RU2428983C2 - Methods of applying (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thuasolyl)-1,8-naphthydirine-3-carboxylic acid for treatment of cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: methods in accordance with invention relate to introduction of enantiomerically pure (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methyamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiasolyl)-1,8-naphthydirine-3-carboxylic acid in dose from 50 to 90 mg/m² for treatment of myelogenous leukemia leukemia and in dose from 45 to 75 mg/m² for treatment of ovary cancer.

EFFECT: extension of arsenal of medications for treatment of ovary cancer and myelogenous leukemia.

37 cl, 15 tbl, 20 dwg, 11 ex

Description

This application claims priority based on US patent applications No. 11/218387 and 11/218653, both filed September 2, 2005 [and now being converted into provisional US patent applications] and based on provisional US patent applications No. 60/789093 and 60/788927, simultaneously filed April 3, 2006, and 60/810285, filed June 1, 2006. The contents of all these applications are fully incorporated into this description by reference.

1. The field to which the present invention relates

The present application provides methods for treating, preventing or controlling cancer, including certain types of leukemia, by administering enantiomerically pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid, which is also known as SNS-595 AG-7352. Dosages, dosing regimens and dosages of SNS-595 and its administration are also provided.

2. Background of the invention

SNS-595 is (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid of the following structure:

SNS-595 is known for its antitumor activity. In the literature, treatment of SNS-595 of the following forms of cancer has been proposed: bladder cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, melanoma, myeloma, neuroblastoma (i.e. e. 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 are described, for example, in US patent applications No. 2005-0203120; 2005-0215583 and 2006-0025437, the contents of which by reference to them are fully incorporated into the present description.

There remains a need for safe and effective dosages and dosage regimens for administering SNS-595 in the treatment, prevention, or control of various forms of cancer, including leukemia.

3. Summary of the invention

SNS-595 is a known cytotoxic agent used against various types of cancer. In the present description discusses new methods of treatment, including the treatment of certain forms of leukemia. In addition, unusual dosage ranges, regimens, and pharmaceutical doses are described.

Describes the treatment, prevention or fight against cancer using SNS-595, its pharmaceutical compositions and a unique dosage system. In general, types of cancer that can be treated, prevented, or combated using the methods described herein include, but are not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer intestines), cancer of the esophagus, cancer of the head and neck, liver cancer, lung cancer (both small cell and non small cell), melanoma, myeloma, neuroblastoma (i.e. CNS cancer), ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, sarcoma (including osteosarcoma), skin cancer (in lyuchaya squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, and uterine cancer. Cancer may be recurrent, resistant, or resistant to treatment by conventional methods.

In certain embodiments, the cancer includes hematologic malignancies, including, without limitation, leukemia, lymphoma (non-Hodgkin’s lymphoma), Hodgkin’s disease (also called Hodgkin’s lymphoma), and myeloma. Various forms of leukemia include, but are not limited to, chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, and acute myeloid leukemia. Leukemia can be relapsing, resistant, or treatment resistant. In certain embodiments, the hematologic malignant disease is promyelocytic leukemia, T-cell leukemia, or lymphoblastic leukemia.

In addition, methods for treating, preventing, or combating cancer are provided by administering SNS-595 in a specific manner. In a specific embodiment, the methods include administering to the mammal a dose of from about 1 mg / m ² to 150 mg / m ² , from about 1 mg / m ² to 100 mg / m ² , from 1 mg / m ² to 75 mg / m ² , from 15 mg / m ² to 80 mg / m ² or from about 3 mg / m ² to 24 mg / m ² SNS-595 based on body surface area. In a specific embodiment, the methods comprise administering to the mammal a dose of about 15 mg / m ² , 25 mg / m ² or 50 mg / m ² SNS-595 based on body surface area. Additional dosages and administration regimens are described in more detail below in the present description.

Dosage and administration regimens for solid cancers are also provided herein. The administered dose of SNS-595 may be delivered in a single dose, such as, for example, intravenous administration lasting 10-15 minutes (e.g., a single bolus injection) or over a period of time, such as, for example, a 24-hour period (e.g., continuous administration over a period of time or in separate bolus doses over time) and, if necessary, repeated, for example, until the patient has achieved stabilization or the reverse development of the disease, or until the patient progresses to a disease Ania or develop unacceptable toxicity.

In some embodiments, SNS-595 may be administered to a patient in cycles. Cyclic treatment involves the administration of an active agent over a period of time, followed by the administration of the remaining dose over a period of time, and repeating such sequential administration. Cyclic treatment can reduce the development of resistance to one or more treatment methods, avoid or reduce the side effects of one or more treatment methods, and / or increase the effectiveness of treatment.

In another embodiment, SNS-595 is administered in combination with another drug (the “second active agent”) or another treatment method commonly used to treat, prevent or fight cancer, or the dosage methods described in the present description for SNS-595 can be used in combination treatment regimens. Second active agents include known small molecule agents, as well as anti-cancer, antitumor or cytotoxic agents and large molecule agents (e.g., proteins and antibodies), examples of which are described herein, as well as stem cells or umbilical cord blood. Examples of such conventional methods of treatment include, but are not limited to, surgical treatment, chemotherapy, radiation therapy, hormone therapy, biological therapy, immunotherapy, blood transfusion, and combinations thereof.

Thus, in a specific embodiment, the present description provides combinations for the treatment, prevention and control of solid tumors. In another embodiment, the present description provides combinations for the treatment, prevention and control of leukemia and lymphomas.

Also provided are pharmaceutical compositions, unit dosage forms and dosage regimens that include SNS-595 and a second, or additional, active agent. Second active agents include certain combinations, or “shakes,” of drugs or treatments.

4. Brief Description of the Drawings

Figure 1 shows the dynamics of changes in time of the concentration of SNS-595 among different groups of patients receiving the drug according to the qwk × 3 scheme.

Figure 2 illustrates the formation of nuclear foci in HCT116 cells after treatment with SNS-595, etoposide, bleomycin and cisplatin;

figure 3 shows the quantitative determination of foci by measuring the intensity of fluorescence of the foci;

figure 4 illustrates the dependence of the formation of foci on the dose and time;

5 shows cells with more than 2 foci as a function of time and SNS-595 concentration;

6 illustrates DNA damage caused by SNS-595 and etoposide in the presence and absence of caffeine, which is an inhibitor of ATM and ATR;

Fig. 7 shows DNA damage caused by SNS-595 and etoposide in the presence (MO59K cells) and absence (MO59J cells) of PK-DNA;

figa-c show the synergistic / additive effect of co-administration of SNS-595 with various cytotoxic agents on colon carcinoma cells HCT 116 and

fig.8d shows the synergistic / additive effect of co-administration of SNS-595 with various cytotoxic agents on H460 lung cancer cells;

Fig. 9 shows a combination index when SNS-595 is administered simultaneously with the selection of DNA damaging agents and antimetabolites on the SKOV3 (+ / +) and (- / -) ovarian cancer cell lines with respect to p53 expression shown respectively as black and gray rhombuses; and

figa-d demonstrate the effect of co-administration of SNS-595 with various cytotoxic agents on colon carcinoma cells of HCT 116.

11 shows dose linearity when administered 3 times a week (qwk × 3; circles = 1 week; triangles = 2 weeks) and once every 3 weeks (q3wk; diamonds) SNS-595 in patients with advanced solid tumors.

12 is a comparison of the antitumor activity of SNS-595, etoposide, doxorubicin and irinotecan in a CCRF-CEM xenograft model.

On Fig presents a comparison of the antitumor activity of SNS-595 (at a dose of 20 mg / kg and 25 mg / kg), etoposide, doxorubicin and irinotecan model xenograft LM3-Jck.

On Fig shows the cell structure of the bone marrow 6 weeks after the initial injection of SNS-595 in female mice CD-1. SNS-595 was administered on day 0 and day 4. All images are shown with a magnification of 10 ×;

on Fig presents the reaction of neutrophils to a dose of SNS-595;

on Fig presents the number of neutrophils at various doses of SNS-595 to the 8th day;

on Fig presents the number of leukocytes at various doses of SNS-595 to the 8th day;

on Fig presents the number of platelets at various doses of SNS-595 to the 8th day;

on Fig presents the change in percent body weight at various time intervals after the introduction of SNS-595 and

20 shows bone marrow suppression 12 days after administration of 20 mg / kg SNS-595.

5. Definitions

While there are no other definitions, all technical and scientific terms used in the present description have the same meaning that is generally accepted among specialists in this field. The contents of all cited patents, applications, published applications and other publications are fully incorporated into this description by reference. In the event that in the present description there are many definitions of the term, in the absence of other indications, those that are given in this section have an advantage.

As used herein, enantiomerically pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl ) -1,8-naphthyridine-3-carboxylic acid essentially does not contain (-) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl ] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid (i.e., in enantiomeric excess). In other words, the “(+)” form of 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) The -1,8-naphthyridine-3-carboxylic acid is substantially free of the “(-)” form of the compound and is thus present in an enantiomeric excess of the “(-)" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound includes more than 75% by mass, more than 80% by mass, more than 85% by mass, more than 90% by mass, more than 91% by mass, more than 92% of the mass., more than 93% of the mass., more than 94% of the mass., more than 95% of the mass., more than 96% of the mass., more than 97% of the mass. enantiomers.

Used in the present description, and while there are no other indications, the term "enantiomerically pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4 -oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid "refers essentially to about 80% of the mass. (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1.8- naphthyridine-3-carboxylic acid and not more than about 20% of the mass. (-) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8- naphthyridine-3-carboxylic acid, at least about 90% of the mass. (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1.8- naphthyridine-3-carboxylic acid and not more than about 10% of the mass. (-) - enantiomer of at least about 95% of the mass. (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1.8- naphthyridine-3-carboxylic acid and not more than about 5% of the mass. (-) - enantiomer of at least about 97% of the mass. (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1.8- naphthyridine-3-carboxylic acid and not more than about 3% of the mass. (-) - enantiomer.

Used in the present description, and unless otherwise indicated, the terms “treat”, “treat” and “treat” refer to relieve or reduce the severity of the symptom associated with the disease or condition being treated.

The term "prevention" includes inhibition of a symptom of a particular disease or disorder. In some embodiments, patients with a family history of cancer are candidates for prophylactic regimens. In general, the term "prevention" refers to the administration of the drug before the onset of symptoms, in particular to patients at risk of developing cancer.

Used in the present description, and unless otherwise indicated, the term “control” includes preventing the recurrence of a particular disease or disorder in a patient suffering from it, prolonging the time of remission in a patient suffering from a disease or disorder, reducing mortality of patients and / or maintaining a reduction in severity or avoidance a symptom associated with a disease or condition that is being fought against.

As used herein, the term “individual” is an animal, usually a mammal, including a human, such as a patient.

Used in the present description, the term "cancer" includes, without limitation, solid tumors and tumors of the blood system. The term "cancer" refers to a disease of skin tissues, organs, blood and blood vessels, including, without limitation, cancer of the bladder, bone or blood, brain, mammary glands, cervix, chest cavity, colon, endometrium, esophagus, eyes, head, kidneys, liver, lungs, oral cavity, neck, ovaries, pancreas, prostate, rectum, stomach, testicle, throat and uterus.

Used in the present description, the term "hematological malignant disease" refers to the cancer forming the blood and immune systems of the body - bone marrow and lymphatic tissue. Such forms of cancer include leukemia, 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 myeloid leukemia. Leukemia may be recurrent, refractory, or resistant to conventional treatment.

As used herein, the term “promyelocytic leukemia” or “acute promyelocytic leukemia” refers to a malignant bone marrow disease 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, the term "acute lymphocytic leukemia (ALL)", also known as "acute lymphoblastic leukemia", refers to a malignant disease caused by abnormal growth and development of early non-granular white blood cells or lymphocytes.

Used in the present description, the term "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 normally can attack cells infected with viruses, foreign cells and cancer cells, and produce substances that regulate the immune response.

The term "recurrent" refers to a situation in which patients who have remission of cancer after treatment have cancer cells return.

The term "refractory or stable" refers to the circumstance in which patients, even after intensive treatment, have residual cancer cells in their bodies.

As used herein, the term “IC ₅₀ ” refers to the amount, concentration, or dosage of a particular test compound that achieve 50% inhibition of the maximum response in an assay that measures such a response.

Used in the present description, and while there are no other definitions, the terms "therapeutically effective amount" and "effective amount" of a compound refer to an amount sufficient to provide a therapeutic beneficial effect in the treatment, prevention and / or fight against 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 generally improves treatment, reduces or avoids the symptoms or causes of a disease or disorder, or increases the therapeutic efficacy of another therapeutic agent.

Used in the present description, and unless otherwise indicated, the term "pharmaceutically acceptable salt" includes, without limitation, salts of acidic or basic groups that may be present in the compounds described in this description. Under certain acidic conditions, the compound can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable salts of such basic compounds are those which form salts including pharmacologically acceptable anions, including, without limitation, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate , chloride, bromide, iodide, citrate, dihydrochloride, edetate, edisilate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollyl arsylate, hexylresorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate tension, malate, maleate, mandelate, mesylate, methylsulfate, nutmeg, napsylate, nitrate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide and pamoate. Under certain basic conditions, the compound may form base salts with various pharmacologically acceptable cations. Non-limiting examples of such salts include alkali metal or alkaline earth metal salts, in particular calcium, magnesium, sodium, lithium, zinc, potassium and iron salts.

Used in the present description, and unless otherwise indicated, the term "hydrate" means a compound represented in the present description, or its salt, which, in addition, includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

Used in the present description, and unless otherwise indicated, the term "solvate" means a solvate formed by the association of one or more molecules of a solvent with a compound of the present description. The term “solvate” includes hydrates (eg, monohydrate, dihydrate, trihydrate, tetrahydrate and the like)).

The terms “coadministration” and “in combination with” include the administration of two therapeutic agents (eg, SNS-595 and another anticancer agent or a second agent), either simultaneously, jointly or sequentially, without specific time limits. 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 unit dosage forms.

The term "supportive treatment agent" refers to any substance that treats, prevents or cures the side effect caused by treatment with SNS-595.

6. Detailed description of the invention

6.1 SNS-595

The compound for use in the methods and compositions described herein is enantiomerically pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid, which is also known as SNS-595 or AG-7352. 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 obtained by methods known to a person skilled in the art, for example, in accordance with the procedure for obtaining according to example C-1 of US patent No. 5817669, entitled "Compounds, methods for their preparation and antitumor agents", issued October 6, 1998, and Japanese Patent Application No. Hei 10-173986, filed by Chikugi et al., the entire contents of which are incorporated herein by reference. Certain illustrative pharmaceutical compositions, including SNS-595, and methods for their use are described in patent applications US No. 2005-0203120; 2005-0215583 and 2006-0025437, the contents of which are fully incorporated into this description by reference.

6.2 Methods of use

Proliferating cells undergo four phases of the cell cycle: G ₁ , S, G ₂ and M. These phases were first identified by observing dividing cells as cells passed through DNA synthesis, which became known as synthesis or S-phase of the cell cycle and mitosis and is known as mitotic or M-phase or S-phase of the cell cycle. The observed time intervals between the completion of DNA synthesis and mitosis and the interval between mitosis until the next cycle of DNA synthesis are known as phases G ₁ and G _2, respectively. Non-proliferating cells that retain the ability to proliferate under appropriate conditions are at rest or in a state of G ₀ and are usually characterized as excitatory of the cell cycle.

SNS-595 is a cell cycle inhibitor and stops cells at the G ₂ interface. Without being limited to a specific theory, SNS-595 mediates the activation of the DNA-PK pathway (DNA protein kinase), which ultimately leads to apoptotic cell death. These phenomena are specific for the S phase, i.e. they occur only during the S phase of the cell cycle. Without being limited to a specific theory, treatment with SNS-595 leads to an increase in the number of double-strand DNA breaks that form during the S phase. This damage inhibits the ability of the cell to synthesize DNA and lengthens the time that the cell spends on the S phase. Once DNA damage is detected, apoptosis markers quickly appear in the cells. 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 lacking p73, compared to cells containing p73.

