily of membrane proteins, which are called adenosine triphosphate (ATP) -binding cassette (ABC) proteins, which are ATP-dependent transporters and / or Behave as an ion channel for a wide range of hydrophobic substrates. P-gp is a multi-transmembrane glycoprotein. Transfection experiments with the P-gp gene (mdr1) provide drug-sensitive tumor cells by providing an energy-dependent efflux pump that reduces the cellular concentration of cytotoxic drugs (thus allowing cell survival) Is given an MDR.

  P-gp is the liver, renal adrenal cortex and proximal tubule capillaries, and intestinal epithelium (including, for example, large and small intestinal columnar cells); brain, testis, and placental capillary endothelial cells; And is expressed in hematopoietic stem cells of the bone marrow. It has excretion, protection and barrier functions. P-gp is constitutively expressed or selected in many human cancers and is therapeutic (anthracycline (eg, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone), vinca (eg, vincristine, vinblastine, vinorelbine) , Vindesine), topoisomerase-II inhibitors (eg, etoposide, teniposide), taxanes (eg, paclitaxel, docetaxel), and others (eg, gleevec, myrotag, dactinomycin, mitramycin).

  The considerable messiness of drug transport by P-gp and other MDR-related transporters is widespread for the compound, which will not itself be cytotoxic, but will inhibit MDR transport. Evoked a serious study. The initial demonstration of verapamil as a P-gp inhibitor was followed by a number of additional compounds that have been reported to inhibit drug transport and thus sensitize MDR cells to chemotherapeutic drugs. These “first generation” MDR drugs, variously referred to as chemical enhancers, MDR reversals, modulators, or converters, include compounds of various structures and functions (eg, calcium channel blockers (eg, verapamil), immunity) Inhibitors (eg, cyclosporin A), antibiotics (eg, erythromycin), antimalarials (eg, quinine), and others (eg, vicicodal, tarikidar, valspodal)).

  First generation MDR drugs were not specifically developed to suppress MDR. They often have other pharmacological activities, as well as a relatively low affinity for MDR transporters, and these have therefore been limited in use. For example, P-gp has a low affinity for verapamil and thus requires a level of cardiotoxicity for sufficient modulator activity. Despite the fact that only low blood levels could be obtained in Phase II trials, 5 out of 22 patients responded to the combination of verapamil and VAD (vincristine, doxorubicin, and dexamethasone). Four responders had increased P-gp expression and function. Therefore, verapamil has demonstrated clinical utility in drug resistance to be overcome. Cyclosporine A modifies the pharmacokinetics of co-administered cytotoxic drugs, resulting in a significant increase in exposure to the tumor regression drug, thus complicating interpretation of clinical trials.

  Further characterization of the P-gp pharmacophore gives the identification of “second generation” modulators based on the first generation, but first by eliminating their non-MDR pharmacological effects. Specifically selected or designed to reduce generational side effects. For example, compounds such as the R-enantiomer of verapamil (R-verapamil) and dexniguldipine did not work well as MDR drugs in clinical studies, probably because of them against P-gp. This still does not reach a significant inhibition of MDR in vivo at an acceptable dose.

  A more promising second generation modulator with higher affinity for P-gp was Valspodal (non-immunosuppressive cyclosporin D derivative). Although early clinical trials were encouraged, further studies revealed significant pharmacokinetic interactions with several anticancer drugs. Although suspended by Novartis, Valspodal was studied in a Phase III study in elderly people with acute myeloid leukemia. Enrollment in the Balspodal arm was stopped, probably because of excessive premature mortality due to PK interactions. Although the number of patients is limited, patients (n = 22) in the control arm (pretreated cells exhibit in vitro valspodal regulatory dye excretion) are patients with no excretion (n = 11) (complete remission, No response and mortality was 41%, 41%, and 13% compared to 91%, 9%, and 0%; P = 0.03), but had a worse result than Valspodal The results were almost the same (Baer 2002). Moreover, for patients with valspodal-regulated excretion, the mean disease-free survival was 5 months in the control arm and 14 months in the case of valspodal (P = 0.07).

  The second generation MDR modulator with activity against both P-gp and MRP1 (another ABC transporter associated with multidrug resistance) was Virikodal. Vertex studied the drug in soft tissue sarcoma, ovarian cancer, small cell carcinoma, and numerous other Phase II studies. However, both Virikodal and Valspodal were substrates for P450 isozyme 3A4. Competition between the cytotoxic drug and the P-gp inhibitor against cytochrome P450 3A4 resulted in an unexpected PK interaction and increased the blood concentration of the cytotoxic drug, and thus greater toxicity to the patient. The general response of clinical researchers has been to reduce the dose of cytotoxic drugs. However, the PK interaction is unpredictable and cannot be determined in advance. As a result, blood cytotoxic drug levels were either very high resulting in excessive toxicity or very low resulting in reduced efficacy. In addition to P-gp suppression, a number of second generation modulators function as substrates for other transporters, particularly the ABC family, which prevents normal healthy cells from protecting themselves from cytotoxic drugs. Could reduce the ability to do.

(Summary of Invention)
The present invention relates to dosage forms and treatment regimens for patients with solid tumors, leukemias, and other malignancies that provide increased rates of complete remission and increased survival without cancer. Particularly desirable are dosage forms and treatment regimens for AML patients that provide increased rates of complete remission in newly diagnosed AML patients, leukemia-free survival and increased overall survival. Use of a combination of P-gp inhibitors (eg, zoschidar and chemotherapeutic drugs (eg, daunorubicin and cytarabine)) increases the therapeutic activity of the chemotherapeutic drugs and solid tumors, leukemias, and other malignancies This advantage can be given in the treatment of tumors.

  Accordingly, in a first aspect, a method of treating a malignant tumor is provided, the method comprising administering zoskidal, daunorubicin, and cytarabine to a patient in need of treatment.

  In an embodiment of the first aspect, the malignant tumor is acute myeloid leukemia.

  In an embodiment of the first aspect, the malignant tumor is newly diagnosed acute myeloid leukemia.

In an embodiment of the first aspect, the step of administering zoskidal, daunorubicin and cytarabine to the patient in need of treatment comprises administering about 300 mg of zoskidal to the patient continuously over a period of about 6 hours to about 24 hours. Administered intravenously in an amount of ˜800 mg; daunorubicin is administered intravenously to the patient at a rate of about 20 mg / m ² / day to about 100 mg / m ² / day for about 3 days, wherein daunorubicin administration is Cytarabine is administered intravenously to the patient in an amount of about 50 mg / m ² / day to about 150 mg / m ² / day for about 7 days, beginning about 1 hour to about 5 hours after the start of administration of , Including steps.

