MX2008002843A - Methods of using (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylam ino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-c arboxylic acid for treatment of cancer. - Google Patents

Abstract

Methods of treating, preventing or managing cancer, including certain leukernias are disclosed. The methods encompass the administration of enantiomerically pure (+)-l,4- dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-l-pyrrolidinyl]-4- oxo-l-(2-thiazolyl)-l,8- naphthyridine-3-carboxylic acid. Also provided are methods of treatment using this compound with chemotherapy, radiation therapy, hormonal therapy, biological therapy or immunotherapy. Pharmaceutical compositions and single unit dosage forms suitable for use in the methods are also disclosed.

Description

METHODS FOR USING ACID (+) -1, 4-DIHYDRO-7- [(3S, 4S) -3-METOXY-4- (METHYLAMINO) -1-PIRROLIDINYL] -4-OXO-1- (2-TIAZOLYL) - 1, 8- NAFTIRIDIN-3-CARBOXÍLICO FOR TREATMENT OF CANCER This request claims priority to the US Patent Applications Nos. 11 / 218,387 and 11 / 218,653, which were filed on September 2, 2005, [and now are converted to provisional US applications,] and to US Provisional Nos. 60 / 789,093 and 60 / 788,927, both filed on April 3, 2006 and 60 / 810,285, filed on June 1, 2006. All of these applications are incorporated in their entirety for reference. 1. FIELD Methods for treating, preventing, or managing cancer, including specific leukemias, are provided herein by administering (+) - 1, -dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) acid. Enantiomerically pure 1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxyl, which is also known as SNS-595 or AG-7352. Doses, dosing regimens and dosages for SNS-595 and its administration are also provided. 2. BACKGROUND SNS-595 is chemically named (+) - 1, 4-dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- ( 2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid, and has the following structure: The SNS-595 is known for its anti-tumor activity. The treatment of the following cancers with SNS-595 has been proposed in the literature: bladder cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, melanoma , myeloma, neuroblastoma (ie, CNS cancer), ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, sarcoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer and uterine cancer. Various dosage regimens have been reported, for example, see, US Patent Application Publication Nos. 2005-0203120; 2005-0215583 and 2006-0025437, of which all are incorporated herein by reference in their entirety. There continues to be a need for dosages and safe and effective dosing regimens to administer SNS-595 to treat, prevent and manage various cancers, including leukemias. 3. COMPENDIUM SNS-595 is a known cytotoxic agent with utility against various cancers. In the present we discuss novel methods of treatment, including the treatment of specific leukemias. In addition, single dose dosage ranges, regimens and pharmaceuticals are described. The treatment, prevention or management of cancer is described using SNS-595, pharmaceutical compositions thereof and its unique dosage. Generally, the types of cancers that can be treated, prevented or managed using the methods provided herein include, but are not limited to: bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer , cancer of the head and neck, liver cancer, lung cancer (small cell and non-small cell), melanoma, myeloma, neuroblastoma (ie, CNS cancer), ovarian cancer, pancreatic cancer, prostate cancer, cancer kidney, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, and uterine cancer. The cancer may be reoccurring, refractory or resistant to conventional therapy. In certain embodiments, the cancer includes hematologic malignancies, including, but not limited to, leukemias, lymphomas (Non-Hodgkin's Lymphoma), Hodgkin's disease (also called Hodgkin's Lymphoma), and myeloma. The various forms of leukemias include, but are not limited to, chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia. Leukemia can be repeated, refractory or resistant. In certain modalities, the hematologic malignancy is promyelocytic leukemia, T cell leukemia or lymphoblastic leukemia. Methods to treat, prevent or manage cancer are also provided by administering SNS-595 in a certain way. In a certain embodiment, the methods comprise administering to a mammal a dose of about 1 mg / m2 to 150 mg / m2, about 1 mg / m2 to 100 mg / m2, 1 mg / m2 to 75 mg / m2, 15 mg / m2 at 80 mg / m2 or approximately 3 mg / m2 at 24 mg / m2 of SNS-595, based on body surface area. In a certain embodiment, the methods comprise administering to a mammal a dose of approximately 15g / m2, 25g / m2 or 50 mg / m2 of SNS-595, based on the body surface area. The dosage and additional dosage regimens are described in greater detail herein in the following. The dosage and dosage regimens for solid cancers are also provided herein. The administered dose of SNS-595 can be delivered as a single dose such as, for example, a rapid IV injection of 10-15 minutes duration (eg, a single bolus injection) or over time such as, for example, a 24-hour period (eg, continuous infusion over time or divided bolus doses over time) and repeated as necessary, eg, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. In some modalities, SNS-595 can be administered cyclically to a patient. The therapy in cycles involves the administration of the active agent during a period of time, followed by a rest for a period of time and repeating this sequential administration. Cycle therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies and / or improve the effectiveness of the treatment. In another modality, the SNS-595 is administered in combination with another drug ("second active agent") or other therapy conventionally used to treat, prevent or manage cancer, or the SNS-595 dosage methods described herein may be applied in combination therapy schemes. The second active agents include known small molecule, anti cancer, antitumor or cytotoxic agents and large molecules (eg, proteins and antibodies), examples of which are provided herein, as well as stem cells or umbilical cord blood. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy, immunotherapy, blood transfusions and combinations thereof. Thus, in a certain embodiment, combinations for the treatment, prevention and management of solid tumors are provided herein. In another embodiment, combinations are provided for the treatment, prevention and management of leukemias and lympholas. Also provided are pharmaceutical compositions, unique unit dosage forms and dosage regimens, which comprise SNS-595, and a second or additional active agent. The second active agents include specific combinations, or "cocktails," of drugs or therapy or both. 4. BRIEF DESCRIPTION OF THE FIGURES FIGURE 1 represents the plasma concentrations of SNS-595 over time between the various groups of patients medicated in the qwk x3 program. FIGURE 2 illustrates the formation of nuclear foci in HCT116 cells after treatment with SNS-595, etoposide, bleomycin, and cisplatin; FIGURE 3 represents the quantification of foci when measuring the fluorescent intensity of the foci; FIGURE 4 illustrates the dose and time dependence of foci formation; FIGURE 5 shows cells with more than 2 foci as a function of time and concentration of SNS-595; FIGURE 6 illustrates DNA damage induced by SNS-595 and etoposide in the presence and absence of caffeine, which is an inhibitor of ATM and ATR. FIGURE 7 shows DNA damage induced by SNS-595 and etoposide in the presence (M059K cells) and absence (M059J cells) of DNA-PK; FIGURES 8a-c demonstrate a synergistic / additive effect of the co-dosing of SNS-595 with various cytotoxic agents on colon carcinoma HCT 116 cells; and FIGURE 8d demonstrates a synergistic / additive effect of the co-dosing of SNS-595 with various cytotoxic agents in H460 lung cancer cells; FIGURE 9 shows the combination index when the SNS-595 is dosed simultaneously with a selection of agents and antimetabolites that damage the DNA in the ovarian cancer cell line SK0V3 (+ / +) and (- / -) for the expression of p53, shown as black and gray diamonds, respectively; and FIGURES lOa-d demonstrate the effect of co-dosing of SNS-595 with various cytotoxic agents on colon carcinoma HCT 116 cells. FIGURE 11 provides the dose linearity of three weekly doses (qwk x3; circles = week 1; triangles = week 2) and doses once every three weeks (q3wk; diamonds) of SNS-595 in patients with advanced solid tumors. FIGURE 12 provides a comparison of the anti-tumor activities of SNS-595, etoposide, doxorubicin and irinotecan in the CCRF-CEM model of xenoinj ertos. FIGURE 13 provides a comparison of the anti-tumor activities of SNS-595 (at 20 mg / kg and 25 mg / kg), etoposide, doxorubicin and irinotecan in the LM3-Jck model of xenoinj ertos. FIGURE 14 shows cellularity in bone marrow 6 days after the initial injection of SNS-595 in female CD-1 mice. SNS-595 was administered on day 0 and day 4. All images are shown in an amplification lOx; FIGURE 15 provides the response of neutrophils to the dose of SNS-595; FIGURE 16 provides the neutrophil count at various doses of SNS-595 on day 8; FIGURE 17 provides the WBC count at various doses of SNS-595 on day 8; FIGURE 18 provides the platelet count at various doses of SNS-595 on day 8; FIG. 19 provides the percentage change in body weight at various time intervals after administering SNS-595; and FIGURE 20 shows the inversion of the effect on the bone marrow on day 12 after administering 20 mg / kg of SNS-595.

. DEFINITIONS Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published requests and other publications cited are incorporated for reference in their entirety. In the case where there is a plurality of definitions for a term in the present, those in this section prevail, unless otherwise stipulated. As used herein, (+) - 1, 4-dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- ( 2-thiazolyl) -1,8-naphthyridine-3-carboxylic enantiomerically pure is substantially free of (-) -1,4-dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) - 1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid (ie, in excess enantiomeric). In other words, the "(+)" form of 1,4-dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-l- ( 2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid is substantially free of the "(-)" form of the compound and, thus, is in enantiomeric excess of the form "(-)". The term "enantiomerically pure" or "pure enantiomer" denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight , more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight of the enantiomer. As used herein, and unless otherwise indicated, the term "(+) - 1, -dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) -1- acid pyrrolidinyl] -4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid enantiomerically pure "refers to at least about 80% by weight of (+) -1,4-dihydro- 7- [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid and at most about 20 % by weight of (-) -1,4-dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) acid -1,8-naphthyridine-3-carboxylic acid, at least about 90% by weight of (+) -1,4-dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) - 1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid and at most about 10% by weight of the (-) enantiomer, at least about 95% by weight of acid (+) -1,4-dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo- 1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid and at most about 5% by weight of the (-) enantiomer, at least about 97% by weight of (+) -1, -dihydro- 7- [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid and at most about 3 % by weight of the (-) enantiomer. As used herein, and unless otherwise indicated, the terms "treat," "treating," and "treatment" refer to alleviating or reducing the severity of a symptom associated with the disease or condition being treated. . The term "prevention" includes the inhibition of a symptom of the particular disease or disorder. In some modalities, patients with a family history of cancer are candidates for preventive regimens. Generally, the term "prevent" refers to the administration of the drug before the onset of symptoms, particularly for patients at risk of cancer. As used herein, and unless otherwise indicated, the term "driving" encompasses preventing the recurrence of the particular disease or disorder in a patient who has suffered from it, prolonging the time a patient remains in remission have suffered from the disease or disorder, reduce mortality rates of patients and / or maintain a reduction in severity or evasion of a symptom associated with the disease or condition being managed. As used herein, "subject" is an animal, typically a mammal, including a human, such as a patient. As used herein, the term "cancer" includes, but is not limited to, solid tumors and tumors of blood origin. The term "cancer" refers to the disease of skin tissues, organs, blood and vessels, including, but not limited to, cancers of the bladder, bone or blood, brain, breast, cervix, breast, colon, endometrium, esophagus, eye, head, kidney, liver, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testicles, throat and uterus. As used herein, "hematologic malignancy" refers to cancer of the blood formation system and the body's immune-bone marrow and lymphatic tissue. Such cancers include leukemias, lymphomas (Non-Hodgkin's Lymphoma), Hodgkin's disease (also called Hodgkin's Lymphoma) and myeloma. The term "leukemia" refers to malignant neoplasms of blood forming tissues. Leukemia includes, but is not limited to, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia and acute myeloblastic leukemia. The leukemia can be repeated, refractory or resistant to conventional therapy. As used herein, "promyelocytic leukemia" or "acute promyelocytic leukemia" refers to a malignancy of the bone marrow in which there is a deficiency of mature blood cells in the myeloid cell line and an excess of immature cells called promyelocytes. . It is usually marked by an exchange of parts of chromosomes 15 and 17. As used herein "acute lymphocytic leukemia (ALL)", also known as "acute lymphoblastic leukemia," refers to a malignant disease caused by the growth and abnormal development of white blood cells or premature non-granular lymphocytes. As used herein "T cell leukemia" refers to a disease in which certain cells of the lymphoid system, called T lymphocytes or T cells, are malignant. T cells are white blood cells that can normally attack cells infected with viruses, foreign cells and cancer cells, and produce substances that regulate the immune response. The term "recidivist" refers to a situation where patients who have had a remission of cancer after therapy have a return of cancer cells. The term "refractory or resistant" refers to a circumstance where patients, even after intensive treatment, have residual cancer cells in their body. As used herein, IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximum response in an assay that measures such a response. As used herein, and unless otherwise specified, the terms "therapeutically effective amount" and "effective amount" of a compound refer to an amount sufficient to provide a therapeutic benefit in the treatment, prevention and / or management of a disease, to delay or minimize one or more symptoms associated with the disease or disorder being treated. The terms "therapeutically effective amount" and "effective amount" may encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of the disease or disorder, or increases the therapeutic efficacy of another therapeutic agent. As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salt" includes, but is not limited to, salts of acidic or basic groups that may occur in the compounds provided herein. Under certain acidic conditions, the compound can form a wide variety of salts with various inorganic and organic acids. Acids which can be used to prepare pharmaceutically acceptable salts of such basic compounds are those which form salts comprising pharmacologically acceptable anions including, but not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate , chloride, bromide, iodide, citrate, dihydrochloride, edetate, edisilate, stellate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylaminosanilate, hexylresorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate , muscato, napsilate, nitrate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide and pamoate. Under certain basic conditions, the compound can form base salts with various pharmacologically acceptable cations. Non-limiting examples of such salts include alkali metal or alkali metal metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium and iron salts. As used herein and unless otherwise indicated, the term "hydrate" means a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. As used herein and unless otherwise indicated, the term "solvate" means a solvate formed from the association of one or more solvent molecules with a compound provided herein. The term "solvate" includes hydrates (eg, monohydrate, dihydrate, trihydrate, tetrahydrate and the like). The terms "co-administration" and "in combination with" include the administration of two therapeutic agents (eg, SNS-595 and another agent against cancer or second agent) in a manner that is either simultaneous, concurrent or sequential with nonspecific limits of time. . In one embodiment, both agents are present in the cell or in the patient's body at the same time, or exert their biological or therapeutic effect at the same time. In one embodiment, the two therapeutic agents are in the same composition or unit dosage form. In another embodiment, the two therapeutic agents are in separate compositions or dosage unit forms. The term "symptomatic care agent" refers to any substance that treats, prevents or manages an adverse effect of treatment with SNS-595. 6. DETAILED DESCRIPTION 6. 1 SNS-595 The compound, for use in the methods and compositions provided herein, is (+) - 1, -dihydro-7- [(3S, S) -3-methoxy-4- (methylamino) - 1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid enantiomerically pure, which is also known as SNS-595 or AG-7352. The SNS-595 has the following chemical structure: In certain embodiments, pharmaceutically acceptable salts, solvates, hydrates or prodrugs of SNS-595 are used in the methods and compositions provided herein. SNS-595 can be prepared by methods known to one skilled in the art, for example, according to the preparation procedure for Example Cl of US Patent No. 5,817,669, entitled "Compounds, processes for the preparation of and agents against tumors, "issued October 6, 1998, and in Japanese Patent Application No. Hei 10-173986, to Chikugi et al., both of which are incorporated herein by reference in their entirety. Certain exemplary pharmaceutical compositions comprising SNS-595, and methods for using same, are described in US Patent Application Publication Nos. 2005-0203120; 2005-0215583 and 2006-0025437, of which all are incorporated herein by reference in their entirety. 6. 2 METHODS OF USE Proliferating cells are subjected to four phases of the cell cycle: d, S, G2 and M. These phases were first identified by observing dividing cells as the cells progressed through DNA synthesis; which came to be known as the synthesis phase or S of the cell cycle and mitosis and is known as the mitotic phase or M or S phase of the cell cycle. The gaps observed in the time between the completion of DNA synthesis and mitosis, and between mitosis to the next cycle of DNA synthesis are like phases Gl and G2 with all due respect. Non-proliferating cells, which retain the ability to proliferate under the appropriate conditions, are inactive or in the Go state and are typically characterized by having left the cell cycle. SNS-595 is a cell cycle inhibitor and stops cells in the G2 interface. Without being limited by a particular theory, SNS-595 mediates the activation of the DNA-PK pathway, which eventually leads to apoptotic cell death. These events are specific to the S phase, that is, they occur only during the S phase of the cell cycle. Unrestrained by a particular theory, treatment with SNS-595 results in an increase in the number of double-stranded DNA breaks that are formed during S phase. This damage blocks the cell's ability to synthesize DNA and prolongs time that the cell consumes in the S phase. Once the DNA damage is detected in the cells, markers for apoptosis quickly appear. This rapid onset of apoptosis appears to be dependent on p73, as shown by a more than 11-fold decrease in sensitivity to SNS-595 in cells bypassed in p73, compared to cells containing p73. As exemplified by FIGURE 7, the formation of active double-strand breaks, in a dose-dependent manner, repair mediated by DNA-PK and the apoptotic cell machinery including, but not limited to: i) DNA-PK expression; ii) phosphorylation of H2AX; iii) phosphorylation of c-Abl; iv) phosphorylation of p53; v) phosphorylation of p73; vi) expression of p21; vii) activation of caspase 9; and viii) activation of caspase 3. When DNA damage is sufficiently severe, so that double-stranded breaks can not be repaired through association of non-homologous ends (NHEJ), the cell rapidly enters apoptosis. Some cells are able to reach the G2 phase but are subsequently stopped (mediated by cdc2 / cyclin B) since the cells are too damaged to enter the M phase and eventually also become apoptotic. Without being limited by a particular theory, given that SNS-595 is selective for S phase, the doses of SNS-595 that are cytotoxic for proliferating cells (which are thus progressing through the cell cycle, including the phase S) are not lethal for non-proliferating cells. 6. 2.1 Solid Tumors Accordingly, methods for treating, managing or preventing cancers are provided herein, which comprise administering a dose of about 1 mg / m2 to about 100 mg / m2 of SNS-595 to a mammal in need of such treatment, management or prevention. Types of cancer include, but are not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, cancer of the head and neck, liver cancer, lung cancer (from small cell and non-small cell), melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), stomach cancer, cancer testicular, thyroid cancer and uterine cancer. In one embodiment, methods include treating, preventing, or managing colon, pancreatic, breast, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, melanoma, nasopharyngeal, neuroendocrine, ovarian, renal, salivary gland, small cell lung, or cell carcinoma cancers. fusiform 6. 2.2 Leukemias In one embodiment, the methods provided herein encompass treating, preventing or managing various types of leukemias, such as chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia and acute myeloblastic leukemia. In some embodiments, methods include treating, preventing or managing acute leukemia, such as AML, which includes, but is not limited to, undifferentiated AML, myeloblastic leukemia (Mi), myeloblastic leukemia (M2), promyelocytic leukemia (M3). or variant M3 [M3V]), myelomonocytic leukemia (M4 or variant M4 with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (? ß), megakaryoblastic leukemia (M7). In some modalities, acute lymphocytic leukemia (ALL) includes leukemia that originates in the blastocyst of the bone marrow (B cells), thymus (T cells), and lymph nodes. Acute lymphocytic leukemia is classified into categories according to the Franco-American-British Morphological Classification Scheme (FAB) as Ll - lymphoblasts that appear mature (T cells or pre B cells), L2 - Immature and pleomorphic lymphoblasts (shaped in a manner diverse) (T cells or pre B cells) and L3 - lymphoblasts (B cells, Burkitt cells). In one embodiment, acute myelogenous leukemia is undifferentiated AML (MO).