As illustrated in FIG. 7, the formation of double-strand breaks activates a dose-dependent manner mediated by DNA-PC repair and apoptotic cell mechanics, including, without limitation: i) expression of DNA-PC; ii) phosphorylation of histone 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 severe enough so that double-strand breaks cannot be restored by the non-homologous terminal compound (NHEJ), the cell quickly enters apoptosis. Some cells are able to reach the G ₂ phase, but subsequently stop (mediated by cdc2 / cyclin B) because the cells are too damaged to enter the M phase and also eventually become apoptotic. Without being limited to a specific theory, since SNS-595 is selective for the S phase, doses of SNS-595 that are cytotoxic to proliferating cells (thus passing through the cell cycle, including the S phase), are non-lethal for non-proliferating cells.

6.2.1 Solid tumors

Accordingly, the present description provides methods of treating, combating or preventing cancerous tumors, comprising administering a dose of from about 1 mg / m ² to about 100 mg / m ² SNS-595 to a mammal in need of such treatment, control or prevention. Cancer types include, but are not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, head and neck cancer, liver cancer, lung cancer (and small cell, and not small cell), melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer and uterine cancer. In one embodiment, the methods include treating, preventing, or combating cancer of the colon, pancreas, breast, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, melanoma, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, kidney cancer, salivary gland cancer, small cell lung or spindle cell carcinoma.

6.2.2 Leukemia

In one embodiment, the methods provided herein include treating, preventing, or combating various types of leukemia, such as chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, and acute myeloid leukemia.

In some embodiments, the methods encompass the treatment, prevention, or control of acute leukemia, such as AML, which includes, without limitation, undifferentiated AML (M0), myeloid leukemia (M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3, or variant M3 [M3V]), myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), megakaryoblastic leukemia (M7). In some embodiments, acute lymphocytic leukemia (ALL) includes leukemia that originates from blast cells of bone marrow (B cells), thymus (T cells), and lymph nodes. Acute lymphocytic leukemia is classified according to the French-American-British (FAB) morphological classification scheme as L1 - lymphoblasts that appear to be mature (T cells or pre-B cells), L2 - immature and pleomorphic (various forms) lymphoblasts (T- cells or pre-B cells) and L3 - lymphoblasts (B cells, Burkitt cells).

In one embodiment, acute myelogenous leukemia is undifferentiated AML (M0).

In one embodiment, acute myelogenous leukemia is myeloid leukemia (M1).

In one embodiment, acute myelogenous leukemia is myeloid leukemia (M2).

In one embodiment, acute myelogenous leukemia is promyelocytic leukemia (M3 or variant M3 [M3V]).

In one embodiment, acute myelogenous leukemia is myelomonocytic leukemia (M4 or variant M4 with eosinophilia [M4E]).

In one embodiment, acute myelogenous leukemia is monocytic leukemia (M5).

In one embodiment, acute myelogenous leukemia is erythroleukemia (M6).

In one embodiment, acute myelogenous leukemia is megakaryoblastic leukemia (M7).

In one embodiment, acute lymphocytic leukemia originates from bone marrow blast cells (B cells).

In one embodiment, acute lymphocytic leukemia originates from the thymus (T cells).

In one embodiment, acute lymphocytic leukemia originates from lymph nodes.

In one embodiment, acute lymphocytic leukemia is an L1 type characterized by appearing mature lymphoblasts (T cells or pre-B cells).

In one embodiment, acute lymphocytic leukemia is an L2 type characterized by immature and pleomorphic (diverse forms) lymphoblasts (T cells or pre-B cells).

In one embodiment, acute lymphocytic leukemia is an L3 type characterized by lymphoblasts (B cells, Burkitt cells).

In certain embodiments, acute myelogenous leukemia is promyelocytic leukemia or lymphoblastic leukemia. In certain embodiments, acute lymphocytic leukemia is T cell leukemia. In one embodiment, the methods provided herein encompass methods of treating, preventing, or controlling 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 leukemia, such as chronic myelogenous leukemia (CML). Thus, SNS-595 treatment may provide an alternative for patients who do not respond to other treatments. In some embodiments, such other treatment methods encompass Gleevac® treatment. In some embodiments, provided herein are methods of treating Philadelphia positive for chronic myelogenous leukemia (Ph + CML). In some embodiments, provided herein are methods of treating Philadelphia chromosome-positive chronic myelogenous leukemia, (Ph + CML) resistant to Gleevac®.

The methods described herein cover the treatment of patients who have previously been treated for cancer but who do not respond to standard methods of treatment, as well as those who have not previously received treatment. Methods of treating patients, regardless of their age, are also covered, although some diseases or disorders are more likely to occur in certain age groups. In addition, methods are provided for treating patients who have undergone surgical treatment while attempting to treat the disease or condition in question, as well as those who have not undergone surgical treatment. Due to the fact that patients with cancer have heterogeneous clinical manifestations and various clinical outcomes, the treatment prescribed for the patient may vary depending on his / her prognosis. An experienced clinician will be able to easily identify, without undue experimentation, certain secondary agents, types of surgery, and types of standard treatment that are not based on drugs that can be effectively used to treat an individual patient with cancer.

The administered dose of SNS-595 can be delivered in a single dose, such as, for example, intravenous administration lasting 10-15 minutes (e.g., a single bolus injection), or over a period of time, such as, for example, a 24-hour period (e.g., continuous administration over time or fractional bolus doses over time), and, if necessary, is repeated, for example, until the patient has stabilized or reverse development of the disease occurs, or until the patient has progressed the disease or do not show Xia unacceptable toxic effects. For example, a stable disease for solid tumors generally means that the perpendicular diameter of the measured lesions did not increase by 25% or more from 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)). A stable disease or its absence is determined by methods known in the art, such as assessing the symptoms of a patient, physical examination, imaging of a tumor that was imaged using radiography, CAT (transaxial computed tomography), PET (positron emission tomography), or MRI scan ( magnetic resonance imaging) and other generally accepted assessment methods.

In another embodiment, the dose is about 10-100 mg / m ² . In another embodiment, the dose is about 30-75 mg / m ² . In another embodiment, the dose is about 40-80 mg / m ² . In another embodiment, the dose is about 50-90 mg / m ² . In another embodiment, the dose is about 15-80 mg / m ² .

In another embodiment, the dose is about 20-30 mg / m ² . In another embodiment, the dose is about 25-35 mg / m ² . In another embodiment, the dose is about 40-50 mg / m ² . In another embodiment, the dose is about 45-55 mg / m ² . In another embodiment, the dose is about 50-60 mg / m ² . In another embodiment, the dose is about 55-65 mg / m ² . In another embodiment, the dose is about 60-70 mg / m ² . In another embodiment, the dose is about 65-75 mg / m ² . In another embodiment, the dose is about 70-80 mg / m ² . In another embodiment, the dose is about 75-85 mg / m ² . In another embodiment, the dose is about 80-90 mg / m ² . In another embodiment, the dose is about 85-95 mg / m ² . In another embodiment, the dose is about 90-100 mg / m ² .

In other embodiments, SNS-595 is administered to a combination with another drug (“second active agent”) or other therapy for treating, controlling, or preventing cancer. Second active agents include small molecules and large molecules (for example, proteins and antibodies), examples of which are presented in the present description, as well as stem cells or umbilical cord blood. Methods or methods of treatment that can be used in combination with the administration of SNS-595 include, but are not limited to, surgical treatment, immunotherapy, biological therapy, radiation therapy, and other types of non-drug therapy currently used to treat, prevent, or fight cancer. In the present description, various dosage regimens for administering SNS-595 alone and / or in combination treatment are discussed.

Pharmaceutical compositions (e.g., unit dosage forms) that can be used in the methods disclosed herein are also provided. Certain pharmaceutical compositions include SNS-595

and a second active agent.

6.3. Doses and dosage regimens

In one embodiment, the methods for treating, preventing, or combating cancerous lesions described herein comprise administering to a patient, based on body surface area, a dose of SNS-595 from about 1 mg / m ² to 150 mg / m ² . In another embodiment, the methods include administering a dose of SNS-595 from about 1 mg / m ² to 100 mg / m ² . In another embodiment, the methods include administering a dose of SNS-595 from about 1 mg / m ² to 75 mg / m ² . In another embodiment, the methods include administering a dose of SNS-595 from about 1 mg / m ² to 60 mg / m ² . In another embodiment, the methods include administering a dose of SNS-595 from about 1 mg / m ² to 50 mg / m ² . In another embodiment, the methods include administering a dose of SNS-595 from about 1 mg / m ² to 48 mg / m ² . In another embodiment, the methods include administering a dose of SNS-595 from about 1 mg / m ² to 24 mg / m ² . In another embodiment, the methods include administering a dose of SNS-595 from about 3 mg / m ² to 27 mg / m ² based on body surface area. In another embodiment, the methods comprise administering a dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² based on body surface area. In another embodiment, the methods include administering a dose of SNS-595 from about 10 mg / m ² to 90 mg / m ² based on body surface area. In another embodiment, the methods include administering a dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² based on body surface area. The surface area of the body can be calculated, for example, according to the Mosteller formula, in which

BSA (body surface area) = square root [(height (cm) × weight (kg) / 3600].

In another embodiment, the dose is from 3 mg / m ² to 24 mg / m ² based on body surface area. In another embodiment, the dose is from 3 mg / m ² to 18 mg / m ² based on body surface area. In another embodiment, the dose is from 3 mg / m ² to 15 mg / m ² . In another embodiment, the dose is 1 mg / m ² , 2 mg / m ² , 3 mg / m ² , 4 mg / m ² , 5 mg / m ² , 6 mg / m ² , 7 mg / m ² , 8 mg / m ² , 9 mg / m ² , 10 mg / m ² , 11 mg / m ² , 12 mg / m ² , 13 mg / m ² , 14 mg / m ² , 15 mg / m ² , 16 mg / m ² , 17 mg / m ² , 18 mg / m ² , 19 mg / m ² , 20 mg / m ² , 21 mg / m ² , 22 mg / m ² , 23 mg / m ² , 24 mg / m ² , 25 mg / m ^2, 26mg / m ² 27mg / m ² 30mg / m ² 36mg / m ² 42mg / m ² 48mg / m ² 50mg / m ^2, 55 mg of / m ² , 60 mg / m ² or 65 mg / m ² calculated on the surface area of the body. In another embodiment, the dose is 3 mg / m ² , 6 mg / m ² , 9 mg / m ² , 12 mg / m ² , 15 mg / m ² , 18 mg / m ² , 21 mg / m ² , 24 mg / m ² , 25 mg / m ² , 27 mg / m ² , 36 mg / m ² , 48 mg / m ² or 50 mg / m ² .

In one embodiment, the dose is 15 mg / m ² based on body surface area. In another embodiment, the dose is 25 mg / m ² based on body surface area. In another embodiment, the dose is 30 mg / m ² based on body surface area. In one embodiment, the dose is 50 mg / m ² based on body surface area.

In another embodiment, the dose is from 15 mg / m ² to 80 mg / m ² based on body surface area. In another embodiment, the dose is from 15 mg / m ² to 75 mg / m ² based on body surface area. In another embodiment, the dose is from 20 mg / m ² to 65 mg / m ² . In another embodiment, the dose is from 30 mg / m ² to 50 mg / m ² . In another embodiment, the dose is 15 mg / m ² , 20 mg / m ² , 25 mg / m ² , 30 mg / m ² , 35 mg / m ² , 40 mg / m ² , 45 mg / m ² , 50 mg / m ² , 55 mg / m ² , 60 mg / m ² , 65 mg / m ² , 70 mg / m ² , 75 mg / m ² or 80 mg / m ² based on body surface area.

The administered dose of SNS-595 can be expressed in units other than mg / m ² . For example, doses can be expressed as mg / kg. The average specialist in this field may well convert the dose from mg / m ² to mg / kg, knowing the growth or weight of the individual, or both of these indicators (see http: ///www.fda.gov/cder/cancer/animalframe.htm) . For example, a dose of 1 mg / m ² to 30 mg / m ² for a person weighing 65 kg is approximately equal to from 0.026 mg / kg to 0.79 mg / kg. In another example, a dose of 3 mg / m ² for a person weighing 65 kg is approximately equal to 0.078 mg / kg. In another example, a dose of 15 mg / m ² to 80 mg / m ² for a person weighing 65 kg is approximately equal to from 0.39 mg / kg to 2.11 mg / kg.

In certain embodiments, the administered dose of SNS-595 can be delivered in a single dose, such as, for example, an intravenous infusion lasting 10-15 minutes (e.g., a single bolus intravenous injection), or over a period of time, such as, for example, a 24-hour period (for example, continuous infusion over time or fractional bolus doses over time), and, if necessary, is repeated, for example, until the patient has stabilized or reverse development of the disease occurs, or until no patient roizoydet disease progression or unacceptable toxic effects manifest. A stable disease or its absence is determined by methods known in the art, such as evaluating the symptoms of a patient, physical examination, and other generally accepted methods of evaluation.

The amount of pharmaceutical composition administered in accordance with the methods provided herein will depend on the mammal to be treated, the severity of the disorder or symptoms of the disorder, the route of administration, frequency of administration and judgment of the prescribing physician.

In some embodiments, the frequency of administration is in the range from a dose administered about 1 time per day to a dose administered about 1 time per month. In certain embodiments, administration is performed once a day, once every 2 days, twice a week, once a week, once every 2 weeks, once every 3 weeks or once every 4 weeks. In one embodiment, the pharmaceutical composition provided herein is administered once a week.

In certain embodiments, SNS-595 is cyclically administered to a patient. Cyclic treatment involves administering an active agent for a period of time, followed by rest for a period of time, and repeating this sequential administration. Cyclic treatment can reduce the development of resistance to one or more treatment methods, avoid or reduce the side effects of one of the treatments, and / or increase the effectiveness of the treatment.

Therefore, in one embodiment, SNS-595 is administered once a week in single or fractional doses in a cycle of 3 to 6 weeks for the rest of the period of about 1 to about 30 days. In another embodiment, SNS-595 is administered once a week in single or divided doses for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 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 embodiments, the waiting period is 14 days. In some embodiments, the waiting period is 28 days. In some embodiments, the waiting period continues until sufficient bone marrow recovery occurs. The frequency, number and duration of the administration cycles can be increased or decreased. Thus, another embodiment encompasses the administration of SNS-595 for more cycles than usual when administered separately.

In one embodiment, the methods provided herein include i) administering to a patient a dose of SNS-595 from about 1 mg / m ² to 150 mg / m ² ; ii) a waiting period of at least 1 day when SNS-595 is not administered to the mammal; and iii) administering to the patient a different dose of SNS-595 from about 1 mg / m ² to 150 mg / m ² . In one embodiment, steps ii) -iii) are repeated multiple times. In another embodiment, the method comprises administering a dose of 1 mg / m ² to 100 mg / m ² in steps i) and iii).

In one embodiment, for example in methods of treating certain leukemia, the methods provided herein include i) administering to a mammal a dose of SNS-595 of about 10-150 mg / m ² ; ii) a waiting period of at least 1 day when SNS-595 is not administered to the mammal; iii) administering to the mammal a different dose of SNS-595 of about 10-150 mg / m ^2; and iv) repeating steps ii) -iii) multiple times. In another embodiment, the method comprises administering a dose of 10-100 mg / m ² in steps i) and iii).

In one embodiment, the methods provided herein include i) administering to a patient a dose of SNS-595 from about 1 mg / m ² to 75 mg / m ² ; ii) a waiting period of at least 1 day when SNS-595 is not administered to the mammal; and iii) administering to the patient a different dose of SNS-595 from about 1 mg / m ² to 75 mg / m ² . In one embodiment, steps ii) -iii) are repeated multiple times.

In one embodiment, the methods provided herein include i) administering to a patient a dose of SNS-595 from about 1 mg / m ² to 48 mg / m ² ; ii) a waiting period of at least 1 day when SNS-595 is not administered to the mammal; and iii) administering to the patient a different dose of SNS-595 from about 1 mg / m ² to 48 mg / m ² . In one embodiment, steps ii) -iii) are repeated multiple times.

