KR20170118936A - Methods of using (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid for treatment of cancer - Google Patents

Abstract

The present invention relates to a method of treating, preventing or managing cancer, including certain leukemias. This method can be used to prepare enantiomerically pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3- methoxy- 4- (methylamino) -1- pyrrolidinyl] - (2-thiazolyl) -l, 8-naphthyridine-3-carboxylic acid. The present invention also relates to methods of treatment using such compounds in conjunction with chemotherapy, radiation therapy, hormonal therapy, biological therapy or immunotherapy. And to pharmaceutical compositions and single unit dosage forms suitable for use in such methods.

Description

(+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy- 4- (methylamino) -1- pyrrolidinyl] METHODS OF USING (+) - 1,4-DIHYDRO-7 - [(3S, 4S) -3-METHOXY-4- (2-THIAZOLYL) -1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACID FOR TREATMENT OF CANCER}

This application is a continuation-in-part of U.S. Provisional Application No. 11 / 218,387 and 11 / 218,653 filed September 2, 2005, all of which are now incorporated into the United States provisional application, and U.S. Provisional Application No. 60 / 789,093 and 60 / 788,927, and U.S. Provisional Application No. 60 / 810,285, filed June 1, 2006, All of these applications are incorporated herein by reference.

1. Field

The present invention relates to an enantiomerically pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy- 4- (methylamino) 4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid to treat, prevent or manage cancer including certain leukemia. Also, the present invention relates to administration, dosage regimen and dosage of SNS-595 and its administration.

2. Background

SNS-595 is a compound of formula (I) wherein the chemical name is (+) - 1,4-dihydro-7 - [(3S, 4S) -3- methoxy- - (2-thiazolyl) -l, 8-naphthyridine-3-carboxylic acid,

SNS-595 is known for its anti-tumor activity. The treatment of the following cancers with SNS-595 has been suggested in the literature: bladder cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, melanoma, myeloblastoma Cancer, pancreatic cancer, prostate cancer, kidney cancer, sarcoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer and uterine cancer. Various dosage regimens are reported, for example, in U.S. Patent Application Publication Nos. 2005-0203120, 2005-0215583, and 2006-0025437, all of which are incorporated herein by reference.

There is a continuing need for safe and effective administration and administration of SNS-595 in the treatment, prevention and management of various cancers including leukemia.

3. Overview

SNS-595 is a known cytotoxic agent with efficacy against various cancers. New therapeutic methods including treatment of certain leukemia are discussed herein. In addition, unique dosage ranges, therapies and pharmaceutical dosages are disclosed.

Prevention or management of cancer using SNS-595, its pharmaceutical composition and unique administration are disclosed. In general, the types of cancer that can be treated, prevented or managed using the methods provided herein include but are not limited to bladder cancer, breast cancer, cervical cancer, colon cancer (including rectal colon cancer), esophageal cancer, head and neck cancer, liver cancer, 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), melanoma, myeloma, neuroblastoma And the like, but the present invention is not limited thereto. Cancer may recur, be unresponsive, or have resistance to conventional treatment.

In certain embodiments, the cancer including blood cancer includes, but is not limited to, leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also referred to as Hodgkin's lymphoma), and myeloma. Various forms of leukemia include, but are not limited to, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia. Leukemia can be recurrent, unresponsive, or resistant. In certain embodiments, the blood cancer is pre-eccentric constituent leukemia, T-cell leukemia or lympho-leukemia.

The present invention further relates to a method of treating, preventing or managing cancer by administering SNS-595 in a specific manner. In certain embodiments, the method comprises administering to the mammal 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 / From about 15 mg / m 2 to about 80 mg / m 2, or from about 3 mg / m 2 to about 24 mg / m 2 of the dose of SNS-595. In certain embodiments, the method comprises administering to a mammal an amount of SNS-595 at a dose of about 15 g / m 2, 25 g / m 2 or 50 mg / m 2, based on body surface area. Additional administration and dosage regimens are described in more detail below.

The present invention also relates to administration and dosage regimens for solid cancers. The dose of administered SNS-595 may be administered as a single dose, such as an IV push, in a single dose, e.g., a 10 to 15 minute period (e.g., a single bolus injection) May be delivered over a period of time (e. G., Continuous infusion over time or divided daily administration over time), e. G. Until the patient experiences a stable disease or regression, or until the patient experiences disease progression or tolerability Repeat as often as necessary until you experience untoward toxicity.

In certain embodiments, SNS-595 may be administered to a patient on a periodic basis. Circulatory therapy includes the administration of the active agent for a predetermined period of time, followed by a rest period for a predetermined period of time, and repeating such sequential administration. Circulatory therapy can reduce the formation of resistance to one or more therapies, or it can avoid or reduce the side effects of one of the therapies and / or improve the efficacy of the treatment.

In another embodiment, SNS-595 is administered in conjunction with another drug ("second active agent") or other treatment commonly used in cancer treatment, prevention or management, or in combination with the SNS- The administration method of 595 can be applied to the setting of concurrent treatment. The second active agent includes known small molecules, anticancer agents, antitumor agents or cytotoxic agents and macromolecules (e.g., proteins and antibodies), as well as examples provided herein, as well as stem cells or cord blood. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy, immunotherapy, transfusion, and combinations thereof.

