MX2008000225A - Treatment of patients with cancer using a calicheamicin-antibody conjugate in combination with zosuquidar - Google Patents

Abstract

The present invention relates to a method of treating patients with solid tumors, leukemias, and other malignancies using a combination of zosuquidar and a calicheamicin-antibody conjugate, such as Mylotarg. The invention is also directed to pharmaceutical formulations comprising zosuquidar and calicheamicin-antibody conjugates. The formulations are particularly effective in treating relapsed Acute Myelogenous Leukemia (AML) and metastatic breast cancer.

Description

TREATMENT OF PATIENTS WITH CANCER USING A CONJUGATE OF CALIQUEAMICIN A-ANTIBODY IN COMBINATION WITH ZOSUQUIDAR Related Request This application claims the benefit of US Provisional Application No. 60 / 696,756 filed on July 6, 2005, US Application No. 1 1 / 416,833 filed May 3, 2006, and US Application No. 1 1 / 41 6,992 filed on May 3, 2006, which are expressly incorporated by reference in their entirety, and which are considered part of this specification. Field of the invention The present invention relates to a method for treating patients with solid tumors, leukemias and other malignancies using a combination of zosuquidar and a calicheamicin-antibody conjugate, such as gemtuzumab ozogamicin (Mylotarg). The invention is also died to pharmaceutical formulations containing zosuquide and calicheamicin-antibody conjugate. The formulations are particularly effective in treating the reappearance of Acute Myelogenous Leukemia (AML). BACKGROUND OF THE INVENTION The field of oncology is in the midst of an important evolution. In the past, cancer treatment had been dominated by empirical treatments, such as "one serves for all" based on types and stages of tumors. The toxic chemotherapy drugs have dominated the treatment in an impressive way despite having a low cure rate, particularly against the most common cancers and against those with known metastatic disease. Now, the treatments under development are died against specific proteins. This specificity is based on a more robust knowledge of the mechanisms of cancer, which often cross over many tumor types. These treatments are designed to work on defined subsets of patients, commonly based on the expression and function of the target protein rather than on the type of tumor, and often in combination with standard chemotherapies. Advances in the molecular analysis of cancers will allow the identification of these subsets of patients and the coupling of the desired therapeutic substances to novel diagnostic approaches. The future of oncology rests on defining the disease in molecular terms (ie, genetics, genomics, proteomics) and adjusting the therapies according to the individual properties of the tumor and normal cells. This new paradigm will predetermine likely responders, evaluate responses earlier, and adjust treatment based on continuous molecular analyzes of tumors. Drug resistance is one of the many more problems that must be overcome in order to achieve successful treatment of human tumors with chemotherapy. Clinically, drug resistance, a characteristic of intrinsically resistant tumors (eg, colon, kidney, and pancreas), may be evident at the beginning of therapy. Alternatively, resistance acquired to the drug is the result when tumors initially respond to therapy, but become refractory to subsequent treatments. Once a tumor has acquired resistance to a specific chemotherapeutic agent, it is common to observe collateral resistance to other structurally similar agents. The cellular mechanisms of drug resistance include apoptosis, drug absorption, DNA repair, altered drug targets, drug sequestration, detoxification, and efflux pumps (see, for example, Dalton WS Semin. Oncol. : 60, 1 993). Multidrug resistance (M DR), the ability of cancer cells to become resistant to the agent or agents actively used for therapy, as well as other drugs that are not structurally and functionally related, is a form of resistance to the drug particularly Insidious This form of drug resistance is described in greater detail in Kuzmich et al, "Detoxification Mechanisms and Tumor Cell Resistance to Anticancer Drugs," particularly in section VI I "The Multidrug-Resistant Phenotype (M DR)," Medical Research Reviews, Vol. 1 1, No. 2, 1 85-21 7, particularly 208-21 3 (1 991); and in Georges et al, "Multidrug resistance and Chemosensitization: Therapeutic Implications for Cancer Chemotherapy, "Advances in Pharmacology, Vol. 21, 185-220 (1990) While the M DR can be produced by a variety of factors, one of the much more anticipatory forms of MDR is of the associated type. with overexpression of P-glycoprotein (P-gp) P-gp is a member of a super family of membrane proteins, called adenosine triphosphate (ATP) binding cassette proteins, which be as ATP-dependent transporters and / or ion channels for a wide variety of hydrophobic substrates P-gp is a glycoprotein with multiple transmembrane range Transfection experiments with the P-gp gene (mdr1) have conferred M DR to tumor cells sensitive to the drug by providing them with a energy-dependent efflux pump that decreases the ihtracellular concentration of the cytotoxic agent, thereby allowing the survival of the cell.P-gp is expressed in the bile canaliculi normal of the liver, in the adrenal cortex and in the proximal tubules of the kidney, and in the intestinal epithelium, including the columnar cells of the large and small intestines; in the capillary endothelial cells of the brain, in the testes, and placenta; and in the hematopoietic stem cells of the bone marrow. It has excretory, protective and barrier functions. P-gp is constitutively expressed or selected in many human cancers, and confers resistance to therapeutic agents including anthracyclines (eg, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone), vincas (eg, vincristine, vinblastine, vinorelbine, vindesine), Topoisomerase-1 inhibitors (eg, etoposide, teniposide), taxanes (eg, paclitaxel, docetaxel), and others (eg, Gleevec, Mylotarg, dactinomycin , mithramycin). The relative promiscuity of drug transport by P-gp and other transporters associated with MDR inspired a broad search for compounds that might not be cytotoxic in themselves, but could inhibit MDR transport. The initial demonstration of verapamil as a P-gp inhibitor was ; followed by many additional compounds that are reported to inhibit drug transport and thereby sensitize cells to M DR with respect to chemotherapeutic drugs. Variously called chemosensitizers, M DR reversion agents, modulators, or converters, this "first generation" drug M DR included compounds of various structure and function, such as calcium channel blockers (eg, yerapamil), immunosuppressants (eg example, cyclosporin A), antibiotics (e.g., erythromycin), antimalarials (e.g., quinine), and others (e.g., biricodar, tariquidar, valspodar). The first-generation MDR drugs were not specifically developed to inhibit MDR. Frequently they had other pharmacological activities, as well as a relatively low affinity for M DR transporters and therefore had limited application. For example, P-gp had a low affinity for vepramil, which required cardiotoxic levels for the complete modulating activity. Despite the fact that only low serum levels could be obtained in a Phase I I trial, 5 of 22 patients responded to a combination of verapamil and VAD (vincristine, doxorubicin, and dexamethasone). Four of the responders had high expression and function of P-gp. Thus, vepramil has been shown to have some clinical utility for overcoming drug resistance. Cyclosporin A alters the pharmacokinetics of coadministered cytotoxic agents, producing a significantly increased oncolytic exposure, thereby confusing the interpretation of clinical tests. The additional characterization of the P-gp pharmacopora led to the identification of "second generation" modulators based on the first generation, but selected or designed specifically to reduce the side effects of the latter by eliminating their non-MDR pharmacological actions. Compounds such as the R enantiomers of verapamil (R-verapamil) and dexniguldipine are no more successful than M DR drugs in clinical studies, much more likely because their affinity for P-gp is still insufficient to produce significant inhibition of M DR. in vivo in tolerable doses. A more promising second-generation modulator with a higher affinity for P-gp was valspodar, a non-immunosuppressive cyclosporin D derivative. Although the initial tests were encouraging, subsequent work revealed significant pharmacokinetic interactions with several anticancer drugs.