In one embodiment, the methods provided herein include i) administering to a patient a dose of SNS-595 from about 1 mg / m ² to 24 mg / m ² ; ii) a waiting period of at least 1 day when SNS-595 is not administered to the mammal; and iii) administering to the patient a different dose of SNS-595 from about 1 mg / m ² to 24 mg / m ² . In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the method comprises administering a dose of about 3 mg / m ² to 24 mg / m ² in steps i) and iii). In yet another embodiment, the method comprises administering a dose of about 15 mg / m ² in steps i) and iii). In yet another embodiment, the method comprises administering a dose of from about 1 mg / m ² to 40 mg / m ² , from about 1.5 mg / m ² to 30 mg / m ² , from about 2 mg / m ² to 25 mg / m ² or from about 3 mg / m ² to 24 mg / m ² in steps i) and iii).

In another embodiment, the method comprises administering a dose of about 15 mg / m ² to 80 mg / m ² in steps i) and iii). In yet another embodiment, the method comprises administering a dose of from about 15 mg / m ² to 75 mg / m ² in steps i) and iii). In yet another embodiment, the method comprises administering a dose of about 20 mg / m ² to 65 mg / m ² , about 30 mg / m ² to 50 mg / m ² , about 35 mg / m ² , about 40 mg / m ² or about 45 mg / m ² in steps i) and iii).

In the methods described above, for example, if the waiting period was 6 days, then the initial dose of SNS-595 is administered on the 1st day (stage i); the waiting period is 6 days (stage ii), and the next dose of SNS-595 is administered on the 8th day (stage iii). Other illustrative time periods 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 embodiment, the waiting period is at least 2 days, and steps ii) through iii) are repeated at least 3 times. In another embodiment, the waiting period is at least 3 days, and steps ii) through iii) are repeated at least 5 times. In another embodiment, the waiting period is at least 3 days, and steps ii) through iii) are repeated at least 3 times. In another embodiment, the waiting period is at least 3 days, and steps ii) through iii) are repeated at least 5 times. In another embodiment, the waiting period is at least 6 days, and steps ii) through iii) are repeated at least 3 times. In another embodiment, the waiting period is at least 6 days, and steps ii) through iii) are repeated at least 5 times. In another embodiment, the waiting period is at least 14 days, and steps ii) through iii) are repeated at least 3 times. In another embodiment, the waiting period is at least 20 days, and steps ii) through iii) are repeated at least 3 times. In another embodiment, the waiting period is at least 20 days, and steps ii) through iii) are repeated at least 5 times. In another embodiment, the waiting period is at least 28 days, and steps ii) through iii) are repeated at least 3 times. In another embodiment, the waiting period is at least 27 days, and steps ii) through iii) are repeated at least 5 times. In another embodiment, the waiting period is at least 28 days, and steps ii) through iii) are repeated at least 5 times.

In another embodiment, the dosage method comprises administering to the mammal a dose of SNS-595 2 times a week (administration on the 1st, 4th, 8th and 11th days). In another embodiment, the dosage method comprises administering to the mammal a dose of SNS-595 once a week. In another embodiment, the dosage method comprises administering to the mammal a dose of SNS-595 every 2 weeks. In another embodiment, the dosage method comprises administering to the mammal a dose of SNS-595 every 3 weeks. In another embodiment, the dosage method comprises administering to the mammal a dose of SNS-595 every 4 weeks.

In another embodiment, the dosage method comprises a cycle, the cycle comprising administering a dose of SNS-595 to a mammal once a week for 3 weeks, followed by a period of at least 14 days when SNS-595 is not administered to the mammal, and the cycle is repeated time. In another embodiment, the period during which no SNS-595 is administered is 14 days. In another embodiment, the period during which SNS-595 is not administered is 21 days.

In another embodiment, the methods provided herein include i) administering to the mammal a dose of SNS-595 from about 1 mg / m ² to 100 mg / m ² once a week for 3 weeks; ii) a waiting period of 14 days when no amount of SNS-595 is administered to the mammal; and iii) administering to the mammal a different dose of SNS-595 from about 1 mg / m ² to 100 mg / m ² once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to the mammal a dose of SNS-595 from about 1 mg / m ² to 75 mg / m ² once a week for 3 weeks; ii) a waiting period of 14 days when no amount of SNS-595 is administered to the mammal; and iii) administering to the mammal a different dose of SNS-595 from about 1 mg / m ² to 75 mg / m ² once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to the mammal a dose of SNS-595 from about 1 mg / m ² to 60 mg / m ² once a week for 3 weeks; ii) a waiting period of 14 days when no amount of SNS-595 is administered to the mammal; and iii) administering to the mammal a different dose of SNS-595 from about 1 mg / m ² to 60 mg / m ² once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, methods provided herein include: i) administering to a mammal a dose of SNS-595 of about 1-50 mg / m ² once a week for 3 weeks; ii) a waiting period of 14 days when no amount of SNS-595 is administered to the mammal; iii) administering to the mammal a different dose of SNS-595 about 1-50 mg / m ² once a week for 3 weeks; and iv) repeating steps ii) -iii) multiple times.

In another embodiment, the methods provided herein include i) administering to a mammal a dose of SNS-595 from about 1 mg / m ² to 48 mg / m ² once a week for 3 weeks; ii) a waiting period of 14 days when no amount of SNS-595 is administered to the mammal; and iii) administering to the mammal a different dose of SNS-595 from about 1 mg / m ² to 48 mg / m ² once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to the mammal a dose of SNS-595 from about 1 mg / m ² to 24 mg / m ² once a week for 3 weeks; ii) a waiting period of 14 days when no amount of SNS-595 is administered to the mammal; and iii) administering to the mammal a different dose of SNS-595 from about 1 mg / m ² to 24 mg / m ² once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to a mammal a dose of SNS-595 from about 2 mg / m ² to 40 mg / m ² once a week for 3 weeks; ii) a waiting period of 14 days when no amount of SNS-595 is administered to the mammal; and iii) administering to the mammal a different dose of SNS-595 from about 2 mg / m ² to 40 mg / m ² once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to a mammal a dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² once a week for 3 weeks; ii) a waiting period of 14 days when no amount of SNS-595 is administered to the mammal; and iii) administering to the mammal a different dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to a mammal a dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² once a week for 3 weeks (e.g., administration in a 1st, 8- th and 15th days); ii) a waiting period of at least 28 days when no mammal is given any amount of SNS-595; and iii) administering to the mammal a different dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to the mammal a dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² 2 times a week for 2 weeks (administration in the 1st, 4th, 8th and 11th days); ii) a waiting period of at least 28 days when no mammal is given any amount of SNS-595; and iii) administering to the mammal a different dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² 2 times a week for 2 weeks (administration on the 1st, 4th, 8th and 11th days ) In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to a mammal a dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² once a week for 3 weeks (e.g., administration in a 1st, 8- th and 15th days); ii) a waiting period of 28 days when no amount of SNS-595 is administered to the mammal; and iii) administering to the mammal a different dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to the mammal a dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² 2 times a week for 2 weeks (administration in the 1st, 4th, 8th and 11th days); ii) a waiting period of 28 days when no amount of SNS-595 is administered to the mammal; and iii) administering to the mammal a different dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² 2 times a week for 2 weeks (administration on the 1st, 4th, 8th and 11th days ) In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to a mammal a dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² once a week for 3 weeks; ii) a waiting period of 14 days when no amount of SNS-595 is administered to the mammal; and iii) administering to the mammal a different dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to a mammal a dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² once a week for 3 weeks (e.g., administration at 1, 8- th and 15th days); ii) a waiting period of at least 28 days when no mammal is given any amount of SNS-595; and iii) administering to the mammal a different dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to the mammal a dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² 2 times a week for 2 weeks (administration in the 1st, 4th, 8th and 11th days); ii) a waiting period of at least 28 days when no mammal is given any amount of SNS-595; and iii) administering to the mammal a different dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² 2 times a week for 2 weeks (administration on the 1st, 4th, 8th and 11th days ) In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to a mammal a dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² once a week for 3 weeks (e.g., administration at 1, 8- th and 15th days); ii) a waiting period of 28 days when no amount of SNS-595 is administered to the mammal; and iii) administering to the mammal a different dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² once a week for 3 weeks. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include i) administering to the mammal a dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² 2 times a week for 2 weeks (administration in the 1st, 4th, 8th and 11th days); ii) a waiting period of 28 days when no amount of SNS-595 is administered to the mammal; and iii) administering to the mammal a different dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² 2 times a week for 2 weeks (administration on the 1st, 4th, 8th and 11th days ) In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the method comprises administering to a patient a dose of SNS-595 from 1 mg / m ² to 100 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least 3 times. In another embodiment, the method comprises administering to a patient a dose of SNS-595 from 1 mg / m ² to 75 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least 3 times. In another embodiment, the method comprises administering to a patient a dose of SNS-595 from 1 mg / m ² to 60 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least 3 times. In another embodiment, the method comprises administering to a patient a dose of SNS-595 from 1 mg / m ² to 48 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least 3 times. In another embodiment, the method comprises administering to a patient a dose of SNS-595 from 1 mg / m ² to 24 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least 3 times. In another embodiment, the dose of SNS-595 is from about 2 mg / m ² to 40 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least 3 times. In another embodiment, the dose of SNS-595 is from about 3 mg / m ² to 24 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least 3 times. In another embodiment, the dose of SNS-595 is about 15 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least 3 times.

In another embodiment, the method comprises administering a dose of SNS-595 from 15 mg / m ² to 80 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least 3 times. In another embodiment, the method comprises administering a dose of SNS-595 from 15 mg / m ² to 75 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least 3 times. In another embodiment, the method comprises administering a dose of SNS-595 from 20 mg / m ² to 65 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least 3 times. In another embodiment, the method comprises administering a dose of SNS-595 from 30 mg / m ² to 50 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least 3 times.

In some embodiments, the method comprises administering to a patient a dose of SNS-595 from about 1 mg / m ² to 40 mg / m ² once a week (for example, administration on days 1, 8, and 15), where Week 1 includes a treatment cycle, and the treatment cycle is repeated at least 3 times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering to a patient a dose of SNS-595 from about 1 mg / m ² to 40 mg / m ² 2 times a week (administration on the 1st, 4th, 8th and 11th days), where a period of 1 week includes a treatment cycle, and the treatment cycle is repeated at least 3 times with a subsequent waiting period of at least 28 days. In some embodiments, the method comprises administering to a patient a dose of SNS-595 from about 1 mg / m ² to 40 mg / m ² once a week (for example, administration on days 1, 8, and 15), where Week 1 includes a treatment cycle, and the treatment cycle is repeated at least 3 times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering to a patient a dose of SNS-595 from about 1 mg / m ² to 40 mg / m ² 2 times a week (administration on the 1st, 4th, 8th and 11th days), where a period of 1 week includes a treatment cycle, and the treatment cycle is repeated at least 3 times with a subsequent waiting period of at least 28 days.

In some embodiments, the method comprises administering to a patient a dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² once a week (for example, administration on days 1, 8, and 15), where Week 1 includes a treatment cycle, and the treatment cycle is repeated at least 3 times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering to a patient a dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² 2 times a week (administration on the 1st, 4th, 8th and 11th days), where a period of 1 week includes a treatment cycle, and the treatment cycle is repeated at least 3 times with a subsequent waiting period of at least 28 days. In some embodiments, the method comprises administering to a patient a dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² once a week (for example, administration on days 1, 8, and 15), where Week 1 includes a treatment cycle, and the treatment cycle is repeated at least 3 times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering to a patient a dose of SNS-595 from about 3 mg / m ² to 24 mg / m ² 2 times a week (administration on the 1st, 4th, 8th and 11th days), where a period of 1 week includes a treatment cycle, and the treatment cycle is repeated at least 3 times with a subsequent waiting period of at least 28 days.

In some embodiments, the method comprises administering to the patient a dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² once a week (for example, administration on days 1, 8 and 15), where the period Week 1 includes a treatment cycle, and the treatment cycle is repeated at least 3 times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering to a patient a dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² 2 times a week (administration on the 1st, 4th, 8th and 11th days), where a period of 1 week includes a treatment cycle, and the treatment cycle is repeated at least 3 times with a subsequent waiting period of at least 28 days. In some embodiments, the method comprises administering to the patient a dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² once a week (for example, administration on days 1, 8 and 15), where the period Week 1 includes a treatment cycle, and the treatment cycle is repeated at least 3 times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering to a patient a dose of SNS-595 from about 15 mg / m ² to 80 mg / m ² 2 times a week (administration on the 1st, 4th, 8th and 11th days), where a period of 1 week includes a treatment cycle, and the treatment cycle is repeated at least 3 times with a subsequent waiting period of at least 28 days.

In another embodiment, the method comprises administering to the mammal a dose of SNS-595 from about 1 mg / m ² to 50 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least 2 times. In another embodiment, the dose is from about 2 mg / m ² to 40 mg / m ² . In another embodiment, the dose is from about 3 mg / m ² to 24 mg / m ² . In another embodiment, the dose is from about 4 mg / m ² to 20 mg / m ² .

6.4 Illustrative dosage regimens

The following are illustrative dosage regimens for certain types of cancer. These dosage regimens are intended to be illustrative but not exclusive.

In one aspect, a method for treating a solid tumor is provided. The method includes:

i) administering to the patient a dose of SNS-595 from about 1 mg / m ² to 100 mg / m ² ;

ii) a waiting period of at least 6 days when SNS-595 is not administered to a subject at all;

iii) administering to the patient a different dose of SNS-595 from about 1 mg / m ² to 100 mg / m ² ; and

iv) repeating steps ii) -iii) many times.

In another aspect, a method for treating solid tumors comprises administering to a patient a dose of SNS-595 from about 1 mg / m ² to 75 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least twice . In another embodiment, the dose is from about 15 mg / m ² to 80 mg / m ² . In another embodiment, the dose is from about 3 mg / m ² to 24 mg / m ² .

In another aspect, a method for treating solid tumors comprises administering to a patient a dose of SNS-595 from about 15 mg / m ² to 40 mg / m ² once a week for 3 weeks, followed by a period of at least 2 weeks, during which the SNS -595 is not administered to the indicated subject, and where the cycle is repeated many times. In another embodiment, the dose is from about 15 mg / m ² to 35 mg / m ² . In another embodiment, the dose is from about 20 mg / m ² to 30 mg / m ² . In another embodiment, the dose is from about 20 mg / m ² to 25 mg / m ² .

In another aspect, a method for treating solid tumors comprises administering to a patient a dose of SNS-595 from about 35 mg / m ² to 80 mg / m ² 1 time over a 3-week period, where the 3-week period includes a treatment cycle and the treatment cycle is repeated, according to at least twice.

In another aspect, the present disclosure provides a method for treating hematologic malignant diseases. Such methods in certain embodiments include administering to a patient a dose of SNS-595 from about 20 mg / m ² to 60 mg / m ² .

In patients who are believed to have received intensive pretreatment (“patients receiving intensive pretreatment”), the method comprises administering to the patient a dose of SNS-595 from 35 mg / m ² to 60 mg / m ² 1 time over a 3-week period where the 3-week period includes a treatment cycle, and the treatment cycle is repeated at least twice. In another embodiment, a method of treating a patient receiving intensive pretreatment comprises administering a dose of 40 mg / m ² to 50 mg / m ² . In another embodiment, a method of treating a patient receiving intensive pretreatment comprises administering a dose of 45 mg / m ² to 50 mg / m ² . A patient receiving intensive pretreatment is determined as described in Tochler et al., J. Clin. Oncol. 19: 2937-2947 (2001), and represents a patient who has previously received treatment with more than 6 courses of a chemotherapy regimen containing an alkylating agent, more than 2 courses of carboplatin or mitomycin C, any previous course containing nitrosourea, irradiation of 25% of the areas, containing bone marrow, high-dose chemotherapy, requiring repeated stem cell infusions, or with widespread bone metastases.