In an embodiment of the first aspect, the step of administering zoskidal, daunorubicin and cytarabine to the patient in need of treatment comprises administering about 500 mg of zoskidal to the patient continuously over a period of about 6 hours to about 24 hours. A dose of about 700 mg intravenously; daunorubicin is intravenously administered to the patient at a rate of about 40 mg / m ² / day to about 50 mg / m ² / day for about 3 days, wherein daunorubicin administration is Cytarabine is intravenously administered to the patient in an amount of about 90 mg / m ² / day to about 110 mg / m ² / day for about 7 days, starting about 1 hour to about 4 hours after the start of administration of , Including steps.

In an embodiment of the first aspect, the step of administering zoskidal, daunorubicin and cytarabine to the patient in need of treatment comprises administering about 500 mg of zoskidal to the patient continuously over a period of about 6 hours to about 24 hours. An amount of about 700 mg is administered intravenously; daunorubicin is administered intravenously to the patient at a rate of about 45 mg / m ² / day for about 3 days, where daunorubicin is administered about 1 hour after the start of administration of Zoskidal. Starting about 4 hours after; and cytarabine is intravenously administered to the patient in an amount of about 100 mg / m ² / day for about 7 days continuously.

In an embodiment of the first aspect, the step of administering zoskidal, daunorubicin and cytarabine to the patient in need of treatment comprises administering about 500 mg of zoskidal to the patient continuously over a period of about 6 hours to about 24 hours. An amount of about 700 mg is administered intravenously; daunorubicin is administered intravenously to the patient at a rate of about 45 mg / m ² / day for about 3 days, where daunorubicin is administered about 1 hour after the start of administration of Zoskidal. Starting about 4 hours after; and cytarabine is intravenously administered to the patient in an amount of about 100 mg / m ² / day for about 7 days continuously.

In an embodiment of the first aspect, the step of administering zosquidar, daunorubicin and cytarabine to the patient in need of treatment comprises administering about 500 mg to about 700 mg of zoschidar continuously to the patient over about 6 days over about 6 hours. The dose is administered intravenously; daunorubicin is administered intravenously to the patient at a rate of about 45 mg / m ² / day for about 3 days, wherein daunorubicin is administered from about 1 hour after the start of zosquidar administration for about 4 hours. Starting later; and administering cytarabine intravenously to the patient in an amount of about 100 mg / m ² / day for about 7 days continuously.

In an embodiment of the first aspect, the step of administering zosquidar, daunorubicin and cytarabine to a patient in need of treatment comprises intravenously administering an amount of about 550 mg wherein zoschidar is continuously administered to the patient over about 6 hours over about 6 hours. Daunorubicin is administered intravenously to the patient at a rate of about 45 mg / m ² / day for about 3 days, where daunorubicin administration begins about 1 hour after the start of zoscidal administration; and cytarabine is administered Administering intravenously to a patient in an amount of about 100 mg / m ² / day for about 7 days continuously.

  In a second embodiment, a pharmaceutical kit is provided for use in the treatment of newly diagnosed acute myeloid leukemia, the kit comprising at least one dose of zoskidal; the patient having at least one positive efflux pump An indicator for performing at least one diagnosis to determine whether it exhibits activity and positive P-gp expression or function; and at least one positive efflux pump activity and positive P-gp expression or function Indices for administering Zoschidar in combination with daunorubicin and cytarabine to treat newly administered acute myeloid leukemia in patients exhibiting

  In a third embodiment, a method is provided for treating a malignant tumor in a patient, the method performing a diagnostic test, wherein the test determines that the malignant tumor expresses or selects a P-glycoprotein. And administering zoskidal, daunorubicin, and cytarabine to the patient.

  In an embodiment in the third aspect, the malignant tumor is acute myeloid leukemia.

  In an embodiment of the third aspect, the malignant tumor is newly diagnosed acute myeloid leukemia.

  In an embodiment of the third aspect, the malignant tumor is a carcinoma (eg, breast cancer or ovarian cancer).

  In an embodiment in the third aspect, the malignant tumor is a sarcoma.

  In an embodiment of the third aspect, the malignant tumor is a hematological malignancy selected from the group consisting of acute lymphocytic leukemia, chronic myelogenous leukemia, plasma cell epidemic, lymphoma, and myelodysplasia.

  In a fourth embodiment, a method of treating a malignant tumor in a patient is provided, the method performing a diagnostic test, wherein the test determines that the malignant tumor exhibits positive efflux pump activity; Administering daunorubicin and cytarabine to the patient.

  In an embodiment in the fourth aspect, the malignant tumor is acute myeloid leukemia.

  In an embodiment of the fourth aspect, the malignant tumor is newly diagnosed acute myeloid leukemia.

  In an embodiment in the fourth aspect, the malignant tumor is a carcinoma (eg, breast cancer or ovarian cancer).

  In an embodiment in the fourth aspect, the malignant tumor is a sarcoma.

  In an embodiment in the fourth aspect, the malignant tumor is a hematological malignancy selected from the group consisting of acute lymphocytic leukemia, chronic myelogenous leukemia, plasma cell epidemic, lymphoma, and myelodysplasia.

  In a fifth embodiment, a method for treating a malignant tumor in a patient is provided, the method performing a diagnostic test whereby the malignant tumor expresses or selects P-glycoprotein or positive excretion. Measuring pump activity; and administering to the patient a chemotherapeutic agent that is a substrate for Zoschidar and P-glycoprotein.

  In an embodiment of the fifth aspect, the malignant tumor is acute myeloid leukemia.

  In an embodiment in the fifth aspect, the malignant tumor is a carcinoma (eg, breast cancer or ovarian cancer).

  In an embodiment of the fifth aspect, the malignant tumor is a sarcoma.

  In an embodiment of the fifth aspect, the malignant tumor is a hematological malignancy (eg, acute lymphocytic leukemia, chronic myelogenous leukemia, plasma cell epidemic, lymphoma, or myelodysplasia).

  In an embodiment in the fifth aspect, the chemotherapeutic agent is an anthracycline (eg, doxorubicin, daunorubicin, epirubicin, idarubicin, or mitoxantrone).

  In an embodiment in the fifth aspect, the chemotherapeutic agent is a topoisomerase-II inhibitor (eg, etoposide or teniposide).

  In an embodiment of the fifth aspect, the chemotherapeutic agent is vinca (eg, vincristine, vinblastine, vinorelbine, or vindesine).

  In an embodiment in the fifth aspect, the chemotherapeutic agent is a taxane (eg, paclitaxel or docetaxel).

  In an embodiment in the fifth aspect, the chemotherapeutic agent is Gleevec, dactinomycin, mitomycin, mitramycin, or mylotag.

(Detailed description)
The following description and examples illustrate in detail preferred embodiments of the invention. Those skilled in the art will recognize that there are numerous variations and modifications of this invention that are encompassed by its scope. Accordingly, the description of preferred embodiments should not be construed as limiting the scope of the invention.