Although discontinued by Novartis, the bishopdar was studied in a Phase I I study in elderly patients with Acute Myelogenous Leukemia. Recruitment in the valsdopar treatment group was stopped due to excessive early mortality, most likely due to PK interactions. Although the number of patients was limited, patients in the control group whose cells with pretreatment showed modulated dye efflux by in vitro bisispodar (n = 22) had worse results than those without efflux (n = 1 1) (rates of complete remission, absence of response and mortality of 41%, 41%, and 1 8%, compared to 91%, 9%, and 0%, P = 0.03), but with results with vaispodar which were almost identical (Baer 2002). Furthermore, for patients with valsdopar-modulated efflux, the median disease-free survival was 5 months in the control group and 14 months in the bisispodar treatment group (P = 0.07). A second generation M DR modulator with activity against P-gp and M RPI (another ABC transporter associated with multidrug resistance) was the biricodar. Vertex studied the agent in several Phase I studies of soft tissue sarcomas, ovarian cancer, small cell lung cancer, and others. However, the biricodar and the bisispodar are both substrates for isoenzyme 3A4 of P450. The competition between cytotoxic agents and the P4g P-gp inhibitors for P450 3A4 produced unpredictable PK interactions and resulted in serum concentrations increased cytotoxic substances, and therefore, greater toxicity to the patient. A common response of clinical investigators has been to reduce the dose of cytotoxic agents. However, interactions with PK are unpredictable and can not be determined in advance. As a result, serum cytotoxic levels were too high, producing excessive toxicity, or too low, producing a decrease in efficacy. In addition to inhibiting P-gp, many of the second-generation modulators function as substrates for other transporters, particularly the ABC family, whose inhibition could diminish the ability of normal, healthy cells to protect themselves from cytotoxic agents. BRIEF DESCRIPTION OF THE INVENTION Dose forms and treatment regimens for patients with solid tumors, leukemias, and other malignancies that produce increased rates of complete remission and cancer-free survival rates and overall survival rates are desirable. Dosage forms and treatment regimens for patients with relapse of AML who have improved survival rates and higher rates of complete remission are particularly desirable. The combined use of a calicheamicin-antibody conjugate and a P-gp inhibitor such as zosuquidar improves the therapeutic activity of the caliqueamicin-antibody conjugate and can offer such advantages in the treatment of solid tumors, leukemias, and other malignancies.

Accordingly, in a first aspect, a method for treating Acute Myelogenous Leukemia is provided, the method comprising administering to a patient in need thereof, zosuquidar and a calicheamicin-antibody conjugate. In a modality of the first aspect, the Myelogenous Leukemia Acute is a reappearance of Acute Myelogenous Leukemia. In an embodiment of the first aspect, the step of administering a patient in need thereof, zosuquidar and a calicheamicin-antibody conjugate includes administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg / m2 in a time period from about 1 hour to about 24 hours on day 1 of a treatment regimen; administering intravenously to a patient in an amount of about 500 mg / day to about 700 mg / day for about 24 hours on day 1 of the treatment regimen.; administering the calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg / m2 for about 1 hour to about 24 hours on day 1 5 of a treatment regimen; and administering intravenously to a patient in an amount of 500 mg / day to approximately 700 mg / day for approximately 24 hours on day 15 of the treatment regimen. The calicheamicin-antibody conjugate can be Mylotarg. In a modality of the first aspect, the step of administering to a patient in need thereof, zosuquidar and a calicheamicin-antibody conjugate includes administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg / m2 in a period of time from about 1 hour to about 24 hours on day 1 of a treatment regimen; administering zosuquidar intravenously to a patient in an amount of about 500 mg / day to about 700 mg / day for about 48 hours on days 1 and 2 of the treatment regimen; administering the calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg / m2 for about 1 hour to about 24 hours on day 1 5 of a treatment regimen; and administering intravenously to a patient in an amount of 500 mg / day to approximately 700 mg / day for approximately 48 hours on days 1 5 and 1 6 of the treatment regimen. The calicheamicin-antibody conjugate can be Mylotarg. In an embodiment of the first aspect, the step of administering a patient in need thereof, zosuquidar and a calicheamicin-antibody conjugate includes administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of approximately 7 mg / m2 for approximately 1 hour to approximately 24 hours on day 1 of a treatment regimen; administer zosuquidar intravenously to a patient in an amount of 500 mg / day to approximately 700 mg / day for approximately 48 hours on day 1 and day 2 of the treatment regimen; administering the calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg / m2 for about 1 hour to about 24 hours on day 15 of a treatment regimen; and administering intravenous zosuquidar a patient in an amount of 500 rg / day to about 700 mg / day for about 48 hours on day 15 and day 16 of the treatment regimen. The calicheamicin-antibody conjugate can be Mylotarg. In an embodiment of the first aspect, the step of administering a patient in need thereof, zosuquidar and a calicheamicin-antibody conjugate includes administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of approximately 9 mg / m2 for approximately 1 hour to approximately 24 hours on day 1 of a treatment regimen; administering intravenous zosuquidar to a patient in an amount of 500 mg / day to approximately 700 mg / day for approximately 48 hours on day 1 and day 2 of the treatment regimen; administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 7 mg / m2 for about 1 hour to about 24 hours on day 15 of a treatment regimen; and administer zosuquidar intravenously to a patient in an amount of 500 mg / day to approximately 700 mg / d for approximately 48 hours on day 1 5 and day 1 6 of the treatment regimen. The calicheamicin-antibody conjugate can be Mylotarg. In an embodiment of the first aspect, the step of administering a patient in need thereof, zosuquidar and a calicheamicin-antibody conjugate includes administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of approximately 9 mg / m2 for approximately 1 hour to approximately 24 hours on day 1 of a treatment regimen; administering intravenously to a patient in an amount of 500 mg / day to approximately 700 mg / day for about 72 hours on days 1, 2 and 3 of the treatment regimen; administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 9 mg / m2 for about 1 hour to about 24 hours on day 1 5 of a treatment regimen; and administering intravenously to a patient in an amount of 500 mg / day to approximately 700 mg / day for about 72 hours on days 1, 5, 16 and 17 of the treatment regimen. The calicheamicin-antibody conjugate can be Mylotarg. In an embodiment of the first aspect, the step of administering a patient in need thereof, zosuquidar and