Patients who have not previously received treatment for their solid tumors, or who received treatment but are not considered to have received intensive pre-treatment, are receiving minimal pre-treatment (“patients receiving minimal pre-treatment”). For the treatment of patients receiving minimal pretreatment, the method comprises administering to the patient a dose of SNS-595 from 45 mg / m ² to 80 mg / m ² 1 time per 3-week period, where the 3-week period includes a treatment cycle and the treatment cycle is repeated at least twice. In another embodiment, a method of treating a patient receiving minimal pretreatment comprises administering a dose of 50 mg / m ² to 75 mg / m ² . In another embodiment, a method of treating a patient receiving minimal pretreatment comprises administering a dose of 55 mg / m ² to 70 mg / m ² . In another embodiment, a method of treating a patient receiving minimal pretreatment comprises administering a dose of 55 mg / m ² to 65 mg / m ² .

In another aspect, a method of treating hematologic cancer such as leukemia and lymphoma is provided. The method includes:

i) administering to the patient a dose of SNS-595 from about 1 mg / m ² to 50 mg / m ² ;

ii) a waiting period of at least 2 days when SNS-595 is not administered to a subject at all;

iii) administering to the patient a different dose of SNS-595 from 10 mg / m ² to 50 mg / m ² ; and

iv) repeating steps ii) -iii) many times.

In one embodiment, the waiting period is 6 days. In another embodiment, the waiting period is 2 days. In another embodiment, the waiting period is 3 days.

In one embodiment, a method of treating a hematologic malignant disease comprises administering to a patient a dose of SNS-595 of about 20 mg / m ² , 22 mg / m ² , 25 mg / m ² , 27 mg / m ^2, or 30 mg / m ² once a week where a period of 1 week includes a treatment cycle, and the treatment cycle is repeated at least twice. In one embodiment, a method of treating a hematologic malignant disease comprises administering to a patient a dose of SNS-595 of about 25 mg / m ² once a week, where a period of 1 week includes a treatment cycle and the treatment cycle is repeated at least twice.

Other dosage regimens that can be used to treat patients with hematologic malignancies may include from about 25 mg / m ² to about 50 mg / m ² administered 2 times a week for 2 weeks. In another embodiment, dosage regimens for treating hematologic malignancies include from about 30 mg / m ² to about 45 mg / m ² , administered 2 times a week for 2 weeks. In another embodiment, dosage regimens for treating hematologic malignancies include 30, 35, 40, or 45 mg / m ² administered 2 times a week for 2 weeks.

In one embodiment, a method of treating a hematologic malignant disease comprises administering to a patient a dose of SNS-595 of about 40 mg / m ² , 45 mg / m ² , 50 mg / m ² , 55 mg / m ^2, or 60 mg / m ² once every 2 weeks where the 2-week period includes a treatment cycle. In one embodiment, a method of treating a hematologic malignant disease comprises administering to a patient a dose of SNS-595 of about 50 mg / m ² once every 2 weeks, where the 2-week period includes a treatment cycle.

6.5 Combination treatment

In the methods described herein, SNS-595 can be used or combined with other pharmacologically active compounds (the "second active agent"). Certain combinations are believed to work synergistically in the treatment of certain types of cancer. SNS-595 may also work to alleviate side effects associated with certain second active agents, and some second active agents may be used to alleviate side effects associated with SNS-595.

6.5.1 Second active agents

In the methods and compositions described herein, together with SNS-595

one or more second active ingredients or agents may be used. The second active agents may be large molecules (e.g., proteins) or small molecules (e.g., synthetic, inorganic, organometallic or organic molecules).

Examples of active agents, which are large molecules, include, without limitation, hematopoietic growth factors, cytokines and monoclonal and polyclonal antibodies, in particular therapeutic antibodies to cancer antigens. Typical active agents based on large molecules are biological molecules, such as naturally occurring or artificially produced proteins. Proteins that find particular use in the methods and compositions provided herein include proteins that stimulate the survival and / or proliferation of hematopoietic progenitor cells and immunologically active poetic cells in vitro and in vivo . Others stimulate the division and differentiation of committed erythroid progenitors in vitro or in vivo cells. Specific proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II ("rIL2") and IL-2 vaccines against avian leukemia), IL-10, IL-12 and IL-18; interferons, such as interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-1a, interferon gamma-1b; G-CF (factor stimulating the formation of colonies of granulocytes), GM-CSF (factor stimulating the formation of colonies of granulocytes-macrophages) and EPO (erythropoietin).

Specific proteins that can be used in the methods and compositions include, without limitation, filgrastin, which is sold in the United States under the trade name Neupogent® (Amgen, Thousand Oaks, CA), and its derivatives, including, without limitation, pegfilgrastin; sargramostim, which is sold in the United States under the trade name Leukine® (Immunex, Seattle, WA); recombinant EPO, which is sold in the United States under the trade name Epogen® (Amgen, Thousand Oaks, CA); epoetin alfa and darbepoetin alfa.

Recombinant and mutated forms of GM-CSF can be obtained as described in US patent No. 5391485; 5393870 and 5229496, the contents of which are fully incorporated into this description by reference. Recombinant and mutated forms of G-CSF can be obtained as described in US patent No. 4810643; 4,999,291; 5528823 and 5580755, the contents of which are fully incorporated into this description by reference.

Native, naturally occurring, and recombinant proteins are also provided for use in combination with SNS-595. In addition, mutants and derivatives (eg, modified forms) of naturally occurring proteins that exhibit in vivo at least some pharmacological activity of the proteins on which they are based are encompassed. Examples of mutants include, without limitation, proteins that have one or more amino acid residues that differ from the corresponding residues in naturally occurring forms of proteins. Also covered by the term “mutants” are proteins that do not have hydrocarbon moieties typically present in their naturally occurring forms (eg, non-glycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by the fusion of IgG1 or IgG3 with a protein or active portion of a protein of interest (see, for example, Penichet, ML and Morrison, SL, 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 (Riruxan®), bevacizumab (Avastin ^TM ), pertuzumab (Omnitarg ^TM ), tositumomab (Bexxar®), edrecolomab (Panorex®) and G250. SNS-595 can also be combined or used in combination with antibodies against TNF-α (tumor necrosis factor-alpha) and / or antibodies against EGFR (epidermal growth factor receptors), such as, for example, Erbitux® or panitumumab.

Active agents, which are large molecules, can be administered in the form of anti-cancer vaccines. For example, vaccines that secrete or cause the secretion of cytokines such as IL-2, G-CSF and GM-CSF can be used in the provided methods and pharmaceutical compositions of the vaccines (see, for example, Emens, LA, et al., Curr. Opinion Med. Ther. 3 (1): 77-84 (2001).

In contrast to the general rule that drugs with a different mechanism of action should be selected to maximize the likelihood of an additive or synergistic effect (see, for example, Page, R. And Takimoto, C., “Principles of Chemotherapy”, Cancer Management: A Multidisciplinary Approach (2001), p. 23), it has been found that combinations comprising SNS-595 and a second agent that also inhibits DNA synthesis are additive or synergistic.

As used in the present description, the tool inhibits DNA synthesis when it directly or indirectly affects the ability of a cell to synthesize DNA or repair DNA damage. The tool can also directly interact with DNA (for example, bind or intercalate with it) or it can bind to a DNA binding protein that is involved in DNA synthesis or DNA repair. In general, an agent that inhibits DNA synthesis is active during the S phase, but should not be specific to the S phase.

Since SNS-595 acts on the DNA-PK pathway, the second agent may be one that mediates its cytotoxicity through the DNA-PK pathway. One example is an agent that inhibits non-homologous repair of a terminal compound, such as DNA-PK inhibitors. Unless otherwise indicated, the term “DNA-PK inhibitor” as used herein means an agent that inhibits or inhibits DNA-PC mediated signaling pathways. Inhibition of DNA-PK activity can be direct (e.g., the catalytic DNA-PK inhibitor itself) or indirect (e.g., an agent that inhibits the formation of an active DNA-PK complex (DNA-PC, Ku70 and Ku80). Other examples include, but are not limited to, caspase-9 activators, caspase-3 activators, and Hsp90 inhibitors.

Second active agents, which are small molecules, can also be used to alleviate the adverse side effects associated with the administration of SNS-595. However, like some large molecules, many of them are considered capable of providing a synergistic effect when administered with (for example, before, after, and simultaneously) SNS-595. Examples of small molecule second active agents include, but are not limited to, anti-cancer agents, antibiotics, immunosuppressive agents, and steroids.

Examples of anti-cancer agents include, but are not limited to, alkylating agents, anti-neoplastic agents, antimetabolites (e.g., folate analogues, purine analogs, adenosine analogs, pyrimidine analogs and substituted ureas), platinum coordination complexes, topoisomerase II inhibitors, and radiation.

Specific anti-cancer agents include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronin; adoselesin; aldesleukin; altretamine; ambomycin; amethantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; bathimastat; benzodepa; bicalutamide; bisanthrene hydrochloride; bisnafide dimesilate; biselezin; bleomycin sulfate; brechinar sodium; bropyrimine; busulfan; carcinomycin; calosterone; capecitablin; caratsemid; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cyrolemicin; cisplatin; cladribine; Crisnatol Mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; desaguanine, desaguanine mesylate; diazikhon; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromat; epipropidine; epirubicin hydrochloride; erbulosol; erlotinib; esorubicin hydrochloride; estramustine; sodium estramustine phosphate; ethanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; phasarabine; phenretinide; phloxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; phoschidone; fostriecin sodium; gefitinib; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosin; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; loxoxantrone hydrochloride; masoprokol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedep; mitindomide; mitocarcin; mitocromine; mitogillin; Mithalcin; mitomycin; mitosper; mitotan; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; Peliomycin; pemetrexed; pentamustine; peplomycin sulfate; perphosphamide; pipobroman; piposulfan; pyroxantrone hydrochloride; plicamycin; plomestan; porphymer sodium; porphyromycin; predimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine; simtrazen; sodium sparfosate; sparsomycin; spiro germanium hydrochloride; spiramustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxiron; testolactone; thiamiprine; thioguanidine; thioguanine; thiotepa; thiazofurin; tirapazamine; toremifene citrate; trestolone acetate; tricyribine phosphate; trimethrexate; trimerexate glucuronate; triptorelin; tubulozole hydrochloride; uracilitis; uredep; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepyridine sulfate; winglicinate sulfate; vinlerosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; sparrow; zeniplatin; zinostatin; and zorubicin hydrochloride.

Other anti-cancer drugs include, but are not limited to: 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulven; adecenol; adoselesin; aldesleukin; ALL-TK antagonists (thymidine kinase of acute lymphoblastic leukemia); altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenic protein-1; antiandrogen used for prostate carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicoline glycinate; apoptotic gene modulators; regulators of apoptosis; apuric acid; ara-CDP-DL-PTBA (1-β-D-Arabinofuranosylcytosine-5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol); arginine deaminase; asulacrine; atamestan; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azathyrosine; baccatin III derivatives; balanol; bathimastat; antagonists of BCR / ABL (chimeric gene); benzochlorins; benzoylstaurosporin; beta-lactam derivatives; beta aletin; betaclamycin B; betulinic acid; bFGF inhibitor (main fibroblast growth factor); bicalutamide; bisanthrene; bisaziridinylspermin; bisnafide; bistrate A; biselezin; breflat; bropyrimine; Budotitan butionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; capecitabine; carboxamide amino triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cisaprost; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; collismycin A; collismicin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; Cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine oxphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dextrazoxane; dexverapamil; diaziquon; didemnin B; didox; diethylnorspermin; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxyfluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselin; ecomustine; edelfosin; edrecolomab; eflornithine; elemen; emitfur; epirubicin; episteride; estramustine analogue; estrogen agonists; estrogen antagonists; ethanidazole; etoposide phosphate; exemestane; fadrozole; phasarabine; phenretinide; filgrastim; finasteride; flavopyridol; fezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustin; gadolinium texafirin; gallium nitrate; halocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; Heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramanton; ilmofosin; ilomastat; imatinib (e.g. Gleevec®); imiquimod; immunostimulatory peptides; an insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; yobenguang; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladin; isobengazole; isohomogalicondrin B; itetetron; jasplacinolide; kagalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear analogue of polyamine; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; loxoxantrone; loxoribine; lurtotecan; lutetium texafirin; lysophylline; lytic peptides; maytansine; mannostatin A; marimastat; masoprokol; maspin matrilisin inhibitors; matrix metalloproteinase inhibitors; menogaril; Merbaron; meterelin; methioninase; metoclopramide; an inhibitor of MIF (factor inhibiting macrophage migration); mifepristone; miltefosin; myrimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide; fibroblast growth factor mitotoxin - saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, human chorionic gonadotropin; monophosphoryl lipid A + myobacteria cell wall framework; mopidamol; mustard anti-cancer agent; mikaperoxide B; mycobacterial cell wall extract; Miriaporon; N-acetyldyline; N-substituted benzamides; nafarelin; Nagrestip; naloxone + pentazocine; napavin; natterpine; nartograstim; nedaplatin; nemorubicin; non-uronic acid; nilutamide; nisamycin; nitrogen oxide modulators; nitroxide antioxidant; nitrulline; oblimersen (Genasense®); O ⁶ -benzylguanine; octreotide; ocicenone; oligonucleotides; shepriston; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogs; paclitaxel derivatives; palauamine; palmitoylrizoxin; pamidronic acid; panaxitriol; panomiphene; parabactin; pazelliptin; pegaspargase; peldesin; sodium pentosan polysulfate; pentostatin; pentrozole; perflubron; perphosphamide; perilyl alcohol; phenazinomycin; phenyl acetate; phosphatase inhibitors; picybanil; pilocarpine hydrochloride; pyrarubicin; pyritrexime; placentin A; placentin B; plasminogen activator inhibitor; platinum complex; platinum compounds; a platinum triamine complex; porphymer sodium; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazolacridine; pyridoxylated hemoglobin-polyoxyethylene conjugate; raf antagonists (alpha-fetoprotein regulator); altitrexed; ramosetron; ras (acceptor protein) farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; demethylated retelliptin; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogitukin; romurtide; rockvinimex; rubiginon B1; ruboxyl; safingol; sintopin; SarCNU (2-chloroethyl-3-sarcosinamide-1-nitrosourea); sacrophytol A; sargramostim; Sdi 1 mimetics; semustine; inhibitor 1 obtained during the aging period; semantic oligonucleotides; signal transduction inhibitors; sisofiran; sobuzoxan; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermine; sparfosic acid; spicamycin D; spiramustine; splenopeptin; spongistatin 1; squalamine; stipiamide; stromelisin inhibitors; sulfinosine; overactive vasoactive intestinal peptide antagonist; a suradist; suramin; swainsonin; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; telluropyrilium; telomerase inhibitors; temoporfin; teniposide; tetrachloride decoxide; tetrazomine; Taliblastin thiocoralin; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid-stimulating hormone; ethylethiopurpurine tin; tirapazamine; titanocene bichloride; topsentin; toremifene; translation inhibitors; tretinoin; triacetyluridine; tricyribine; trimethrexate; triptorelin; tropisetron; tourosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; growth inhibitory factor derived from urogenital sinus; urokinase receptor antagonists; vapreotide; variolin B; velarezole; veramine; verdins; verteporfin; vinorelbine; winxaltin; vitaxin; sparrow; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Certain second active agents include, but are not limited to, rituximab, oblimersen (Genasense®), remicad, docetaxel, celecoxib, melphalan, dexamethasone (Decardon®), steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temodar, proclad carboplatin, , 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, thiotepa, carboplatin, liposomal daunorubicin, c tarabine, doxetaxel, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin, doxorubicilin, gamicanclacin, paclitaxin, paclitaxin, paclitaxin 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 (5-fluorouracil), wortmannin, gemcitabine, geldanamycin, or a combination thereof.

In other embodiments, the second active agent is a supportive treatment agent. An example of a supportive care agent is an antiemetic. Certain antiemetics include, but are not limited to, phenothiazines, butyrophenones, benzodiazepines, corticosteroids, serotonin antagonists, cannabinoids, and NK ₁ receptor antagonists. Examples of phenothiazine antiemetics include, but are not limited to, prochlorperazine and trimethobenzamide. Examples of butyrophenone antiemetics include, but are not limited to, haloperidol. Examples of benzodiazepine antiemetics include, but are not limited to, lorazepam. Examples of corticosteroid antiemetics include, but are not limited to, dexamethasone. Examples of antiemetics in the form of serotonin antagonists include, without limitation, ondansetron, granisetron and dolasetron. Examples of cannabinoid antiemetics include, but are not limited to, dronabinol. Examples of antiemetic agents in the form of NK ₁ receptor antagonists include, but are not limited to, aprepitant. Dosages and dosage regimens for antiemetics should depend on the particular indication being treated, the age and condition of the patient, and the severity of side effects, and can accordingly be selected by specialists in this field. Examples of dosages and dosage regimens can be found, for example, in The Physician's Desk Reference.