Cancer Targets Many forms of cancer express P-gp and are therefore advantageous from the administration of P-gp efflux pump inhibitors when treated with chemotherapeutic agents that are substrates for P-gp efflux. obtain. For example, most solid tumors, lymphomas, bladder cancer, pancreatic cancer, ovarian cancer, liver cancer, myeloma, and sarcoma are all cancers with P-gp expression greater than 50%. Lymphocytic leukemia also has P-gp expression greater than 50%. Breast cancer P-gp expression is about 30%. In the case of metastatic breast cancer, 63% express P-gp. The methods and formulations of the preferred embodiments are particularly effective in the treatment of any malignancy that exhibits some degree of P-gp expression or function, or in patients with positive P-gp.

  One form of cancer characterized by a high percentage of P-gp expression and function is acute myeloid leukemia. There are 11,000 new cases of AML each year in the United States, and 9,000 new cases in the five major EU countries. In addition, the World Health Organization defines progressive myelodysplastic syndrome (MDS) as AML. There are approximately 4,000 cases of progressive MDS in the United States and 3,000 cases in the five major EU countries. As a result, the target patient population for Zoschidar is about 15,000 patients in the United States and 12,000 in the major European market.

  Adult AML presents a greater treatment challenge when compared to pediatric AML (age 15 years and younger). The 5-year survival rate for pediatric AML is 50% (late 1990), due in part to the more resilient patient population and more sensitive disease. On the other hand, the 5-year survival rate for adult AML is only 13% (late 1990), due in part to numerous complications and more resistant diseases. The 5-year survival rate for patients over 65 years is only 7%.

  About 75% of AML patients are over 60 years old and 71% are positive for P-gp. Clinical outcomes in terms of patient survival are significantly better for patients with negative P-gp than for patients with positive P-gp. That is, a patient with a positive P-gp has a 50% survival rate in about 3 to 4 months, whereas a patient with a negative P-gp has a 50% survival rate in about 15 months. is there. See Campos et al., Blood, 79: 473-476, 1992.

  The standard provoking therapy in the United States for newly diagnosed or new AML patients is cytarabine combined with either idarubicin or daunorubicin (both P-gp substrates). In one study, 71% of AML patients over 60 years of age express moderate to high levels of P-gp. The expression was associated with a decrease in complete remission (CR) rate. The CR rate for AML patients with negative P-gp was 67% compared to 34% for patients with positive P-gp. This combination of high levels of P-gp expression and the almost worldwide use of drugs that are P-gp substrates provides an opportunity for preparation for co-administration of P-gp inhibitors in patients with AML.

Zoskidal US Pat. Nos. 5,643,909 and 5,654,304 are a series of 10,11-methanobenzos useful for increasing the efficacy of existing cancer chemotherapeutic agents and treating multidrug resistance. Disclosed are suberan derivatives. One of those derivatives having good activity, oral availability, and stability is Zoschidar, the following formula: (2R) -anti-5-3- [4- (10,11-difluoromethanodibenzosuber-5-yl) Piperazin-1-yl] -2-hydroxypropoxy) quinoline.

  Three preclinical critical success factors have been identified as limiting traditional generation MDR modulators, and these are true for Zoschidar: 1) It is a potent inhibitor of P-glycoprotein; It is observed that 2) it is selective for P-glycoprotein; and 3) there is no pharmacokinetic interaction with co-administered chemotherapeutic drugs.

Zoschidar is very potent in vitro (K _i = 59 nM) and is one of the most active modulators of P-gp-related resistance described to date. Zoskidal has also demonstrated good in vivo activity in preclinical animal studies. In addition, the compound is not a substrate for P-gp excretion and appears to produce a rather long reversal activity in resistant cells even after withdrawal of the modulator.

  Another important attribute of Zoschidar as an MDR modulator is minimal pharmacokinetic (PK) interaction with several tumor regressions tested in preclinical models. The minimal PK interaction administers a normal dose of tumor regression and also allows a more straightforward interpretation of the clinical outcome.

を有する。 Daunorubicin Daunorubicin is an antibiotic chemotherapy treatment widely used to treat acute myeloid leukemia and acute lymphocytic leukemia. It is produced by the bacterium Streptomyces coeruleorubidi and was approved by the FDA in 1998 as a first-line therapeutic treatment for leukemia. Daunorubicin is typically administered intravenously. It is marketed under the trade names servidin, daunoxom, and liposomal daunorubicin. Daunorubicin has the following structure:

Have

を有する。 Cytarabine Cytarabine is a deoxycytidine analog, cytosine arabinoside (Ara-C), which is metabolically activated to triphosphate nucleotides (Ara-CTP) and acts as a competitive inhibitor of DNA polymerase. , And produces S phase specific cytotoxicity. It is an antineoplastic agent (usually part of a combination chemotherapy regimen) in the treatment of acute lymphocytic and acute myeloid leukemia, the acute phase of chronic myelogenous leukemia, erythroleukemia, and non-Hodgkin lymphoma used. It is typically administered intravenously and subcutaneously, and in the subarachnoid space for the prevention and treatment of meningeal leukemia. Cytarabine has the following structure:

Have

Chemotherapy regimen using zoschidar, daunorubicin and cytarabine The combination of zoschidar (a highly specific and P-gp excretion inhibitor) in combination with the antibiotic chemotherapeutic agent daunorubicin and the antineoplastic agent cytarabine It is effective in the treatment of leukemia, especially newly diagnosed AML. Similarly, the formulations and dosing regimens using zoskidal, daunorubicin and cytarabine are useful for treating AML patients other than newly diagnosed AML patients, or other types of leukemia, lymphoma, or lymphocytic leukemia. Can be used for any kind of treatment. The effective dose of zoschidar and the timing of administration of zoschidar, daunorubicin, and cytarabine are important in achieving an improved complete remission rate and increased survival without leukemia in the newly diagnosed population of AML patients is there.

  Although the methods and formulations of the preferred embodiments are particularly preferred for the treatment of newly diagnosed AML patients, the methods and formulations may be compatible with other drugs and indicators. For example, Zoskidal, daunorubicin, and cytarabine are other types of leukemias or other cancers that express P-gp and / or exhibit P-gp function (eg, many solid tumors, bladder cancer, pancreatic cancer, liver cancer) , Myeloma, carcinoma (eg, breast and ovarian cancer), sarcomas, and hematological malignancies other than AML (eg, acute lymphocytic leukemia, chronic myelogenous leukemia, plasma cell epidemic, lymphoma, myelodysplasia)) Can be administered according to the disclosed or slightly modified dosing regimens.