a calicheamicin-antibody conjugate includes administering a calicheamicin-antibody conjugate intravenously to a patient at a time. speed of about 5 mg / m to about 9 mg / m2 for about 1 hour to about 24 hours on day 1 of a treatment regimen; administering intravenously to a patient in an amount of about 500 mg / day to about 700 mg / day for approximately 24 to 72 hours starting on day 1 of the treatment regimen; administering the calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg / m2 to about 9 mg / m2 for about 1 hour to about 24 hours on day 1 5 of a treatment regimen; and administering intravenously to a patient in an amount of about 500 mg / day to about 700 mg / day for about 24 to 72 hours starting on day 1 5 of the treatment regimen. The calicheamicin-antibody conjugate can be Mylotarg. In a second aspect, a pharmaceutical kit is provided for use in the treatment of recurrence of Acute Myelogenous Leukemia, the kit includes at least one dose of zosuquidar; indications for performing at least one diagnosis to determine if a patient exhibits at least one of: pump activity with positive efflux and positive P-gp expression or function; and indications for administering zosuquidar in combination with a calicheamicin-antibody conjugate to treat reappearance of Acute Myelogenous Leukemia in a patient showing at least one of pump activity with positive efflux and positive P-gp expression or function. In one embodiment of the second aspect, the calicheamicin-antibody conjugate is Mylotarg. In a third aspect, a method for treating a malignancy in a patient is provided, the method comprises the steps of performing a diagnostic examination, by which it is determined that the malignancy expresses or selects glycoprotein P; and administering zosuquidar and a caliqueamicin-antibody conjugate to the patient. In a modality of the third aspect, the malignancy is Acute Myelogenous Leukemia, for example, reappearance of Acute Myelogenous Leukemia. In one embodiment of the third aspect, the malignancy is a carcinoma, for example, breast cancer or ovarian cancer. In a modality of the third aspect, the malignancy is a sarcoma. In a third aspect embodiment, the malignancy is a hematologic malignancy selected from the group consisting of acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, and myelodysplasia. In an embodiment of the third aspect, the calicheamicin-antibody conjugate is Mylotarg. In a fourth embodiment, a method is provided for treating a malignancy in a patient, the method comprising the steps of performing a diagnostic examination, by which it is determined that the malignancy shows pump activity with positive efflux; and administering zosuquidar and a caliqueamicin-antibody conjugate to the patient. In one embodiment of the fourth aspect, the malignancy is Acute Myelogenous Leukemia, for example, reappearance of Acute Myelogenous Leukemia. In one embodiment of the fourth aspect, the malignancy is a carcinoma, for example, breast cancer or ovarian cancer. In one embodiment of the fourth aspect, the malignancy is a sarcoma. In one embodiment of the fourth aspect, the malignancy is a hematologic malignancy selected from the group consisting of acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, and myelodysplasia. In one embodiment of the fourth aspect, the calicheamicin-antibody conjugate is Mylotarg. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The following description and examples illustrate a preferred embodiment of the present invention in detail. Those skilled in the art will recognize that there are numerous variations and modifications of this invention that fall within its scope. Accordingly, the description of a preferred embodiment should not be considered as limiting the scope of the present invention. Cancer goals Many forms of cancer express P-gp, and therefore may benefit from the administration of a pump inhibitor. efflux of P-gp when treated with a chemotherapeutic agent that is a substrate for P-gp efflux. For example, much more solid tumors, lymphomas, bladder cancer, pancreatic cancer, ovarian cancer, liver cancer, myeloma, and sarcoma are all cancers with an expression of P-gp of more than 50%. Lymphocytic leukemia also has an expression of P-gp of more than 50%. The expression of P-gp of breast cancers is approximately 30%. For mestastatic breast cancer, 63% express P-gp. The methods and formulations of preferred embodiments are particularly effective in the treatment of any malignancy that shows some degree of expression or function of P-gp, or in patients that are positive for P-gp. A form of cancer characterized by high expression and function indexes of P-gp is Acute Myelogenous Leukemia. There are approximately 1 1, 000 new cases of AML per year in the United States and 9,000 new cases in the five main countries of the European Union. In addition, the World Health Organization defines advanced myelodysplasia syndrome (MDS) as AML. There are approximately 4,000 cases of M DS in the United States and 3,000 cases in the five major countries of the European Union. As a result, the target population of patients for zosuquidar is approximately 1 5,000 patients in the United States and 1 2,000 in the main European markets. AML in the adult presents greater challenges in treatment when compared with pediatric AML (age <1 5 years). Partly because of a more population resistant to a more sensitive disease, the 5-year survival rate for pediatric AML is 50% (in the late 1990s). In contrast, due in part to multiple co-morbid conditions and a more resistant disease, the 5-year survival rate for AML in adults is only 13% (in the late 1990s). The 5-year survival rate for patients over 65 is only 7%. Approximately 75% of patients with AML are older than 60 years, and 71% are positive for P-gp. Clinical outcomes in terms of patient survival rates are significantly better for patients who are negative for P-gp than for those who are positive for P-gp - a survival rate of approximately 50% at 3-4 months for patients positive for P-gp, against a survival rate of 50% in approximately 1 5 months for patients negative for P-gp. See Campos, et al, Blood, 79: 473-476, 1 992. Approximately 75% of patients with AML will eventually relapse and will be candidates for further treatment. Patients with relapse of AML commonly require prolonged hospitalization, and their prognosis is generally poor. Of these patients with relapse, approximately 80% are positive for P-gp. The basic treatment regimen for AML (ie daunorubicin and idarubicin, both substrates P-gp) had remained unchanged for decades. However, the Mylotarg, of which the calicheamicin component is a P-gp substrate, is now approved as a treatment for patients with AML relapse. Although Mylotarg is only currently approved for use in the treatment of patients with AML relapse, Mylotarg or another calicheamicin-antibody conjugate may also be effective in the treatment of other malignancies that express P-gp- Zosuq uidar U.S. Patent Nos. 5,643,909 and 5,654,304 disclose a series of 1,11-ethanobenzosuberane derivatives useful for improving the efficacy of existing cancer chemotherapeutic substances and for treating multidrug resistance. One of these derivatives, which has good activity, oral bioavailability, and stability, is zosuquidar, a compound of formula (2R) -anti-5-3- [4- (1,1,1-difluoromethanedibenzosuber-5-yl) piperazin -1 -yl] -2-hydroxypropoxy) quinoline.