6.5.2 Illustrative combination treatment methods

In certain embodiments, the methods provided herein comprise administering SNS-595 in combination with one or more second active agents and / or in combination with radiation therapy or surgical treatment. The administration of SNS-595 and the second active agent to the patient can occur simultaneously or sequentially in the same or different routes of administration. The suitability of the particular route of administration used for the particular active agent will depend on the active agent itself (for example, whether it can be administered orally without disruption before entering the blood stream) and the disease being treated. Recommended routes of administration for the second active agent are known to those of ordinary skill in the art (see, for example, Physician's Desk Reference (60th ed., 2006).

In one embodiment, the second active agent is administered intravenously or subcutaneously and 1 or 2 times a day in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from 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, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin -2, IL2, IL8, IL18, IFN (interferon), 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, wortmannin, geldanamycin, gemcitabine, or a combination thereof.

In another embodiment, provided herein are methods of treating, preventing, and / or controlling hematologic malignancies that include administering SNS-595 in combination with (for example, before, during, or after) conventional treatment, including, without limitation, surgical treatment , immunotherapy, biological therapy, radiation therapy or other non-drug therapy currently used for the treatment, prevention and / or fight against cancer. Without limitation by theory, it is believed that SNS-595 can provide additive or synergistic effects when administered simultaneously with conventional treatment.

In certain embodiments, the second active agent is administered in conjunction with SNS-595 or with a delay of 1-50 hours. In certain embodiments, SNS-595 is first administered, followed by the second active agent with a delay of 1-50 hours. In certain embodiments, a second active agent is first administered, followed by the administration of SNS-595 with a delay of 1-50 hours. In some embodiments, the delay is 24 hours.

In one embodiment, SNS-595 can be administered in an amount of from about 1 to about 75 mg / m ² , from 1 to about 60 mg / m ² , from 1 to about 48 mg / m ² , from 1 to about 24 mg / m ² , from 1 to about 50 mg / m ² , from about 1 to about 40 mg / m ² , from about 1 to about 30 mg / m ² , from about 3 to about 30 mg / m ² , from about 3 to about 24 mg / m ² alone or in combination with the second active agent described herein, before, during or after the application of conventional treatment.

In another embodiment, the treatment methods provided herein include a) administering to a patient in need thereof a dose of from about 1 to 75 mg / m ² SNS-595; and b) administering a therapeutically effective amount of a supportive treatment.

In one embodiment, the second active agent is an alkylating agent. In another embodiment, the alkylating agent is an alkyl sulfonate, and the cancer being treated is a leukemia or lymphoma. In another embodiment, the alkyl sulfonate is busulfan. In another embodiment, the alkyl sulfonate is busulfan, and the therapeutically effective amount is a daily dose of at least 1 mg. In another embodiment, the alkyl sulfonate is busulfan, and the therapeutically effective amount is a daily oral dose of from about 2 mg to 8 mg. In another embodiment, the alkyl sulfonate is busulfan, and the therapeutically effective amount is a daily oral dose of from about 1 mg to about 3 mg.

In another embodiment, the alkylating agent is mustard nitrogen, and the cancer being treated is bladder cancer, breast cancer, Hodgkin's disease, leukemia, lung cancer, melanoma, ovarian cancer, or testicular cancer. In another embodiment, the nitrogen mustard is chlorambucil. In another embodiment, the nitrogen mustard is chlorambucil, and the therapeutically effective amount is at least 0.1 mg / kg. In another embodiment, the nitrogen mustard is chlorambucil, and the therapeutically effective amount is a daily oral dose of about 0.1 mg / kg and about 0.2 mg / kg for 3 to 6 weeks. In another embodiment, the nitrogen mustard is chlorambucil, and the therapeutically effective amount is a dose of about 0.4 mg / kg once every 3-4 weeks. In another embodiment, the nitrogen mustard is cyclophosphamide. In another embodiment, the nitrogen mustard is cyclophosphamide and the therapeutically effective amount is an intravenous dose of at least 10 mg / kg. In another embodiment, the nitrogen mustard is cyclophosphamide, and the therapeutically effective amount is an intravenous dose of from about 10 mg / kg to about 15 mg / kg once every 7-10 days. In another embodiment, the nitrogen mustard is cyclophosphamide, and the therapeutically effective amount is an oral daily dose of from about 1 mg / kg to about 5 mg / kg. In another embodiment, the 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 2–3 weeks, no administration of melphalan for 2-4 weeks, and then a daily oral dose of from about 2 mg to about 4 mg . In another embodiment, the nitrogen mustard is melphalan, and the therapeutically effective amount is a daily oral dose of 10 mg / m ² for 4 days every 4-6 weeks.

In another embodiment, the alkylating agent is nitrosourea, and the cancer being treated is a brain tumor, colon and rectal cancer, Hodgkin's disease, liver cancer, lung cancer, lymphoma or melanoma. In another embodiment, the nitrosourea is carmustine. In another embodiment, the nitrosourea is carmustine, and the therapeutically effective amount is at least 150 mg / m ² . In another embodiment, the nitrosourea is carmustine, and the therapeutically effective amount is an intravenous dose of from about 150 mg / m ² to 200 mg / m ² once every 6-8 weeks.

In another embodiment, the alkylating agent is triazene, and the cancer being treated is Hodgkin's disease, melanoma, neuroblastoma, or soft tissue sarcoma. In another embodiment, the triazene is dacarbazine. In another embodiment, the triazene is dacarbazine, and the therapeutically effective amount is a daily intravenous dose of from about 2.0 mg / kg to about 4.5 mg / kg for 10 days, once every 4 weeks. In another embodiment, the triazene is dacarbazine, and the therapeutically effective amount is a daily intravenous dose of 250 mg / m ² for 5 days once every 3 weeks. In another embodiment, the triazene is dacarbazine, and the therapeutically effective amount is an intravenous dose of 375 mg / m ² once every 16 days. In another embodiment, the triazene is dacarbazine, and the therapeutically effective amount is an intravenous dose of 150 mg / m ² for 5 days, once every 4 weeks.

In another embodiment, the second agent is an antitumor antibiotic, and the cancer being treated is bladder cancer, breast cancer, cervical cancer, head and neck cancer, Hodgkin's disease, leukemia, multiple myeloma, neuroblastoma, ovarian cancer, sarcoma, cancer skin, testicular cancer, or thyroid cancer. In another embodiment, the antibiotic is bleomycin. In another embodiment, the antibiotic is bleomycin, and the therapeutically effective amount is at least 10 units / m ² . In another embodiment, the antibiotic is bleomycin, and the therapeutically effective amount is an intravenous, subcutaneous or intramuscular dose of from about 10 units / m ² to about 20 units / m ² once a week or 2 times 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 from about 0.010 mg / kg to about 0.015 mg / kg for 5 days once every 3 weeks. In another embodiment, the antibiotic is dactinomycin, and the therapeutically effective amount is an intravenous dose of 2 mg / m ² once every 3-4 weeks. In another embodiment, the antibiotic is daunorubicin. In another embodiment, the antibiotic is daunorubicin, and the therapeutically effective amount is at least 30 mg / m ² . In another embodiment, the antibiotic is daunorubicin, and the therapeutically effective amount is a daily intravenous dose of from about 30 mg / m ² to 45 mg / m ² for 3 days. In another embodiment, the antibiotic is a liposome preparation of daunorubicin, and the therapeutically effective amount is an intravenous dose of 40 mg / m ² once every 2 weeks. In another embodiment, the antibiotic is doxorubicin, and the therapeutically effective amount is at least 15 mg / m ² . In another embodiment, the antibiotic is doxorubicin, and the therapeutically effective amount is an intravenous dose of from about 60 mg / m ² to about 90 mg / m ² once every 3 weeks. In another embodiment, the antibiotic is doxorubicin, and the therapeutically effective amount is a weekly intravenous dose of from about 15 mg / m ² to about 20 mg / m ² . In another embodiment, the antibiotic is doxorubicin, and the therapeutically effective amount is a cycle comprising a weekly intravenous dose of 30 mg / m ² for 2 weeks, followed by a 2-week period without administration of doxorubicin.

In another embodiment, the second agent is an antimetabolite. In another embodiment, the antimetabolite is a folate analogue and the cancer being treated is breast cancer, head and neck cancer, leukemia, lung cancer, non-Hodgkin lymphoma or osteosarcoma. In another embodiment, the folate analog is methotrexate. In another embodiment, the folate analog is methotrexate and the therapeutically effective amount is at least 2.5 mg. In another embodiment, the folate analog is methotrexate, and the therapeutically effective amount is a daily oral dose of from about 2.5 mg to about 5 mg. In another embodiment, the folate analog is methotrexate, and the therapeutically effective amount is a 2 times daily dose of about 5 mg / m ² to about 25 mg / m ² . In another embodiment, the folate analog is methotrexate, and the therapeutically effective amount is a weekly intravenous dose of 50 mg / m ² once every 2-3 weeks. In another embodiment, the folate analog is pemetrexed. In another embodiment, the folate analog is pemetrexed, and the therapeutically effective amount is at least 300 mg / m ² . In another embodiment, the folate analog is pemetrexed and the therapeutically effective amount is an intravenous dose between about 300 mg / m ² to about 600 mg / m ² 1 times in 2-3 weeks. In another embodiment, the folate analog is pemetrexed, and the therapeutically effective amount is an intravenous dose of 500 mg / m ² once every 3 weeks.

In another embodiment, the antimetabolite is an analogue of purine, and the cancer being treated is cancer of the colon and rectum, leukemia or myeloma. In another embodiment, the purine analog is mercaptopurine. In another embodiment, the folate analog is mercaptopurine and the therapeutically effective amount is at least 1.5 mg / kg. In another embodiment, the purine analog is mercaptopurine, and the therapeutically effective amount is a daily oral dose of from about 1.5 mg / kg to about 5 mg / kg. In another embodiment, the purine analog is thioguanidine. In another embodiment, the purine analog is thioguanidine and the therapeutically effective amount is at least 2 mg / kg. In another embodiment, the purine analog is thioguanidine, and the therapeutically effective amount is a daily oral dose of from about 2 mg / kg to about 3 mg / kg.

In another embodiment, the antimetabolite is an adenosine analogue, and the cancer being treated is leukemia or lymphoma. In another embodiment, the adenosine analog is cladribine. In another embodiment, the adenosine analog is cladribine, and the therapeutically effective amount is at least 0.09 mg / kg. In another embodiment, the adenosine analog is cladribine, and the therapeutically effective amount is a daily intravenous dose of 0.09 mg / kg for 7 days. In another embodiment, the adenosine analog is cladribine, and the therapeutically effective amount is a daily intravenous dose of 4 mg / m ² for 7 days. In another embodiment, the adenosine analog is pentostatin. In another embodiment, the adenosine analog is pentostatin and the therapeutically effective amount is 4 mg / m ² . In another embodiment, the adenosine analog is pentostatin, and the therapeutically effective amount is an intravenous dose of 4 mg / m ² administered every second week. In another embodiment, the adenosine analog is pentostatin, and the therapeutically effective amount is an intravenous dose of 4 mg / m ² once every 3 weeks.

In another embodiment, the antimetabolite is an analog of pyrimidine, and the cancer being treated is bladder cancer, breast cancer, colon and rectal cancer, esophageal cancer, head and neck cancer, leukemia, liver cancer, lung cancer, lymphoma, ovarian cancer , 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 / m ² . In another embodiment, the pyrimidine analog is cytarabine, and the therapeutically effective amount is a daily intravenous dose of 100 mg / m ² for 7 days. In another embodiment, the pyrimidine analog is capecitabine. In another embodiment, the pyrimidine analog is capecitabine, and the therapeutically effective amount is at least a daily dose of 2000 mg / m ² . In another embodiment, the pyrimidine analog is capecitabine and the therapeutically effective amount is a 2 times daily oral dose of from about 1200 mg / m ² to about 1300 mg / m ² for 14 days. In another embodiment, the pyrimidine analog is capecitabine, and the therapeutically effective amount is a 3-week cycle, where a dose of about 1250 mg / m ² is administered 2 times a day for 14 days followed by 1 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 embodiment, the pyrimidine analog is fluorouracil, and the therapeutically effective amount is a daily intravenous dose of from about 300 mg / m ² to about 500 mg / m ² for at least 3 days. In another embodiment, the pyrimidine analog is fluorouracil, and the therapeutically effective amount is a daily intravenous dose of 12 mg / kg for 3-5 days. In another embodiment, the pyrimidine analog is fluorouracil, and the therapeutically effective amount is a weekly intravenous dose of from about 10 mg / kg to about 15 mg / kg.

In another embodiment, the antimetabolite is substituted urea, and the cancer being treated is head and neck cancer, 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 once every 3 days. In another embodiment, the substituted urea is hydroxyurea, and the therapeutically effective amount is a daily oral dose of from about 20 mg / kg to 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 / m ² . In another embodiment, the platinum coordination complex is carboplatin, and the therapeutically effective amount is at least 300 mg / m ² once every 4 weeks. In another embodiment, the platinum coordination complex is carboplatin, and the therapeutically effective amount is at least 360 mg / m ² once every 4 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 / m ² . In another embodiment, the platinum coordination complex is cisplatin, and the therapeutically effective amount is a daily intravenous dose of 20 mg / m ² for 4-5 days, once every 3-4 weeks. In another embodiment, the platinum coordination complex is cisplatin, and the therapeutically effective amount is an intravenous dose of 50 mg / m ² once every 3 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 / m ² . In another embodiment, the platinum coordination complex is oxaliplatin, and the therapeutically effective amount is from about 50 mg / m ² to about 100 mg / m ² . In another embodiment, the platinum coordination complex is oxaliplatin, and the therapeutically effective amount is an intravenous infusion of from about 50 mg / m ² to about 100 mg / m ² once every 2 weeks. In another embodiment, the platinum coordination complex is oxaliplatin, and the therapeutically effective amount is an intravenous infusion of from about 80 mg / m ² to about 90 mg / m ² once every 2 weeks. In another embodiment, the platinum coordination complex is oxaliplatin, and the therapeutically effective amount is a 2-hour intravenous infusion of 85 mg / m ² once every 2 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 / m ² . In another embodiment, the topoisomerase II inhibitor is etoposide, and the therapeutically effective amount is from about 50 mg / m ² to about 100 mg / m ² . In another embodiment, the topoisomerase II inhibitor is etoposide, and the therapeutically effective amount is an intravenous dose of from about 35 mg / m ² to about 50 mg / m ² / day, at least 3 times in 5 days, 1 time in 3 or 4 weeks. In another embodiment, the topoisomerase II inhibitor is etoposide, and the therapeutically effective amount is an intravenous dose of from about 50 mg / m ² to about 100 mg / m ² at least 3 times in 5 days 1 time in 3 or 4 weeks . In another embodiment, the topoisomerase II inhibitor is etoposide, and the therapeutically effective amount is an oral dose of 100 mg / m ² / day, at least 3 times in 5 days, 1 time in 3 or 4 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 / m ² . In another embodiment, the topoisomerase II inhibitor is teniposide, and the therapeutically effective amount is a weekly dose of 100 mg / m ² . In another embodiment, the topoisomerase II inhibitor is teniposide, and the therapeutically effective amount is a 2 mg weekly dose of 100 mg / m ² . In another embodiment, the topoisomerase II inhibitor is teniposide, and the therapeutically effective amount is a daily dose of from about 20 mg / m ² to about 60 mg / m ² for 5 days. In another embodiment, the topoisomerase II inhibitor is teniposide, and the therapeutically effective amount is a daily dose of from about 80 mg / m ² to about 90 mg / m ² for 5 days.