  Zoskidal, daunorubicin, and cytarabine, or some other therapeutic agent, can be administered in the form of a pharmaceutically acceptable salt (eg, trihydrochloride). As used herein, the terms “pharmaceutically acceptable salt” and “pharmaceutically acceptable salt” are broad and used in their ordinary sense. Examples include, but are not limited to, salts prepared from pharmaceutically acceptable non-toxic acids or bases. Suitable pharmaceutically acceptable salts include metal salts (eg, aluminum and zinc salts, alkali metal salts (eg, lithium, sodium, and potassium salts), alkali metal salts (eg, calcium and magnesium salts). Organic salts (eg, lysine, N, N′-dibenzylethylenediamine, chloroprocalin, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, and tris salts); and free acids And salts of bases; inorganic salts (eg, sulfates, hydrochlorides, and hydrobromides); and exemplified by sources that are currently in widespread pharmaceutical use and well known to those skilled in the art Other suitable salts (eg Merck Index), any suitable construct itself is The salt can be selected to produce a salt of zoschidar, daunorubicin, or cytarabine, or other therapeutic agent described herein, provided that it is toxic and does not substantially interfere with the desired activity. In addition, pharmaceutically acceptable precursors and derivatives of the compounds can be used, and pharmaceutically acceptable amides, lower alkyl esters, and protected derivatives are also preferred embodiments of the compositions and methods. Suitable for administration include selected therapeutic agents in hydrate form, selected enantiomeric forms of certain therapeutic agents, racemic mixtures of certain therapeutic agents, and the like.

  Contemplated routes of administration include topical, oral, subcutaneous, parenteral, intradermal, intramuscular, intraperitoneal, and intravenous. However, it is particularly preferred that zoskidal, daunorubicin, and / or cytarabine be administered in intravenous form. The combination or individual components can be in any suitable solid or liquid form. Particularly preferred forms include lyophilized forms that are reconstituted for intravenous administration.

  Zoskidal, daunorubicin, and / or cytarabine are, for example, oral, nasal, anal, intestine, buccal, vagina, peroral, stomach, mucous membrane, perlingual, alveoli, gingiva, olfactory, or respiratory It can be formulated into a liquid formulation for mucosal administration. Suitable forms for administration include suspensions, syrups, and elixirs. Where nasal or respiratory (mucosal) administration is desired (eg, aerosol inhalation or gas infusion), the composition can be in one form and dispensed by a pressure spray dispenser, pump dispenser, or aerosol dispenser. obtain. The aerosol is usually under pressure with a hydrocarbon. The pump dispenser is preferably capable of dispensing doses having a metered or specific particle size.

  Preferably, the pharmaceutical composition containing zoskidal, daunorubicin, and / or cytarabine is isotonic with the blood or other body fluids of the patient. Isotonicity of the composition can be achieved using sodium tartrate, propylene glycol, or other inorganic or organic solutes. Sodium chloride is particularly preferred. Buffering agents such as acetic acid and its salts, citric acid and its salts, boric acid and its salts, and phosphoric acid and its salts can be used. Parenteral vehicles include sodium chloride solution, Ringer dextrose, dextrose, and sodium chloride, lactated Ringer's solution, and fixed oil. Intravenous vehicles include fluids and nutrient replenishers, electrolyte replenishers (eg, Ringer dextrose-based agents), and the like.

  The viscosity of the pharmaceutical composition can be maintained at a selected level using a pharmaceutically acceptable thickener. Methylcellulose is preferred because it is readily and economically available and easy to handle. Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer and the like. The preferred concentration of the thickener may depend on the thickener selected. It is preferred to use an amount that can achieve the selected viscosity. Viscous compositions are usually made from solution by the addition of the thickener.

  Pharmaceutically acceptable preservatives can be used to increase the shelf life of the pharmaceutical composition. A variety of preservatives can be used, including, for example, parabens, thimerosal, chlorobutanol, and benzalkonium chloride, but benzyl alcohol may be suitable. A suitable concentration of the preservative may be desired depending on the agent selected in large or small amounts, but is typically from about 0.02% to about 2% based on the total weight of the composition.

  Zoskidal, daunorubicin, and / or cytarabine can be mixed with a suitable carrier, diluent, or excipient (eg, sterile water, saline, glucose, etc.) and depending on the desired route and formulation of administration. Auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling agents or thickening additives, preservatives, fragrances, coloring agents and the like. For example, standard textbooks (eg, “Remington: The Science and Practice of Pharmacy”, Lippincott Williams &Wilkins; 20th edition (June 1, 2003), and “Remington's Pharmaceutical Sciences,” Mack Pub. Co .; 18 See Edition and 19th Edition (December 1985 and June 1990, respectively), which include complex-forming agents, metal ions, polymer compounds (eg, polylactic acid, polyglycolic acid, hydrogel, Dextran, etc.), liposomes, microemulsions, micelles, monolayer or multilayer vehicles, erythrocyte ghosts, or spheroplasts Suitable lipids for liposome formulations include, for example, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponins Including, but not limited to, bile acids, etc. The presence of these additional components is Can affect the general condition, solubility, stability, rate of in vivo release, and rate of in vivo clearance, and according to the intended use, the nature of the carrier will be chosen to suit the chosen route of administration. It is.

  For oral administration, the zosquidar, daunorubicin, and / or cytarabine are tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. It can serve as an agent. Compositions intended for oral administration can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, such as the following agents: sweeteners, fragrances, colorants, and preservatives. One or more may be included. Aqueous suspensions may contain the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions.

  Formulations for oral administration are also as hard gelatin capsules (where the zosquidal, daunorubicin, and / or cytarabine are mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin) or It can be used as a soft gelatin capsule. In the case of soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid, such as water or an oil medium (eg, peanut oil, olive oil, fatty oil, liquid paraffin, or liquid polyethylene glycol). . Stabilizers and microspheres formulated for oral administration may also be used. Capsules can include push-fit capsules composed of gelatin, as well as soft-sealed capsules composed of gelatin, and plasticizers (eg, glycerol or sorbitol). The push-fit capsule comprises zoschidar, daunorubicin, and / or cytarabine, a filler (eg, lactose), a binder (eg, starch), and / or a lubricant (eg, talc and magnesium stearate), And optionally mixed with a stabilizer.

  Tablets can be uncoated or coated by known methods for delaying disintegration and absorption in the gastrointestinal tract and, as a result, can provide a sustained action over a longer period. For example, a time delay material (eg, glyceryl monostearic acid) may be used. When administered in a solid form (eg, tablet form), the solid form typically contains from about 0.0001% or less to about 50% by weight of the active ingredient (eg, including zoschidar, daunorubicin, and / or cytarabine). % By weight (about 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0 .2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1% by weight to about 2, 3, 4, 5, 6, 7, 8 9, 10, 15, 20, 25, 30, 35, 40, or 45% by weight).