Thus, in certain embodiments, this invention relates to combinations for the treatment, prevention and management of solid tumors. In another embodiment, the invention relates to a combination for the treatment, prevention and management of leukemia and lymphoma.

In addition, the present invention relates to pharmaceutical compositions, single-unit dosage forms and administration regimens comprising SNS-595 and a second or further active agent. The second active agent comprises a particular combination of drugs or treatments or both, or "cocktails ".

Enantiomer pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) 4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid is effective for the treatment, prevention or management of cancer including certain leukemia.

4. Brief description of drawing
Figure 1 shows the plasma concentration of SNS-595 over time in various patient cohorts administered in a qwk x 3 schedule.
Figure 2 shows nuclear lesion formation in HCT116 cells after treatment with SNS-595, etoposide, bleomycin and cisplatin.
Fig. 3 shows lesion quantification by measurement of lesion fluorescence intensity.
Figure 4 shows the dependence of lesion formation upon administration and time.
Figure 5 shows cells with more than 2 lesions in terms of time and SNS-595 concentration.
Figure 6 shows DNA damage caused by SNS-595 and etoposide in the presence and absence of caffeine, an inhibitor of ATM and ATR.
Figure 7 shows DNA damage caused by SNS-595 and etoposide under the presence of DNA-PK (MO59K cells) and absence (MO59J cells).
8A to 8C show the synergistic / additive effect of co-administration of SNS-595 and various cytotoxic agents in HCT116 colon carcinoma cells.
Figure 8d shows the synergistic / synergistic effect of simultaneous administration of SNS-595 and various cytotoxic agents in H460 lung cancer cells.
FIG. 9 shows the combination of the selection of DNA damaging agents and metabolic inhibitors in the SKOV3 ovarian cancer cell line (+ / +) and (- / -) for p53 expression shown in black and gray diamonds and SNS-595 Lt; / RTI >
FIGS. 10A to 10D show the effect of co-administration of SNS-595 with various cytotoxic agents in HCT116 colon carcinoma cells.
Figure 11 shows the administration linearity of three weekly doses of SNS-595 (qwk x 3; circle = 1 week; triangle = 2 weeks) and once per 3 weeks (q3wk; diamond) in patients with advanced solid tumors do.
Figure 12 shows a comparison of anti-tumor activity of SNS-595, etoposide, doxorubicin and irinotecan in a CCRF-CEM xenograft model.
Figure 13 shows a comparison of the anti-tumor activity of SNS-595 (at 20 mg / kg and 25 mg / kg), etoposide, doxorubicin and irinotecan in the LM3-Jck xenograft model.
Figure 14 shows cell integrity in SNS-595 early-injection after 6 days of bone marrow in CD-1 mouse females. SNS-595 was administered on days 0 and 4. All images were magnified by 10 magnifications.
Figure 15 shows the neutrophil response to SNS-595 administration.
Figure 16 shows neutrophil counts at various SNS-595 doses up to day 8.
Figure 17 shows WBC counts at various SNS-595 doses up to day 8.
Figure 18 shows platelet counts at various SNS-595 doses up to day 8.
Figure 19 shows the percentage change in body weight at various time intervals after administration of SNS-595.
Figure 20 shows bone marrow reassembled on day 12 after administration of 20 mg / kg SNS-595.

5. Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other documents cited are incorporated herein by reference. If there are plural definitions of a term in this specification, the terms of this definition take precedence unless otherwise specified.

As used herein, enantiomerically pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy- 4- (methylamino) -1- pyrrolidinyl] -4 - (2-thiazolyl) -l, 8-naphthyridine-3-carboxylic acid was prepared from (-) - 1,4-dihydro- - (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid (i.e., enantiomeric excess ). In other words, it is possible to obtain a compound represented by the general formula (1), which is 1,4-dihydro-7 - [(3S, 4S) -3-methoxy- Naphthyridine-3-carboxylic acid is substantially free of the "(-)" form of the compound and is thus an enantiomeric surplus of the "(-)" form . By the term "enantiomeric pure" or "pure enantiomer" is meant that the compound comprises greater than 75 wt%, greater than 80 wt%, greater than 85 wt%, greater than 90 wt%, greater than 91 wt%, greater than 92 wt% , Greater than 94 wt%, greater than 95 wt%, greater than 96 wt%, greater than 97 wt% enantiomers.

As used herein and unless otherwise indicated, the term "enantiomerically pure (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy- 1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid " (3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) (-) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy- 4- (methylamino) -1- pyrrolidinyl] -4 (+) - 1,4-dihydro-7 - [(3S, 4S) - (2-thiazolyl) - 1,8-naphthyridine- (2-thiazolyl) -l, 8-naphthyridine-3-carboxylic acid and about 10% or less by weight of a 3-methoxy- (+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl ] -4-oxo-1- (2-thia (-) - 1,8-naphthyridine-3-carboxylic acid and up to about 5% by weight of the (-) - enantiomer, about 97% , 4S) -3-methoxy-4- (methylamino) -1- pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine- 3% by weight or less of the (-) - enantiomer.

As used herein and unless otherwise indicated, the terms "treat", "treating" and "treatment" refer to alleviating or reducing the severity of symptoms associated with the disease or condition being treated.