6.6. Pharmaceutical Compositions and Dosage Forms

The methods described 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 anti-cancer agent. In clinical practice, SNS-595 can be administered by any conventional route, including, but not limited to, by oral, parenteral, rectal, or by inhalation (for example, in the form of an aerosol). In some embodiments, the compositions provided herein are acidic compositions (e.g., with pH <4). Without being limited by any particular theory, acid compositions provide an appropriate balance of the increased solubility of SNS-595 and the desired pharmaceutical properties (for example, increased patient comfort due to less irritation at the delivery site).

In one embodiment, SNS-595 is administered by intravenous injection. Compositions for parenteral administration may be emulsions or sterile solutions. Propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, for example ethyl oleate, can be used as a solvent or carrier. These compositions may also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, for example, using a bacteriological filter, by irradiation or by heating. They can also be obtained in the form of sterile solid compositions which can be dissolved during use in sterile water or any other injectable sterile medium.

The compositions may also be aerosols. For use in the form of liquid aerosols, the compositions may be stable sterile solutions or solid compositions which are soluble during use in pyrogen-free sterile water, in saline, or any other pharmaceutically acceptable carrier. For use in the form of dry aerosols intended for direct inhalation, the active principle is finely divided and combined with a water-soluble solid diluent or carrier, for example, dextran, mannitol or lactose.

Pharmaceutical compositions can be used in the preparation of separate, unit dosage forms. Pharmaceutical compositions and dosage forms include SNS-595 and one or more excipients.

Pharmaceutical compositions and dosage forms may also include one or more additional active ingredients. Examples of optional second or additional ingredients are described herein.

In certain embodiments, the composition provided herein is a pharmaceutical composition or a separate unit dosage form. The pharmaceutical compositions or unit dosage forms provided herein include a prophylactically or therapeutically effective amount of SNS-595 and usually one or more pharmaceutically acceptable carriers or excipients. The term “carrier” refers to a diluent, adjuvant (eg, Freund’s adjuvant (complete and incomplete)), an excipient, or a vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water or oils, including oils 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. Salt solutions and aqueous solutions of dextrose and glycerol can be used as liquid carriers, in particular for injectable solutions. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences", E.W. Martin

Typical pharmaceutical compositions and dosage forms include one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried peeled milk, glycerin, propylene glycol, water, ethanol and the like. Whether a particular excipient is suitable for inclusion in a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, without limitation, the route by which the dosage form will be administered to an individual and the particular active ingredients in the dosage form. If desired, the composition or separate unit dosage form may also contain small amounts of wetting or emulsifying agents or pH buffering agents.

In addition, pharmaceutical compositions and dosage forms are provided herein that include one or more compounds that reduce the rate at which the active ingredient will break down. 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.

Pharmaceutical compositions and unit dosage forms may take the form of solutions, suspensions, emulsions, powders and the like. Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, together with a suitable amount of carrier so as to provide a form for appropriate administration to an individual. The formulation must be consistent with the route of administration. In one embodiment, the pharmaceutical compositions or unit dosage forms are sterile and are presented in a suitable form for administration to an individual, such as an individual-animal or an individual-mammal, and such as a human.

The pharmaceutical composition provided herein is formulated for compatibility with the 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, mucosal, intratumoral, intrasynovial and rectal administration. In a specific embodiment, the composition is formulated in accordance with conventional procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, intranasal or topical administration to humans. In one embodiment, the pharmaceutical composition is formulated in accordance with conventional procedures for subcutaneous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. If necessary, the composition may also include a solubilizing agent and a local anesthetic, such as lignocaine, to relieve pain at the injection site.

Examples of dosage forms include, but are not limited to, liquid dosage forms suitable for parenteral administration to an individual; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted by dissolution to provide liquid dosage forms suitable for parenteral administration to an individual.

The composition, form and type of dosage forms presented in the present description will usually vary depending on their application. For example, the dosage form used in the initial treatment of the disease may contain larger amounts of one or more active ingredients that it includes than the dosage form used in the supportive treatment of the same infection. Similarly, a parenteral dosage form may contain smaller amounts of one or more active ingredients than a dosage form used to treat the same disease or disorder. These and other aspects in which certain dosage forms described herein are different from one another will be readily apparent to those skilled in the art (see, for example, Remington's Pharmceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000)) .

In general, the ingredients of the compositions provided herein are substituted either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or anhydrous concentrate in a hermetically sealed container, such as an ampoule or sachet, indicating the amount of active agent. When the composition is to be administered by infusion, it can be supplied in an infusion bottle containing sterile water or a pharmaceutical grade saline solution. When the composition is administered by injection, an ampoule with sterile water for injection or saline may be provided so that the ingredients can be mixed before administration.

Typical dosage forms presented in the present description include SNS-595 in the range of from about 1 mg / m ² to about 75 mg / m ² / day or 1 week, administered as a dose administered once a day in the morning, or in the form of fractional doses during the day taken with food. Specific dosage forms presented in the present description, contain about 1, 3, 6, 9, 12, 15, 18, 21, 24, 27 or 30 mg / m ² SNS-595.

6.6.1 Parenteral dosage forms

Parenteral dosage forms can be administered to patients in various ways, including, without limitation, subcutaneous, intravenous (including bolus injection), intramuscular and intraarterial administration. Due to the fact that their administration usually bypasses the natural protective mechanisms of patients, parenteral dosage forms are preferably sterile or capable of being sterilized before administration to the patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready for dissolution or suspension in a pharmaceutically acceptable carrier for injection, suspensions ready for injection, and emulsions.

Suitable carriers 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, USP; aqueous vehicles, such as, without limitation, sodium chloride solution for injection, Ringer's solution for injection, dextrose for injection, dextrose and sodium chloride for injection and Ringer's solution with lactate for injection; water miscible carriers 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, cotton seed 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 disclosed herein may also be included in parenteral dosage forms. For example, cyclodextrin and its derivatives can be used to increase the solubility of the active ingredients (see, for example, US patent No. 5134127, the contents of which are fully incorporated into this description by reference).

6.6.2 Dosage forms for topical application and administration through the mucous membranes

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, nebulized forms, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one skilled in the art ( see, for example, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000); and Introduction to Pharmaceutical Dosage Forms, 4 ^th ed., Lea & Febiger, Philadelphia (1985)). Dosage forms suitable for treating mucous tissues within the oral cavity can be formulated as rinses for the oral cavity or as oral gels. In addition, transdermal dosage forms include a "reservoir type" or "matrix type" transdermal system that can be applied to the skin and worn for a certain period of time to allow penetration of the desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materials that can be used for the mucosal dosage forms provided herein are well known to those skilled in the pharmaceutical art and depend on the particular tissue on which the pharmaceutical composition or drug will be applied. the form. With this in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil and mixtures thereof to form solutions, emulsions or gels that are non-toxic and pharmaceutically acceptable. If desired, humectants or wetting agents may also be added to the compositions and dosage forms. 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 the pharmaceutical composition or dosage form can also be adjusted to improve the delivery of one or more active ingredients. Similarly, the polarity of the 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 preferentially alter the hydrophilicity or lipophilicity of one or more active ingredients in order to improve delivery. In this regard, stearates can serve as an agent that enhances delivery or enhances penetration. To further adjust the properties of the resulting composition, various salts, hydrates or solvates of the active ingredients can be used.

7. EXAMPLES

Certain embodiments presented herein are illustrated by the following non-limiting example.

Example 1: Pharmaceutical composition suitable for injection or intravenous infusion

Acid compositions (<pH 4) provided the appropriate balance of increased solubility of SNS-595 and the desired pharmaceutical properties (eg, increased patient comfort, resulting in less irritation at the delivery site). An illustrative example of a suitable composition includes 10 mg SNS-595 per 1 ml of an aqueous solution of 4.5% sorbitol, the pH of which is adjusted to 2.5 with methanesulfonic acid. One workflow for preparing such a solution includes the following procedures to obtain a concentration of 100 mg / 10 ml: 100 mg SNS-595 and 450 mg D-sorbitol are added to distilled water; the volume is adjusted to a volume of 10 ml; and the pH of the resulting solution was adjusted to 2.5 with methanesulfonic acid. The resulting composition is also suitable for lyophilization. The lyophilized form is then reconstituted by dissolving with sterile water to an appropriate concentration before use.

Example 2: Data from a clinical trial of SNS-595 in patients with advanced solid cancer

The safety and effectiveness of SNS-595 was investigated in two dose-increasing studies. As demonstrated below, SNS-595 provides good safety profiles and evidence of antitumor activity in patients with refractory solid tumors.

SNS-595 was administered to patients with advanced solid cancerous tumors as an intravenous infusion over 10 minutes according to 2 regimens. In the first regimen (A), a weekly dose of SNS-595 was administered for 3 weeks, followed by at least a 7-day period without administration (qwk × 3). In the second regimen (B), a dose of SNS-595 was administered once every 3 weeks (q3wk).

In both schemes, the initial dose of SNS-595 was 3 mg / m ² , and the doses were increased in successive groups of 3. Doses were doubled until the first drug-related side effect occurred, equal to or greater than the 2nd degree, or to the first abnormal values of laboratory tests. Then the doses were increased according to the modified Fibonacci regimen.

Within 42 days of the study, no other therapy, such as mitomycin-C, BCNU, nitrosourea, or MAb, was performed.

In study A, 21 patients (9 men, 12 women) were treated in 6 groups (dose range 3-24 mg / m ² / week). In the study In 41 patients (25 men, 16 women) were treated in 9 groups (dose range 3-75 mg / m ² / week). The median age was 61 years (study A) and 59 years (study B), gender 12 women / 9 men (study A), 16 women / 25 men (study B), all patients had initial status according to the functional criteria of the European Joint Oncological Group (ECOG PS) was 0-2. The criteria for inclusion in the study were refractory solid tumors and adequate organ function. Table 1 presents the demographic data of patients in both studies.

Table 1
Patient Demographics qwk × 3 q3wk Total (The number treated) 21 41 62 Floor Men 9 (43%) 25 (61%) 34 (55%) Women 12 (57%) 16 (39%) 28 (45%) Ethnic background Asian origin 2 (10%) 12%) 3 (5%) Blacks 2 (10%) 4 (10%) 6 (10%) Hispanics 0 12%) 12%) Hawaii / Pacific Indigenous People 0 2 (5%) 2 (3%) Europeans 17 (81%) 33 (81%) 50 (81%) Age (years) Average 59.3 58.5 58.8 Median 61 59 60 Interval 19-81 33-79 19-81 Previous treatments Mr 9 (43%) 17 (41%) 26 (42%) HP 12 (57%) 24 (59%) 36 (58%)

Table 2 provides a list of the types of tumors that were treated in both studies.

table 2
Types of tumors that have been treated qwk × 3 q3wk Total (The number treated) 21 41 62 Ovarian cancer one 9 10 Colon cancer 3 6 9 Not small cell lung cancer 0 6 6 Pancreas cancer 3 2 5 Kidney cancer one four 5 Melanoma one 3 four Adenocarcinoma (of unknown origin) 0 3 3 Breast cancer 2 0 2 Sarcoma 0 3 3 Cholangiocarcinoma one one 2 Mesothelioma 2 0 2 Neuroendocrine tumor one one 2 Bladder cancer 0 one one Leiomyosarcoma one one 2 Liposarcoma one 0 one Muller duct cancer 0 one one Nasopharyngeal cancer one 0 one Salivary Gland Cancer one 0 one Small cell lung cancer one 0 one Spindle Cell Carcinoma one 0 one

In patients to whom the drug was administered in accordance with Scheme A, samples for determining pharmacokinetic parameters were taken on the 1st and 15th day of treatment and analyzed using non-compartmental analysis. Plasma SNS-595 concentrations were determined using sound LC-MS / MS analysis (liquid chromatography - mass spectrometry / mass spectrometry). AUC (area under the curve) increased proportionally with the dose and average AUC _inf and was in the range from 1.7 to 15 μg / h / ml, respectively, for dose levels from 3 to 24 mg / m ² . The final half-life is approximately 19 hours. After dosing once every 3 weeks, evidence of drug-dependent changes in pharmacokinetic parameters was not observed. Figure 1 shows the change in concentrations of SNS-595 over time among different groups of patients. Table 3 presents the pharmacokinetic parameters for patients to whom the drug was administered in accordance with scheme A.

Table 3
Average pharmacokinetic parameters in the 1st and 3rd weeks Dose (mg / m ² ) N (1st week, 3rd week) T _1/2 , h C _max (μg / ml) AUC _inf (mcg · h / ml) CI _obs (l / hr ² ) V _asobs (l / m ² ) 3 7 (4.3) 23.3 ± 7.2 0.577 ± 0.795 1.71 ± 0.20 1.77 ± 0.23 52.7 ± 18.2 6 6 (3.3) 13.5 ± 2.2 0.531 ± 0.28 2.09 ± 0.53 3.05 ± 0.84 51.0 ± 8.22 12 6 (3.3) 19.9 ± 5.3 1.84 ± 2.7 6.81 ± 1.68 1.87 ± 0.53 44.6 ± 8.53 fifteen 10 (5.5) 26.4 ± 15.2 0.865 ± 0.318 10.8 ± 4.7 1.59 ± 0.56 43.8 ± 7.90 eighteen 6 (4.2) 15.8 ± 4.2 1.69 ± 0.83 8.50 ± 2.86 2.36 ± 0.88 47.19 ± 8.06 24 1 (1.0) 24.2 0.6 15,2 1,58 50,0 average value 18.5 ± 4.6 - - 2.22 ± 0.58 47.6 ± 10.7 Interval 10-33 0.6-1.8 2-15 1.4-4.3 30-75

In patients to whom the drug was administered in accordance with Scheme B, pharmacokinetic parameters were evaluated in 36 patients (21 receiving intensive pretreatment and 15 patients receiving minimal pretreatment) after a single dose of 3 to 75 mg / m ² . Excretion (CL), volume of distribution, and final elimination half-life (T _1/2 ) remained unchanged in all patients up to a dose of 48 mg / m ² . In patients receiving minimal preliminary treatment, the pharmacokinetic parameters remained unchanged up to a dose of 75 mg / m ² . CL was 2.2 l / h / m ² (range 1.0-3.8 l / h / m ² ), the distribution volume was 53 l / m ² (range 31-76 l / m ² ), and T _{1 / 2} was 21 hours (interval 13-49 hours). The exposure was the same for both those who received intensive and those who received minimal preliminary treatment, and it linearly increased with increasing doses to 48 mg / m ² . Exposure in patients receiving minimal pretreatment showed a more linear dose-dependent AUC (area under the curve) at a dose level of 60 mg / m ² . Table 4 shows the pharmacokinetic parameters in patients receiving the drug in accordance with Scheme B.

Table 4
Pharmacokinetic parameters at the 3rd week Dose (mg / m ² ) n T _1/2 hour C _max (μg / ml) AUC _inf (mcg · h / ml) CI _obs (l / hr ² ) V _asobs (l / m ² ) 3 3 16.4 ± 4.8 0.139 ± 0.08 1.14 ± 0.26 2.72 ± 0.58 57.7 ± 8.7 6 2 22.2 ± 1.9 0.347 ± 0.22 3.04 ± 0.32 1.98 ± 0.21 59.8 ± 0.5 12 3 18.0 ± 4.1 2.25 ± 1.07 6.32 ± 0.22 1.90 ± 0.07 45.2 ± 8.9 24 3 15.7 ± 3.2 2.70 ± 2.57 12.63 ± 0.86 1.91 ± 0.13 40.7 ± 8.8 36 6 22.5 ± 4.2 3.38 ± 1.92 18.05 ± 0.73 2.00 ± 0.08 61.4 ± 12.8 48 10 26.4 ± 13.1 3.08 ± 1.92 29.41 ± 11.34 1.92 ± 0.91 58.8 ± 14.5 60 8 25.0 ± 17.9 3.86 ± 1.68 40.71 ± 23.67 1.88 ± 0.88 48.0 ± 7.3 75 four 25.0 ± 4.9 5.05 ± 1.72 46.09 ± 6.12 1.65 ± 0.22 56.3 ± 9.4 average value 21.3 ± 5.3 - - 2.0 ± 0.4 53.2 ± 4.1 Interval 13-56 0.1-5 1-46 1-3,8 31-76

In Study A, pharmacokinetics were evaluated on days 1 and 15 (after administration of the first and third doses). As can be seen from table 5, SNS-595 exhibits highly reproducible pharmacokinetics and low variability between patients. After repeated administration, no accumulation or change in pharmacokinetic parameters was observed. Exposure increased linearly over an 8-fold dose interval (1.6-15 μg · h / ml), excretion (CL), distribution volume (Vss) and T _1/2 averaged 2 l / h / m ² , 48, respectively l / m ² , 19 hours and did not change from the 1st to the 15th days.