  Tablets may contain zoskidal, daunorubicin, and / or cytarabine in admixture with non-toxic pharmaceutically acceptable excipients (eg, containing inert substances). For example, a tablet may be made by compression or molding, optionally with one or more additional ingredients. Compressed tablets are compressed in a suitable machine by mixing the active ingredients in free-flowing form (eg powder or granules) with a binder, lubricant, inert diluent, surfactant or dispersant as appropriate. Can be manufactured. 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 or capsule preferably contains no more than about 10 mg or about 1000 mg of zoschidar, daunorubicin, and / or cytarabine, from about 20, 30, 40, 50, 60, 70, 80, 90 or 100 mg to about 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, or 900 mg is more preferable. Most preferably, the tablets or capsules are provided in a range of doses that are acceptable for administering divided doses. Thus, the appropriate dose and the number of doses administered per day can be advantageously selected. In certain embodiments, it may be preferred to contain zosquidar, daunorubicin, cytarabine, and any other therapeutic agent used in combination in a single tablet or other dosage form, but in certain embodiments, Zoskidal, daunorubicin, cytarabine, and other therapeutic agents in separate dosage forms (eg, zoschidar, daunorubicin, and cytarabine each in separate dosage forms, or daunorubicin and cytarabine in one dosage form and zoschidar alone in another form ) May be desired. Combinations of dosage forms can also be used, for example, orally and intravenously.

  Suitable inert materials include diluents (eg, carbohydrates, mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextran, starch, etc.) and inorganic salts (eg, calcium triphosphate, calcium phosphate, sodium phosphate, calcium carbonate) Sodium carbonate, magnesium carbonate, and sodium chloride). Disintegrants or granulating agents can be used in the formulation, such as starch (eg, corn starch), alginic acid, sodium starch glycolate, amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxy May include methylcellulose, natural sponges, and bentonites, insoluble cationic exchange resins, powdered gums (eg, agar, karaya, and tragacanth), and alginic acid and its salts.

  The binder can be used to obtain hard tablets. The binder includes a substance derived from a natural product (for example, acacia, tragacanth, starch, gelatin, methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.).

  Lubricants (eg, stearic acid and its magnesium or calcium salts, polytetrafluoroethylene, liquid paraffin, vegetable oil, wax, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, starch, talc, pyrogenic silica, hydrated silica Aluminum acid etc.) may be included in the tablet formulation.

  Surfactants also include, for example, anionic disintegrants (eg, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate), cationic disintegrants (eg, benzalkonium chloride, and benzethionium chloride), and Non-ionic disintegrants such as polyethylene hydrogenated castor oil, glycerol monostearate, polysorbate, sucrose fatty acid ester, methylcellulose, and carboxymethylcellulose may be used.

  Sustained release formulations may be used in which zoskidal, daunorubicin, and / or cytarabine are incorporated into an inert matrix that is allowed to release by either diffusion or leaching mechanisms. A delayed disintegrating matrix can also be included in the formulation. Other delivery systems can include time-release, delayed release, or sustained release delivery systems. The nanoparticle system or nanoparticle form of the active ingredient may be advantageously used in certain embodiments.

  Coating agents include, for example, non-enteric materials (eg, methylcellulose, ethylcellulose, hydroxyethyl cell source, methylhydroxy-ethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, sodium carboxymethylcellulose, polyvidone, polyethylene glycol, and enteric materials (eg, Phthalates)). Dyestuffs and pigments may be added for identification or to identify different combinations of active compound doses.

  When administered orally in liquid form, a liquid carrier (eg, water, petroleum ether, oil of animal or vegetable origin (eg, peanut oil, mineral oil, soybean oil, or sesame oil), or synthetic oil) is added to the zoschidal, Can be added to daunorubicin and / or cytarabine. Saline solutions, dextrose, other sugar solutions, and glycols (eg, ethylene glycol, propylene glycol, polyethylene glycol) are also suitable liquid carriers. The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oil layer can be a vegetable oil (eg, oil, rascay oil), a mineral oil (eg, liquid paraffin), or a mixture thereof. Suitable emulsifiers include naturally occurring gums (eg acacia gum and tragacanth gum), naturally occurring phosphatides (eg soy lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (eg sorbitan monooleic acid). ), And condensation products of these partial esters with ethylene oxide (eg, polyoxyethylene sorbitan monooleic acid). The emulsion may also contain sweetening and flavoring agents.

  Zoskidal, daunorubicin, and / or pulmonary delivery of cytarabine may also be used. The zoskidal, daunorubicin, and / or cytarabine are delivered to the lungs during inhalation and traverse from the lung epithelial line to the bloodstream. A wide range of mechanical devices designed for pulmonary delivery of therapeutic products can be used, including nebulizers, metered dose inhalers, and powder inhalers, all of which are known in the art. But is not limited to these). These devices use formulations suitable for dispersion of zoskidal, daunorubicin, and / or cytarabine. Typically, each formulation is specific to the type of device used, and this includes the use of appropriate propellant materials in addition to therapeutically useful diluents, adjuvants, and / or carriers. May be included.

  The zoskidal, daunorubicin, cytarabine, and / or other optional active ingredients have an average particle size of 0.1 μm or less to 10 μm or more (about 0.2, 0.3, 0.4, 0.5,. 6, 0.7, 0.8, or 0.9 μm to about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5. Pulmonary delivery in particulate form with 0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, or 9.5 μm is more preferred) It is advantageous to produce for Pharmaceutically acceptable carriers for pulmonary delivery of zoskidal, daunorubicin, and / or cytarabine include carbohydrates such as trehalose, mannitol, xylitol, sucrose, lactose, and sorbitol. Other ingredients for use in the formulation include dipalmitoyl phosphatidylcholine (DPPC), 1,2-sn-dioleoylphosphatidylcholine (DOPE), distelyl phosphatidylcholine (DSPC), and dioleoylphosphatidyl- Choline (DOPC) may be included. Natural or synthetic surfactants (including, for example, polyethylene glycols, and dextrans (eg, cyclodextrins)) can be used. Bile salts and other related enhancers, as well as cellulose and cellulose derivatives, and amino acids may also be used. Liposomes, microcapsules, microspheres, inclusion complexes, and other types of carriers can also be used.

  Pharmaceutical formulations suitable for using nebulizers (either jet or ultrasound) typically have concentrations of about 0.01 mg or less to 100 mg or more of each of zoschidar, daunorubicin, and / or cytarabine per mL of solution ( From about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg per mL of solution to about 15, 20, 25, 30, 35, 40, 45, per mL of solution, 50, 55, 60, 65, 70, 75, 80, 85, or 90 mg), preferably dissolved in or suspended in water, dasunorubicin, and / or cytarabine. The formulation may also include a buffering agent and one saccharide (eg, for protein stabilization and regulation of osmotic pressure). The nebulizer formulation may also include a surfactant to reduce or prevent interfacial-induced aggregation of zoschidar, daunorubicin, and / or cytarabine caused by atomization of the solution in forming an aerosol.

  Formulations for use with metered dose inhaler devices usually include finely divided powder containing the active ingredient suspended in the propellant with the aid of a surfactant. The propellant can include conventional propellants such as chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, and hydrocarbons. Preferred propellants include trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, 1,1,1,2-tetrafluoroethane, and combinations thereof. Suitable surfactants include sorbitan trioleate, soy lecithin, and oleic acid.