The term "prevention" includes the inhibition of a particular disease or disorder symptom. In certain embodiments, a patient with a family history of cancer is a candidate for prophylactic therapy. Generally, the term "preventing " refers to the administration of a drug prior to the onset of symptoms, particularly to a patient at risk of developing cancer.

As used herein and unless otherwise indicated, the term "managing" means preventing a recurrence of a particular disease or disorder in a patient who has suffered a particular disease or disorder, and preventing a patient Prolonging the time to survive the period, reducing the mortality rate of the patient, and / or maintaining a reduction in the severity or the prevention of symptoms associated with the disease or condition being managed.

As used herein, an "individual" is an animal, usually a mammal, including a person, such as a patient.

As used herein, the term "cancer" includes but is not limited to solid tumors and blood-mediated tumors. The term "cancer" refers to a disease or condition associated with a cancer, such as a bladder, bone or blood, brain, breast, cervix, thorax, colon, endometrium, esophagus, eye, tofu, kidney, liver, lung, Testicular, throat, and uterine cancer, including, but not limited to, skin tissue, organs, blood, and blood vessel diseases.

As used herein, the term "blood cancer" refers to the blood-forming and immune system of the body, and cancer of the bone marrow and lymphoid tissues. Such cancers include leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also referred to as Hodgkin's lymphoma), and myeloma.

The term "leukemia" refers to a malignant neoplasm of blood-forming tissue. Leukemias include, but are not limited to, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia. Leukemia may be relapsed, unresponsive, or resistant to conventional therapy.

As used herein, "pre-constituent leukemia" or "acute promyelocytic leukemia" refers to mature blood cells in the myelofibral line of the cell, and bone marrow cells that are deficient in excess immature cells, Cancer. It is generally characterized by partial exchange of chromosomes 15 and 17.

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

As used herein, "T-cell leukemia" refers to a disease in which certain cells of the lymphatic system, referred to as T lymphocytes or T cells, are malignant. T cells are leukocyte cells that can normally attack virus-infected cells, foreign and cancer cells, and produce substances that regulate the immune response.

The term " recurred "refers to a situation in which cancer cells recur in a patient with a remission period of cancer after treatment.

The term " unresponsive or resistant "refers to a situation in which a patient has residual cancer cells even after intensive treatment.

As used herein, IC ₅₀ refers to the amount, concentration, or dose of a particular test compound that achieves a 50% inhibition of the maximal response in an assay measuring the above reaction.

As used herein and unless otherwise stated, the terms "therapeutically effective amount" and "effective amount" of a compound provide therapeutic advantages in the treatment, prevention and / or management of disease, Or to delay or minimize one or more symptoms associated with the disease. The terms "therapeutically effective amount" and "effective amount" may include amounts that improve overall treatment, reduce or avoid the symptoms or causes of the disease or disorder, and improve the therapeutic efficacy of another therapeutic agent.

As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salts" includes, but is not limited to, salts of acidic or basic groups that may be present in the compounds provided herein. Under certain acidic conditions, the compounds can form various salts with various inorganic and organic acids. Acids that may be used to produce pharmaceutically acceptable salts of such basic compounds include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, bromide, iodide , Dihydrochloride, edetate, eddylate, estholate, ethylate, fumarate, glucosate, gluconate, glutamate, glycolylarsanylate, hexylresorcinate, hydrabamine, hydroxynaphtho Maleate, maleate, mandelate, mesylate, methyl sulfate, non-skate, lead silicate, nitrate, pantothenate, phosphate / diphosphate, polygalacturon Nitrate, salicylate, stearate, succinate, sulfate, tannate, Stuttgart rate, Theo clay agent, but to form the salt containing pharmaceutically acceptable anion, including tea iodide and pamoate in the tree, but is not limited to this. Under certain basic conditions, the compounds can form base salts with various pharmacologically acceptable cations. Non-limiting examples of such salts include alkali metal or alkaline earth metal salts, especially calcium, magnesium, sodium, lithium, zinc, potassium and iron salts.

As used herein and unless otherwise indicated, the term "hydrate" refers to a compound or a compound provided herein that further comprises a stoichiometric or non-stoichiometric amount of water bound by a non-shared intermolecular force Means salt.

As used herein and unless otherwise indicated, the term "solvate" refers to a solvate formed by the binding of one or more solvent molecules to a compound provided herein. The term "solvate" includes hydrates (e.g., monohydrate, dihydrate, trihydrate,

The terms "co-administration" and "concurrently" include administration of two therapeutic agents (e.g., SNS-595 and another anti-cancer agent or second agent) simultaneously, simultaneously or sequentially . In one embodiment, all of the agents are present simultaneously in the cell or in the body of a patient, or exhibit biological or therapeutic efficacy at the same time. In one embodiment, the two therapeutic agents are present in the same composition or unit dosage formulation. In another embodiment, the two therapeutic agents are present in separate compositions or unit dosage forms.

The term " patient-controlled formulation "refers to any substance that treats, prevents or manages adverse effects from SNS-595 therapy.

6. Detailed Description

6.1 SNS-595

The compounds for use in the methods and compositions provided herein are 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. SNS-595 has the following formula:

In certain embodiments, a pharmaceutically acceptable salt, solvate, hydrate or prodrug of SNS-595 is used in the methods and compositions provided herein.