In study B, pharmacokinetics were evaluated on the 1st day after the first dose; exposure increased linearly over a 24-fold dose interval (1.1-46 mcg · h / ml), CL, Vss and T _1/2 averaged 2 l / h / m ² , 53 l / m ² , 21 hours, respectively .

Average pharmacokinetic parameters are presented for both studies in table 5.

Table 5
Average pharmacokinetic parameters at the 1st and 3rd week qwk × 3
1st week qwk × 3
3rd week q3wk n twenty 16 39 The range of doses (mg / m ² ) 3-24 3-18 3-75 AUC _inf interval (μg / h / ml) 2-15 2-7 1-46 T _1/2 (hour) ± standard deviation 22 ± 11 19 ± 8 21 ± 5 CI _obs (l / h / m ² ) ± standard deviation 1.9 ± 0.7 2.2 ± 0.9 2.0 ± 0.4 V _asobs (l / m ² ) ± standard deviation 48 ± 12 47 ± 8 53 ± 4

11 shows the linearity of doses in studies A and B.

Table 6 presents the data of hematological effects observed in the studies.

Table 6
Hematologic effects Dose Scheme n Anc
≤500 Fever
with neutropenia 3 mg / m ² qwk × 3 four 0 0 6 mg / m ² qwk × 3 3 0 0 12 mg / m ² qwk × 3 3 0 0 15 mg / m ² qwk × 3 6 0 0 18 mg / m ² qwk × 3 four 0 0 24 mg / m ² qwk × 3 one 0 0 3 mg / m ² q3wk 3 0 0 6 mg / m ² q3wk 3 0 0 12 mg / m ² q3wk 3 0 0 24 mg / m ² q3wk 3 0 0 36 mg / m ² q3wk 6 0 0 48 mg / m ² q3wk 6 one 0 48 mg / m ² (HP) q3wk 5 2 0 60 mg / m ² q3wk 8 3 one 75 mg / m ² q3wk four 0 0 n = number of patients in the group
* Absolute neutrophil count (cells / μl) ≤500, lasting more than 7 days

As used herein, the term “maximum tolerated dose” or “MTD” refers to a dose level below a dose of SNS-595, where ≥2 of 6 patients experienced dose-limiting toxicity (DLT). The term “intensive pretreatment” 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 (X-ray)> 25% of bones. The term “receiving minimal pretreatment or“ MR ”refers to a patient who does not meet the definition of“ HP ”(see Tolcher et al., JCO 2001; 19: 2937-2947).

As used herein, the term “dose limiting toxicity” (DLT) refers to an absolute neutrophil count (ANC) of ≤500 for ≥7 days, or a febrile state with neutropenia, or a sharp decrease in platelet count <25,000, or bleeding, or non-hematologic side effects (AE) ≥3rd degree (as described in version 3.0 of the Common Terminological Criteria for Adverse Events CTCAE v3.0)), where adverse events required> 14 days of delayed dose administration.

Tables 7–9 provide safety data for both studies.

Table 7
Frequent (> 10% of patients) side effects Body system qwk × 3 q3wk Total Preferred period n = 21 n = 41 n = 62 Heart disorders peripheral edema 0/4 * Gastrointestinal Disorders abdominal pain 1/5 0/8 1/13 (8%)

constipation 0/7 1/12 1/19 (5%) diarrhea 0/4 0/8 0/12 (0%) nausea 0/8 2/26 2/34 (6%) vomiting 0/5 1/17 1/22 (5%) General state fatigue 1/4 1/13 2/17 (12%) Metabolic and nutritional disorders anorexia 0/7 0/7 (0%) Musculoskeletal and connective tissue disorders back pain 0/7 0/7 (0%) limb pain 0/5 Nervous system disorders dizziness 0/6 0/6 (0%) headache 0/3 0/8 0/11 (0%) Disorders of the skin and subcutaneous tissue baldness 0/8 0/8 (0%) * Number of patients with a degree of disorder ≥3 / number of patients with a disorder of any degree

Table 8
Hematologic effects qwk × 3 q3wk Total n = 21 n = 41 n = 62 Grade 4 Neutropenia (ANC <500 / mm ³ ) 0 10 (24%) 10 (16%) Fever with neutropenia 0 12%) 12%) 4th degree thrombocytopenia (<25000 / mm ³ ) 0 2 (5%) 2 (3%)

Table 9
Serious adverse events (SAE), possibly related
with the study drug SAE Advantage STCAE in comparison with the degree of 3.0 1 patient for each of the following qwk × 3 q3wk Sepsis Not observed Grade 3 Vomiting Not observed Grade 3 Pneumonia Not observed Grade 3 Fever with neutropenia Not observed Grade 2 Pancytopenia Not observed Grade 4 Thrombosis Not observed Grade 2

As can be seen from the data presented, neutropenia was dose limiting toxicity (DLT) for both studies. In study A, dose limiting toxicity (DLT) in the form of neutropenia was observed in the first patient at 24 mg / m ² . Then 5 patients were treated with a dose of 18 mg / m ² at which 2 developed DLT in the form of neutropenia. In study B, in patients receiving intensive pretreatment, dose limiting toxicity (DLT) in the form of grade 4 neutropenia for more than 7 days was observed at a dose of 60 mg / m ² . For patients receiving minimal pretreatment, one case of dose limiting toxicity was observed at a dose of 75 mg / m ² .

MTD (maximum tolerated dose) for Study A was 15 mg / m ² ; MTD for study B was 48 mg / m ² for patients receiving intensive pretreatment (HP) and 60 mg / m ² for patients receiving minimal pretreatment (MR).

For both studies, 2 patients had grade 4 thrombocytopenia; cases of non-hematologic toxicity were predominantly 1/2 degrees without dose-limiting gastrointestinal toxicity or neurotoxicity.

Table 10 presents evidence of the clinical activity of SNS-595 for both studies. In Study A, the best response to treatment was observed in one patient who achieved a partial response (PR) and in 6 patients who achieved disease stabilization (SD) (interval 16-24 weeks). According to the study B, the best response to treatment was observed in one patient with PR and 11 with SD (interval 18-58 weeks). Table 11 provides details of partial / minor treatment responses (PR / MR) in both studies.

Table 10
Evidence of clinical activity Initial dosage (mg / m ² ) Introduction scheme Tumor type Treatment week Best response
for treatment 6 qwk × 3 Renal cell tumor 16 SD 12 qwk × 3 Leiomyosarcoma 16 SD Melanoma 16 SD fifteen qwk × 3 Mesothelioma 28 PR Mesothelioma eighteen SD Nasopharyngeal tumor 16 SD 24 qwk × 3 Salivary Gland Tumor 24 SD 3 q3wk Lung tumor eighteen SD 6 q3wk Renal cell tumor eighteen SD 12 q3wk Lung tumor 53 SD 24 q3wk Adenocarcinoma (of unknown origin) eighteen SD 36 q3wk Ovarian tumor eighteen SD Colon tumor 33 SD 48 q3wk Ovarian tumor 24 PR Ovarian tumor thirty SD Lung tumor 46 SD 60 q3wk Ovarian tumor 33 SD Neuroendocrine tumor 58 SD 75 q3wk Muller duct tumor 46 SD

Table 11
Partial / minor treatment response details (PR / MR) Best response to treatment Tumor Criterion Baseline C2 C4 C6 PR Ovarian tumor CA125 (μl / ml) 467 272 176 120 Paraaortic node (cm) 1.7 1,6 1,5 1.3 Aortic node (cm) 2,4 2.0 2.2 2.0 Iliac node (cm) 5.5 5,0 4.7 3.9 SD (MR) Nasopharyngeal tumor Right upper lobe nodule 1 (cm) 2,3 1,5 - - Right upper lobe nodule 2 (cm) 1,5 1.3 - - Left upper lobe nodule (cm) 1,1 1,0 - - Reed segment of the lung 1,6 1,5 - - SD (MR) Ovarian tumor CA125 (μl / ml) 567 811 419 274 Liver metastases (cm) 7.4 6.9 5.7 5.7 Aortic node (cm) 1.7 1,5 1,2 1.8 Paraaortic node (cm) 1.8 1,1 1,1 1,2 SD (MR) Ovarian tumor CA125 (μl / ml) fifty eighteen 16 fifteen Rectosigmoid node (cm) 2.5 0,0 0,0 0,0 3 metastases
without changes SD (MR) Muller duct tumor The node of the middle lobe of the right lung (cm) 3.9 3.9 3,7 2,4 The node of the upper lobe of the right lung (cm) 4.7 4,5 4,5 5,0 The node of the middle and lower lobe of the right lung (cm) 2.5 2.5 2.5 2.6

Significantly, SNS-595 shows evidence of clinical activity in patients with advanced solid cancerous tumors, including two patients who have achieved partial treatment responses and 17 patients who have achieved disease stabilization for more than 16 weeks.

As can be seen from the data presented, SNS-595 was well tolerated and showed clinical activity with the introduction of 1 time per week, and 1 time in 3 weeks. Dose-limiting toxicity was non-cumulative neutropenia. SNS-595 demonstrated predicted pharmacokinetics with low variability among different patients and in one patient. After repeated administration, no pharmacokinetic parameters were observed.

Suitable dosages for treating solid tumors in patients in need thereof include 48 mg / m ² once every 3 weeks and 15 mg / m ² once a week, as described in this example.

Example 3: Screening and Microscopy of High Content

Cells were seeded as incompletely fused populations and allowed them to grow for 36 hours. Then the cells were treated with the compound at a given concentration for a given period of time. Cells were fixed using 4% formaldehyde and treated with 0.1% Triton. Cells were exposed to primary antibodies for 1 hour at 25 ° C at a dilution of 1: 100 in 10% FBS / PBS (fetal calf serum / saline solution with phosphate buffer) (anti-pATM (antibody against protein mutated by ataxia-telangiectasia) - Chemicon, anti-gH2AX (anti-phosphorylated histone antibody) - Cell Signaling Technology). 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 performed in 10% FBS / PBS at a concentration of 500 ng / ml. High-content screening was performed on a Cellomics Arrayscan instrument using the Spot Detector algorithm.

Figure 2 shows HCT116 cells that were treated with various compounds for 6-hour time periods. Cells were then fixed and analyzed to determine the state of protein phosphorylation (gH2AX images obtained using a fluorescence microscope, pATM images obtained with an ArrauScan VTi device). As can be seen in the drawing, processing SNS-595 leads to the formation of nuclear foci.

Figures 3-5 illustrate the dependence of focal formation on dose and time. Then the cells were fixed and analyzed for the content of phospho-ATM. Cellomics Arrayscan software was used to identify foci (Figure 3, orange spots). Quantitative determination of the foci was carried out by measuring either the fluorescent intensity of the foci (Fig. 4), or cells with more than 2 foci (Fig. 5) as a function of time and SNS-595 concentration.

Example 4: MTT Analysis and Sensitizing Treatment Methods

Cells were seeded at 4000 cells per well in a 96-well plate, incubated for 24 hours and then treated with the compound for 72 hours. Cells were then incubated with 5% MTT ([3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] for 1-2 hours and lysed. MTT was read calorimetrically at 570 nm and EC ₅₀ (effective concentration causing 50% cytotoxic effect) was determined using linear regression analysis.

Sensitization was carried out by various types of chemical treatment. Cells were pretreated for 16 hours with a chemical sensitizer before drug addition (concentrations were as follows: caffeine, 2 mM, DNA-PK II inhibitor (obtained), 10 μM, and wortmannin, 100 nM. The data are presented in table 12. Sensitization was measured as the multiplicity of the reduction of EC ₅₀ , causing cytotoxicity, according to the measurement by MTT analysis.

Table 12
DNA Damage Dependence on SNS-595 Compound The mechanism of the degree of symmetry breaking
(Dsb) ATRFLOX ¹ DNAPKcs (- / -) ² Caffeine ³ Cell line Stop at phase G2 ⁴ Delay S ⁵ Determination of apoptosis time ⁶ SNS-595 Dependent
from replication one 10 0.5 NST-116 + + 0.4 Etoposide Topoisomerase II one 7 8 ATRFLOX ¹ + + 0.35 Bleomycin Chemical one four 10 DNAPKcs (- / -) ² + + 0.25 Camptothecin Dependent
from replication of topoisomerase I 5 0.7 6 Caffeine ³ - + 0.25 ¹ HCT-116 cells with 6 times lower levels of ATR (caffeine-sensitive activated protein kinase DNA).
² MO59J (DNAPKcs (- / -)) compared to MO59K (DNAPKcs (+ / +)).
³ HCT-116 cells treated with 2 mM caffeine to interrupt the activity of both ATM and ATR kinases.
⁴ FACS analysis (fluorescence lymphocyte separation method), asynchronous cell population.
⁵ FACS analysis, synchronous cell population.
⁶ Cell cycle fraction to achieve 50% maximum caspase-3 activation when administered at a concentration 30 times the EC ₅₀ for cytotoxicity.

These data indicate that SNS-595 is unusually dependent on PIKK (a kinase related to phosphoinositide kinase). Although both ATM / ATR and DNA-PC are activated after processing SNS-595, only DNA-PC is required for DNA repair, and cells are sensitized to SNS-595 only when DNA-PC activity decreases. ATM / ATR mediates the stop of G2 monitoring points. Loss of G2 control points does not sensitize cells to SNS-595. Unlike SNS-595, all other tested DSB inducing agents use ATM / ATR for repair and exhibit sensitization when either ATM or PC-DNA activity is inhibited.

Example 5: DNA damage repair in the absence of ATM and ATR kinases that capture DNA damage

HCT-116 cells were treated with 10 mM SNS-595 or 10 mM etoposide for 6 hours with or without 2 mM caffeine. Then the compound was removed and the cells were allowed to recover for 16 hours. Cells were analyzed to identify gH2AX foci before and after leaching of the drug. As can be seen in Fig.6, DNA damage caused by SNS-595, is easily restored in the absence of ATM or ATR. In contrast, other drugs (e.g. etoposide) use ATM and ATR for DNA repair. Caffeine treatment inhibits the activity of ATM and ATR, leading to defects in homologous recombination, nucleotide excision repair and mismatch repair.

Example 6: Repair DNA damage in the absence of DNA-FC, catching DNA damage

Cells MO59K (wt) and MO59J (DNAPKcs (- / -)) were treated with 10 mM SNS-595 or 10 mM etoposide for 6 hours. Then the compound was removed and the cells were allowed to recover for 16 hours. Cells were analyzed for gH2AX lesions before and after leaching. As can be seen in Fig.7, DNA damage caused by SNS-595, is not effectively restored in the absence of DNA-FC. In comparison, damage caused by other drugs (eg, etoposide) is easily repaired.

Example 7: Combination Studies with SNS-595

Cell lines and cell culture: HCT116 and NCI-H460 cell lines were obtained from ATCC (American Type Culture Collection). SKOV3 (p53 (- / -) and SKOV3 (p53 (+ / +)

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 per well (excluding SKOV3 (p53 (- / -)) in a 96-well plate, incubated for 24 hours and then treated with the compound. Compound treatment lasted 72 hours. Then the cells were incubated with 5% MTT for 1-2 hours and lysed. MTT was read calorimetrically at 570 nm. The dead cell fraction was determined by the following formula:

Dead cell fraction = 1 - [Absolute amount of sample wells - Average amount (Absolute amount of control without cells)] / [Average amount (Absolute amount of control containing only DMSO (dimethyl sulfoxide)) - Average amount (Absolute amount of control without cells)].

Study of the schemes: When the compounds were administered according to the scheme, which included leaching, the cells were washed with 100 μl of fresh warm medium for 30 minutes, followed by another washing after 90 minutes.