Given the limitations of previous generations modulators of M DR, three critical critical success factors were identified and met for zosuquidar: 1) it is a potent inhibitor of glycoprotein P; 2) is selective for P glycoprotein; and 3) no pharmacokinetic interaction is observed with co-administered chemotherapy. Zosuquidar is extremely potent in vitro (Kj = 59 nM) and is among the most active modulators of resistance associated with P-gp described to date. Zosuquidar has also shown good in vivo activity in pre-clinical studies with animals. In addition, the compound does not appear to be a substrate for P-gp efflux, which results in a relatively long duration of reversal activity in resistant cells even after the modulator has been removed. Another significant characteristic of zosuquidar as modulator of M DR is the minimal pharmacokinetic (PK) interactions with several oncolytics tested in pre-clinical models. This minimal interaction with PK allows for the administration of normal doses of oncolytics and also a more direct interpretation of the clinical results. Mylotarg Mylotarg (gemtuzumab ozogamicin) was approved in May 2000 for the treatment of relapsed CD33-positive AML patients aged over 60 years. The Wyeth and Celltech Mylotarg is based on chemotherapy with targeted antibodies. The highly specific antibody of Mylotarg recognizes a molecule cell surface, CD33, which is abundant in AML cells in 90% of patients with AML, but is absent from normal blood stem cells, whose seeds originate from normal blood and immune cells. The antibody is linked to calicheamicin, a potent chemotherapeutic agent. The antibody selectively targets selectively targeted leukemic blasts, and supplies them with calicheamicin. The chemical structure of Mylotarg is given below.

There is an increasing body of evidence that suggests that Mylotarg is also an MDR substrate and is subject to the P-gp efflux pump. In several studies, it has been shown that the cytotoxic effect of Mylotarg is inversely correlated with the amount of P-gp present. Two modulators of MDR, valspodar and the quinolone derivative MS-209, have both shown that revert resistance to Mylotarg in CD33 (+) leukemic cells that express P-gp, and clinical trials are being carried out in combination with cyclosporins. In registration tests for the treatment of older patients using Mylotarg alone, a complete remission index (CR + CRp) of 26% was observed. In addition to Mylotarg, other calicheamicin conjugates and a P-gp substrate can also be used to treat malignancies according to preferred embodiments. Suitable P-gp substrates include, but are not limited to, anthracyclines (eg, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone), vinca (eg, vincristine, vinblastine, vinorelbine, vindesine), Topoisomerase-1 inhibitors. (e.g., etoposide, teniposide), taxanes (e.g., paclitaxel, docetaxel), and others (e.g., Gleevec, Mylotarg, dactinomycin, mithramycin). Chemotherapeutic regimens using Zosuquidar and Mylotarg The combination of zosuquidar, a highly specific and safe P-gp efflux inhibitor, in combination with the calicheamicin-Mylotarg antibody conjugate is effective for the treatment of leukemias, especially AML in patients with relapse. . Zosuquidar in combination with calicheamicin-antibody conjugates other than Mylotarg may also be effective in the treatment of solid tumors and other malignancies. The effective dose of zosuquidar and the programming of the administration of the zosuquidar and Mylotarg are critical to achieve improved complete remission rates and improved overall and leukemia-free survival rates in the population of patients with relapse of AML. While methods and formulations of preferred modalities are especially preferred for the treatment of patients with relapse of AML, the methods and formulations can be adapted to other drugs and indications. For example, Zosuquidar and Mylotarg can be administered according to the dose regimens described, or with slightly modified dose regimens, for the treatment of other types of leukemia or other cancers that express P-gp and / or that show P-function. -gp, for example, many solid tumors, bladder cancer, pancreatic cancer, liver cancer, myeloma, carcinomas (e.g., breast cancer and ovarian cancer), sarcomas, and hematologic malignancies other than AML (e.g., acute leukemia) lymphoblastic, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, myelodysplasia). Alternatively, a P-gp efflux inhibitor other than zosuquidar may be employed with the calicheamicin-antibody conjugate. Zosuquidar or some other therapeutic agents can be administered in the form of a pharmaceutically acceptable salt, for example, the trichlorohydrate salt. The terms "pharmaceutically acceptable salts" and "a pharmaceutically acceptable salt thereof" as used herein are broad terms and are used in their sense ordinary, including, without limitation, to refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases. Appropriate pharmaceutically acceptable salts include metal salts, for example, aluminum, zinc salts, alkali metal salts such as lithium, sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts; organic salts, for example, salts of Usina,? ,? '- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, and tris; salts of acids and free bases; inorganic salts, for example, sulfate, hydrochloride, and hydrobromide; and other salts which are currently in wide pharmaceutical use and which are listed in sources well known to those skilled in the art, such as, for example, the Merck index. Any suitable constituent can be selected to make a zosuquitar salt or other therapeutic agents described herein, provided that it is non-toxic and does not substantially interfere with the desired activity. In addition to salts, pharmaceutically acceptable precursors and derivatives of the compounds may be employed. The pharmaceutically acceptable amides, the lower alkyl esters, and the protected derivatives may also be suitable for use in compositions and methods of preferred embodiments. Also selected therapeutic agents in hydrated form, selected enantiomeric forms of certain therapeutic agents, racemic mixtures are suitable for administration. of certain therapeutic agents, and the like. The contemplated routes of administration include topical, oral, subcutaneous, parenteral, intradermal, intramuscular, intraperitoneal, and intravenous. However, it is particularly preferred to administer zosuquidar and / or Mylotarg intravenously. The combination or individual components can be in any suitable liquid or solid form. A particularly preferred form comprises a lyophilized form that is reconstituted for intravenous administration. The zosuquidar and / or the caliqueamicina-antibody conjugate can be formulated in liquid preparations for example, for oral, nasal, anal, rectal, buccal, vaginal, peroral, intragastric, mucosal, perlingual, alveolar, gingival, in the olfactory mucosa. or respiratory Appropriate forms for this administration include suspensions, syrups, and elixirs. If nasal or respiratory (mucosal) administration is desired (eg, inhalation or aerosol insufflation), the compositions may be in a form and may be dispensed by a compressible spray dispenser, a pump dispenser or an aerosol dispenser. The aerosols are usually under pressure by means of a hydrocarbon. The pump dispensers may preferably dispense a metered dose or a dose with a particular particle size. Pharmaceutical compositions containing zosuquide and / or the calicheamicin-antibody conjugate are preferably isotonic with the blood or other body fluid of the patient. The Isotonicity of the compositions 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 salts thereof, citric acid and salts thereof, boric acid and salts thereof, and phosphoric acid and salts thereof can be employed. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer, and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. The viscosity of the pharmaceutical compositions can be maintained at a selected level using a pharmaceutically acceptable thickening agent. Methylcellulose is preferred because it is readily and economically available and it is easy to work with it. 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 selected thickening agent. Preferably an amount that can achieve the selected viscosity is used. Viscous compositions are usually prepared from solutions by the addition of these thickening agents. A pharmaceutically acceptable preservative can be employed to increase the shelf life of the pharmaceutical compositions. Benzyl alcohol can be appropriate, although a variety of preservatives may also be employed including, for example, parabens, thimerosal, chlorobutanol, and benzalkonium chloride. An appropriate concentration of the preservative is commonly from about 0.02% to about 2% based on the total weight of the composition, although higher or lower amounts may be desirable depending on the agent selected. The zosuquidar and / or the calicheamicin-antibody conjugate may be in admixture with a suitable carrier, diluent or excipient such as sterile water, physiological saline, glucose, and the like, and may contain auxiliary substances such as wetting agents or emulsifiers, regulatory agents of pH, gelling or viscosity improving additives, preservatives, flavoring agents, colors, and the like, depending on the route of administration and the desired preparation. See, for example, standard texts such as "Remington: The Science and Practice of Pharmacy", Lippincott Williams & Wilkins; 20th edition (June 1, 2003) and "Remington's Pharmaceutical Sciences," Mack Pub. Co.; 1 8th and 1 9th editions (December 1985, and June 1 990, respectively). These preparations may include complexing agents, metal ions, polymeric compounds such as polyacetic acid, polyglycolic acid, hydrogels, dextran, and the like, liposomes, microemulsions, mycelia, unilamellar or multilamellar vesicles, phantom erythrocytes or spheroplasts. Suitable lipids for the liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. The presence of these additional components can influence the physical state, solubility, stability, release rate in vivo, and elimination rate in vivo, and therefore are chosen according to the application to which they are directed, in such a way that the characteristics of the carrier are adjusted to the selected administration route. For oral administration, the zosuquide and / or the calicheamicin-antibody conjugate can be provided as a tablet, aqueous suspension or in oil, powder or dispersible granule, emulsion, hard or soft capsule, syrup, or elixir. Compositions directed for oral administration can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and can include one or more of the following agents: sweeteners, flavoring agents, coloring agents and preservatives. The aqueous suspensions may contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. Formulations for oral administration may also be provided as hard gelatin capsules, wherein the zosuquide and / or the calicheamicin-antibody conjugate are mixed with a solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as capsules of soft gelatin. In soft capsules, the active ingredients may be dissolved or suspended in suitable liquids, such as water or an oily medium, such as peanut oil, olive oil, fatty oils, liquid paraffin, or liquid polyethylene glycols. Stabilizers and microspheres formulated for oral administration can also be used. The capsules can include gelatin-made two-part capsules, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The two-piece capsules may contain the zosuquidar and / or the calicheamicin-antibody conjugate in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc and magnesium stearate and, optionally, stabilizers. The tablets can be uncoated or coated by known methods to delay disintegration and absorption in the gastrointestinal tract and thus provide a prolonged action for a longer period of time. For example, a retarder material such as glyceryl mono stearate can be used. When administered in solid form, e.g. in tablet form, the solid form commonly contains from about 0.001% by weight or less to about 50% by weight or more of active ingredient (s) including zosuquidar and / or the Caliqueamycin-antibody conjugate, preferably from 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, 1 5, 20, 25, 30, 35, 40, or 45% by weight.

The tablets may contain the zosuquidar and / or the caliqueamicin-antibody conjugate in admixture with pharmaceutically acceptable non-toxic excipients including inert materials. For example, a tablet may be prepared by compression or molding, optionally, with one or more additional ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersant. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Preferably, each tablet or capsule contains from about 10 mg or less to about 1,000 mg or more of each of zosuquitar and / or calicheamicin-antibody conjugate, more preferably from about 20, 30, 40, 50, 60, 70, 80, 90, or 1000 mg to about 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, or 900 mg. Much more preferably, tablets or capsules are provided in a range of doses that allow dosages to be administered divided into a dose appropriate for the patient, and therefore the number of doses to be administered daily can be conveniently selected. While in some embodiments it may be preferred to incorporate zosuquidar, calicheamicin-antibody conjugate, and any other therapeutic agent used in combination with it in a single tablet or other dosage form, in some embodiments it may be desirable to provide zosuquidar, calicheamicin-antibody conjugate, and other therapeutic agents in separate dosage forms, for example, zosuquidar in a separate dose form of the calicheamicin-antibody conjugate . Combinations of dosage forms, for example, oral and intravenous, can also be used. Suitable inert materials include diluents, such as carbohydrates, mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, starch, and the like, and inorganic salts such as calcium triphosphate, calcium phosphate, sodium phosphate, calcium carbonate. , sodium carbonate, magnesium carbonate, and sodium chloride. Disintegrating or granulating agents may be included in the formulation, for example, starches such as corn starch, alginic acid, sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramilopectin, sodium alginate, gelatin, orange peel, carboxymethyl cellulose Acid, natural sponge and bentonite, insoluble cation exchange resins, powdered gums such as agar, karaya tragacanthine, alginic acid and salts thereof. Binders can be used to form a hard tablet. The binders include materials from natural products such as acacia, tragacanth, starch, gelatin, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, and the like.