SNS-595 may be prepared by methods known to those skilled in the art, for example, in Example C-1 of U.S. Patent No. 5,817,669 entitled " Compounds, Methods for Making Same and Antineoplastic ", issued Oct. 6, May be produced by the method of manufacture for the application Hei 10-173986 (Chikugi et al.), Which is incorporated herein by reference. Specific examples of pharmaceutical compositions comprising SNS-595 and methods of their use are described in United States Patent Application Publication Nos. 2005-0203120, 2005-0215583 and 2006-0025437, both of which are incorporated herein by reference References are cited for reference.

6.2 How to use

The cells undergoing proliferation undergo the four steps of the cell cycle, G ₁ , S, G ₂ and M. These steps are first known as the S phase or synthesis and mitosis of the cell cycle and are observed by observing the cells undergoing cleavage as the cell progresses through known DNA synthesis as M or S phase of mitosis or cell cycle. The observed time intervals between completion of DNA synthesis and mitosis, and between mitosis and the next cycle of DNA synthesis are G ₁ and G ₂ , respectively. Non-proliferating cells possessing the ability to proliferate under appropriate conditions are at rest or in the G ₀ state, typically characterized by the presence of a cell cycle.

SNS-595 is a cell cycle inhibitor, thereby stopping cells in G ₂ interphase. Without wishing to be bound by any particular theory, SNS-595 mediates activation of the DNA-PK pathway and ultimately leads to apoptotic cell death. This situation has S-specificity, that is, they occur only during S phase of the cell cycle. While not wishing to be bound by any particular theory, treatment with SNS-595 increases the number of double-stranded DNA damage that occurs in the S phase. Such damage inhibits the ability of cells to synthesize DNA and prolongs the time the cells are in the S phase. Once DNA damage is detected in the cell, a marker for apoptosis appears quickly. This rapid onset of apoptosis has been shown to be p73 dependent, as it has been shown to reduce the reduction of SNS-595 sensitivity in p73 no-label cells by more than 11-fold compared to p73-containing cells.

As illustrated in Fig. 7, when the formation of double-stranded lesions is activated in a dose-dependent manner, DNA-PK can be expressed by: i) DNA-PK expression; ii) H2AX phosphorylation; iii) c-Abl phosphorylation; iv) p53 phosphorylation; v) p73 phosphorylation; vi) p21 expression; vii) caspase-9 activation; And viii) mediating restoration and apoptotic cell machinery, including caspase-3 activation, but are not limited thereto. If DNA damage is severe enough to prevent double-strand damage from being restored through non-homologous end connections (NHEJ), the cell rapidly progresses to apoptosis. Certain cells can reach the G ₂ phase because they are too damaged to proceed to the M phase and eventually become apoptotic, but are subsequently stopped (mediated by cdc 2 / Cyclin B). While not intending to be bound by any particular theory, since SNS-595 has S-selectivity, the administration of SNS-595, which is cytotoxic to proliferating cells (and thus through the cell cycle including the S group) It is non-destructive to cells.

6.2.1 Solid tumors

Accordingly, there is provided a method of treating, managing or preventing cancer comprising administering to a mammal in need of treatment, management or prevention of SNS-595 at a dose of about 1 mg / m 2 to about 100 mg / m 2. Types of cancer include bladder cancer, breast cancer, cervical cancer, colon cancer (including rectal cancer), esophageal cancer, head and neck cancer, liver cancer, lung cancer (both small and non-small cell), melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, But are not limited to, cancer, kidney cancer, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer and uterine cancer. In one embodiment, the method is for the treatment of colon, pancreas, breast, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, melanoma, nasopharyngeal, neuroendocrine, ovarian, renal, salivary, small cell lung cancer, Prevention or management.

6.2.2 Leukemia

In one embodiment, this includes treating, preventing or managing various types of leukemia such as chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia and acute myeloblastic leukemia.

In certain embodiments, the method is used to treat acute leukemias such as undifferentiated AML (M0), myeloblastic leukemia (M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]), Prevention, or management of AML, including Sudanese nuclear leukemia (M4 or M4 variants with eosinophilia [M4E]), mononuclear leukemia (M5), leukemia (M6), and macroglobulinemic leukemia (M7) However, it is not limited to the above-mentioned leukemia. In certain embodiments, acute lymphoblastic leukemia (ALL) comprises leukemia originating from bone marrow (B-cells), thymus (T-cells), and lymphocyte stem cells. Acute lymphocytic leukemia is characterized by L1-mature lymphocytes (T-cells or pro-B-cells), L2-immature and polymorphic forms (various forms) by the French-American-British (FAB) ) Lymphocyte (T-cell or pro-B-cell) and L3-lymphocyte (B-cell; Burkitt cell).

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

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

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

In one embodiment, the acute myelogenous leukemia is pre-molar constituting leukemia (M3 or M3 variant [M3V]).

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

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

In one embodiment, the acute myelogenous leukemia is an autoimmune leukemia (M6).

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

In one embodiment, acute lymphoblastic leukemia is derived from a cell of bone marrow (B-cell).

In one embodiment, acute lymphoblastic leukemia is from a thymus (T-cell).

In one embodiment, acute lymphoblastic leukemia is from a lymph node.