Statistical analysis: Data (dead cell fraction) were analyzed using Calculsyn.V2 software (Biosoft), and are presented in the present description as the value of the combined indicator for the exposed fraction (Fa) = 0.5. All data is shown with a "mustache" showing 95% confidence intervals of the average value.

A combination is considered additive if it gives a combined index of 0.85-1.2. A combination is considered synergistic if it gives a combined score of less than 0.85, and a combination is considered antagonistic if it gives a combined score of more than 1.2 (see FIGS. 8-10).

As seen in FIGS. 8a-8d, SNS-595, administered simultaneously with various cytotoxic agents to the HCT116 colon carcinoma cell line (8a, 8b and 8c) and the H460 lung cancer cell line (8 (d)), showed significant synergistic or at least additive combined indicators. As shown in FIG. 9, SNS-595, administered simultaneously with selected DNA damaging agents and antimetabolites, did not show a significant change in the combined indicators between the SKOV3 ovarian cancer cell line with or without p53 expression.

As can be seen in FIGS. 10a-10d, SNS-595 could have been antagonistic when administered simultaneously with SNS-595 or administered with a delay of 24 hours with docetaxel (see FIGS. 10a and 10c) and gemcitabine (see FIGS. 10b and 10d) ) on colon carcinoma cells HCT116. Antagonism could be reduced by first administering SNS-595 (see FIGS. 10c and 10d, simultaneous administration and administration with a delay of 24 hours) compared with first administration of other agents (see FIGS. 10a and 10b, simultaneous administration and administration with a delay 24 hours). Additivity or possibly synergy was achieved when the cells were treated with the first agent, washed and then treated with the second agent (see FIGS. 10a-d, 2-hour washing and 24-hour washing).

Example 8: MTT Cell Viability Analysis - Leukemia Cells

The following cell lines were used in this analysis: HL-60 (promyelocytic leukemia); Jurkat (T cell leukemia); CCRF-CEM (lymphoblastic leukemia); CEM / C2 (Captecane Resistant CCRF-CEM Derivative).

Cells were seeded in 96-well plates at 3,000 cells per well and incubated for 16 hours. Dilutions of the compound were performed in DMSO with 10 mM 3-fold dilutions. Titrations were diluted 1: 100 in medium to achieve final concentrations of the compound. The contents of the 96-well plate were aspirated and dilutions of the compound in medium (100 ml / well) were added. MTT analysis was performed after 72 hours of incubation at 37 ° C. Briefly, 20 ml of MTT solution was added to each well. Cells were incubated at 37 ° C for 1-2 hours. Cells were lysed by adding 100 ml / well of lysis buffer, and MTT was solubilized overnight at 37 ° C. Plates were read on a Spectromax instrument with spectral absorption measurements at 570 nM. IC _{50 was} calculated (data are presented in table 13) using regression analysis inside the GraphRad Prism prism. As presented in table 13, SNS-595 exhibits high antiproliferative activity against the tested lines of hematological cells.

Table 13
IC ₅₀ data for various cell lines IC ₅₀ ng / ml Cell line SNS-595 Etoposide Doxorubicin Irinotecan Hl-60 53 136 24 905 Jurkat 23 Not determined Not determined Not determined CCRF-CEM eighteen Not determined 3 479 CEM / C2 10 Not determined 17 44,400

Example 9: Xenograft Models

The fractions of LM3-Jck human malignant lymphoma tumors (2-3 mm squares) were transplanted subcutaneously to nude mice. Tumors were allowed to grow to a diameter of approximately 7-14 mm. Mice were selected in pairs in the untreated group and in the irinotecan treatment group (100 mg / kg intravenously once every 4 days × 3), doxorubicin (12 mg / kg intravenously, one injection), etoposide (12 mg / kg intravenously , 1 time per day × 5) and SNS-595 (25 and 20 mg / kg intravenously, 1 time in 7 days × 5). Acceptable toxicity was defined as the average group weight loss of 30% or less, and no more than one toxic death among 6 treated animals. The antitumor activity of the drugs was evaluated 21 days after the start of administration.

The fractions of acute lymphoblastic leukemia CCRF-CEM tumors in the form of squares of 2-3 mm in size were transplanted subcutaneously to “naked” mice. Tumors were allowed to grow to a diameter of approximately 8-20 mm. Mice were selected in pairs in the untreated group and in the irinotecan group (100 mg / kg intravenously 1 time in 4 days × 3), doxorubicin (12 mg / kg intravenously, 1 time in 7 days × 3), etoposide ( 12 mg / kg intravenously, 1 time per day × 5) and SNS-595 (25 and 20 mg / kg intravenously, 1 time in 7 days × 5). Acceptable toxicity was defined as the average group weight loss of 30% or less, and no more than one toxic death among 6 treated animals. The antitumor activity of the drugs was evaluated 20 and 21 days after the start of administration. Table 14 provides tumor inhibition (TI) and survival data for the CCRF-CEM and LM3-Jck xenograft models.

Table 14
Comparative antitumor activity of SNS-595 and other anticancer drugs CCRF-CEM LM3 - JcK Treatment Dose (mg / kg) IR (%) Number of survivors
from the group IR (%) Number of survivors
from the group SNS-595 q7d X3, IV twenty - * - 98.9 * 6/6 25 98.1 * 6/6 * 98.5 * 6/6 Irinotecan q4d x3, IV one hundred 99.7 * 5/6 97.7 * 6/6 Doxorubicin q7d X3, IV 12 50.3 * 6/6 57.2 * 6/6 Etoposide qd X5, IV 12 28.3 6/6 3.0 6/6

As can be seen from the data in table 14, SNS-595, introduced at a dose of 20 and 25 mg / kg, shows a high antitumor activity against malignant lymphoma LM3-Jck with complete reverse tumor development. The tumor inhibition rate (IR) of SNS-595 was similar to that of irinotecan and above etoposide and doxorubicin in the xenograft model and CCRF-CEM, and LM3-Jck.

Example 10: Bone Marrow / Cytology Analysis

Female CD-1 mice were injected intravenously with 5, 10, 15, or 20 mg / kg SNS-595 on day 0 and day 4. Blood was taken on the 6th, 8th and 12th days after the initial injection for hematological analysis. The thighs were removed on day 6, fixed in Streck solution and stained with hematoxylin and eosin before analyzing the number of bone marrow cells. 2 days after the second administration of SNS-595, a dose-dependent decrease in the number of cells appeared in the bone marrow isolated from the femur. At 20 mg / kg, the number of cells decreased to 7.5%, while the number of circulating neutrophils decreased from the level before administration of 1244 ± 55 cells / ml to the lowest level of 51 ± 24 cells / ml of blood on day 8. Subsequently, there was a reactive increase in the absolute number of neutrophils, and it soon returned to normal levels. The total white blood cell count also reached its lowest level on day 8, but returned to normal levels. A dose-dependent decrease in the number of hematopoietic bone marrow cells is shown in FIG. The drawing shows the number of cells in the bone marrow 6 days after the initial injection of SNS-595 in various doses.

On Fig shows the number of neutrophils from blood samples on the 4th, 6th, 8th and 12th days after the initial injection. As can be seen in FIG. 16, all dose administration groups of SNS-595 showed a significant decrease in the number of neutrophils in peripheral blood by day 8. As can be seen in FIG. 17, in animals receiving injections of SNS-595 at a dose of 20 mg / kg, on day 8 there were less than 50 cells / ml.

On Fig shows that on the 8th day there is a small platelet reaction to the injection of SNS-595. On Fig shows the change in percent body weight at different times after the introduction of SNS-595. On Fig shows the response of the bone marrow in the form of an increase in the number of cells after their decrease in response to the introduction of the drug on the 12th day after injection of SNS-595 at a dose of 20 mg / kg

Example 11: Data from clinical trials of SNS-595 in patients with malignant hematological diseases

SNS-595 was administered as a slow intravenous infusion in patients with advanced and refractory acute leukemia. Diagnoses included AML (19 patients) and ALL (2 patients). All patients had a disease refractory to the previous treatment, or recurring after it (on average, 3 previous treatment regimens (interval 1-6).

A total of 21 patients (9 women and 12 men; average age = 64 years, interval 21-80 years) were treated in 5 groups using two regimens. In the first regimen (A), a weekly dose of SNS-595 was administered for 3 weeks followed by a period of 7 days without administration (qwk × 3). In the second scheme (B), a dose of SNS-595 was administered 2 times a week for 2 weeks (biwk × 2). The cycle duration, including days without drug administration, was 28 days for both regimens. In Scheme A there were only 3 doses per cycle, and in Scheme B there were only 4 doses per cycle. Additional cycles were allowed if patients achieved stabilization of the disease or a better result. The initial dose was 18 mg / m ² according to Scheme A and 9 mg / m ² according to Scheme B, and the dosage was increased in the group. Groups of 3-6 patients receiving specific doses of the drug were determined using a modified Fibonacci sequence.

SNS-595 pharmacokinetic analyzes were performed on plasma samples collected during the 1st cycle. Table 15 presents the specific pharmacokinetic parameters obtained as a result of the study.

Table 15
Pharmacokinetic parameters Dose (mg / m ² ) Scheme T _1/2 hour AUC _inf mcg / hr / ml CI _obs l / hr ² V _ssobs l / m ² eighteen qwk × 3 24 ± 4 8.0 ± 1.4 2.3 ± 0.4 72 ± 21 27 qwk × 3 22 ± 10 17.8 ± 5 1.6 ± 0.4 47 ± 21 9* biwk × 2 24 ± 5 4.3 ± 1.3 2.3 ± 0.7 65 ± 2 13.5 * biwk × 2 21 ± 7 5.9 ± 2.9 2.5 ± 1.2 61 ± 6 * The same pharmacokinetics after the 4th, 8th and 11th days of administration

Plasma SNS-595 concentrations were determined using an approved LC-MS / MS assay. The plasma effects at the first two dose levels for each regimen increased linearly, leading to the area under the concentration dynamics curve over time of 4.3-17.8 μg · h / ml for doses of 9-27 mg / m ² . The values of excretion, Vss, and final half-life were the same in patients with solid tumors and averaged 2 l / h / m ² , 58 l / m ² and 23 hours, respectively. In 6 patients, distributed across all dosage groups in table 15, after the first cycle, a decrease in the number of blasts in peripheral blood by more than 50% was noted.

Up to a dose of 27 mg / m ² in the qwk × 3 regimen or up to 13.5 mg / m ² in the biwk × 2 regimen, no dose limiting toxicity (DLT) was observed. Signs of non-dose-limiting toxicity included nausea / vomiting, diarrhea, and mucositis. Grade 4 neutropenia was observed in only one patient.

For other groups of patients, 38 mg / m ² and 50 mg / m ² , respectively, were administered in accordance with Scheme A (qwk × 3). Another group of patients was administered doses of 19 mg / m ² and 25 mg / m ² , respectively, in accordance with Scheme B (biwk × 2). Safety data is shown in table 16.

Table 16
Serious adverse events (SAE), possibly related
with the study drug The name of the phenomenon STCAE in comparison with the degree of 3.0 Each of the following events was observed in 1 patient. qwk × 3 biwk × 2 Pneumonia with neutropenia 3 degree Not observed Neutropenia infection 3 degree Not observed Neutropenia fever Not observed 4 degree Infection Not observed 3 degree

Useful dosage regimens for treating hematologic malignancies may include from about 50 mg / m ² to about 80 mg / m ² administered once a week for 3 weeks. Another dose useful in the treatment of hematologic malignancies is from about 55 mg / m ² to about 75 mg / m ² administered once a week for 3 weeks. Other doses useful in the treatment of hematologic malignancies include 60, 65, 70 or 75 mg / m ² administered once a week for 3 weeks.

Other dosage regimens used to treat patients with hematologic malignancies may include from about 25 mg / m ² to about 50 mg / m ² administered 2 times a week for 2 weeks. Another dose useful in the treatment of hematologic malignancies is from about 30 mg / m ² to about 45 mg / m ² , administered 2 times a week for 2 weeks. Other doses useful in the treatment of hematologic malignancies include 30, 35, 40 or 45 mg / m ² administered 2 times a week for 2 weeks.

Embodiments of the invention described above are intended to be illustrative only, and those skilled in the art will understand or, using only ordinary experimentation, will be able to establish numerous equivalents of certain compounds, materials and procedures. It is believed that all such equivalents are included in the scope of the invention and are covered by the attached claims.

Claims (37)

1. A method of treating acute myelogenous leukemia, comprising administering to a person from about 50 to about 90 mg / m ² enantiomerically pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino ) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid. 2. The method according to claim 1, where the leukemia is recurrent, refractory or resistant to conventional treatment. 3. The method according to claim 1 or 2, where the dose is from about 50 mg / m ² to about 80 mg / m ² administered once a week. 4. The method according to claim 3, where the dose is from about 55 mg / m ² to about 75 mg / m ² . 5. The method according to claim 3, where the dose is about 60 mg / m ² . 6. The method according to claim 3, where the dose is about 65 mg / m ² . 7. The method according to claim 3, where the dose is about 70 mg / m ² . 8. The method according to claim 3, where the dose is about 75 mg / m ² . 9. The method according to claim 1, where the dose is administered 1 time per week for 3 weeks. 10. The method according to claim 1, where the dose, which is from about 50 mg / m ² to about 90 mg / m ² twice a week. 11. The method according to claim 10, where the dose is from about 80 mg / m ² to about 90 mg / m ² . 12. The method of claim 10, wherein the dose is from about 65 mg / m ² to about 75 mg / m ² . 13. The method according to any one of claims 10-12, where the dose is administered within 2 weeks. 14. The method according to claim 1, where enantiomerically pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1 - (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid is administered as an intravenous injection. 15. The method according to 14, where the dose is administered as an intravenous infusion lasting 10-15 minutes 16. A method of treating ovarian cancer, comprising administering to a person in need of treatment a dose of about 45 mg / m ² to 75 mg / m ² enantiomerically pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3- methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid. 17. The method according to clause 16, where the dose is from about 45 mg / m ² to about 55 mg / m ² . 18. The method according to clause 16, where the dose is approximately 48 mg / m ² . 19. The method according to clause 16, where the dose is from about 55 mg / m ² to about 65 mg / m ² . 20. The method according to clause 16, where the dose is approximately 60 mg / m ² . 21. The method according to clause 16, where the dose is from about 65 mg / m ² to about 75 mg / m ² . 22. The method according to clause 16, where the dose is approximately 75 mg / m ² . 23. The method according to clause 16, where the dose of enantiomerically pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo- 1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid is administered once every three weeks. 24. The method according to clause 16, where the dose of enantiomerically pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo- 1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid is administered once every four weeks. 25. The method according to clause 16, where the dose is a single dose, administered as an intravenous infusion lasting 10-15 minutes 26. The method according to any one of paragraphs.16-25, where the cancer is recurrent, refractory or resistant to conventional treatment. 27. The method according to clause 16, where the cancer is recurrent. 28. The method according to clause 16, where the cancer is refractory or resistant to conventional treatment. 29. The method according to p, where the usual treatment includes treatment with a platinum coordination complex. 30. The method according to clause 29, where the cancer is an ovarian cancer resistant to treatment with platinum compounds. 31. The method according to claim 1 or 16, further comprising administering a therapeutically effective dose of the second agent. 32. The method according to p, where the second active agent is a therapeutic antibody to a cancer antigen, hematopoietic growth factor, cytokine, anticancer agent, antibiotic, COX-2 inhibitor, immunomodulatory agent, immunosuppressive agent, corticosteroid, or pharmacologically active mutant, or its derivative. 33. The method according to p, where the antibody is an anti-EGFR antibody. 34. The method according to p, where the antibody is erbitux or panitumumab. 35. The method according to p, where the second active agent is an alkylating agent, antineoplastic antibiotic, antimetabolite, platinum coordination complex, topoisomerase II inhibitor or radiation. 36. The method of claim 32, wherein the second active agent is etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin, carboplatin, premerexed, methotrexate, Ara-C, 5-FU, wortmannin, geldanamycin, gemcitabine, or a combination thereof. 37. The method of claim 32, wherein the second active agent is docetaxel, doxorubicin, daunorubicin, irinotecan, gefitinib, erlotinib, or a combination thereof.

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