In one modality, acute myelogenous leukemia is myeloblastic leukemia (MI). In one modality, acute myelogenous leukemia is myeloblastic leukemia (M2). In one embodiment, acute myelogenous leukemia is promyelocytic leukemia (M3 or M3 variant [M3V]). In one modality, acute myelogenous leukemia is myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]). In one embodiment, acute myelogenous leukemia is monocytic leukemia (M5). In one modality, acute myelogenous leukemia is erythroleukemia (M6). In one modality, acute myelogenous leukemia is megakaryoblastic leukemia (M7). In one embodiment, acute lymphocytic leukemia originates in the blastocyst of the bone marrow (B cells). In one embodiment, acute lymphocytic leukemia originates in the thymus (T cells). In one modality, acute lymphocytic leukemia originates in the lymph nodes. In one modality, acute lymphocytic leukemia is type Ll, characterized by lymphoblasts that appear mature (T cells or pre B cells). In one modality, acute lymphocytic leukemia is type L2, characterized by immature and pleomorphic lymphoblasts (shaped in different ways). (T cells or pre B cells) In one embodiment, acute lymphocytic leukemia is type L3, characterized by lymphoblasts (B cells, Burkitt cells) In certain embodiments, acute myelogenous leukemia is promyelocytic leukemia or lymphoblastic leukemia. In certain modalities, acute lymphocytic leukemia is T-cell leukemia., methods provided herein encompass methods to treat, prevent or manage promyelocytic leukemia, T-cell leukemia or lymphoblastic leukemia. In one embodiment, T-cell leukemia is peripheral T-cell leukemia, T-cell lymphoblastic leukemia, cutaneous T-cell leukemia, and adult T-cell leukemia. In some embodiments, SNS-595 is used to treat drug-resistant leukemias, such as chronic myelogenous leukemia (CML). In this way, treatment with SNS-595 can provide an alternative for patients who do not respond to other treatment methods. In some embodiments, such other methods of treatment include treatment with Gleevac®. In some embodiments, methods of treating Philadelphia chromosome positive chronic myelogenous leukemia (Ph + CML) are provided herein. In some embodiments, methods of treating Philadelphia-positive chronic myelogenous leukemia (Ph + CML) resistant to Gleevac® are provided herein. The methods provided herein encompass treating patients who have previously been treated for cancer, but who are not sensitive to standard therapies, as well as those who have not been previously treated. Methods for treating patients regardless of the patient's age are also covered, although some diseases or disorders are more common in certain age groups. In addition methods are provided for treating patients who have undergone surgery in an attempt to treat the disease or condition in question, as well as those who have not. Since patients with cancer have heterogeneous clinical manifestations and variable clinical consequences, the treatment given to a patient may vary, depending on their prognosis. The experienced clinician will be able to easily determine, without undue experimentation, the specific secondary agents, types of surgery and types of standard non-drug therapy that can be effectively used to treat an individual patient with cancer. The administered dose of SNS-595 can be delivered as a single dose such as, for example, a rapid IV injection of 10-15 minutes duration (eg, a single bolus injection) or over time such as, for example, a 24-hour period (eg, continuous infusion over time or divided bolus doses over time) and repeated as necessary, eg, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. For example, stable disease, for solid tumors, generally means that the perpendicular diameter of the lesions that can be measured has not increased by 25% or more since the last measurement. See, for example, Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92 (3): 205-216 (2000). Stable disease, or lack of it, is determined by methods known in the art, such as evaluation of the patient's symptoms, physical examination, visualization of the tumor from which images have been acquired using X-ray, CAT, PET scanning. or MRI and other commonly accepted modalities of evaluation. In another embodiment, the dose is approximately 10 mg / m2- 100 mg / m2. In another embodiment, the dose is approximately 30 mg / m2-75 mg / m2. In another embodiment, the dose is approximately 40 mg / m2-80 mg / m2. In another embodiment, the dose is approximately 50 mg / m2- 90 mg / m2. In another embodiment, the dose is approximately 15 mg / m2-80 mg / m2. In another embodiment, the dose is approximately 20 mg / m2-30 mg / m2. In another embodiment, the dose is approximately 25 mg / m2- 35 mg / m2. In another embodiment, the dose is approximately 40 mg / m2- 50 mg / m2. In another embodiment, the dose is approximately 45 mg / m2- 55 mg / m2. In another embodiment, the dose is approximately 50 mg / m2- 60 mg / m2. In another modality, the dose is approximately 55 mg / m2- 65 mg / m2. In another embodiment, the dose is approximately 60 mg / m2-70 mg / m2. In another embodiment, the dose is approximately 65 mg / m2-75 mg / m2. In another embodiment, the dose is approximately 70 mg / m2-80 mg / m2. In another embodiment, the dose is approximately 75 mg / m2-85 mg / m2. In another embodiment, the dose is approximately 80 mg / m-90 mg / m2. In another embodiment, the dose is approximately 85 mg / m2-95 mg / m2. In another embodiment, the dose is approximately 90 mg / m2- 100 mg / m2. In other embodiments, SNS-595 is administered in combination with another drug ("second active agent") or another therapy to treat, manage or prevent cancer. The second active agents include small molecules and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells or umbilical cord blood. The methods or therapies that may be used in combination with the administration of an SNS-595 include, but are not limited to, surgery, immunotherapy, biological therapy, radiation therapy and other non-drug-based therapies currently used to treat, prevent or manage cancer. Various dosage regimens for the administration of SNS-595 alone and / or in combination therapy are discussed herein. Pharmaceutical compositions (e.g., unique unit dosage forms) that can be used in the methods described herein are also provided. Particular pharmaceutical compositions comprise SNS-595 and a second active agent. 6. 3 DOSAGE AND DOSAGE REGIMES In one embodiment, methods for treating, preventing or managing cancers, provided herein, comprise administering to a patient, on the basis of body surface area, a dose of about 1 mg / m2 to 150. mg / m2 of SNS-595. In another embodiment, the methods comprise administering a dose of about 1 mg / m2 to 100 mg / m2 of SNS-595. In another embodiment, the methods comprise administering a dose of about 1 mg / m2 to 75 mg / m2 of SNS-595. In another embodiment, the methods comprise administering a dose of about 1 mg / m2 to 60 mg / m2 of SNS-595. In another embodiment, the methods comprise administering a dose of about 1 mg / m2 to 50 mg / m2 of SNS-595. In another embodiment, the methods comprise administering a dose of about 1 mg / m2 to 48 mg / m2 of SNS-595. In another embodiment, the methods comprise administering a dose of about 1 mg / m2 to 24 mg / m2 of SNS-595-. In another embodiment, the methods comprise administering a dose of about 3 mg / m2 to 27 mg / m2 of SNS-595 based on the body surface area. In another embodiment, the methods comprise administering a dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 based on the body surface area. In another embodiment, the methods comprise administering a dose of about 10 mg / m2 to 90 mg / m2 of SNS-595 based on the body surface area. In another embodiment, the methods comprise administering a dose of about 15 mg / m2 to 80 mg / m2 of SNS-595 based on the body surface area. Calculations of body surface area can be calculated, for example, with the osteller formula where: BSA (m2) = square root of [(height (cm) x weight (kg) / 3600]. is 3 mg / m2 to 24 mg / m2 based on the body surface area In another modality, the dose is 3 mg / m2 to 18 mg / m2 based on the body surface area. is 3 mg / m2 to 15 mg / m2 In another modality, the dose is 1 mg / m2, 2 mg / m2, 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 30 mg / m2, 36 mg / m2, 42 mg / m2, 48 mg / m2, 50 mg / m2, 55 mg / m2, 60 mg / m2 or 65 mg / m2 based on body surface area In another modality, the dose is 3 mg / m2, 6 mg / m2, 9 mg / m2, 12 mg / m2, 15 mg / m2, 18 mg / m2, 21 mg / m2 24 mg / m2, 25 mg / m2, 27 mg / m2, 36 mg / m2, 48 mg / m2 or 50 mg / m2. In one embodiment, the dose is 15 mg / m2 based on the body surface area. In another embodiment, the dose is 25 mg / m2 based on the body surface area. In another embodiment, the dose is 30 mg / m2 based on the body surface area. In one embodiment, the dose is 50 mg / m2 based on the body surface area. In another embodiment, the dose is 15 mg / m2 to 80 mg / m2 based on the body surface area. In another embodiment, the dose is 15 mg / m2 to 75 mg / m2 based on the body surface area. In another embodiment, the dose is 20 mg / m2 to 65 mg / m2. In another embodiment, the dose is 30 mg / m2 to 50 mg / m2. In another modality, the dose is 15 mg / m2, 20 mg / m2, mg / m2, 30 mg / m2, 35 mg / m2, 40 mg / m2, 45 mg / m2, 50 mg / m2, 55 mg / m2, 60 mg / m2, 65 mg / m2, 70 mg / m2, 75 mg / m2 or 80 mg / m2 based on body surface area.

The administered dose of SNS-595 can be expressed in units other than mg / m2. For example, the doses can be expressed as mg / kg. Someone with ordinary skill in the art can easily know how to convert doses from mg / m2 to mg / kg to give the height or weight or both of a subject (see, http: /// www. Fda.gov/cder/cancer/ animalframe.htm). For example, a dose of 1 mg / m2 to 30 mg / m2, for a 65 kg human, is approximately equal to 0.026 mg / kg to 0.79 mg / kg. In another example, a dose of 3 mg / m2, for a human of 65 kg, is approximately equal to 0.078 mg / kg. In another example, a dose of 15 mg / m2 to 80 mg / m2, for a 65 kg human, is approximately equal to 0.39 mg / kg to 2.11 mg / kg. In certain embodiments, the administered dose of SNS-595 may be delivered as a single dose such as, for example, a rapid IV injection of 10-15 minutes in duration (eg, a single bolus IV injection) or in the course of time such as, for example, a 24-hour period (eg, continuous infusion over time or divided bolus doses over time) and repeated as necessary, eg, until the patient experiences a stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. Stable disease, or lack of it, is determined by methods known in the art, such as evaluation of the patient's symptoms, physical examination and other commonly accepted modalities of evaluation. The amount of the pharmaceutical composition, administered according to the methods provided herein, will depend on the mammal being treated, the severity of the disorder or symptom of the disorder, the manner of administration, the frequency of administration and the judgment of the attending physician. recipe. In some embodiments, the frequency of administration is in the range of about one daily dose to about one monthly dose. In certain modalities, administration is once a day, once every two days, twice a week, once a week, once every two weeks, once every three weeks or once every four weeks. In one embodiment, the pharmaceutical composition provided herein is administered on a weekly basis. In certain modalities, SNS-595 is administered in a cyclic manner to a patient. Cycle therapy involves the administration of an active agent over a period of time, followed by a break for a period of time, and repeating this sequential administration. Cycle therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improve the effectiveness of the treatment.