Lubricants may be included, such as stearic acid and its calcium or magnesium salts, polytetrafluoroethylene, liquid paraffin, vegetable oils, waxes, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, starch, talc, fumed silica, hydrated silicoaluminate, and similar in the tablet formulations. Surfactants, for example, anionic detergents such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate, cationic detergents such as benzalkonium chloride and benzethonium chloride, and / or nonionic detergents such as polyoxyethylene hydrogenated castor oil, glycerol mono stearate, polysorbates, sucrose fatty acid ester, methyl cellulose, and carboxymethyl cellulose. Controlled release formulations may be employed wherein the zosuquide and / or the calicheamicin-antibody conjugate are incorporated in an inert matrix that allows release by diffusion or filtration mechanisms. Matrices that degenerate slowly into the formulation can also be incorporated. Other management systems may include delivery systems with scheduled release, with delayed release, or with prolonged release. The nanoparticle systems and the nanoparticle forms of the active ingredients can be advantageously employed in some embodiments. Coatings can be used, for example, non-materials enteric agents such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methylhydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxy methyl cellulose sodium, providone, polyethylene glycols, and enteric materials such as esters of italic acid. Dyes and pigments can be added for identification or to characterize different combinations of active compound doses. When administered orally in liquid form, an liquid carrier such as water, petroleum, oils of animal or vegetable origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils can be added to the zosuquidar. and / or the calicheamicin-antibody conjugate. Physiological saline, dextrose, other saccharide solutions, and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are also suitable liquid carriers. The pharmaceutical compositions may also take the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or peanut oil, a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents include gums of natural origin such as gum acacia and gum tragacanth, phosphatides of natural origin, such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono oleate, and products of condensation of these partial esters with ethylene oxide, such as polyoxyethylene mono-oleate sorbitan. The emulsions also it may contain sweeteners and flavoring agents. One can also employ pulmonary administration of zosuquidar and / or the caliqueamicin-antibody conjugate. The zosuquidar and / or caliqueamicin-antibody conjugate is delivered to the lungs while inhaling, and traverses the pulmonary epithelial lining to the bloodstream. A wide range of mechanical devices designed for pulmonary administration of therapeutic products can be employed, including, but not limited to, nebulizers, metered dose inhalers and powder inhalers all of which are familiar to those skilled in the art. These devices employ formulations suitable for the dispensing of zosuquidar and / or the caliqueamicin-antibody conjugate. Commonly, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to diluents, adjuvants, and / or carriers useful in therapy. Zosuquidar, calicheamicin-antibody conjugate, and / or other optional active ingredients are advantageously prepared for pulmonary administration in the form of particles with an average particle size from 0.1 μm or less to 10 μm or more, more preferably from about 0.2, 0.3 μm. , 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 pm to about 1 .0, 1 .5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, or 9.5 pm. The pharmaceutically acceptable carriers for pulmonary administration of zosuquidar and / or the caliqueamicin-antibody conjugate include carbohydrates such as trehalose, mannitol, xylitol, sucrose, lactose, and sorbitol. Other ingredients for use in formulations may include dipalmitoylphosphatidylcholine (DPPC), 1,2-sn-dioleoylphosphatidylcholine (DOPE), disteroylphosphatidylcholine (DSPC), and dioleoylphosphatidyl choline (DOPC). Natural or synthetic surfactants can be used, including polyethylene glycol and dextrans, such as cyclodextran. Bile salts and other related improvers can also be used, as well as cellulose and cellulose derivatives, and amino acids. Liposomes, microcapsules, microspheres, inclusion complexes, and other types of carriers can also be used. Pharmaceutical formulations suitable for use with a nebulizer, either jet or ultrasonic, commonly contain the zosuquidar and / or the calicheamicin-antibody conjugate dissolved or suspended in water at a concentration of about 0.01 mg or less up to 1000 mg or more of each of zosuquidar and the caliqueamicin-antibody conjugate per mL of solution, preferably from about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg per mL of solution to about 1 5, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 mg per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for protein stabilization and osmotic pressure regulation). The nebulizer formulation may also contain a surfactant to reduce or prevent surface-induced aggregation of the zosuquidar and / or the Caliqueamicin-antibody conjugate produced by the atomization of the solution when forming the aerosol. Formulations for use with a metered dose inhaler device generally include a finely divided powder containing the active ingredients suspended in a propellant with the aid of a surfactant. The propellant may include conventional propellants, such as chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, and hydrocarbons. Preferred propellants include trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, 1,1,1-tetrafluoroethane, and combinations thereof. Suitable surfactants include sorbitan trioleate, soy lecithin, and oleic acid. Formulations suitable for dispensing from a powder inhaler device commonly contain a finely divided dry powder containing zosuquitar and / or the calicheamicin-antibody conjugate, optionally including a bulking agent, such as lactose, sorbitol, sucrose, mannitol, trehalose, or xylitol, in an amount that facilitates the dispersion of the powder from the device, commonly from about 1% by weight or less to 99% by weight or more of the formulation, preferably from about 5, 1, 5, 20, 25, 30, 35, 40, 45, or 50% by ! weight up to about 55, 60, 65, 70, 75, 80, 85, or 90% by weight of the formulation. When zosuquidar and / or caliqueamicin-antibody conjugate are administered by intravenous, cutaneous injection, subcutaneous, parenteral, or other injection, preferably are in the form of aqueous or oleaginous solutions parenterally, pyrogen-free. The suspensions may be formulated according to methods well known in the art using suitable dispersing or wetting agents and suspending agents. The preparation of acceptable aqueous solutions with appropriate pH, isotonicity, stability, and the like is within the skill of the art. A preferred pharmaceutical composition for injection preferably contains an isotonic vehicle such as 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 such as those known in the art. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, any soft fixed oil, including synthetic monoglycerides and diglycerides, may be employed. In addition, fatty acids such as oleic acid can also be used in the preparation of injectable preparations. The pharmaceutical compositions may also contain stabilizers, preservatives, buffers, antioxidants, and other additives known to those skilled in the art. The duration of the injection can be adjusted depending on various factors, and may include a single injection administered over the course of a few seconds or less to 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 0 1 1, 1 2, 1 3, 1 4, 1 5, 1 6, 1 7, 1 8, 1 9, 20, 21, 22, 23, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, 54, 60, 66, 72, 78, 84, 90, or 96 hours or more of continuous intravenous administration. The zosuquidar and / or the caliqueamicin-antibody conjugate can be administered systemically or locally, by means of a liquid or gel, or as an implant or device. The compositions of the preferred embodiments may additionally employ adjunct components that are conventionally found in pharmaceutical compositions in their established form in the art and at their established levels in the art. Thus, for example, the compositions may also contain compatible pharmaceutically active materials for combination therapy (such as complementary P-gp inhibitors, chemotherapeutic agents, and the like), or may contain materials useful for the physical formulation of various dosage forms of the preferred modalities, such as excipients, colorants, perfumes, thickening agents, stabilizers, preservatives and antioxidants. The zosuquidar and / or the caliqueamicin-antibody conjugate can be provided to a doctor or other health professional who will administer it in the form of a kit. The kit is a package that houses one or more containers containing zosuquidar and / or the calicheamicin-antibody conjugate in appropriate form and instructions for administering the pharmaceutical composition to a subject. The case may optionally also contain one or more additional therapeutic agents. The kit may optionally contain one or more diagnostic tools and instructions for use, for example, a diagnosis to measure efflux pump activity or P-gp expression or function. For example, a kit comprising a single composition containing