  Formulations suitable for dispersion from powder inhaler devices typically contain zoskidal, daunorubicin, and / or cytarabine, and optionally contain bulking agents (eg, lactose, sorbitol, sucrose, mannitol, trehalose, or xylitol). The micronized dry powder in an amount that promotes dispersion of the powder from the device (typically from about 1% to 99% by weight of the formulation, preferably from about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 weight percent to about 55, 60, 65, 70, 75, 80, 85, or 90 weight percent).

  Forms of parenterally acceptable aqueous solutions or oily suspensions without fever when zoskidal, daunorubicin, and / or cytarabine are administered intravenously, dermally, subcutaneously, parenterally, or by other injections It is preferable that Suspensions may be formulated according to methods well known in the art using suitable dispersing or wetting agents and suspending agents. The manufacture of an acceptable aqueous solution having the appropriate pH, isotonicity, stability, etc. is within the ordinary knowledge in the art. Preferred pharmaceutical compositions for injection include isotonic vehicles (eg, 1,3-butanediol, water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, dextrose, and sodium chloride solution, lactated Ringer's solution, Or other vehicles known in the art. In addition, sterile fixed oils can usually be employed as a solvent or suspending medium. For this purpose any fixed oil product may be employed including, for example, synthetic monoglycerides and diglycerides. In addition, fatty acids such as oleic acid can be used as well in the formulation of injectable formulations. The pharmaceutical composition may also include stabilizers, preservatives, buffering agents, antioxidants, and other additives known to those skilled in the art.

  The duration of the injection can be adjusted depending on a variety of factors, which can be from a few seconds or less to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 continuous intravenous administration. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, 54, 60 66, 72, 78, 84, 90, or a single injection over a period of 96 hours or more. In certain embodiments, the injection may be administered over a period of 5, 6, 7, 8, 9, 10 or more days.

  The zosquidal, daunorubicin, and / or cytarabine may be administered systemically or locally, in a liquid or gel, or as an implant or device.

  Preferred embodiment compositions may further use adjunct ingredients normally present in pharmaceutical compositions in a manner established in those fields and at levels established in those fields. Thus, for example, the composition may contain additional compatible pharmaceutically active substances (eg, additional P-gp inhibitors, chemotherapeutic agents, etc.) for combination therapy, or in preferred embodiments Substances that are useful in various dosage forms that are physically formulated (eg, excipients, dyes, fragrances, thickeners, stabilizers, preservatives, and antioxidants) may be included.

  Zoskidal, daunorubici, and / or cytarabine may be provided in the form of a kit to the administering physician or other medical professional. The kit is a package containing one or more containers containing zosquidar, daunorubicin, and / or cytarabine in a suitable form and instructions for administering the pharmaceutical composition to a subject. The kit can also optionally include one or more additional therapeutic agents. The kit may optionally include one or more diagnostic tools and instructions for use (eg, a diagnostic agent for measuring efflux pump activity, or P-gp expression or function). For example, a kit containing a single composition containing zoskidal, daunorubicin, and / or cytarabine in combination with one or more other therapeutic agents may be provided, or zoskidal, daunorubicin, and / or cytarabine, and Another pharmaceutical composition may be provided that contains another therapeutic agent. The kit can also include separate doses of zosquidal, daunorubicin, and / or cytarabine for continuous or sequential administration. The kit includes a suitable delivery device (eg, syringe, inhalation device, etc.) along with instructions for administering zoskidal, daunorubicin, and / or cytarabine, and any other therapeutic agent. The kit may optionally include instructions for storage, reconstruction (if available), and administration of any or all contained therapeutic agents. The kit can include a number of containers that reflect the number of doses to be given to the subject.

  In a particularly preferred embodiment, a kit for the treatment of AML (especially newly diagnosed AML) is provided comprising zoskidal, daunorubicin and cytarabine, and instructions for administering each. In another particularly preferred embodiment, one or more diagnostic agents for measuring the expression and / or efflux pump activity (function) of zoschidar, daunorubicin, and / or cytarabine and P-gp are implemented A kit for the treatment of newly diagnosed AML is provided, including instructions for. The kit can also include instructions, assays, and / or diagnostics for determining whether the patient has AML.

  The combination of zoskidal, daunorubicin, and cytarabine may be administered to patients with leukemia, solid tumors, or other malignancies. It is particularly preferred to administer the combination when P-gp expression is positive, or to use the combination in the treatment of malignant tumors that exhibit P-gp expression or function. Cancer targets in which more than 50% of patients exhibit P-gp expression are particularly preferred for treatment by the combination of the preferred embodiments. The following dosage regimes for AML also include other leukemias, solid tumors, bladder cancer, pancreatic cancer, liver cancer, myeloma, carcinomas (eg, breast and ovarian cancer), sarcomas, and other hematological malignancies (eg, Acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell epidemic, lymphoma, myelodysplasia) may be suitable.

Treatment of Acute Myeloid Leukemia The combination of Zoskidal, daunorubicin, and cytarabine is most preferably administered to newly diagnosed AML patients. However, the combination can also be administered prophylactically to patients suspected of having AML for confirmation of diagnosis, or to AML patients other than newly diagnosed AML patients (eg, relapsed AML patients). Can do. The route of administration, dosage, and number of doses can vary depending on the age of the patient, the condition as a relapsed or newly diagnosed AML patient, and the severity of the disease.

  Contemplated amounts of Zoschidar in intravenous administration to treat newly diagnosed AML range from about 400 mg / day or less to about 1,600 mg / day or more (about 500, 600, or 700 mg / day to about 900, 1000 1100, 1200, 1300, 1400, or 1500 mg / day is preferred, with 700 mg / day being most preferred). During the treatment regimen, the zosquidal is preferably administered on 2, 3 or 4 separate days. The dose can be from about 6 to about 90 hours (from about 12, 18, 24, 30, 36, or 42 hours to about 54, 60, 66, 72, 78, or 84 depending on the treatment regimen. Time periods are more preferred, with about 24, 48, or 72 hours being most preferred). The zosquidal is preferably administered on day 1 of the treatment regimen. In certain embodiments, another zosquidar is administered on days 2, 2 and 3, or on days 2, 15 and 16. However, in certain embodiments, one, two, three, or more additional doses may be administered on the other day of the treatment regimen.

The intended amount of daunorubicin in intravenous administration to treat newly diagnosed AML is from about 10 mg / m ² / day or less to about 100 mg / m ² / day or more administered at the beginning of Zoskidal infusion, or About 1, 2, 3, 4, 5, or 6 hours after the start of infusion of Zoskidal or up to more. The dose is from about 25 mg / m ² / day or less to about 90 mg / m ² / day or more (about 30, 35, or 40 mg / m ² / day or less to about 50, 55, 60, 65, 70, 75, 80 or preferably 85 mg / ^{m 2} / day, at the rate of the most preferred) to about 45 mg / ^{m 2} / day, about 2 or about 2. over a period of from 5 days to about 3.5 or about 4 days (approximately 3 days It is preferred to administer intravenously continuously.