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

In one embodiment, acute lymphoblastic leukemia is type L2, which is characterized by immature and multifocal (having various forms) lymphoid (T-cells or pro-B-cells).

In one embodiment, acute lymphoblastic leukemia is of the L3 type, characterized by lymphoblastic (B-cells; Burkitt cells).

In certain embodiments, the acute myelogenous leukemia is pre-eccentric or leukemia. In certain embodiments, the lymphocytic leukemia is T-cell leukemia. In one embodiment, the methods provided herein include methods of treating, preventing, or managing pre-eccentric constitutive leukemia, T-cell leukemia, or lymphoblastic leukemia. In one embodiment, T-cell leukemia is peripheral T-cell leukemia, T-cell lymphocyte leukemia, skin T-cell leukemia and adult T-cell leukemia.

In certain embodiments, SNS-595 is used to treat drug-resistant leukemias such as chronic myelogenous leukemia (CML). Thus, treatment with SNS-595 may provide alternative therapies to patients who do not respond to other treatment modalities. In certain embodiments, such other methods of treatment include treatment with Gleevac (R). In certain embodiments, a method of treating Philadelphia chromosome positive chronic myelogenous leukemia (Ph + CML) is provided. In a particular embodiment, a method of treating Philadelphia chromosome-positive chronic myelogenous leukemia (Ph + CML) with Gleevac (R) resistance is provided.

The methods provided herein include treating patients who have received prior therapy for cancer but are non-responsive to standard therapy as well as patients who have not received prior treatment. It also includes a method of treating a patient regardless of the age of the patient, although the particular disease or disorder is more common in certain age groups. This includes treating patients who have undergone surgery to treat the disease or condition, as well as patients who have not undergone surgery. Since patients with cancer have heterogeneous clinical findings and various clinical outcomes, the treatment presented to the patient may vary according to the patient's prognosis. Skilled clinicians will be able to readily determine the type of standard treatment based on the particular secondary agent, surgical type, and non-drug that can be effectively used to treat each cancer patient, without undue experimentation.

The dose of administered SNS-595 may be administered as a single dose, such as an IV push, in a single dose, e.g., a 10 to 15 minute period (e.g., a single bolus injection) May be delivered over a period of time (e. G., Continuous infusion over time or divided daily administration over time), e. G. Until the patient experiences a stable disease or regression, or until the patient experiences disease progression or tolerability Repeat as often as necessary until you experience untoward toxicity. For example, a stable disease for a solid tumor generally means that the vertical diameter of the measurable lesion has not been increased by more than 25% from the final measurement. See, for example, Response Evaluation Criteria in Solid Tumor (RECIST) Guidelines, Journal of National Cancer Institute 92 (3): 205-216 (2000). Stable disease or lack thereof can be determined by methods known in the art, for example, evaluation of patient symptoms, visualization of the tumor that has been visualized using, for example, X-ray, CAT, PET or MRI scans and other commonly accepted evaluation techniques .

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

In another embodiment, the dosage is about 20 mg / m 2 to 30 mg / m 2. In another embodiment, the dosage is about 25 mg / m 2 to 35 mg / m 2. In another embodiment, the dosage is about 40 mg / m 2 to 50 mg / m 2. In another embodiment, the dosage is about 45 mg / m 2 to 55 mg / m 2. In another embodiment, the dose is from about 50 mg / m 2 to 60 mg / m 2. In another embodiment, the dosage is from about 55 mg / m2 to about 65 mg / m2. In another embodiment, the dosage is about 60 mg / m 2 to about 70 mg / m 2. In another embodiment, the dose is from about 65 mg / m 2 to about 75 mg / m 2. In another embodiment, the dosage is about 70 mg / m 2 to 80 mg / m 2. In another embodiment, the dosage is from about 75 mg / m 2 to about 85 mg / m 2. In another embodiment, the dosage is about 80 mg / m 2 to 90 mg / m 2. In another embodiment, the dosage is about 85 mg / m 2 to 95 mg / m 2. In another embodiment, the dosage is about 90 mg / m 2 to 100 mg / m 2.

In other embodiments, SNS-595 is administered in combination with another drug ("second active agent") to treat, manage, or prevent cancer or another therapy. The second active agent includes stem cells or cord blood as well as small molecules and macromolecules (e. G., Proteins and antibodies) provided in the examples herein. Methods or therapies that may be used in conjunction with administration of SNS-595 include surgery, immunotherapy, biological therapy, radiation therapy and other non-drug based therapies currently used to treat, prevent or manage cancer , But is not limited thereto. Various dosage regimens for administration and / or concurrent treatment of SNS-595 alone are discussed herein.

Also provided is a pharmaceutical composition (e.g., a single unit dosage formulation) that can be used in the methods disclosed herein. Certain pharmaceutical compositions comprise SNS-595 and a second active agent.