Consequently, in one embodiment, SNS-595 is administered weekly in single doses or divided into a cycle of three to six weeks with a rest period of about 1 to about 30 days. In another modality, SNS-595 is administered weekly in single or divided doses for one week, two weeks, three weeks, four weeks, five weeks or six weeks with a rest period of 1, 3, 5, 7, 9, 12, 14, 16, 18, 20, 22, 24, 26, 28, 29 or 30 days. In some modalities, the waiting period is 14 days. In some modalities, the waiting period is 28 days. In one modality, the waiting period is until there is sufficient recovery of the bone marrow. The frequency, number and length of the dosing cycles can be increased or decreased. In this way, another modality covers the administration of SNS-595 for more cycles than those typical when administered alone. In one embodiment, methods provided herein comprise: i) administering a dose of about 1 mg / m2 to 150 mg / m2 of SNS-595 to a patient; ii) wait a period of at least one day where the mammal is not administered any SNS-595; and iii) administer another dose of approximately 1 mg / m2 to 150 mg / m2 of SNS-595 to the patient. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the method comprises administering a dose of 1 mg / m2- 100 mg / m2 in steps i) and iii). In one embodiment, for example, in methods for treating certain leukemias, methods provided herein comprise: i) administering a dose of about 10 mg / m2-150 mg / m2 of SNS-595 to a mammal; ii) wait a period of at least one day where the mammal is not administered any SNS-595; iii) administer another dose of approximately 10 mg / m2-150 mg / m2 of SNS-595 to the mammal; and, iv) repeating steps ii) -iii) a plurality of times. In another embodiment, the method comprises administering a dose of 10 mg / m2- 100 mg / m2 in steps i) and iii). In one embodiment, methods provided herein comprise: i) administering a dose of about 1 mg / m2 to 75 mg / m2 of SNS-595 to a patient; ii) wait a period of at least one day where the mammal is not administered any SNS-595; and iii) administer another dose of approximately 1 mg / m2 to 75 mg / m2 of SNS-595 to the patient. In one embodiment, steps ii) -iii) are repeated a plurality of times. In one embodiment, methods provided herein comprise: i) administering a dose of about 1 mg / m2 to 48 mg / m2 of SNS-595 to a patient; ii) wait a period of at least one day where the mammal is not administered any SNS-595; and iii) administer another dose of approximately 1 mg / m2 to 48 mg / m2 of SNS-595 to the patient. In one embodiment, steps ii) -iii) are repeated a plurality of times. In one embodiment, the methods provided herein comprise: i) administering a dose of about 1 mg / m2 to 24 mg / m2 of SNS-595 to a patient; ii) wait a period of at least one day where the mammal is not administered any SNS-595; and iii) administer another dose of approximately 1 mg / m2 to 24 mg / m2 of SNS-595 to the patient. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the method comprises administering a dose of about 3 mg / m2 to 24 mg / m2 in steps i) and iii). In yet another embodiment, the method comprises administering a dose of about 15 mg / m2 in steps i) and iii). In yet another embodiment, the method comprises administering a dose of about 1 mg / m2 to 40 mg / m2, about 1.5 mg / m2 to 30 mg / m2, about 2 mg / m2 to 25 mg / m2 or about 3 mg / m2 at 24 mg / m2 in stages i) and iii). In another embodiment, the method comprises administering a dose of about 15 mg / m2 to 80 mg / m2 in steps i) and iii). Still in another modality, the method comprises administering a dose of about 15 mg / m2 to 75 mg / m2 in steps i) and iii). In still another embodiment, the method comprises administering a dose of about 20 mg / m2 to 65 mg / m2, about 30 mg / m2 to 50 mg / m2, about 35 mg / m2, about 40 mg / m2 or about 45 mg / m2. m2 in stages i) and iii). In the above methods, for example, if the waiting period is 6 days, then the initial dose of SNS-595 is administered on Day 1 (stage i); the waiting period is six days (stage ii); and the next dose of SNS-595 is administered on Day 8 (step iii). Other exemplary periods of time include 2 days, 3 days, 5 days, 7 days, 10 days, 12 days, 13 days, 14 days, 15 days, 17 days, 20 days, 27 days, and 28 days. In another modality, the waiting period is at least 2 days and stages ii) to iii) are repeated at least three times. In another modality, the waiting period is at least 3 days and stages ii) to iii) are repeated at least five times. In another modality, the waiting period is at least 3 days and stages ii) to iii) are repeated at least three times. In another modality, the waiting period is at least 3 days and stages ii) to iii) are repeated at least five times. In another modality, the waiting period is at least 6 days and stages ii) to iii) are repeated at least three times. In another modality, the waiting period is at least 6 days and stages ii) to iii) are repeated at least five times. In another modality, the waiting period is at least 14 days and stages ii) to iii) are repeated at least three times. In another modality, the waiting period is at least 20 days and stages ii) to iii) are repeated at least three times. In another modality, the waiting period is at least 20 days and stages ii) to iii) are repeated at least five times. In another modality, the waiting period is at least 28 days and stages ii) to iii) are repeated at least three times. In another modality, the waiting period is at least 27 days and stages ii) to iii) are repeated at least five times. In another modality, the waiting period is at least 28 days and stages ii) to iii) are repeated at least five times. In another embodiment, the dosage method comprises administering a dose of SNS-595 twice a week (dosing on days 1, 4, 8 and 11) to a mammal. In another embodiment, the dosage method comprises administering a weekly dose of SNS-595 to a mammal. In another embodiment, the dosage method comprises administering a dose of SNS-595 to a mammal every two weeks. In another embodiment, the dosage method comprises administering a dose of SNS-595 to a mammal every three weeks. In another embodiment, the dosage method comprises administering a dose of SNS-595 to a mammal every four weeks.