The intended amount of cytarabine in intravenous administration to treat newly diagnosed AML is from about 10 mg / day or less to about 3,000 mg / day administered at the beginning of zoskidal infusion or after initiation of zoskidal infusion. More than a day. The dose is about 50 mg / m ² / day or less to about 200 mg / m ² / day or more (about 60, 70, 80, or 90 mg / m ² / day or less to about 110, 120, 130, 140, 150, 160 , 170, 180 or 190 mg / ^{m 2} / day is preferred, at a rate of most preferred) to about 100 mg / ^{m 2} / day, from about 1,2,3,4,5 or 6 days to about 8,9, or Intravenous administration is preferably continuous over a period of up to 10 days or more (preferably about 7 days).

A particularly preferred dosage regimen for newly diagnosed AML is continuous intravenous administration of zoskidal over 550 mg over 6 hours (3 days), continuous intravenous cytarabine at a rate of 100 mg / m ² / day Administration (7 days) and intravenous administration of daunorubicin at a dose of 45 mg / m ² / day, where daunorubicin infusion begins 1 hour after the start of infusion of zosquidar. Another particularly preferred dosage regimen is continuous intravenous administration of 500-700 mg / day of Zoschidar (preferably a period of 1-24 hours, more preferably a period of about 6-24 hours, most preferably a period of about 24 hours Preferred) (3 days), continuous intravenous administration of cytarabine at a rate of 100 mg / m ² / day (7 days), and intravenous administration of daunorubicin at a dose of about 45 mg / m ² / day (3 days) Where daunorubicin infusion begins 1 to 4 hours after the start of zosquidal infusion. In the above embodiment, the daunorubicin infusion begins after a specific time has elapsed after the start of the infusion of zosquidal, but in other embodiments, other onset times may be preferred, e.g. Immediately after the start of the injection or during the injection, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours or more after the start of the Zoskidal injection.

  The above dosage regimes for the treatment of newly diagnosed AML may also be compatible with the treatment of recurrent AML, as well as metastatic breast cancer or other carcinomas.

  Although the above method of the preferred embodiment has been described primarily in connection with the treatment of AML, the method also includes daunorubicin, a P-gp substrate, and other malignancies that exhibit a significant degree of P-gp expression. It is particularly effective when used to treat.

(Experiment)
Patients with AML were 72 hours beginning on day 1 and 4 hours prior to initiation of treatment with daunorubicin (45 mg / m ² intravenously on days 1, 2 and 3) for Zoschidar (700 mg / day continuous) Treatment for 72 hours. Cytarabine (100mg / ^{m 2} / day) also as a continuous intravenous infusion days 1-7, starting after the first administration of daunorubicin was administered. Blood samples were collected from time to time for pharmacokinetic and pharmacodynamic studies. Pharmacokinetic drug measurements were performed by HPLC. Pharmacokinetic assessment of cellular P-gp function was performed using a cumulative assay with DiOC2 and flow cytometry. P-gp function was evaluated on circulating natural killer (NK) cells and leukemia blasts. FIG. 1 shows the relationship between blood zoschidal levels and P-gp function inhibition. Average values of 3 patients at each time point are shown. Zoschidal peak levels were achieved 24 hours after the start of drug infusion. Zoschidal levels remained fairly stable at 180-207 nm / ml for the remainder of the infusion period. 72 hours after cessation of zosquidal infusion, blood zoschidal levels immediately dropped to about 50-60 nm / mL at 80-96 hours.

  P-gp function for both NK cells and leukocyte blasts was strongly suppressed within 2 hours after the start of Zoskidal infusion. Inhibition of P-gp function can be attributed to Zoschidar because treatment with daunorubicin and cytarabine started at the 4 hour time point. Inhibition of P-gp functional activity was maintained during the infusion period and lasted for at least 12 hours after cessation of Zoskidal infusion. These results can give a fairly short-term infusion of Zoschidar, which allows a constant suppression of P-gp function of white blood cells after stopping the infusion and adverse events (eg, , Indicates that it is possible to reduce the incidence of central nervous system toxicity).

  All references cited herein, including but not limited to published and unpublished applications, patents, and academic literature, are hereby incorporated by reference in their entirety. And are incorporated herein by reference. In the event that many publications, incorporated by reference, and patents or patent applications conflict with the disclosure contained herein, the specification may supersede any and / or those that conflict. Is intended to take precedence over

  As used herein, the term “comprising” is synonymous with “including”, “containing”, “characterizing”, and is inclusive. Or can be interpreted in various ways and does not exclude further undescribed elements or method steps.

  It should be understood that all numbers representing the amount of active ingredient, reaction conditions, and others used in the specification are modifications in all examples by the term “about”. Therefore, unless stated otherwise, the numerical parameters described herein are approximations that can be varied depending on the desired properties to be obtained. Although very rare, it does not attempt to limit the application of equivalent doctrine to the scope of any claim in any application claiming priority to this application, Such parameters should be interpreted in the light of significant number of digits and normal rounding methods.

  The above description discloses several methods and materials of the present invention. The present invention is susceptible to changes in methods and materials, as well as changes in manufacturing methods and equipment. Such modifications will be apparent to those skilled in the art from consideration of the present disclosure or practice of the invention disclosed herein. In conclusion, the invention is not intended to be limited to the specific embodiments disclosed herein, but rather encompasses all modifications and variations that are within the spirit and scope of the invention.

Claims (47)