6.3 Dose and dosage regimen

In one embodiment, the cancer treatment, prevention, or management methods provided herein include administering SNS-595 at a dose of about 1 mg / m 2 to 150 mg / m 2 based on the body surface area of the patient. In another embodiment, the method comprises administering SNS-595 at a dose of about 1 mg / m 2 to 100 mg / m 2. In another embodiment, the method comprises administering SNS-595 at a dose of about 1 mg / m 2 to 75 mg / m 2. In another embodiment, the method comprises administering SNS-595 at a dose of about 1 mg / m 2 to 60 mg / m 2. In another embodiment, the method comprises administering a dose of about 1 mg / m 2 to 50 mg / m 2 of SNS-595. In another embodiment, the method comprises administering a dose of about 1 mg / m 2 to 48 mg / m 2 of SNS-595. In another embodiment, the method comprises administering SNS-595 at a dose of about 1 mg / m 2 to 24 mg / m 2. In another embodiment, the method comprises administering SNS-595 at a dose of about 3 mg / m 2 to 27 mg / m 2 based on body surface area. In another embodiment, the method comprises administering SNS-595 at a dose of about 3 mg / m 2 to 24 mg / m 2 based on body surface area. In another embodiment, the method comprises administering SNS-595 at a dose of about 10 mg / m 2 to 90 mg / m 2 based on body surface area. In another embodiment, the method comprises administering SNS-595 at a dose of about 15 mg / m 2 to 80 mg / m 2 based on body surface area. The body surface area calculation can be calculated, for example, by the following equation:

In another embodiment, the dosage is 3 mg / m 2 to 24 mg / m 2 based on the body surface area. In another embodiment, the dosage is 3 mg / m 2 to 18 mg / m 2 based on the body surface area. In another embodiment, the dosage is 3 mg / m 2 to 15 mg / m 2. In another embodiment, the dosage is in the range of 1 mg / m2, 2 mg / m2, 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / 14 mg / m 2, 15 mg / m 2, 16 mg / m 2, 17 mg / m 2, 8 mg / m 2, 9 mg / m 2, 10 mg / m 2, 11 mg / 24 mg / m 2, 25 mg / m 2, 26 mg / m 2, 27 mg / m 2, 18 mg / m 2, 19 mg / m 2, 20 mg / 60 mg / m 2 or 65 mg / m 2, 30 mg / m 2, 36 mg / m 2, 42 mg / m 2, 48 mg / m 2, 50 mg / In another embodiment, the dosage is 3 mg / m2, 6 mg / m2, 9 mg / m2, 12 mg / m2, 15 mg / m2, 18 mg / m2, 21 mg / 27 mg / m 2, 36 mg / m 2, 48 mg / m 2 or 50 mg / m 2.

In one embodiment, the dosage 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 dosage is 30 mg / m < 2 > based on body surface area. In one embodiment, the dose is 50 mg / m 2 based on the body surface area.

In another embodiment, the dosage is from 15 mg / m 2 to 80 mg / m 2 based on the body surface area. In another embodiment, the dosage is from 15 mg / m 2 to 75 mg / m 2 based on the body surface area. In another embodiment, the dosage is 20 mg / m2 to 65 mg / m2. In another embodiment, the dosage is from 30 mg / m 2 to 50 mg / m 2. In another embodiment, the dosage is in the range of 15 mg / m2, 20 mg / m2, 25 mg / m2, 30 mg / m2, 35 mg / m2, 40 mg / m2, 45 mg / 60 mg / m 2, 65 mg / m 2, 70 mg / m 2, 75 mg / m 2 or 80 mg / m 2.

The dose of administered SNS-595 may be expressed in units other than mg / m 2. For example, the dosage can be expressed in mg / kg. Those skilled in the art are aware of how to convert doses from mg / m 2 to mg / kg for the height, weight or both of the presented subjects (http: ///www.fda.gov/cder/cancer/animalframe.htm Reference). For example, in the case of 65 kg person, the dosage of 1 mg / m 2 to 30 mg / m 2 corresponds to about 0.026 mg / kg to 0.79 mg / kg. In another example, a dosage of 3 mg / m < 2 > for a 65 kg person corresponds to approximately 0.078 mg / kg. In another example, a dosage of 15 mg / m 2 to 80 mg / m 2 for a 65 kg person corresponds to approximately 0.39 mg / kg to 2.11 mg / kg.

In certain embodiments, the dose of SNS-595 administered is administered as a single dose, such as an IV push of a single dose, e.g., a 10 to 15 minute period (e.g., a single bolus injection) For example 24 hours (e.g., continuous infusion over time, or divided daily infusion over time), e.g., until the patient experiences a stable disease or regression, or until the patient has progressed to disease progression Repeat as necessary until you experience unacceptable toxicity. Stable disease or lack thereof is determined using methods known in the art, such as evaluation of patient symptoms, examination and other commonly accepted evaluation techniques.

The amount of the pharmaceutical composition administered by the method provided herein is determined according to the mammal to be treated, the severity of the disease or symptoms of the disease, the method of administration, the frequency of administration, and the judgment of the prescribing physician.

In certain embodiments, the frequency of administration is within the range of about one day dosing or about one month dosing. In certain embodiments, the administration is once daily, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the pharmaceutical compositions provided herein are administered on a weekly basis.

In certain embodiments, SNS-595 was administered to the patient periodically. Cycling therapies include the administration of the active agent for a predetermined period of time, then stopping the administration for a predetermined period of time, and repeating such sequential administration. Cycling therapies may reduce the formation of resistance to one or more of one or more therapies, or may avoid or reduce the side effects of one of the therapies and / or improve the efficacy of the treatment.