In another embodiment, the dosing method comprises a cycle wherein the cycle comprises administering a dose of SNS-595 to a mammal once a week for three weeks, followed by a period of at least 14 days where SNS is not administered. -595 to the mammal and wherein the cycle is repeated a plurality of times. In another modality, the period where SNS-595 is not administered is 14 days. In another modality, the period where SNS-595 is not administered is 21 days. In another embodiment, the methods provided herein comprise: i) administering a dose of about 1 mg / m2 to 100 mg / m2 of SNS-595 to a mammal once a week for 3 weeks; ii) wait for a period of 14 days where the mammal is not administered any SNS-595; and iii) administering another dose of about 1 mg / m2 to 100 mg / m2 of SNS-595 to the mammal once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 1 mg / m2 to 75 mg / m2 of SNS-595 to a mammal once a week for 3 weeks; ii) wait for a period of 14 days where the mammal is not administered any SNS-595; and iii) administer another dose of approximately 1 mg / m2 to 75 mg / m2 of SNS-595 to the mammal once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 1 mg / m2 to 60 mg / m2 of SNS-595 to a mammal once a week for 3 weeks; ii) wait for a period of 14 days where the mammal is not administered any SNS-595; and iii) administer another dose of approximately 1 mg / m2 to 60 mg / m2 of SNS-595 to the mammal once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 1 mg / m2- 50 mg / m2 of SNS-595 to a mammal once a week for 3 weeks; ii) wait for a period of 14 days where the mammal is not administered any SNS-595; iii) administer another dose of approximately 1 mg / m2- 50 mg / m2 of SNS-595 to the mammal once a week for 3 weeks; and, iv) repeating steps ii) -iii) a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 1 mg / m2 to 48 mg / m2 of SNS-595 to a mammal once a week for 3 weeks; ii) wait for a period of 14 days where the mammal is not administered any SNS-595; and iii) administer another dose of approximately 1 mg / m2 to 48 mg / m2 of SNS-595 to the mammal once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 1 mg / m2 to 24 mg / m2 of SNS-595 to a mammal once a week for 3 weeks; ii) wait for a period of 14 days where the mammal is not administered any SNS-595; and iii) administering another dose of about 1 mg / m2 to 24 mg / m2 of SNS-595 to the mammal once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 2 mg / m2 to 40 mg / m2 of SNS-595 to a mammal once a week for 3 weeks; ii) wait for a period of 14 days where the mammal is not administered any SNS-595; and iii) administering another dose of about 2 mg / m2 to 40 mg / m2 of SNS-595 to the mammal once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to a mammal once a week for 3 weeks; ii) wait for a period of 14 days where the mammal is not administered any SNS-595; and iii) administer another dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to the mammal once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to a mammal once a week for 3 weeks (eg, dosing in the days 1, 8 and 15); ii) wait for a period of at least 28 days where the mammal is not administered any SNS-595; and iii) administer another dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to the mammal once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to a mammal twice a week for 2 weeks (dosing on days 1, 4, 8 and 11); ii) wait for a period of at least 28 days where the mammal is not administered any SNS-595; and iii) administer another dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to the mammal twice a week for 2 weeks (dosing on days 1, 4, 8 and 11). In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to a mammal once a week for 3 weeks (eg, dosing in the days 1, 8 and 15); ii) wait for a period of 28 days where the mammal is not administered any SNS-595; and iii) administer another dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to the mammal once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to a mammal twice a week for 2 weeks (dosing on days 1, 4, 8 and 11); ii) wait for a period of 28 days where the mammal is not administered any SNS-595; and iii) administer another dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to the mammal twice a week for 2 weeks (dosing on days 1, 4, 8 and 11). In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 15 mg / m2 to 80 mg / m2 of SNS-595 to a mammal once a week for 3 weeks; ii) wait for a period of 14 days where the mammal is not administered any SNS-595; and iii) administering another dose of approximately 15 mg / m2 to 80 mg / m2 of SNS-595 to the mammal once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 15 mg / m2 to 80 mg / m2 of SNS-595 to a mammal once a week for 3 weeks (eg, dosing in the days 1, 8 and 15); ii) wait for a period of at least 28 days where the mammal is not administered any SNS-595; and iii) administering another dose of approximately 15 mg / m2 to 80 mg / m2 of SNS-595 to the mammal once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 15 mg / m2 to 80 mg / m2 of SNS-595 to a mammal twice a week for 2 weeks (dosing on days 1, 4, 8 and 11); ii) wait for a period of at least 28 days where the mammal is not administered any SNS-595; and iii) administer another dose of approximately 15 mg / m2 to 80 mg / m2 of SNS-595 to the mammal twice a week for 2 weeks (dosing on days 1, 4, 8 and 11). In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 15 mg / m2 to 80 mg / m2 of SNS-595 to a mammal once a week for 3 weeks (eg, dosing in the days 1, 8 and 15); ii) wait for a period of 28 days where the mammal is not administered any SNS-595; and iii) administering another dose of approximately 15 mg / m2 to 80 mg / m2 of SNS-595 to the mammal once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the methods provided herein comprise: i) administering a dose of about 15 mg / m2 to 80 mg / m2 of SNS-595 to a mammal twice a week for 2 weeks (dosing on days 1, 4, 8 and 11); ii) wait for a period of 28 days where the mammal is not administered any SNS-595; and iii) administer another dose of approximately 15 mg / m2 to 80 mg / m2 of SNS-595 to the mammal twice a week for 2 weeks (dosing on days 1, 4, 8 and 11). In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the method comprises administering a dose of 1 mg / m2 to 100 mg / m2 of SNS-595 to a patient once a week, wherein the period of one week comprises a treatment cycle and the treatment cycle. it is repeated at least three times. In another embodiment, the method comprises administering a dose of 1 mg / m2 to 75 mg / m2 of SNS-595 to a patient once a week, wherein the period of one week comprises a treatment cycle and the treatment cycle. it is repeated at least three times. In another embodiment, the method comprises administering a dose of 1 mg / m2 to 60 mg / m2 of SNS-595 to a patient once a week, wherein the period of one week comprises a treatment cycle and the treatment cycle. it is repeated at least three times. In another embodiment, the method comprises administering a dose of 1 mg / m2 to 48 mg / m2 of SNS-595 to a patient once a week, wherein the period of one week comprises a treatment cycle and the treatment cycle. it is repeated at least three times. In another embodiment, the method comprises administering a dose of 1 g / m2 to 24 mg / m2 of SNS-595 to a patient once a week, wherein the period of one week comprises a treatment cycle and the treatment cycle it is repeated at least three times. In another embodiment, the dose is from about 2 mg / m2 to 40 mg / m2 once a week, wherein the period of one week comprises a treatment cycle and the treatment cycle is repeated at least three times. In another embodiment, the dose is from about 3 mg / m2 to 24 mg / m2 once a week, wherein the one week period comprises one treatment cycle and the treatment cycle is repeated at least three times. In another embodiment, the dose is about 15 mg / m2 once a week, wherein the period of one week comprises a treatment cycle and the treatment cycle is repeated at least three times. In another embodiment, the method comprises administering a dose of 15 mg / m2 to 80 mg / m2 of SNS-595 to a patient once a week, wherein the period of one week comprises a treatment cycle and the treatment cycle it is repeated at least three times. In another embodiment, the method comprises administering a dose of 15 mg / m2 to 75 mg / m2 of SNS-595 to a patient once a week, wherein the period of one week comprises a treatment cycle and the treatment cycle. it is repeated at least three times. In another embodiment, the method comprises administering a dose of 20 mg / m2 to 65 mg / m2 of SNS-595 to a patient once a week, wherein the period of one week comprises a treatment cycle and the treatment cycle. it is repeated at least three times. In another embodiment, the method comprises administering a dose of 30 mg / m2 to 50 mg / m2 of SNS-595 to a patient once a week, wherein the period of one week comprises a treatment cycle and the treatment cycle. it is repeated at least three times. In some embodiments, the method comprises administering a dose of about 1 mg / m2 to 40 mg / m2 of SNS-595 to a patient once a week (e.g., dosage on days 1, 8 and 15), where the period of one week comprises a treatment cycle and the treatment cycle is repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering a dose of about 1 mg / m2 to 40 mg / m2 of SNS-595 to a patient twice a week (dosing on days 1, 4, 8 and 11), wherein the One week period comprises a treatment cycle and the treatment cycle is repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering a dose of about 1 mg / m2 to 40 mg / m2 of SNS-595 to a patient once a week (eg, dosing on days 1, 8 and 15), wherein the one-week period includes a treatment cycle and the treatment cycle is repeated at least three times, followed by a waiting period of 28 days. In some embodiments, the method comprises administering a dose of about 1 mg / m2 to 40 mg / m2 of SNS-595 to a patient twice a week (dosing on days 1, 4, 8 and 11), wherein the One week period comprises a treatment cycle and the treatment cycle is repeated at least three times, followed by a waiting period of 28 days. In some embodiments, the method comprises administering a dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to a patient once a week (eg, dosing on days 1, 8 and 15), wherein the one-week period includes a treatment cycle and the treatment cycle is repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering a dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to a patient twice a week (dosing on days 1, 4, 8 and 11), wherein the One week period comprises a treatment cycle and the treatment cycle is repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering a dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to a patient once a week (eg, dosing on days 1, 8 and 15), wherein the one-week period includes a treatment cycle and the treatment cycle is repeated at least three times, followed by a waiting period of 28 days. In some embodiments, the method comprises administering a dose of about 3 mg / m2 to 24 mg / m2 of SNS-595 to a patient twice a week (dosing on days 1, 4, 8 and 11), wherein the One week period comprises a treatment cycle and the treatment cycle is repeated at least three times, followed by a waiting period of 28 days. In some embodiments, the method comprises administering a dose of about 15 mg / m2 to 80 mg / m2 of SNS-595 to a patient once a week (eg, dosing on days 1, 8 and 15), wherein the one-week period includes a treatment cycle and the treatment cycle is repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering a dose of about 15 mg / m2 to 80 mg / m2 of SNS-595 to a patient twice a week (dosing on days 1, 4, 8 and 11), wherein the One week period comprises a treatment cycle and the treatment cycle is repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering a dose of about 15 mg / m2 to 80 mg / m2 of SNS-595 to a patient once a week (eg, dosing on days 1, 8 and 15), wherein the one-week period includes a treatment cycle and the treatment cycle is repeated at least three times, followed by a waiting period of 28 days. In some modalities, the method comprises administering a dose of approximately 15 mg / m2 to 80 mg / m2 of SNS-595 to a patient twice a week (dosing on days 1, 4, 8 and 11), wherein the period of The week includes a treatment cycle and the treatment cycle is repeated at least three times, followed by a waiting period of 28 days. In another embodiment, the method comprises administering a dose of about 1 mg / m2- 50 mg / m2 of SNS-595 to a mammal once a week, wherein the period of one week comprises a treatment cycle and the cycle of treatment is repeated at least twice. In another embodiment, the dose is approximately 2 mg / m2- 40 mg / m2. In another embodiment, the dose is approximately 3 mg / m2-24 mg / m2. In another embodiment, the dose is approximately 4 mg / m2-20 mg / m2. 6. 4 EXEMPLARY DOSING REGIMES Exemplary dosing regimens, in relation to specific cancers, are provided in the following. These dosing regimens are intended to be illustrative, but not exclusive. In one aspect, a method for treating a solid tumor is provided. The method comprises: i) administering a dose of about 1 mg / m2 to 100 mg / m2 of SNS-595 to a patient; ii) wait for a period of at least six days, where the subject is not administered any SNS-595; iii) administer another dose of approximately 1 mg / m2 to 100 mg / m2 of SNS-595 to the patient; and, iv) repeating steps ii) -iii) a plurality of times. In another aspect, a method for treating solid tumors comprises administering a dose of about 1 mg / m2 to 75 mg / m2 of SNS-595 to a patient once a week, wherein the period of one week comprises a treatment cycle. and the treatment cycle is repeated at least twice. In another embodiment, the dose is approximately 15 mg / m2 to 80 mg / m2. In another embodiment, the dose is approximately 3 mg / m2 to 24 mg / m2. In another aspect, the method for treating solid tumors comprises administering a dose of about 15 mg / m2 to 40 mg / m2 of SNS-595 to a patient once a week for three weeks, followed by a period of at least two weeks where SNS-595 is not administered to the subject and where the cycle is repeated a plurality of times. In another embodiment, the dose is approximately 15 mg / m2 to 35 mg / m2. In another embodiment, the dose is approximately 20 mg / m2 to 30 mg / m2. In another embodiment, the dose is about 20 mg / m2 to 25 mg / m2. In another aspect, the method for treating solid tumors comprises administering a dose of about 35 mg / m2 to 80 mg / m2 of SNS-595 to a patient once in a period of three weeks, wherein the period of three weeks comprises a treatment cycle and the treatment cycle is repeated at least twice. In another aspect, a method for treating hematological malignancies is provided herein. In a certain embodiment, such methods comprise administering a dose of about 20 mg / m2 to 60 mg / m2 of SNS-595 to a patient. In patients who are considered strongly pretreated ("strongly pretreated patients"), the method comprises administering a dose of 35 mg / m2 to 60 mg / m2 of SNS-595 to a patient once in a period of three weeks, wherein the A three-week period comprises a treatment cycle and the treatment cycle is repeated at least twice. In another embodiment, the method for treating a strongly pretreated patient comprises administering a dose of 40 mg / m2 to 50 mg / m2. In another embodiment, the method for treating a strongly pretreated patient comprises administering a dose of 45 mg / m2 to 50 mg / m2. A strongly pretreated patient is defined as described by Tolcher et al., J. Clin. Oncol. 19: 2937-2947 (2001) and is a patient who has previously been treated with more than six courses of a chemotherapy regimen containing alkylating agents, more than two courses of carboplatin or mitomycin C, any previous regimen containing nitrosourea, irradiation to 25% of the areas that contain bone marrow, chemotherapy in high doses that requires reinfusions of hematopoietic stem cells or metastasis widely spread to the bone. Patients who have not previously been treated for their solid tumors or who have been treated but not considered to be strongly pretreated, are minimally pretreated ("minimally pretreated patients"). To treat minimally pretreated patients, the method comprises administering a dose of 45 mg / m2 to 80 mg / m2 of SNS-595 to a patient once in a period of three weeks, wherein the period of three weeks comprises a cycle of treatment and the treatment cycle is repeated at least twice. In another embodiment, the method for treating a minimally pretreated patient comprises administering a dose of 50 mg / m2 to 75 mg / m2. In another modality, the method to treat a patient pretreated in minimal form comprises administering a dose of 55 mg / m2 to 70 mg / m2. In another embodiment, the method for treating a minimally pretreated patient comprises administering a dose of 55 mg / m2 to 65 mg / m2. In another aspect, a method for treating a blood cancer, such as leukemias and lymphomas, is provided. The method comprises: i) administering a dose of 10 mg / m2- 50 mg / m2 of SNS-595 to a patient; ii) wait for a period of at least two days, where the subject is not administered any SNS-595; iii) administer another dose of 10 mg / m2- 50 mg / m2 of SNS-595 to the patient; and, iv) repeating steps ii) -iii) a plurality of times. In one modality, the waiting period is six days. In another modality, the waiting period is two days. In another modality, the waiting period is three days. In one embodiment, the method for treating hematologic malignancy comprises administering a dose of approximately 20 mg / m2, 22 mg / m2, 25 mg / m2, 27 mg / m2 or 30 mg / m2 of SNS-595 to a patient once a week, where the period of one week comprises a treatment cycle and the treatment cycle is repeated at least twice. In one embodiment, the method for treating hematologic malignancy comprises administering a dose of approximately 25 mg / m2 of SNS-595 to a patient once a week, wherein the period of one week comprises a treatment cycle and the cycle of treatment is repeated at least twice. Other dosage schedules useful for the treatment of patients with hematological malignancies may include approximately 25 mg / m2 to approximately 50 mg / m2 administered twice a week for two weeks. In another embodiment, the dosing schedules used in the treatment of hematological malignancies include about 30 mg / m2 to about 45 mg / m2 administered twice a week for two weeks. In another embodiment, the dosage programs for the treatment of hematological malignancies include 30, 35, 40 or 45 mg / m2 administered twice a week for two weeks. In one embodiment, the method for treating hematologic malignancy comprises administering a dose of approximately 40 mg / m2, 45 mg / m2, 50 mg / m2, 55 mg / m2 or 60 mg / m2 of SNS-595 to a patient once in two weeks, where the two-week period comprises a treatment cycle. In one embodiment, the method for treating hematologic malignancy comprises administering a dose of approximately 50 mg / m2 of SNS-595 to a patient once in two weeks, wherein the two week period comprises a treatment cycle. 6. 5 COMBINATION THERAPY In the methods and compositions provided herein, SNS-595 can be used with or combined with other pharmacologically active compounds ("second active agents"). It is believed that certain combinations work synergistically in the treatment of particular types of cancers. SNS-595 may also function to alleviate the adverse effects associated with certain second active agents, and some second active agents may be used to alleviate the adverse effects associated with SNS-595. 6. 5.1 Second Active Agents One or more second ingredients or active agents can be used in the methods and compositions provided herein in conjunction with SNS-595. The second active agents may be large molecules (eg, proteins) or small molecules (eg synthetic inorganic, organometallic or organic molecules). Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines and monoclonal and polyclonal antibodies, particularly therapeutic antibodies to cancer antigens. Typical large molecule active agents are biological molecules, such as proteins that occur naturally or are artificially made. Proteins that are particularly useful, in the methods and compositions provided herein, include proteins that stimulate the survival and / or proliferation of hematopoietic precursor cells and immunologically active poietic cells in vitro or in vivo. Others stimulate the division and differentiation of erythroid progenitors committed in cells in vitro or in vivo. Particular proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II ("rIL2") and canaripox IL-2), IL-10, IL-12 and IL-18; interferons, such as interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon beta-I a, and interferon gamma-I b; GM-CF and GM-CSF; and EPO. Particular proteins that can be used in the methods and compositions include, but are not limited to: filgrastim, which is sold in the United States under the trade name Neupogen® (Amgen, Thousand Oaks, CA) and its derivatives including, but not limited to to pegfilgrastim; sargramostim, which is sold in the United States under the trade name Leukine® (Immunex, Seattle, A); Recombinant EPO, which is sold in the United States under the trade name Epogen® (Amgen, Thousand Oaks, CA); epoetin alfa; and darbepoetin alfa. The recombinant and mutated forms of GM-CSF can be prepared as described in US Pat. Nos. 5,391,485; 5,393,870 and 5,229,496, all of which are incorporated herein by reference. The recombinant and mutated forms of G-CSF can be prepared as described in US Pat. Nos. 4,810,643; 4,999,291; 5,528,823 and 5,580,755, all of which are incorporated herein by reference. Native proteins are also provided, which occur naturally and recombinants for use in combination with SNS-595. Mutants and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit, in vivo, at least some of the pharmacological activity of the proteins on which they are based are also encompassed. Examples of mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding residues in the naturally occurring forms of the proteins. Also by the term "mutants" are meant proteins that lack portions of carbohydrates normally present in their naturally occurring forms (e.g., non-glycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgG1 or IgG3 to the protein or active portion of the protein of interest. See, for example, Penichet, M.L. and Orrison, S.L., J. Immunol. Methods 248: 91-101 (2001). Antibodies that can be used in combination with SNS-595 include monoclonal and polyclonal antibodies. Examples of antibodies include, but are not limited to, trastuzumab (Herceptin®), rituximab (Rituxan®), bevacizumab (Avastin ™), pertuzumab (Omnitarg ™), tositumomab (Bexxar®), edrecolomab (Panorex®) and G250. SNS-595 can also be combined with or used in combination with anti-TNF-a antibodies and / or anti-EGFR antibodies such as, for example, Erbitux® or panitumumab. The large molecule active agents can be administered in the form of cancer vaccines. For example, vaccines that secrete or elicit the secretion of cytokines such as IL-2, G-CSF and GM-CSF can be used in the methods and pharmaceutical compositions provided. See, for example, Emens, L.A., et al., Curr. Opinion Mol Ther. 3 (1): 77-84 (2001). In contrast to the general rule that drugs with different mechanisms of action should be selected to maximize the likelihood of additivity or synergy (see, for example, Page, R. and Takimoto, C, "Principles of Chemotherapy", Cancer Management: A Multidisciplinary Approach (2001), p.23), it was found that combinations comprising SNS-595 and a second agent that also prevents DNA synthesis are additive or synergistic. As used herein, an agent prevents DNA synthesis when it directly or indirectly affects a cell's ability to synthesize DNA or repair damage to DNA. The agent can interact directly with the DNA (for example, bind to or interspersed with) or can bind to a DNA binding protein that is involved in DNA synthesis or DNA repair. In general, an agent that prevents DNA synthesis is active during the S phase but does not need to be specific for the S phase. Since the SNS-595 affects the DNA-PK pathway, the second agent can be an agent that mediates its cytotoxicity through the DNA-PK route. An example is an agent that inhibits repair by association of non-homologous ends, such as DNA-PK inhibitors. As used herein and unless otherwise indicated, the term "DNA-PK inhibitor" means an agent that inhibits or interferes with a DNA-PK-mediated signaling pathway. The inhibition of DNA-PK activity can be direct (eg, a catalytic inhibitor of DNA-PK itself) or indirect (eg, an agent that interferes with the formation of the active DNA-PK complex (DNA-PK, Ku70 and Ku80)). Other examples include, but are not limited to, ligase IV inhibitors and agents that increase apoptosis such as, but not limited to, caspase-9 activators, caspase-3 activators, and Hsp90 inhibitors. The second active agents that are small molecules can also be used to alleviate the adverse effects associated with the administration of SNS-595. However, like some large molecules, it is believed that many are capable of providing a synergistic effect when administered (eg, before, after or simultaneously) with SNS-595. Examples of second small molecule active agents include, but are not limited to, anticancer agents, antibiotics, immunosuppressive agents and steroids. Examples of anti-cancer agents include, but are not limited to, alkylating agents, antineoplastic agents, antimetabolites (eg, folate analogs, purine analogs, asine analogs, pyrimidine analogs and substituted ureas), platinum coordination complexes, Topoisomerase II inhibitors and radiation. Specific agents against cancer include, but are not limited to: acivicin; aclarabicin; benzoyl hydrochloride; Acronine; adozelesina; aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlina; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesine sulomycin sulfate; Sodium brequinar; biririmine; busulfan; cactinomycin; calusterona; capecitablin; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor); clórambucil; Corylemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; Dacarbazine; Dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; Doxorubicin hydrochloride; droloxifene; Droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromato; epipropidine; epirubicin hydrochloride; erbulozole; erlotinib; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprin; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; Fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gefitinib; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosin; iproplatin; irinotecano; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; Maytansine; mechlorethamine hydrochloride; Megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; sodium methotrexate; metoprine; meturedepa; mitinomide; mitocarcin; mitochromin; mitogilin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargasá; Peliomycin; pemetrexed; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; pentamethane; sodium porfimer; porphyromycin; Prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazoturin; riboprine; safingol; safingol hydrochloride; semustine; simtrazeno; sodium esparfosate; Esparsomycin; Spirogermanium hydrochloride; spiromustine; Spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; taxi driver; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; Teroxirone; testolactone; tiamiprine; thioguanidine; thioguanine; thiotepa; thiazofurine; tirapazamine; Toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uramustine; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidin sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zipiplatine; zinostatin; and zorubicin hydrochloride. Other drugs against cancer include, but are not limited to: 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acilfulveno; adecipenol; adozelesina; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrografol; inhibitors of angiogenesis; antagonist D; antagonist G; antarelix; morphogenetic protein 1 of dorsal anti-differentiation; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; afidicolin glycinate; modulators of apoptosis genes; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azathirosine; Baccatin III derivatives; balanol batimastat; BCR / ABL antagonists; benzoclorins; benzoylstaurosporine; beta lactam derivatives; beta-aletine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylpermine; bisnafida; bistratene A; bizelesin; breflato; biririmine; budotitan; Butioninsulfoximine; calcipotriol; calfostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; inhibitor derived from cartilage; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; clorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; colismicin A; colismicin B; combretastatin A; combretastatin analogue; conagenina; crambescidin 816; crisnatol; cryptophycin 8; Cryptophycin A derivatives; curacin A; cyclopentantraquinones; Cycloplatam; cipemycin; cytarabine ocphosphate; cytolytic factor; Cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnospermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylespiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmicin SA; ebselen; ecomustine; edelfosin; Edrecolomab; eflornithine; elemeno; emitefur; epirubicin; epristérido; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium-texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulina; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifen; idramantone; ilmofosin; ilomastat; imatinib (for example, Gleevec®); imiquimod; immunostimulatory peptides; Insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguan; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazol; isohomohalicondrine B; itasetron; j asplaquinolide; kahalalide F; lamelarin N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolestatin; letrozole; Leukemia inhibitory factor; alpha leukocyte interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analog; lipophilic disaccharide peptide; lipophilic platinum compounds; lisoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecano; lutetium texaphyrin; lyophilin; lithic peptides; Maytansine; Manoestatin A; marimastat; masoprocol; maspina; Matrilisin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide; fibroblast growth factor mitotoxin-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, human chorionic gonadotropin; monophosphoryl lipid A + cell wall of myobacterium sk; mopidamol; mustard agent against cancer; micaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavina; nafterpina; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; Nitric oxide modulators; nitroxide antioxidant; nitrulin; oblimersen (Genasense®); O6-benzylguanine; octreotide; oquicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracine; cytokine inducer; ormaplatin; osaterone; Oxaliplatin; oxaunomycin; paclitaxel; Paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrizoxin; pamidronic acid; panaxitriol; panomiphene; parabactin; pazeliptina; pegaspargasa; peldesina; pentosan sodium polysulfate; pentostatin; pentrozole; perflubron; perfosfamide; perilyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetina A; placetina B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; sodium porfimer; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; immune modulator based on protein A; inhibitor of protein kinase C; inhibitor of protein kinase C, protein kinase C inhibitors, microalgal; inhibitors of protein tyrosine phosphatase; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; conjugate of pyridoxylated hemoglobin-polyoxyethylene; Raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; Demethylated reteliptine; rhenium etidronate Re 186; rhizoxin; ribozymes; RII retinamide; roituquine; romurtida; roquinimex; Rubiginone Bl; ruboxil; safingol; saintopine; SarCNU; sarcofitol A; sargramostim; Sdi 1 mimetics; semustine; inhibitor 1 derived from senescence; sense oligonucleotides; inhibitors of signal transduction; sizofiran; Sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; Esparfosic acid; Spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stihadid; stromelysin inhibitors; Sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista suramin; Swainsonin; talimustine; tamoxifen methylodide; tauromustine; tazarotene; tecogalan sodium; tegafur; telurapyrilio; telomerase inhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine; Taliblastine; thiocoraline; thrombopoietin; mimetic thrombopoietin; timalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin etiletiopurpurine; tirapazamine; titanocene bichloride; topsentin; toremifene; inhibitors of translation; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turbot tyrosine kinase inhibitors; Tyrphostins; inhibitors UBC; ubenimex; growth inhibitory factor derived from the urogenital sinus; Urokinase receptor antagonists; vapreotide; Variolin B; velaresol; veramina; verdinas; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zipiplatine; zilascorb; and zinoestatin estimalmer. Second specific active agents include, but are not limited to, rituximab, oblimersen (Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin , procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (for example, PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin ( Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt®), sulindac and etoposide. In certain embodiments, the second active agent is etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin, carboplatin, pemetrexed, methotrexate, Ara-C, 5-FU, wortmanin, gemcitabine, geldanamycin, or a combination thereof. In other embodiments, the second active agent is a symptomatic care agent. An example of a symptomatic care agent is an antiemetic. Specific antiemetic agents include, but are not limited to, phenothiazines, butyrophenones, benzodiazapines, corticosteroids, serotonin antagonists, cannabinoids and receptor antagonists. Examples of phenothiazine antiemetics include, but are not limited to, prochlorperazine and trimethobenzamide. Examples of the butyrophenone antiemetic include, but are not limited to, haloperidol. Examples of the benzodiazepine antiemetic include, but are not limited to, lorazepam. Examples of the antiemetic of corticosteroids include, but are not limited to, dexamethasone. Examples of the serotonin antagonist antiemetic include, but are not limited to, ondansetron, granisetron and dolasetron. Examples of the cannabinoid antiemetic include, but are not limited to, dronabinol. Examples of NKi receptor antagonists include, but are not limited to, aprepitant. Dosages and dosing regimens of antiemetic agents should depend on the specific indication being treated, age and condition of a patient, and the severity of adverse effects, and can therefore be adjusted by those skilled in the art. Examples of dosages and dosing regimens can be found, for example, in The Physician's Desk Reference. 6. 5.2 Exemplary Methods of Combination Therapy In certain embodiments, methods provided herein comprise administering SNS-595 in combination with one or more second active agents, and / or in combination with radiation therapy or surgery. The administration of SNS-595 and the second active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration. The desirability of a particular route of administration employed for a particular active agent will depend on the active agent itself (for example, if it can be administered orally without decomposing before entering the bloodstream) and the disease being treated. The recommended routes of administration for the second active agents are known to those of ordinary skill in the art. See, for example, Physicians' Desk Reference (60th ed., 2006). In one embodiment, the second active agent is administered intravenously or subcutaneously and once or twice a day in an amount of about 1 to about 1,000 mg, about 5 to about 500 mg, about 10 to about 375 mg or from about 50 to about 200 mg. In one embodiment, the second active agent is rituximab, oblimersen (Genasense®), GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan, pentoxiflline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, inhibitor of COX-2, IL2, IL8, IL 18, IFN, Ara-C, vinorelbine or a combination thereof. In certain embodiments, the second active agent is etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin, carboplatin, pemetrexed, methotrexate, Ara-C, 5-FU, wortmanin, geldanamycin, gemcitabine, or a combination thereof. In another embodiment, methods are provided herein to treat, prevent and / or manage hematological malignancies, which comprise administering SNS-595 in conjunction with (eg, before, during or after) conventional therapy including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy or other non-drug therapy currently used to treat, prevent or manage cancer. Without being limited by theory, it is believed that SNS-595 can provide additive or synergistic effects when given concurrently with conventional therapy. In certain embodiments, the second active agent is co-administered with SNS-595 or administered 1-50 hours late. In certain modalities, SNS-595 is administered first, followed by administration with the second active agent with 1-50 hours delay. In other embodiments, the second active agent is administered first, followed by administration of SNS-595 with 1-50 hours delay. In some modality, the delay is 24 hours. In one embodiment, SNS-595 can be administered in an amount of about 1 to about 75 mg / m2, about 60 mg / m2, 1 to about 48 mg / m2, 1 to about 24 mg / m2, 1 to about 50 mg / m2, approximately 1 to approximately 40 mg / m2, approximately 1 to about 30 mg / m2, about 3 to about 30 mg / m2, about 3 to about 24 mg / m2 alone or in combination with a second active agent described herein, before, during or after the use of conventional therapy . In another embodiment, the methods provided herein comprise: a) administering to a patient, in need thereof, a dose of about 1 mg / m2 a 75 mg / m2 of SNS-595 and b) administer a therapeutically effective amount of a symptomatic care agent. In one embodiment, the second agent is an alkylating agent. In another embodiment, the alkylating agent is an alkyl sulfonate and the cancer being treated is leukemia or lymphoma. In another embodiment, the alkyl sulfonate is bisulfan. In another embodiment, the alkyl sulfonate is busulfan and the therapeutically effective amount is a daily dose of at least 1 mg. In another modality, the alkyl sulfonate is busulfan and the therapeutically effective amount is a daily oral dose of between about 2 mg and 8 mg. In another embodiment, the alkyl sulfonate is busulfan and the therapeutically effective amount is a daily oral dose of between about 1 mg and about 3 mg. In another embodiment, the alkylating agent is a nitrogen mustard and the cancer being treated is bladder cancer, breast cancer, Hodgkin's disease, leukemia, lung cancer, melanoma, ovarian cancer or testicular cancer. In another modality, nitrogen mustard is chlorambucil. In another embodiment, nitrogen mustard is chlorambucil and the therapeutically effective amount is at least 0.1 mg / kg. In another embodiment, nitrogen mustard is chlorambucil and the therapeutically effective amount is a daily oral dose of between about 0.1 mg / kg and about 0.2 mg / kg for three to six weeks. In another embodiment, nitrogen mustard is chlorambucil and the therapeutically effective amount is a dose of 0.4 mg / kg every three to four weeks. In another embodiment, nitrogen mustard is cyclophosphamide. In another embodiment, nitrogen mustard is cyclophosphamide and the therapeutically effective amount is an intravenous dose of at least 10 mg / kg. In another embodiment, nitrogen mustard is cyclophosphamide and the therapeutically effective amount is an intravenous dose of between about 10 mg / kg and about 15 mg / kg every seven to ten days. In another embodiment, nitrogen mustard is cyclophosphamide and the therapeutically effective amount is an oral daily dose of between about 1 mg / kg and about 5 mg / kg. In another modality, nitrogen mustard is melphalan. In another embodiment, the nitrogen mustard is melphalan and the therapeutically effective amount is a daily oral dose of at least 2 mg. In another embodiment, the nitrogen mustard is melphalan and the therapeutically effective amount is a daily oral dose of 6 mg for two to three weeks, without melphalan for two to four weeks and then a daily oral dose of between about 2 mg and about 4 mg. mg. In another embodiment, nitrogen mustard is melphalan and the therapeutically effective amount is a daily oral dose of 10 mg / m2 for four days every four to six weeks. In another embodiment, the alkylating agent is a nitrosourea and the cancer being treated is brain tumor, colorectal cancer, Hodgkin's disease, liver cancer, lung cancer, lymphoma or melanoma. In another modality, nitrosourea is carmustine. In another embodiment, the nitrosourea is carmustine and the therapeutically effective amount is at least 150 mg / m2. In another embodiment, the nitrosourea is carmustine and the therapeutically effective amount is an intravenous dose of between about 150 mg / m2 and 200 mg / m2 every six to eight weeks. In another embodiment, the alkylating agent is a triazene and the cancer being treated is Hodgkin's disease, melanoma, neuroblastoma or soft tissue sarcoma. In another modality, the triazene is dacarbazine. In another embodiment, the triazene is dacarbazine and the therapeutically effective amount is a daily intravenous dose of between about 2.0 mg / kg and about 4.5 mg / kg for ten days every four weeks. In another embodiment, the triazene is dacarbazine and the therapeutically effective amount is a daily intravenous dose of 250 mg / m2 for five days every three weeks. In another embodiment, the triazene is dacarbazine and the therapeutically effective amount is an intravenous dose of 375 mg / m2 every sixteen days. In another embodiment, the triazene is dacarbazine and the therapeutically effective amount is an intravenous dose of 150 mg / m2 for five days every four weeks. In another embodiment, the second agent is an antineoplastic antibiotic and the cancer being treated is bladder cancer, breast cancer, cervical cancer, cancer of the head and neck, Hodgkin's disease, leukemia, multiple myeloma, neuroblastoma, ovarian cancer, sarcoma, skin cancer, testicular cancer or thyroid cancer. In another modality, the antibiotic is bleomycin. In another embodiment, the antibiotic is bleomycin and the therapeutically effective amount is at least 10 units / m2. In another embodiment, the antibiotic is bleomycin and the therapeutically effective amount is an intravenous, subcutaneous or intramuscular dose of between about 10 units / m2 and about 20 units / m2 per week or twice a week. In another embodiment, the antibiotic is dactinomycin. In another embodiment, the antibiotic is dactinomycin and the therapeutically effective amount is at least 0.01 mg / kg. In another embodiment, the antibiotic is dactinomycin and the therapeutically effective amount is a daily intravenous dose of between about 0.010 mg / kg and about 0.015 mg / kg for five days every three weeks. In another embodiment, the antibiotic is dactinomycin and the therapeutically effective amount is an intravenous dose of 2 mg / m2 every three or four weeks. In another modality, the antibiotic is daunorubicin. In another embodiment, the antibiotic is daunorubicin and the therapeutically effective amount is at least 30 mg / m2. In another embodiment, the antibiotic is daunorubicin and the therapeutically effective amount is a daily intravenous dose of between about 30 mg / m2 and about 45 mg / m2 for three days. In another embodiment, the antibiotic is a liposomal preparation of daunorubicin and the therapeutically effective amount is an intravenous dose of 40 mg / m2 every two weeks. In another modality, the antibiotic is doxorubicin. In another embodiment, the antibiotic is doxorubicin and the therapeutically effective amount is at least 15 mg / m2. In another embodiment, the antibiotic is doxorubicin and the therapeutically effective amount is an intravenous dose of between about 60 mg / m2 and about 90 mg / m2 every three weeks. In another embodiment, the antibiotic is doxorubicin and the therapeutically effective amount is a weekly intravenous dose of between about 15 mg / m2 and about 20 mg / m2. In another embodiment, the antibiotic is doxorubicin and the therapeutically effective amount is a cycle comprising a weekly intravenous dose of 30 mg / m2 for two weeks followed by two weeks without doxorubicin. In another embodiment, the second agent is an anti-metabolite. In another embodiment, the anti-metabolite is a folate analog and the cancer being treated is breast cancer, head and neck cancer, leukemia, lung cancer, non-Hodgkin's lymphoma, or osteosarcoma. In another embodiment, the folate analogue is methotrexate. In another embodiment, the folate analogue is methotrexate and the therapeutically effective amount is at least 2.5 mg. In another embodiment, the folate analogue is methotrexate and the therapeutically effective amount is a daily oral dose of between about 2.5 mg and about 5 mg. In another embodiment, the folate analogue is methotrexate and the therapeutically effective amount is a dose twice a week of between about 5 mg / m2 and about 25 mg / m2. In another embodiment, the folate analogue is methotrexate and the therapeutically effective amount is a weekly intravenous dose of 50 mg / m2 every two to three weeks. In another embodiment, the folate analogue is pemetrexed. In another embodiment, the folate analogue is pemetrexed and the therapeutically effective amount is at least 300 mg / m2. In another embodiment, the folate analog is pemetrexed and the therapeutically effective amount is an intravenous dose of between about 300 mg / m2 and about 600 mg / m2 every two or three weeks. In another embodiment, the folate analogue is pemetrexed and the therapeutically effective amount is an intravenous dose of 500 mg / m2 every three weeks. In another embodiment, the anti-metabolite is a purine analog and the cancer being treated is colorectal cancer, leukemia or myeloma. In another embodiment, the purine analogue is mercaptopurine. In another embodiment, the purine analogue is mercaptopurine and the therapeutically effective amount is at least 1.5 mg / kg. In another embodiment, the purine analogue is mercaptopurine and the therapeutically effective amount is a daily oral dose of between about 1.5 mg / kg and about 5 mg / kg. In another embodiment, the purine analogue is thioguanidine. In another embodiment, the purine analogue is thioguanidine and the therapeutically effective amount is at least 2 mg / kg. In another embodiment, the purine analogue is thioguanidine and the therapeutically effective amount is a daily oral dose of between about 2 mg / kg and about 3 mg / kg. In another embodiment, the anti-metabolite is an adenosine analog and the cancer that is being treated is leukemia or lymphoma. In another embodiment, the adenosine analogue is cladribine. In another embodiment, the adenosine analogue is cladribine and the therapeutically effective amount is at least 0.09 mg / kg. In another embodiment, the adenosine analogue is cladribine and the therapeutically effective amount is a daily intravenous dose of 0.09 mg / kg for seven days. In another embodiment, the adenosine analogue is cladribine and the therapeutically effective amount is a daily intravenous dose of 4 mg / m2 for seven days. In another embodiment, the adenosine analog is pentostatin. In another embodiment, the adenosine analogue is pentostatin and the therapeutically effective amount is 4 mg / m2. In another embodiment, the adenosine analog is pentostatin and the therapeutically effective amount is an intravenous dose of 4 mg / m2 every two weeks. In another embodiment, the adenosine analog is pentostatin and the therapeutically effective amount is an intravenous dose of 4 mg / m2 every three weeks.