  A method for treating a malignant tumor comprising administering zoskidal, daunorubicin and cytarabine to a patient in need of treatment.   The method of claim 1, wherein the malignant tumor is acute myeloid leukemia.   The method of claim 1, wherein the malignant tumor is newly diagnosed acute myeloid leukemia. The steps of administering zoskidal, daunorubicin and cytarabine to a patient in need of treatment include:
Zoskidal is administered intravenously in an amount of about 300 mg to about 800 mg that is continuously administered to the patient over about 3 days over about 6 hours to about 24 hours;
Daunorubicin is administered intravenously to the patient at a rate of about 20 mg / m ² / day to about 100 mg / m ² / day for about 3 days, wherein daunorubicin is administered about 1 hour after the start of zosquidar administration. Starting after 5 hours; and
Cytarabine is administered intravenously continuously to the patient in an amount of about 50 mg / m ² / day to about 150 mg / m ² / day for about 7 days;
4. The method of claim 3, comprising the steps. The steps of administering zoskidal, daunorubicin and cytarabine to a patient in need of treatment include:
Zoschidal is administered intravenously in an amount of about 500 mg to about 700 mg, wherein the patient is continuously administered over about 3 days over about 6 hours to about 24 hours;
Daunorubicin is intravenously administered to the patient at a rate of about 40 mg / m ² / day to about 50 mg / m ² / day for about 3 days, wherein daunorubicin is administered about 1 hour after the start of zosquidar administration. Starting after 4 hours; and
Cytarabine is administered intravenously continuously to the patient in an amount of about 90 mg / m ² / day to about 110 mg / m ² / day for about 7 days;
4. The method of claim 3, comprising the steps. The steps of administering zoskidal, daunorubicin and cytarabine to a patient in need of treatment include:
Zoschidal is administered intravenously in an amount of about 500 mg to about 700 mg, wherein the patient is continuously administered over about 3 days over about 6 hours to about 24 hours;
Daunorubicin is administered intravenously to the patient at a rate of about 45 mg / m ² / day for about 3 days, wherein daunorubicin administration is initiated about 1 hour to about 4 hours after the start of zosquidar administration; and
Cytarabine is administered intravenously to the patient in an amount of about 100 mg / m ² / day for about 7 days continuously,
4. The method of claim 3, comprising the steps. The steps of administering zoskidal, daunorubicin and cytarabine to a patient in need of treatment include:
Zoschidal is administered intravenously in an amount of about 500 mg to about 700 mg, wherein the patient is continuously administered over about 3 days over about 6 hours to about 24 hours;
Daunorubicin is administered intravenously to the patient at a rate of about 45 mg / m ² / day for about 3 days, wherein daunorubicin administration is initiated about 1 hour to about 4 hours after the start of zosquidar administration; and
Cytarabine is administered intravenously to the patient in an amount of about 100 mg / m ² / day for about 7 days continuously,
4. The method of claim 3, comprising the steps. The steps of administering zoskidal, daunorubicin and cytarabine to a patient in need of treatment include:
Zoschidal is administered intravenously in an amount of about 500 mg to about 700 mg, which is administered to the patient continuously over a period of about 6 hours over about 3 days;
Daunorubicin is administered intravenously to the patient at a rate of about 45 mg / m ² / day for about 3 days, wherein daunorubicin administration is initiated about 1 hour to about 4 hours after the start of zosquidar administration; and
Cytarabine is administered intravenously to the patient in an amount of about 100 mg / m ² / day for about 7 days continuously,
4. The method of claim 3, comprising the steps. The steps of administering zoskidal, daunorubicin and cytarabine to a patient in need of treatment include:
Zoskidal is administered intravenously in an amount of about 550 mg, which is continuously administered to the patient over about 6 hours over about 6 days;
Daunorubicin is administered intravenously to the patient at a rate of about 45 mg / m ² / day for about 3 days, wherein daunorubicin administration begins about 1 hour after the start of zosquidar administration;
Cytarabine is administered intravenously to the patient in an amount of about 100 mg / m ² / day for about 7 days continuously,
4. The method of claim 3, comprising the steps. A pharmaceutical kit for use in the treatment of newly diagnosed acute myeloid leukemia,
At least one dose of zoskidal;
An indicator for making at least one diagnosis to determine whether the patient exhibits at least one positive efflux pump activity and positive P-gp expression or function; and
Indices for administering zoschidar in combination with daunorubicin and cytarabine to treat newly administered acute myeloid leukemia in patients exhibiting at least one positive efflux pump activity and positive P-gp expression or function ,
The kit. A method for treating a malignant tumor in a patient comprising the following steps:
Conducting a diagnostic test, which determines that the malignant tumor expresses or selects P-glycoprotein; and
Administering zoskidal, daunorubicin, and cytarabine to the patient,
Including the method.   The method according to claim 11, wherein the malignant tumor is acute myeloid leukemia.   12. The method of claim 11, wherein the malignant tumor is newly diagnosed acute myeloid leukemia.   12. The method of claim 11, wherein the malignant tumor is a carcinoma.   15. The method of claim 14, wherein the carcinoma is breast cancer.   15. The method of claim 14, wherein the carcinoma is ovarian cancer.   12. The method of claim 11, wherein the malignant tumor is a sarcoma.   The method according to claim 11, wherein the malignant tumor is a hematological malignancy selected from the group consisting of acute lymphocytic leukemia, chronic myelogenous leukemia, plasma cell epidemic, lymphoma, and myelodysplasia. A method for treating a malignant tumor in a patient comprising the following steps:
Conducting a diagnostic test, which determines that the malignant tumor exhibits positive efflux pump activity; and
Administering zoskidal, daunorubicin, and cytarabine to the patient,
The method.   20. The method of claim 19, wherein the malignant tumor is acute myeloid leukemia.   20. The method of claim 19, wherein the malignant tumor is newly diagnosed acute myeloid leukemia.   20. The method of claim 19, wherein the malignant tumor is a carcinoma.   24. The method of claim 22, wherein the carcinoma is breast cancer.   24. The method of claim 22, wherein the carcinoma is ovarian cancer.   20. The method of claim 19, wherein the malignant tumor is a sarcoma.   20. The method according to claim 19, wherein the malignant tumor is a hematological malignancy selected from the group consisting of acute lymphocytic leukemia, chronic myelogenous leukemia, plasma cell epidemic, lymphoma, and myelodysplasia. A method for treating a malignant tumor in a patient comprising the following steps:
A diagnostic test is performed to determine that the malignancy expresses or selects P-glycoprotein or exhibits positive efflux pump activity;
Administering to the patient a chemotherapeutic agent that is a substrate for zoschidar and P-glycoprotein,
Including the method.   28. The method of claim 27, wherein the malignant tumor is acute myeloid leukemia.   28. The method of claim 27, wherein the malignant tumor is a carcinoma.   30. The method of claim 29, wherein the carcinoma is breast cancer.   30. The method of claim 29, wherein the carcinoma is ovarian cancer.   28. The method of claim 27, wherein the malignant tumor is a sarcoma.   28. The method of claim 27, wherein the malignant tumor is a hematological malignancy.   34. The method of claim 33, wherein the hematological malignancy is selected from the group consisting of acute lymphocytic leukemia, chronic myelogenous leukemia, plasma cell epidemic, lymphoma, and myelodysplasia.   28. The method of claim 27, wherein the chemotherapeutic agent is an anthracycline.   36. The method of claim 35, wherein the anthracycline is selected from the group consisting of doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone.   28. The method of claim 27, wherein the chemotherapeutic agent is a topoisomerase-II inhibitor.   28. The method of claim 27, wherein the topoisomerase-II inhibitor is etoposide or teniposide.   28. The method of claim 27, wherein the chemotherapeutic agent is vinca.   40. The method of claim 39, wherein the vinca is selected from the group consisting of vincristine, vinblastine, vinorelbine, and vindesine.   28. The method of claim 27, wherein the chemotherapeutic agent is a taxane.   42. The method of claim 41, wherein the taxane is paclitaxel or docetaxel.   28. The method of claim 27, wherein the chemotherapeutic agent is Gleevec.   28. The method of claim 27, wherein the chemotherapeutic agent is dactinomycin.   28. The method of claim 27, wherein the chemotherapeutic agent is mitomycin.   28. The method of claim 27, wherein the chemotherapeutic agent is mitramycin.   28. The method of claim 27, wherein the chemotherapeutic agent is mylotage.