Consequently, in one embodiment, SNS-595 is administered weekly in single or divided doses over a period of 3 to 6 weeks and administration is discontinued for from about 1 to about 30 days. In another embodiment, SNS-595 is administered weekly in single or divided doses for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks and 1, 3, 5, 7, 9, 12, 14, 16, 18, 20, 22, 24, 26, 28, 29 or 30 days. In certain embodiments, the waiting period is 14 days. In a particular embodiment, the waiting period is 28 days. In one embodiment, the waiting period is until sufficient bone marrow restoration is present. The frequency, number and length of dosing cycles can be increased or decreased. Thus, another embodiment involves administering SNS-595 in more cycles than is usual when administered alone.

In one embodiment, the methods provided herein comprise: i) administering to the patient SNS-595 at a dose of about 1 mg / m 2 to 150 mg / m 2; ii) awaiting a period of one or more days without any SNS-595 administration to the mammal; And iii) administering to the patient another dose of SNS-595 from about 1 mg / m 2 to about 150 mg / m 2. In one embodiment, steps ii) -iii) are repeated a plurality of times. In another embodiment, the method comprises administering a dose of from 1 mg / m 2 to 100 mg / m 2 in steps i) and iii).

In one embodiment, for example, in a method of treating certain leukemias, the methods provided herein comprise i) administering to a mammal SNS-595 at a dose of about 10 mg / m 2 to 150 mg / m 2; ii) awaiting a period of one or more days without any SNS-595 administration to the mammal; And iii) administering to the mammal another dose of SNS-595 at about 10 mg / m2 to 150 mg / m < 2 >, iv) repeating step ii) -iii) a plurality of times. In another embodiment, the method comprises administering a dosage of from 10 mg / m 2 to 100 mg / m 2 in steps i) and iii).

In one embodiment, the methods provided herein comprise i) administering to a patient SNS-595 at a dose of about 1 mg / m 2 to 75 mg / m 2; ii) awaiting a period of one or more days without any SNS-595 administration to the mammal; And iii) administering to the patient another dosage of SNS-595 from about 1 mg / m 2 to about 75 mg / m 2. In one embodiment, steps ii) -iii) are repeated a plurality of times.

In one embodiment, the methods provided herein comprise i) administering to the patient SNS-595 at a dose of about 1 mg / m 2 to 48 mg / m 2; ii) awaiting a period of one or more days without any SNS-595 administration to the mammal; And iii) administering to the patient another dosage of SNS-595 of about 1 mg / m 2 to 48 mg / m 2. In one embodiment, steps ii) -iii) are repeated a plurality of times.

In one embodiment, the methods provided herein comprise i) administering to a patient SNS-595 at a dose of about 1 mg / m 2 to 24 mg / m 2; ii) awaiting a period of one or more days without any SNS-595 administration to the mammal; And iii) administering to the patient another dose of SNS-595 of about 1 mg / m 2 to 24 mg / m 2. In one embodiment, steps ii) -iii) are repeated a plurality of times.

In another embodiment, the method comprises administering a dosage of 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 > in steps i) and iii). In another embodiment, the method further comprises the step of administering to a subject in steps i) and iii) about 1 mg / m 2 to about 40 mg / m 2, about 1.5 mg / m 2 to about 30 mg / And a dose of 3 mg / m 2 to 24 mg / m 2.

In another embodiment, the method comprises administering a dosage of about 15 mg / m 2 to 80 mg / m 2 in steps i) and iii). In another embodiment, the method comprises administering a dosage of about 15 mg / m 2 to 75 mg / m 2 in steps i) and iii). In another embodiment, the method further comprises the step of administering to a patient in steps i) and iii) a dose of about 20 mg / m 2 to about 65 mg / m 2, about 30 mg / m 2 to about 50 mg / About 45 mg / m < 2 >.

In this method, for example, if the waiting period is 6 days, an initial dose of SNS-595 is administered on day 1 (step i); The waiting period is 6 days (step ii); And the next dose of SNS-595 is administered on day 8 (step iii). Examples of other examples include days 2, 3, 5, 7, 10, 12, 13, 14, 15, 17, 20, 27 and 28 days. In another embodiment, the waiting period is at least two days, and steps ii) to iii) are repeated three more times. In another embodiment, the waiting period is at least three days, and steps ii) to iii) are repeated at least five times. In another embodiment, the waiting period is three days or more, and steps ii) to iii) are repeated three or more times. In another embodiment, the waiting period is at least three days, and steps ii) to iii) are repeated at least five times. In another embodiment, the waiting period is six days or more, and steps ii) to iii) are repeated three or more times. In another embodiment, the waiting period is 6 days or more, and steps ii) to iii) are repeated 5 or more times. In another embodiment, the waiting period is at least 14 days, and steps ii) to iii) are repeated three more times. In another embodiment, the waiting period is 20 days or more, and steps ii) to iii) are repeated three or more times. In another embodiment, the waiting period is 20 days or more, and steps ii) to iii) are repeated 5 or more times. In another embodiment, the waiting period is 28 days or more, and steps ii) to iii) are repeated three or more times. In another embodiment, the waiting period is 27 days or more, and steps ii) to iii) are repeated 5 or more times. In another embodiment, the waiting period is 28 days or more, and steps ii) to iii) are repeated 5 or more times.