In another embodiment, the anti-metabolite is a pyrimidine analog and the cancer being treated is bladder cancer, breast cancer, colorectal cancer, esophageal cancer, head and neck cancer, leukemia, liver cancer, lymphoma, cancer ovarian, pancreatic cancer, skin cancer or stomach cancer. In another embodiment, the pyrimidine analog is cytarabine. In another embodiment, the pyrimidine analog is cytarabine and the therapeutically effective amount is at least 100 mg / m2. In another embodiment, the pyrimidine analog is cytarabine and the therapeutically effective amount is a daily intravenous dose of 100 mg / m2 for seven days. In another embodiment, the pyrimidine analogue is capecitabine. In another embodiment, the pyrimidine analogue is capecitabine and the therapeutically effective amount is at least one daily dose of 2000 mg / m2. In another embodiment, the pyrimidine analogue is capecitabine and the therapeutically effective amount is an oral dose twice daily of between about 1200 mg / m2 and about 1300 mg / m2 for 14 days. In another embodiment, the pyrimidine analogue is capecitabine and the therapeutically effective amount is a three week cycle wherein a twice daily dose of approximately 1250 mg / m2 is given for fourteen days followed by a week of rest. In another embodiment, the pyrimidine analog is fluorouracil. In another embodiment, the pyrimidine analog is fluorouracil and the therapeutically effective amount is at least 10 mg / kg. In another example, the pyrimidine analog is fluorouracil and the therapeutically effective amount is a daily intravenous dose of between about 300 mg / m2 and about 500 mg / m2 for at least three days. In another example, the pyrimidine analogue is fluorouracil and the therapeutically effective amount is a daily intravenous dose of 12 mg / kg for three to five days. In another embodiment, the pyrimidine analogue is fluorouracil and the therapeutically effective amount is a weekly intravenous dose of between about 10 mg / kg and about 15 mg / kg. In another embodiment, the anti-metabolite is a substituted urea and the cancer being treated is cancer of the head and neck, leukemia, melanoma or ovarian cancer. In another embodiment, the substituted urea is hydroxyurea. In another embodiment, the substituted urea is hydroxyurea and the therapeutically effective amount is at least 20 mg / kg. In another embodiment, the substituted urea is hydroxyurea and the therapeutically effective amount is an oral dose of 80 mg / kg every three days. In another embodiment, the substituted urea is hydroxyurea and the therapeutically effective amount is a daily oral dose of between about 20 mg / kg and about 30 mg / kg.