zosuquidar and / or the calicheamicin-antibody conjugate may be provided in combination with one or more additional therapeutic agents, or separate pharmaceutical compositions containing zosuquidar, the calicheamicin-antibody conjugate may be provided. , and additional therapeutic agents. The kit may also contain separate doses of zosuquidar and / or the caliqueamicin-antibody conjugate for serial or sequential administration. The kit may contain appropriate delivery devices, for example, syringes, devices for inhalation, and the like, together with instructions for administering zosuquidar and / or the calicheamicin-antibody conjugate and any other therapeutic agent. The kit may optionally contain instructions for storage, reconstitution (if applicable) and administration of any or all of the therapeutic agents included. The kits may include a plurality of containers that reflect the amount of administrations that are to be provided to a subject. In a particularly preferred embodiment, a kit is provided for the treatment of AM L which includes zosuquidar and the caliqueamicin-antibody conjugate and instructions for administer each one. In another particularly preferred embodiment, a kit for the treatment of AML including zosuquidar and one or more diagnostics or instructions for performing one or more diagnostics is provided to determine the expression and / or efflux pump activity of P-gp. The kit can also include instructions, an analysis, and / or a diagnosis to determine if a patient has AML. The zosuquidar and the calicheamicin-antibody conjugate can be administered to a patient having a leukemia, a solid tumor, or other malignancy. It is particularly preferred to administer the combination when the expression of P-gp is positive, or to use the combination in the treatment of a malignancy showing expression or function of P-gp. Cancer targets that show an expression of P-gp > 50% of patients are particularly preferred for treatment by combinations of preferred modalities. The dose regimens described below for AML may also be appropriate for the treatment of other leukemias, solid tumors, bladder cancer, pancreatic cancer, liver cancer, myeloma, carcinomas (e.g., breast cancer and ovarian cancer), sarcomas, and other hematologic malignancies (eg, acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, myelodysplasia). Treatment of Acute Myeloquine Leukemia Zosuquidar and caliqueamicin-antibody conjugate can be administered to patients suffering from leukemia, tumors solid, or other malignancies before confirmation of the expression or function of P-gp, or to patients with AML other than patients with relapse of AML. However, the therapy is preferably administered to newly diagnosed patients or in combination with or sequentially after chemotherapy in patients with AML relapse. The route of administration, amount administered, and frequency of administration may vary depending on the patient's age, condition of patient with relapse of AML or not previously treated, and severity of the condition. The contemplated amounts of the calicheamicin-antibody conjugate for intravenous administration to treat relapse of AML are from about 10 mg / day or less to about 1000 mg / day or more administered in one, two or more days separately. The dose is preferably administered intravenously at a rate of about 1 mg / m2 or less to about 10 mg / m2 or more continuously over the course of about 2, 3, or 4 hours to about 6, 7, 8, 9, 1 0, 1 1, 12, 1 3, 14, 1 5, 16, 1 7, 1 8, 1 9, 20, 21, 22, 23, or 24 hours, more preferably in the course of about 2 hours to about 6 hours; however, administration at a rate of 5 mg / m2, 7 mg / m2, or 9 mg / m2 for about 2 hours is particularly preferred. Preferably, doses of the calicheamicin-antibody conjugate are administered on day 1 and day 1 5 of the treatment regimen. However, in some modalities, the second dose can be administered on day 5, 6, 7, 8, 9, 1 0, 1 1, 1 2, 1 3, 14, 1 6, 1 7, 1 8, 1 9, 20, 21, or 22, or another day of the treatment regimen. Other dosage regimens include administering a total of three doses during a week. Preferably, the calicheamicin-antibody conjugate is Mylotarg. Other calicheamicin-antibody conjugates include calicheamicin conjugates with any appropriate P-gp substrate, as described herein above. The contemplated amounts of zosuquidar for intravenous administration to treat relapse of AML are from about 400 mg / day or less to about 1,600 mg / day or more, preferably from about 500 or 600 mg / day to about 700, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 mg / day, and much more preferably from about 500 mg / day to about 800 mg / day. It is generally preferred to start the zosuquidar infusion from about 1 hour or less to about 6 hours or more before administration of the calicheamicin-antibody conjugate. In the course of a treatment regimen, zosuquidar is preferably administered in two, three, four or five days separately. The dose is preferably administered intravenously continuously over the course of about 6 to 90 hours, more preferably over the course of 6, 12, 1 8, 24, 30, 36, or 42 hours to about 54, 60, 66, 72 , 78, or 84 hours, much more preferably for approximately 24 hours, 48 hours, or 72 hours, depending on the regime of treatment. Preferably zosuquidar is administered on day 1 of the treatment regimen. In some modalities, more zosuquidar is given on day 2, days 2 and 3, or days 2, 1 5, and 1 6. However, in some modalities, one, two, or three or more additional doses may be administered in other days of the treatment regimen. Table 1 provides various dose regimens that you can use to treat relapse of AML. Table 1 .

* Only if level 1 has a dose-limiting toxicity (DLT). Tables 2 and 3 provide alternative dose regimens that can be used to treat relapse of AML.

Table 2 * Only if level 1 has a limiting toxicity of the PLT dose). AML relapse treatment A clinical study was conducted to determine the efficacy of Mylotarg in the treatment of relapse of AM L. It was determined that the complete remission index (CR + CRp) for patients negative to P-gp treated with Mylotarg was 64% (N = 36). In contrast, the complete remission index for P-gp positive patients was only 9% (N = 22). This indicates that the efflux of P-gp plays an important role in the survival rates for AML relapse, and further indicates that the inhibition of P-gp efflux, for example, by administering zosuquidar or another efflux inhibitor of P-gp, has the potential to significantly improve response rates in patients positive for P-gp. All references cited herein, including, but not limited to, published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and form a part of this specification. To the extent that publications and patents or patent applications incorporated by reference contradict the description contained in the specification, the specification shall prevail and / or take precedence over any of these contradictory materials. The term "comprises" as used herein is synonymous with "includes", "contains" or "is characterized by", and is inclusive or with open ends and does not exclude additional elements or method steps not listed. All numbers that express amounts of ingredients, reaction conditions and the like used in the specification should be understood as modified in all cases by the term "approximately." Agree with this, unless otherwise indicated, the numerical parameters set forth herein are approximations that may vary depending on the desired properties sought. Finally, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claim in any claim that claims priority over the present application, each numerical parameter must be interpreted in light of the number of significant digits and the approximation approach by ordinary rounding. The above description describes various methods and materials of the present invention. This invention is susceptible to modifications in methods and materials, as well as alterations in manufacturing methods and equipment. Such modifications will be apparent to those skilled in the art from a consideration of this description or of the practice of the invention described herein. Accordingly, it is not intended that this invention be limited to the specific embodiments described herein, but that it cover all modifications and alternatives that fall within the true scope and spirit of the invention.

Claims (9)

1. CLAIMS 1 . A method for treating Acute Myelogenous Leukemia, the method comprises administering to a patient in need thereof, zosuquidar and a caliqueamicin-antibody conjugate.
2. 2. The method of claim 1, further characterized in that Acute Myelogenous Leukemia is reappearance of Acute Myelogenous Leukemia.
3. The method of claim 2, further characterized in that the step of administering a patient in need thereof, zosuquidar and a calicheamicin-antibody conjugate includes: administering a calicheamicin-antibody conjugate intravenously to a patient, at a rate of about 5 mg / m2 in a period of time from about 1 hour to about 24 hours on day 1 of a treatment regimen; administering intravenously to a patient in an amount of about 500 mg / day to about 700 mg / day for approximately 24 hours on day 1 of the treatment regimen; administering the calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg / m2 for about 1 hour to about 24 hours on day 1 5 of a treatment regimen; and administering zosuquidar intravenously to a patient in an amount of 500 mg / day until approximately 700 mg / day for approximately 24 hours on day 1 5 of the treatment regimen.