In another embodiment, the second agent is a platinum coordination complex and the cancer being treated is bladder cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, leukemia, lung cancer, lymphoma , ovarian cancer, sarcoma, testicular cancer or uterine cancer. In another embodiment, the platinum coordination complex is carboplatin. In another embodiment, the platinum coordination complex is carboplatin and the therapeutically effective amount is at least 300 mg / m2. In another embodiment, the platinum coordination complex is carboplatin and the therapeutically effective amount is at least 300 mg / m2 every four weeks. In another embodiment, the platinum coordination complex is carboplatin and the therapeutically effective amount is 300 mg / m2 every four weeks. In another embodiment, the platinum coordination complex is carboplatin and the therapeutically effective amount is at least 360 mg / m2 every four weeks. In another embodiment, the platinum coordination complex is cisplatin. In another embodiment, the platinum coordination complex is cisplatin and the therapeutically effective amount is at least 20 mg / m2. In another modality, the platinum coordination complex is cisplatin and the therapeutically effective amount is a daily intravenous dose of 20 mg / m2 for four to five days every three to four weeks. In another embodiment, the platinum coordination complex is cisplatin and the therapeutically effective amount is an intravenous dose of 50 mg / m2 every three weeks. In another embodiment, the platinum coordination complex is oxaliplatin. In another embodiment, the platinum coordination complex is oxaliplatin and the therapeutically effective amount is at least 75 mg / m2. In another embodiment, the platinum coordination complex is oxaliplatin and the therapeutically effective amount is between about 50 mg / m2 and about 100 mg / m2. In another embodiment, the platinum coordination complex is oxaliplatin and the therapeutically effective amount is an IV infusion of between about 50 mg / m2 and about 100 mg / m2 every two weeks. In another embodiment, the platinum coordination complex is oxaliplatin and the therapeutically effective amount is an IV infusion of between about 80 mg / m2 and about 90 mg / m2 every two weeks. In another embodiment, the platinum coordination complex is oxaliplatin and the therapeutically effective amount is a two hour IV infusion of 85 mg / m2 every two weeks. In another embodiment, the second agent is a topoisomerase II inhibitor and the cancer being treated is Hodgkin's disease, leukemia, small cell lung cancer, sarcoma or testicular cancer. In another embodiment, the topoisomerase II inhibitor is etoposide. In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is at least 35 mg / m2. In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is between about 50 mg / m2 and about 100 mg / m2. In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is an intravenous dose of between about 35 mg / m2 and about 50 mg / m2 per day at least three times in five days every three or four weeks. In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is an intravenous dose of between about 50 mg / m2 and about 100 mg / m2 per day at least three times in five days every three or four weeks. In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is an oral dose of 100 mg / m2 per day at least three times in five days every three or four weeks. In another embodiment, the topoisomerase II inhibitor is teniposide. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is at least 20 mg / m2. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is a weekly dose of 100 mg / m2. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is one dose twice a week of 100 mg / m2. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is a daily dose of between about 20 mg / m2 and about 60 mg / m2 for five days. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is a daily dose of between about 80 mg / m2 and about 90 mg / m2 for five days. 6. 6 PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS The methods provided herein use pharmaceutical compositions containing SNS-595 and pharmaceutically acceptable carriers, such as diluents or adjuvants, or in combination with another active ingredient, such as another agent against cancer. In clinical practice, SNS-595 can be administered by any conventional route, including but not limited to the oral, parenteral, rectal or inhalation form (for example in the form of aerosols). In some embodiments, the compositions provided herein are acidic compositions (e.g., pH < 4). Without being limited by a particular theory, the acid compositions provide the appropriate balance of increased solubility of SNS-595 and desirable pharmaceutical properties (eg, increased comfort of the patient by causing less irritation at the delivery site). In one embodiment, SNS-595 is administered by an IV injection. Compositions for parenteral administration may be sterile emulsions or solutions. It can be used, as solvent or vehicle, of propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, for example ethyl oleate. These compositions may also contain adjuvants, in particular wetting agents, isotonicity agents, emulsifiers, dispersants and stabilizers. The sterilization can be carried out in various ways, for example using a bacteriological filter, by radiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium. The compositions can also be aerosols. For use in the form of liquid aerosols, the compositions may be stable sterile solutions or solid compositions dissolved at the time of use in sterile pyrogen-free water, saline or any other pharmaceutically acceptable vehicle. For use in the form of dry aerosols intended to be inhaled directly, the active ingredient is finely divided and combined with a diluent or water-soluble solid carrier, for example dextran, mannitol or lactose. The pharmaceutical compositions can be used in the composition of single unit dosage unit forms. The pharmaceutical compositions and dosage forms comprise SNS-595 and one or more excipients. The pharmaceutical compositions and dosage forms may also comprise one or more additional active ingredients. Examples of second, optional, or additional, optional ingredients are described herein. In certain embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. The pharmaceutical compositions and the unique unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of SNS-595, and typically one or more pharmaceutically acceptable carriers or excipients. The term "carrier" refers to a diluent, adjuvant (eg, Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic substance is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. In certain embodiments, water is a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous solutions of dextrose and glycerol can also be used as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those experienced in the pharmacy art, and examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form will be administered to a subject. and the specific active ingredients in the dosage form. The unique unit dosage form or composition, if desired, may also contain minor amounts of wetting agents or emulsifiers, or pH buffering agents. Herein are further provided pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers. The pharmaceutical compositions and unique unit dosage forms can take the form of solutions, suspensions, emulsion, powders and the like. Such compositions and dosage forms will contain a prophylactic or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, together with a suitable amount of carrier to provide the form for the appropriate administration to the subject. The formulation must adapt to the mode of administration. In one embodiment, the pharmaceutical compositions or single unit dosage forms are sterile and in a form suitable for administration to a subject, such as an animal subject, or a mammalian subject and such as a human subject. A pharmaceutical composition provided herein is formulated to be compatible with its intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, topical, transmucosal, intra-tumoral, intra-synovial, and rectal administration. In a specific embodiment, the composition is formulated according to routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, intranasal or topical administration to humans. In one embodiment, a pharmaceutical composition is formulated according to routine procedures for subcutaneous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to relieve pain at the site of injection. Examples of dosage forms include, but are not limited to: liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (eg, crystalline or amorphous solids) which can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.

The composition, conformation and type of the dosage forms provided herein will typically vary depending on their use. For example, a dosage form used in the initial treatment of the disease may contain larger amounts of one or more of the active ingredients comprising, than a dosage form used in the maintenance treatment of the same infection. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients comprising, than an oral dosage form used to treat the same disease or disorder. These and other ways, in which the specific dosage forms encompassed herein will vary from one another, will be readily apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000). Generally, the ingredients of the compositions provided herein are supplied either separately or mixed in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as water, ampoule or sachet indicating the amount of active agent. Where the composition should be administered by infusion, it can be distributed by an infusion bottle containing water or sterile pharmaceutical grade saline. Where the composition is administered by injection, a vial of sterile water or saline may be provided so that the ingredients can be mixed prior to administration. Typical dosage forms provided herein comprise SNS-595 within a range of about 1 mg / m2 to about 75 mg / m2 per day, or weekly, given as a single dose once a day in the morning or as a dose divided throughout the day taken with food. The particular dosage forms provided herein have approximately 1, 3, 6, 9, 12, 15, 18, 21, 24, 27 or 30 mg / m2 of SNS-595. 6. 6.1 Parenteral Dosage Forms Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Since their administration typically eludes the natural defenses of patients against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles, such as, but not limited to, Sodium Chloride Injection, Ringer's Solution Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Injection of Ringer's Lactose Solution; miscible vehicles in water such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. Compounds that increase the solubility of one or more of the active ingredients described herein may also be incorporated into parenteral dosage forms. For example, cyclodextrin and its derivatives can be used to increase the solubility of the active ingredients. See, for example, U.S. Patent No. 5,134,127, which is incorporated herein by reference. 6. 6.2 Topical and Mucosal Dosage Forms In certain embodiments, transdermal, topical, and mucosal dosage forms are provided herein. The transdermal, topical and mucosal dosage forms provided herein include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions or other forms known to someone with experience in the technique. See, for example, Remington's Pharmaceutical Sciences, 20th ed. , Mack Publishing, Easton PA (2000); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Suitable dosage forms for treating mucosal tissues within the oral cavity can be formulated as mouth rinses or as oral gels. In addition, the transdermal dosage forms include "reservoir type" or "matrix type" patches which can be applied to the skin and used for a specific period of time to allow the penetration of a desired amount of active ingredients. Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide topical and mucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a composition will be applied. pharmaceutical or dosage form given. With that in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butan-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof. same to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable. Humidifiers or humectants may also be added to the pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, for example, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000). The pH of a pharmaceutical composition or dosage form can also be adjusted to improve the delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to favorably alter the hydrophilicity or lipophilicity of one or more active ingredients to improve delivery. In this regard, stearates can serve as a liquid carrier for the formulation, as an emulsifying agent or surfactant or as an agent that improves delivery or improves penetration. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition. 7. EXAMPLES Certain embodiments provided herein are illustrated by the following non-limiting Example.

Example 1: Pharmaceutical Composition Suitable for Intravenous Infusion or Injection Acidic compositions (< pH 4) provided the appropriate balance of increased solubility of SNS-595 and desirable pharmaceutical properties (e.g., increased patient comfort by causing less irritation at the site of supply). An illustrative example of a suitable composition comprises: 10 mg of SNS-595 per mL of 4.5% sorbitol aqueous solution which is adjusted to a pH of 2.5 with methanesulfonic acid. A protocol to elaborate such a solution includes the following to elaborate a presentation of 100 mg / 10 mL: 100 mg of SNS-595 and 450 mg of D-sorbitol are added to distilled water; the volume is increased to a volume of 10 mL; and the pH of the resulting solution is adjusted to 2.5 with methanesulfonic acid. The resulting composition is also suitable for lyophilization. The lyophilized form is then reconstituted with sterile water at the appropriate concentration before use.

Example 2: Clinical Trial Data of SNS-595 in Patients with Advanced Solid Tumor Cancer The safety and efficacy of SNS-595 were investigated in two increasing dose studies. As demonstrated in the following, SNS-595 provides good safety profiles and evidence of activity against tumors in patients with refractory solid tumors. SNS-595 was administered to patients with advanced solid cancers with an IV infusion for 10 minutes in 2 programs. In the first program (A), a weekly dose of SNS-595 was administered for three weeks followed by at least 7 days at rest (qwk x3). In the second program (B), a dose of SNS-595 was administered once every three weeks (q3wk). In both programs, the starting dose of SNS-595 was 3 mg / m2, and the doses were increased by sequential groups of 3. The doses were doubled until the first related or adverse event in or above Grade 2 or until the first abnormal laboratory value. The doses were then increased by a modified Fibonacci scheme.