4. 4. The method of claim 3, further characterized in that the calicheamicin-antibody conjugate is Mylotarg.
5. The method of claim 2, further characterized in that the step of administering a patient in need thereof, zosuquidar and a calicheamicin-antibody conjugate includes: administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of approximately 5 mg / m2 in a period of time from about 1 hour to about 24 hours on day 1 of a treatment regimen; administering intravenously to a patient in an amount of about 500 mg / day to approximately 700 mg / day for approximately 48 hours on days 1 and 2 of the treatment regimen; administering the calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg / m2 for about 1 hour to about 24 hours on day 1 5 of a treatment regimen; and administering intravenously to a patient in an amount of 500 mg / day to approximately 700 mg / day for approximately 48 hours on days 15 and 16 of the treatment regimen.
6. 6. The method of claim 5, further characterized in that the calicheamicin-antibody conjugate is Mylotarg.
7. 7. The method of claim 2, further characterized in that the step of administering to a patient in need thereof, zosuquidar and a calicheamicin-antibody conjugate includes: administering a calicheamicin-antibody conjugate intravenously to a patient, at a rate of about 7 mg / m2 for about 1 hour to about 24 hours on day 1 of a treatment regimen; administering intravenously to a patient in an amount of 500 mg / day to approximately 700 mg / day for approximately 48 hours on day 1 and day 2 of the treatment regimen; administering the calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg / m2 for about 1 hour to about 24 hours on day 1 5 of a treatment regimen; and administering intravenously to a patient in an amount of 500 mg / day to approximately 700 mg / day for about 48 hours on day 1 5 and day 1 6 of the treatment regimen.
8. 8. The method of claim 7, further characterized in that the calicheamicin-antibody conjugate is Mylotarg. The method of claim 2, further characterized in that the step of administering a patient in need thereof, zosuquidar and a calicheamicin-antibody conjugate includes: administering a calicheamicin-antibody conjugate via intravenously to a patient, at a rate of about 9 mg / m2 for about 1 hour to about 24 hours on day 1 of a treatment regimen; administering intravenously to a patient in an amount of 500 mg / day to approximately 700 mg / day for approximately 48 hours on day 1 and day 2 of the treatment regimen; administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 7 mg / m2 for about 1 hour to about 24 hours on day 1 5 of a treatment regimen; and administering intravenously to a patient in an amount of 500 mg / day to approximately 700 mg / day approximately 48 hours on day 1 and day 1 6 of the treatment regimen. The method of claim 9, further characterized in that the calicheamicin-antibody conjugate is Mylotarg. eleven . The method of claim 2, further characterized in that the step of administering to a patient in need thereof, zosuquidar and a calicheamicin-antibody conjugate includes: administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of approximately 9 mg / m2 for approximately 1 hour to approximately 24 hours on day 1 of a treatment regimen; administer zosuquidar intravenously to a patient in an amount of 500 mg / day to approximately 700 mg / day, for approximately 72 hours on days 1, 2 and 3 of the treatment regimen; administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 9 mg / m2 for about 1 hour to about 24 hours on day 1 5 of a treatment regimen; and administering intravenously to a patient in an amount of 500 mg / day to approximately 700 mg / day for about 72 hours on days 1, 5, 16 and 17 of the treatment regimen. The method of claim 1, further characterized in that the calicheamicin-antibody conjugate is Mylotarg. The method of claim 2, further characterized in that the step of administering to a patient in need thereof, zosuquidar and a calicheamicin-antibody conjugate includes: administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg / m2 to about 9 mg / m2 for about 1 hour to about 24 hours on day 1 of a treatment regimen; administering intravenously to a patient in an amount of about 500 mg / day to approximately 700 mg / day for approximately 24 to 72 hours beginning on day 1 of the treatment regimen; administering the calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg / m2 to about 9 mg / m2 for about 1 hour to about 24 hours on day 1 5 of a treatment regimen; and administering intravenously zosuquidar a patient in an amount of about 500 mg / day to about 700 mg / day for about 24 to 72 hours beginning on day 1 5 of the treatment regimen. The method of claim 13, further characterized in that the calicheamicin-antibody conjugate is Mylotarg. 1 5. A pharmaceutical kit for use in the treatment of recurrence of acute myelogenous leukemia, the kit includes: at least one dose of zosuquidar; indications for performing at least one diagnosis to determine if a patient exhibits at least one of: pump activity with positive efflux and positive P-gp expression or function; and indications for administering zosuquidar in combination with a calicheamicin-antibody conjugate to treat reoccurrence of Acute Myelogenous Leukemia in a patient showing at least one of: pump activity with positive efflux and positive P-gp expression or function. The pharmaceutical kit of claim 1, further characterized in that the calicheamicin-antibody conjugate is Mylotarg. 1 7. A method to treat a malignancy in a patient, the method comprises the steps of: performing a diagnostic test, by which it is determined that the malignancy expresses or selects glycoprotein P; and administering zosuquidar and a caliqueamicin-antibody conjugate to the patient. The method of claim 1, further characterized in that the malignancy is Acute Myelogenous Leukemia.
9. 9. The method of claim 17, further characterized in that the malignancy is reappearance of Myelogenous Leukemia. Sharp 20. The method of claim 1 7, further characterized in that the malignancy is a carcinoma. twenty-one . The method of claim 20, further characterized in that the carcinoma is breast cancer. 22. The method of claim 20, further characterized in that the carcinoma is ovarian cancer. 23. The method of claim 1 7, further characterized in that the malignancy is a sarcoma. The method of claim 17, further characterized in that the malignancy is a hematologic malignancy selected from the group consisting of acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, and myelodysplasia. 25. The method of claim 1, further characterized because the caliqueamicin-antibody conjugate is Mylotarg. 26. A method for treating a malignancy in a patient, the method comprising the steps of: performing a diagnostic examination, by which it is determined that the malignancy shows pump activity with positive efflux; and administering zosuquidar and a caliqueamicin-antibody conjugate to the patient. 27. The method of claim 26, further characterized in that the malignancy is Acute Myelogenous Leukemia. The method of claim 26, further characterized in that the malignancy is reappearance of Acute Myelogenous Leukemia. 29. The method of claim 26, further characterized in that the malignancy is a carcinoma. 30. The method of claim 29, further characterized in that the carcinoma is breast cancer. 31 The method of claim 29, further characterized in that the carcinoma is ovarian cancer. 32. The method of claim 26, further characterized in that the malignancy is a sarcoma. 33. The method of claim 26, further characterized in that the malignancy is a hematological malignancy selected from the group consisting of acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, and Myelodysplasia 34. The method of claim 26, further characterized in that the calicheamicin-antibody conjugate is Mylotarg.