No other therapy, for example the drugs mitomycin-C, BCNU, nitrosourea or therapy with MAb, occurred within 42 days of the study. In study A, 21 patients (9 men, 12 women) were treated in 6 groups (dose range 3-24 mg / m2 / wk). In study B, 41 patients (25 men, 16 women) were treated in 9 groups (dose range 3-75 mg / m2 / wk). The mean ages were 61 years (Study A) and 59 years (Study B), sex 12F / 9M (Study A), 16F / 25M (Study B), all patients had a Functional Status of European Cooperative Group in Oncology (ECOG PS) of baseline of 0-2. The eligibility of the patients included refractory solid tumors and adequate organ function. Table 1 provides the demographics of the patients in both studies.

Table 1: Demographics of patients Table 2 provides a list of tumor types treated in both studies.

Table 2: Types of Treated Tumors For patients medicated according to Program A, PK samples were collected on Treatment Days 1 and 15 and examined using non-compartmental analysis. The plasma concentrations of SNS-595 were determined using a validated LC-MS / MS assay. The AUC (area under the curve) increased proportionally with dose and mean AUCmf and varied between 1.7 and 15 pg * hr / ml, respectively, for dose levels of 3 to 24 mg / m2. The terminal half-life is approximately 19 hours. No evidence of drug-dependent alterations was observed in pharmacokinetic parameters after 3 weekly doses. FIGURE 1 represents the plasma concentrations of SNS-595 over time between the various groups of patients. Table 3 provides the pharmacokinetic parameters for medicated patients according to program A.

Table 3: Average Pharmacokinetic Parameters Week 1 and Week 3 For patients medicated according to program B, pharmacokinetic parameters were evaluated in 36 patients (21 strongly pretreated and 15 pretreated in minimal form) after a single dose of 3 to 75 mg / m2. Depuration (CL), volume of distribution, and terminal half-life (T½) remained unchanged in all patients up to 48 mg / m2. In minimal pre-treated patients, PK parameters remained unchanged up to 75 mg / m2. The LC was 2.2 L / hr / m2 (range of 1.0-3.8 L / hr / m2), the volume of distribution was 53 L / m2 (intervals of 31-76 L / m2), and T1 2 was approximately 21 hr (range of 13-49 hr). Exposure was similar for strong and minimally pretreated patients and was increased linearly with doses up to 48 mg / m2. The exposure for pre-treated patients minimally showed a greater than the linear AUC (area under the curve) of the doses at the 60 mg / m2 dose level. Table 4 shows the pharmacokinetic parameters for patients dosed according to program B.

Table: Pharmacokinetic Parameters in Week 3 In study A, pharmacokinetics were evaluated on Days 1 and 15 (after the first and third doses). As shown in Table 5, SNS-595 shows highly reproducible pharmacokinetics and low variability among patients. No accumulation or change in pharmacokinetic parameters was observed after repeated dosing. The exposure was increased linearly over a range of 8 doses (1.6-15 yg-hr / mL), clearance (CL), volume of distribution (Vss) and T½ averaged 2 L / hr / m2, 48 L / m2, 19 hr, respectively, and did not change from Day 1 to 15.

In study B, pharmacokinetics were assessed on Day 1 after the first dose; the exposure was increased linearly over the interval of 24 times the dose (1.1-46 g-hr / mL), CL, Vss, and T½ averaged 2 L / hr / m2, 53 L / m2, and 21 hours, respectively . The pharmacokinetic parameters are provided for both studies in Table 5.

Table 5: Average Pharmacokinetic Parameters in Week 1 and Week 3 FIGURE 11 shows the linearity of the dose in Studies A and B. Table 6 provides the data for the hematological effects observed in the studies.

Table 6: Hematological Effects Dosage Schedule n # # A C Ne tropenia < 500 Febrile 3 mg / m2 qwk x3 4 0 0 6 mg / m2 qwk x3 3 0 0 12 mg / m2 qwk x3 3 0 0 15 mg / m2 qwk x3 6 0 0 18 mg / m2 qwk x3 4 0 0 24 mg / m2 qwk x3 1 0 0 3 mg / m2 q3wk 3 0 0 6 mg / m2 q3wk 3 0 0 12 mg / m2 q3wk 3 0 0 24 mg / m2 q3wk 3 0 0 36 mg / m2 q3wk 6 0 0 48 mg / m2 q3wk 6 1 0 48 mg / m2 (HP) q3wk 5 2 0 60 mg / m2 q3wk 8 3 1 75 mg / m2 q3wk 4 0 0 n = number of patients in the group * Amount of Absolute eutrophils (ovalules / uL) < 500 that last for more than 7 days In the description herein, the term "maximum tolerated dose" or "MTD" refers to the dose level below a dose of SNS-595 where > 2 of 6 patients experienced dose-limited toxicity (DLT). The term, "strongly pre-treated" or "HP" refers to a patient who has previously received > 6 courses of an alkylating agent, chemotherapy or > 2 courses of platinum, mitomycin-C or any nitrosourea, or XRT a > 25% bone. The term, "minimally pre-treated" patient or "MP" refers to a patient who does not meet the HP definition. (See, Tolcher et al, JCO 2001; 19: 2937-29 7). As used herein, dose-limited toxicity (DLT) refers to the absolute neutrophil count (ANC) < 500 during > 7 days or febrile neutropenia or lower platelet point < 25,000 or bleeding or non-hepatologic adverse events (AE) > Grade 3 (as described in Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE v3.0)), where adverse events required > 14 days of dose delay. Tables 7-9 provide safety data for both studies.

Table 7: Frequent adverse events (> 10% of patients) *do not. of patients with Grade > 3) No. of patients without any Degree Table 8: Hematological Effects Table 9: Serious Adverse Events (SAE) Possibly Related to the Study Drug As observed from the data, neutropenia was dose-limited toxicity (DLT) for both studies. In study A, the dose-limited toxicity (DLT) of neutropenia was observed in the first patient at the 24 mg / m2 level. 5 patients were then treated at 18 mg / m2 where 2 developed DLT of neutropenia. In study B, for heavily pretreated patients, dose-limited toxicity (DLT) consisting of Grade 4 neutropenia for more than 7 days was observed at 60 mg / m2. For minimally pretreated patients, dose-limited toxicity was observed at a dose of 75 mg / m2. The BAT for study A was 15 mg / m2; BAT for study B was 48 mg / m2 for heavily pretreated (HP) patients and 60 mg / m2 for minimally pretreated patients (MP). For both studies, two patients had grade 4 thrombocytopenia; the non-haematological toxicities were mainly grade 1/2 without gastrointestinal toxicity or dose-limited neurotoxicity. Table 10 provides evidence of clinical activity of SNS-595 for both studies. For study A, the best responses included one patient who achieved a partial response (PR) and six who achieved stable disease SD (range of 16-24 weeks). For study B, the best responses included a PR and 11 SD (range of 18-58 weeks). Table 11 provides details of the Partial / Minor Responses (PR / MR) in both studies.

Table 10: Evidence of Clinical Activity Table 11: Details of Partial / Minor Responses (PR / MR) Significantly, SNS-595 shows evidence of clinical activity in patients with advanced solid cancers including two patients who achieved partial responses and seventeen patients who achieved stable disease for more than sixteen weeks. As observed from the data, SNS-595 was well tolerated and showed chemical activity with a dosage of 1 week and once every three weeks. The dose-limited toxicity was non-cumulative neutropenia. SNS-595 demonstrated predictable pharmacokinetics with low patient-patient variability. No change in pharmacokinetic parameters was observed after repeated dosing. Useful doses for solid tumor treatments in patients in need thereof include 48 mg / m2 once in three weeks and 15 mg / m2 weekly as described in this Example.

Example 3: Selection of High Content and Microscopy Cells were plated as sub-confluent populations and allowed to grow for 36 hours. The cells were then treated with the compound at the given concentration, during the given period of time. The cells were used fixing 4% formaldehyde and permeabilized with 0.1% triton. The cells were exposed to primary antibodies for 1 hour at 25 ° C at a dilution of 1: 100 in 10% FBS / PBS (anti-pATM-Chemicon, anti-gH2AX-Cell Signaling Technology). The cells were exposed to secondary antibodies for 1 hour at 25 ° C at a dilution of 1: 100 in 10% FBS / PBS. Hoechst staining was carried out in 10% FBS / PBS at concentrations of 500ng / ml. The selection of high content was carried out on a Cellomics Arrayscan instrument using the Spot Detector algorithm.

FIGURE 2 shows HCT116 cells that were dosed with various compounds for periods of 6 hours. Then the cells were fixed and analyzed for the protein phosphorylation state (gH2AX obtained using a fluorescence microscope, pATM images obtained with the ArrayScan VTi). As seen in the figure, treatment with SNS-595 led to the formation of nuclear foci. FIGURES 3-5 illustrate the dependence of focus formation on dose and time. Then the cells were fixed and analyzed for phospho-ATM. The Cellomics Arrayscan software was used to identify the foci (FIGURE 3, orange dots). The quantification of foci was carried out by measuring the fluorescence intensity of the foci (FIGURE 4) or the cells with more than 2 foci (FIGURE 5) as a function of time and concentration of SNS-595.

Example 4: MTT Assay and Sensitization Treatments The cells were plated at 4000 cells per well in a 96-well plate, incubated for 24 hours and then treated with the compound for 72 hours. The cells were then incubated with 5% MTT for 1-2 hours and lysed. The MTT was read colorimetrically at 570nm and the EC50 were determined using linear regression analysis.

The sensitization was carried out with various chemical treatments. The cells were pre-treated for 16 hours with chemical sensitizer before the addition of the drug (the concentrations were as follows: caffeine, 2mM, inhibitor II of DNAPK (brand), lOuM, and wortmanin, ?????. are provided in Table 12. Sensitization was measured as the decrease in EC50 times for cytotoxicity as measured by an MTT assay.

Table 12. Dependence of the DNA damage sensor of SNS-595 1 HCT-116 cells with 6 times lower ATR levels. 5 2 M059J (DNAPKcs (- / -)) vs M059K (DNAPKcs (+ / +)). 3 HCT-116 cells treated with 2mM caffeine to destabilize ATM and ATR kinase activities. 4 Analysis of FACS, population of asynchronous cells. 5 Analysis of FACS, population of synchronous cells 10 6 Fraction of the cell cycle to achieve 50% of the maximum activation of caspase-3 if it is dosed at 30 times above the EC50 for cytotoxicity.

The data indicates that the SNS-595 shows a unique PIKK dependency. While ATM / ATR and DNAPK are activated after treatment with SNS-595, only DNAPK is required for DNA repair and the cells are sensitive to SNS-595 only when the activity of DNAPKcs is decreased. ATM / ATR mediates a stop at checkpoint G2. The loss of the G2 checkpoint does not sensitize the SNS-595 cells. In contrast to SNS-595, all other DSB-inducing agents tested use ATM / ATR for repair, and show sensitization when ATM or DNAPK activities are inhibited.

Example 5: Repair of DNA damage in the absence of ATM and ATR kinases that detect DNA damage HCT-116 cells were treated with 10 mM SNS-595 or 10 mM etoposide for 6 hours with or without 2mM caffeine. The compound was then removed and the cells allowed to recover for 16 hours. The cells were analyzed for gH2AX foci before and after elimination by the drug. As seen in FIGURE 6, DNA damage induced by SNS-595 is rapidly repaired in the absence of ATM and ATR. In contrast, other drugs, (e.g., Etoposides), use ATM and ATR for DNA repair. The caffeine treatment inhibits ATM and ATR activities, which leads to defects in homologous recombination, nucleotide excision repair and incompatibility repair.

Example 6: Repair of DNA damage in the absence of the DNA-PK kinase that detects DNA damage M059K cells (wild type) and M059J (DNAPKcs (- / -)) were treated with 10 mM SNS-595 or etoposide 10 mM for 6 hours. The compound was then removed and the cells allowed to recover for 16 hours. The cells were analyzed for gH2AX foci before and after elimination by washing the drug. As seen in FIGURE 7, damage by SNS-595 is not repaired effectively in the absence of DNA-PK. In comparison, the damage induced by other drugs (e.g. Etoposide) is repaired quickly.

Example 7: Combination Studies with SNS-595 Cell Lines and Cell Culture: Cell lines HCT116 and NCI-H460 were obtained from ATCC. SKOV3 (p53 - / -) and SKOV3 (p53 + / +) were obtained from the laboratory of Dr. George Stark of the Lerner Institute of the Cleveland Clinic. All cell lines were cultured in RPMI medium supplemented with 10% FBS, 1% Sodium Bicarbonate solution and 1% Antibiotic Solution (Cellgro). MTT assay: Cells were plated at 4000 cells per well (except SKO V3 (p53 - / -) which was plated at 8000 cells per well) in a 96-well plate, incubated for 24 hours and then treated with the compound. The treatment with the compound lasted 72 hours. The cells were then incubated with 5% MTT for 1-2 hours, and lysed. The MTT was read colorimetrically at 570 nm. The fraction of dead cells was determined by the following formula: Fraction of dead cells = 1 - [Abs of the sample well - Average (Abs of the control without cells)] / [Average (Abs of the control of only DMSO) - Average (abs of the control without cells)] Programming studies: When the compounds were dosed with a program that included a washout, the cells were washed with ??? μ? of a warm medium freshly prepared for 30 minutes, followed by another wash after 90 minutes. Statistical Analysis: The data (Fraction of dead cells) were analyzed using Calculsyn. V2 (Biosoft) and are represented here as the value of the Combination index in the affected Fraction (Fa) = 0.5. All data are shown with error bars indicating confidence intervals at 95% of the mean value.

A combination is said to be additive if it produces a Combination Index of 0.85-1.2. A combination is said to be synergistic if it produces a Combination Index of less than 0.85 and a combination is said to be antagonistic if it produces a combination index of more than 1.2. See FIGURES 8-10. As seen in FIGURES 8a-8d, the SNS-595 dosed simultaneously with various cytotoxics in the HCT116 colon carcinoma cell line (8a, 8b and 8c) and the lung cancer cell line H460 8 (d) showed significantly synergistic or at least additive combination indices . As seen in FIGURE 9, SNS-595 dosed simultaneously with a selection of DNA-damaging agents and antimetabolites did not show a significant change in the combination rate between the SKO V3 cell line of ovarian cancer with or without p53 expression . As seen in FIGS. 10a-10d, SNS-595 could be antagonistic when SNS-595 was co-dosed, or dosed with a 24-hour delay, with docetaxel (see FIGURES 10a and 10c) and gemcitabine (see FIG. , FIGURES 10b and 10d) in HCT116 colon carcinoma cells. Antagonism could have been reduced by dosing the SNS-595 first (see, FIGURES 10c and lOd, co-dose and 24 hours) versus dosing the other agents first (see FIGURES 10a and 10b, co-dose and 24 hours). The activity or possible synergy was achieved when the cells were treated with the first agent, washed and then treated with the second agent (see FIGURES lOa-d, wash for 2 hours and wash for 24 hours).

Example 8: Cell Viability Assay MTT-Leukemia Cells: The following cell lines were used in this assay: HL-60 (promyelocytic leukemia); Jurkat (T-cell leukemia); CCRF-CEM (lymphoblastic leukemia); CEM / C2 (camptothecan-resistant derivative of CCRF-CEM). The cells were cultured in 96-well plates at 3000 cells per well and incubated for 16 hours. Dilutions of the compound were made in DMSO from 10 μM with triple dilutions. The triturations were diluted 1: 100 in a medium to achieve final concentrations of the compound. The 96-well plates were aspirated and the dilutions of the compound in the medium were added (100ml / well). The MTT analysis was carried out after 72 hours of incubation at 37 ° C. Briefly, 20ml of MTT solution was added to each well. The cells were incubated at 37 ° C for 1-2 hours. The cells were used with the addition of 100 ml / well of cell lysis buffer and the MTT was solubilized overnight at 37 ° C. The plates were read on a spectromax machine with absorbance measurement at 570nM. IC50's were calculated (data provided in Table 13) using regression analysis within GraphPad Prism. As provided in Table 13, SNS-595 shows potent antiproliferative activity against the hematological cell lines tested.

Table 13: IC50 data for various cell lines Example 9: Xenograft Models LM3-Jck tumor lobes of human malignant lymphoma (2-3mm square) were transplanted subcutaneously in nude mice. The tumors were allowed to grow to approximately 7-14 mm in diameter. Mice were matched in pairs of groups without treatment, treatment with irinotecan (100 mg / kg, IV, q4d x 3), doxorubicin (12 mg / kg, IV, single injection), etoposide (12 mg / kg, IV , qld x5), and SNS-595 (25 and 20 mg / kg, IV, q7d x 5). Acceptable toxicity was defined as a mean group weight loss of 30% or less and no more than one toxic death among 6 treated animals. The activities against drug tumors were assessed 21 days after the start of administration.

Lobes of CCRF-CEM tumors of acute lymphoblastic leukemia in 2-3 mm squares were transplanted subcutaneously in nude mice. The tumors were allowed to grow to approximately 8-20 mm in diameter. Mice were matched in pairs in untreated groups, treated with irinotecan (100 mg / kg, IV, q4d x 3), doxorubicin (12 mg / kg, IV, q7d x 3), etoposide (12 mg / kg, IV, qldx5), and SNS-595 (25 and 20 mg / kg, IV, q7d x 5). Acceptable toxicity was defined as a mean group weight loss of 30% or less and no more than one toxic death among 6 treated animals. The activities against drug tumors were evaluated 20 or 21 days after the start of administration. Table 14 provides the data for tumor inhibition (TI) and the survival rate in the xenograft models CCRF-CEM and LM3-Jck.

Table 14: Comparative activity against tumors of SNS-595 and other anti-cancer drugs As observed from the data in Table 14, SNS-595 administered at 20 and 25 mg / kg shows strong antitumor activity with complete regressions of tumors against malignant lymphoma LM-3 Jck. The tumor inhibition (IR) rate of SNS-595 was similar to that of irinotecan and superior to that of etoposide and doxorubicin in the xenograft models CCRF-CEM and LM3-Jck.

Example 10: Bone marrow / cytology assay Female CD-1 mice were administered with 5, 10, 15, or 20 mg / kg of SNS-595 intravenously on Day 0 and Day 4. Blood was collected on days 6, 8, and 12 after the initial injection for blood tests. Femurs were removed on day 6, fixed in Streck and stained with H &E before analysis of bone marrow cellularity. Two days after the second administration of SNS-595, the bone marrow isolated from the femurs showed a reduction in dose-dependent cellularity. At 20 mg / kg, the cellularity was reduced to 7.5%, while the surrounding neutrophils were reduced from a pre-dose level of 1244 ± 55 cells / mL to a lower point of 51 ± 24 cells / mL in the blood on day 8. Absolute neutrophil counts subsequently reversed and returned promptly to normal levels. Total WBCs also reached a low point on day 8, but returned to normal levels. The dose-dependent decrease in hematopoietic cellularity of the bone marrow is shown in FIGURE 14. FIGURE shows cellularity in the bone marrow 6 days after the initial injection of SNS-595 at various doses. FIGURE 15 shows neutrophil counts of blood samples on days 4, 6, 8, and 12 after the initial injection. As seen in FIGURE 16, all dose groups of SNS-595 demonstrated a significant decrease in peripheral neutrophils on day 8. As observed in FIGURE 17, animals that received injections of 20 mg / kg of SNS -595 had less than 50 cells / ml on day 8. FIGURE 18 shows that there is a lower platelet response on day 8 to the injection of SNS-595. FIGURE 19 shows the percentage change in body weight at various times after administering SNS-595. FIGURE 20 shows the reversal of the effect on bone marrow on day 12 after injection of 20 mg / kg of SNS-595.

Example 11: Clinical Trial Data of SNS-595 in Patients with Hematologic Malignancies SNS-595 was administered to patients with advanced acute or refractory leukemias as a slow IV injection. Diagnoses included AML (19 patients) and ALL (2 patients). All patients had refractory or recurrent disease of the previous therapy (median of 3 previous regimens (range 1-6)). A total of 21 patients (9 women and 12 men, mean age = 64 years, range 21-80) were treated in five groups using two programs. In the first program (A), a seminal dose of SNS-595 was administered for three weeks followed by 7 days of rest (qwk x3). In the second program (B), a dose of SNS-595 was administered twice a week for two weeks (biwk x2). The duration of the cycle, including rest days, was 28 days for both programs. Program A had a total of 3 doses per cycle, and program B had a total of 4 doses per cycle. Additional cycles were allowed if patients achieved stable or better disease. The starting dose was 18 mg / m2 in program A and 9 mg / m2 in program B, and the dosage was increased by group. Groups of 3-6 patients corresponded to doses using a modified Fibonacci sequence. Pharmacokinetic analyzes for SNS-595 were performed on plasma samples collected during cycle 1. Table 15 provides certain pharmacokinetic parameters derived from the study.

Table 15: Pharmacokinetic parameters * Similar PK after administration on Days 4, 8, and 11. The plasma concentrations of SNS-595 were determined using a validated LC-MS / MS assay. Plasma exposures to the first two dose levels for each program increased linearity, resulting in AUC of 4.3-17.8 pghr / mL for doses of 9-27 mg / m2. CL, Vss and terminal half-lives were similar for those in patients with solid tumors, and averaged ~ 2 L / hr / m2, 58 L / m2, and 23 hours, respectively. Six patients distributed throughout all the dosing groups showed in Table 15 experiencing reductions of more than 50% in the peripheral blasts after cycle 1. No dose-limited toxicities (DLTs) up to 27 mg / m2 have been observed in the program qwk x3 or up to 13.5 mg / m2 in the program biwk x2. Toxicities not limited by dose included nausea / vomiting, diarrhea, and mucus. Grade 4 neutropenic fever was observed only in one patient. Other groups of patients were medicated with dosages of 38 mg / m2 and 50 mg / m2, respectively, according to Program A (qwk x3). Still other groups of patients were medicated with dosages of 19 mg / m2 and 25 mg / m2, respectively, according to Program B (biwk x2). The safety data is shown in Table 16.

Table 16: Serious Adverse Events Possibly Related to the Study Drug Useful dosing calendars for the treatment of hematological malignancies may include from about 50 mg / m2 to about 80 mg / m2 administered once a week for three weeks. Another dose that finds use in the treatment of hematological malignancies is approximately 55 mg / m2 to approximately 75 mg / m2 administered once a week for three weeks. Other doses that find use in the treatment of hematological malignancies include 60, 65, 70 or 75 mg / m2 administered once a week for three weeks.

Other dosage calendars useful for the treatment of patients with hematological malignancies may include approximately 25 mg / m2 to approximately 50 mg / m2 administered twice a week for two weeks. Another dose that finds boom in the treatment of hematological malignancies is approximately 30 mg / m2 to approximately 45 mg / m2 administered twice a week for two weeks. Other doses that find use in the treatment of hematological malignancies include 30, 35, 40, or 45 mg / m2 administered twice a week for two weeks. The embodiments of the invention described in the foregoing are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials and methods. All equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.

Claims (51)

1. CLAIMS 1. A method for treating leukemia, which comprises administering to a mammal a therapeutically effective amount of a (+) -1,4-dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) acid. -1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic enantiomerically pure, wherein the leukemia is a chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia or myelogenous leukemia acute 2. The method of claim 1, wherein the leukemia is acute lymphoblastic leukemia. 3. The method of claim 2, wherein the acute lymphoblastic leukemia originates in the blasts of the bone marrow, thymus or lymph nodes. The method of claim 3, wherein the acute lymphoblastic leukemia is a T cell leukemia. The method of claim 4, wherein the T cell leukemia is a peripheral T cell leukemia, cell lymphoblastic leukemia T, cutaneous T cell leukemia or adult T cell leukemia. The method of claim 1, wherein the leukemia is an acute myelogenous leukemia. The method of claim 1, wherein the acute myelogenous leukemia is a myeloblastic leukemia or promyelocytic leukemia. 8. The method of any of claims 1-7, wherein the leukemia is recidivist, refractory or resistant to conventional therapy. The method of one of claims 1-8, wherein the (+) -1,4-dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] acid] Enantiomerically pure 4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid is administered in a dose of about 1 to about 150 mg / m2. The method of claim 9, wherein the dose is from about 1 to about 75 mg / m2. The method of claim 9, wherein the dose is from about 15 to about 80 mg / m2. The method of one of claims 9-11, wherein the dose is from about 50 mg / m2 to about 80 mg / m2 administered once a week. The method of claim 12, wherein the dose is from about 55 mg / m2 to about 75 mg / m2. The method of claim 12, wherein the dose is about 60 mg / m2. 15. The method of claim 12, wherein the dose is about 65 mg / m2. 16. The method of claim 12, wherein the dose is about 70 mg / m2. 17. The method of claim 12, wherein the dose is about 75 mg / m2. 18. The method of claims 12-17, wherein the dose is administered once a week for three weeks. The method of one of claims 9-11, wherein the dose is from about 25 mg / m2 to about 50 mg / m2 administered twice a week. The method of claim 19, wherein the dose is from about 30 mg / m2 to about 45 mg / m2. 21. The method of claim 19, wherein the dose is about 30 mg / m2. 22. The method of claim 19, wherein the dose is about 35 mg / m2. 23. The method of claim 19, wherein the dose is about 40 mg / m2. 24. The method of claim 19, wherein the dose is about 45 mg / m2. 25. The method of 19-24, where the dose is administered for two weeks. 26. The method of one of claims 1-12, wherein the (+) -1,4-dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] acid] Enantiomerically pure 4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid is administered as an IV injection. 27. The method of claim 26, wherein the dose is administered in a rapid IV injection of 10-15 minutes duration. 28. A method for treating cancer comprising administering a dose of about 1 mg / m2 to 75 mg / m2 of a (+) -1,4-dihydro-7- [(3S, 4S) -3-methoxy-4) acid. - enantiomerically pure ((methylamino) -1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid to a mammal in need thereof. 29. The method of claim 28, wherein the cancer comprises a solid tumor and the dose is from about 3 mg / m2 to 24 mg / m2. 30. The method of claim 28 or 29, wherein the dose is about 15 mg / m2. The method of claim 29 or 30, wherein the method comprises administering a dose of (+) - 1,4-dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) - 1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid enantiomerically pure to a mammal once a week, wherein the period of one week comprises a cycle of treatment and the treatment cycle is repeated at least twice. 32. The method of claim 31, wherein the dose is 15 mg / m2. 33. A method for treating cancer comprising administering a dose of about 15 mg / m2 to 80 mg / m2 of a (+) -1,4-dihydro-7- [(3S, S) -3-methoxy-4- ( methylamino) -1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid enantiomerically pure to a mammal in need thereof. 34. The method of claim 28, wherein the cancer comprises a solid tumor and wherein the dose is from about 6 mg / m2 to about 75 mg / m2. 35. The method of claim 34, wherein a single dose is administered as a rapid IV injection for 10-15 minutes, wherein the mammal is a human patient that has been pretreated strongly. 36. The method of claim 35, wherein the dose is from about 45 mg / m2 to about 55 mg / m2. 37. The method of claim 35, wherein the dose is 48 mg / m2. 38. The method of claim 33, wherein the method comprises administering a dose of 15 mg / m2-80 mg / m2 of (+) -1,4-dihydro-7- [(3S, 4S) -3-) acid. methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid enantiomerically pure to a mammal once a week, wherein the period of a week comprises a treatment cycle and the treatment cycle is repeated at least twice. 39. The method of claim 33, wherein the dose is 60 mg / m2. 40. The method of claim 39, wherein the dose is a single dose administered as a rapid IV injection of 10-15 minutes, wherein the mammal is a human patient that has been minimally pretreated. 41. The method of any of claims 28-38, wherein the cancer is a bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, cancer of the head and neck, liver cancer , lung cancer, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer or hematologic malignancy. 42. The method of any of claims 28-41, wherein the cancer is melanoma, myeloma, neuroblastoma, sarcoma, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma or spindle cell carcinoma. 43. The method of any of claims 1-42, further comprising administering a therapeutically effective dose of a second agent. 44. The method of claim 43, wherein the second active agent is a therapeutic antibody to cancer antigen, hematopoietic growth factor, cytokine, anti-cancer agent, antibiotic, cox-2 inhibitor, immunomodulatory agent, immunosuppressive agent, corticosteroid or a pharmacologically active mutant or derivative thereof. 45. The method of claim 44, wherein the antibody is an anti-EFGR antibody. 46. The method of claim 45, wherein the antibody is Erbitux or panitumumab. 47. The method of claim 43, wherein the second active agent is an alkylating agent, an antineoplastic antibiotic, an antimetabolite, a platinum coordination complex, a topoisomerase II inhibitor or radiation. 48. The method of claim 43, wherein the second active agent is etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin, carboplatin, premetrexed, methotrexate, Ara-C, 5-FU, wortmanin, geldanamycin, gemcitabine or a combination thereof. 49. The method of claim 43, wherein the second active agent is docetaxel, doxorubicin, daunorubicin, irinotecan, gefitinib, erlotinib or a combination thereof. 50. A (+) -1,4-dihydro-7- [(3S, 4S) -3-methoxy-4- (distylamino) -1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) -1 acid, Enantiomerically pure 8-naphthyridine-3-carboxylic acid for use in the treatment of leukemia, wherein the leukemia is a chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia or acute myelogenous leukemia. 51. A use of (+) -1, -dihydro-7- [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-l- (2-thiazolyl) acid - enantiomerically pure 1, 8-naphthyridine-3-carboxylic acid in the manufacture of a medicament for treating leukemia, wherein the leukemia is a chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia or acute myelogenous leukemia.