In another embodiment, the method of administration comprises administering to a mammal a predetermined dose of SNS-595 twice weekly (administered on day 1, day 4, day 8 and day 11). In another embodiment, the method of administration comprises administering to a mammal a weekly dose of SNS-595. In another embodiment, the method of administration comprises administering a predetermined dose of SNS-595 to the mammal at intervals of two weeks. In another embodiment, the method of administration comprises administering a predetermined dose of SNS-595 to the mammal at 3-week intervals. In another embodiment, the method of administration comprises administering a predetermined dose of SNS-595 to the mammal at 4-week intervals.

In another embodiment, the method of administration comprises administering to a mammal a predetermined dose of SNS-595 for three weeks, once per week, followed by a period of not less than 14 days without administering SNS-595 to the mammal And the cycle is repeated a plurality of times. In another embodiment, the period of not administering SNS-595 is 14 days. In another embodiment, the period of not administering SNS-595 is 21 days.

In another embodiment, the methods provided herein comprise i) administering to a mammal about 1 mg / m 2 to 100 mg / m 2 dose of the SNS-595 per week for 3 weeks; ii) awaiting a period of 14 days without any SNS-595 administration to the mammal; And iii) administering to the mammal one dose of SNS-595 at about 1 mg / m 2 to 100 mg / m 2 per week for 3 weeks. In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the method provided herein comprises i) administering to a mammal a dose of about 1 mg / m 2 to about 75 mg / m 2 of the compound per week for 3 weeks; ii) awaiting a period of 14 days without any SNS-595 administration to the mammal; And iii) administering to the mammal one dose of SNS-595 at about 1 mg / m 2 to 75 mg / m 2 per week for 3 weeks. In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the method provided herein comprises i) administering to a mammal about 1 mg / m 2 to 60 mg / m 2 dose of SNS-595 per week for 3 weeks; ii) awaiting a period of 14 days without any SNS-595 administration to the mammal; And iii) administering to the mammal one dose of SNS-595 at about 1 mg / m 2 to 60 mg / m 2 per week for 3 weeks. In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the methods provided herein comprise i) administering SNS-595 at a dose of about 1 mg / m 2 to 50 mg / m 2 per week to the mammal for 3 weeks; ii) awaiting a period of 14 days without any SNS-595 administration to the mammal; iii) another dose of SNS-595 of about 1 mg / m 2 to 50 mg / m 2 is administered to the mammal once a week for 3 weeks; iv) repeating step ii) -iii a plurality of times.

In another embodiment, the methods provided herein comprise i) administering SNS-595 at a dose of about 1 mg / m 2 to 48 mg / m 2 per week to the mammal for 3 weeks; ii) awaiting a period of 14 days without any SNS-595 administration to the mammal; And iii) another dose of SNS-595 at about 1 mg / m 2 to 48 mg / m 2 per week for three weeks to the mammal. In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the methods provided herein comprise i) administering SNS-595 at a dose of about 1 mg / m 2 to 24 mg / m 2 per week to the mammal for 3 weeks; ii) awaiting a period of 14 days without any SNS-595 administration to the mammal; And iii) another dose of SNS-595 at about 1 mg / m 2 to 24 mg / m 2 per week for three weeks in a mammal. In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the method provided herein comprises i) administering to a mammal about 1 to 40 mg / m < 2 > dose of a dose of about 2 mg / m 2 per week for 3 weeks; ii) awaiting a period of 14 days without any SNS-595 administration to the mammal; And iii) another dose of SNS-595 of 2 mg / m 2 to 40 mg / m 2 per week for three weeks to the mammal. In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the methods provided herein comprise i) administering to a mammal about 3 mg / m 2 to 24 mg / m 2 dose of SNS-595 per week for 3 weeks; ii) awaiting a period of 14 days without any SNS-595 administration to the mammal; And iii) administering another dose of SNS-595 at about 3 mg / m 2 to 24 mg / m 2 per week for 3 weeks to the mammal. In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the methods provided herein comprise i) administration of SNS-595 at a dose of about 3 mg / m 2 to 24 mg / m 2 per week for three weeks to a mammal (e.g., day 1, day 8, And 15-day dosing); ii) awaiting a period of at least 28 days without any SNS-595 administration to the mammal; And iii) administering another dose of SNS-595 at about 3 mg / m 2 to 24 mg / m 2 per week for 3 weeks to the mammal. In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the methods provided herein comprise i) administering to a mammal about 3 mg / m 2 to 24 mg / m 2 of a dose of SNS-595 per week for 1 week (1st day, 4th day, 8th day, 11 days); ii) awaiting a period of at least 28 days without any SNS-595 administration to the mammal; And iii) administering another dose of SNS-595 at about 3 mg / m 2 to 24 mg / m 2 to the mammal for two weeks (week 1, day 4, day 8, and day 11) for two weeks . In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the methods provided herein comprise i) administering to a mammal about 3 mg / m 2 to 24 mg / m 2 of a dose of SNS-595 per week for 3 weeks (eg, 1 day, 8 days and 15 Lt; / RTI > ii) awaiting a 28 day period in which no SNS-595 is administered to the mammal; And iii) administering another dose of SNS-595 at about 3 mg / m 2 to 24 mg / m 2 per week for 3 weeks to the mammal. In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the methods provided herein comprise i) administering to a mammal about 2 mg / m 2 to 24 mg / m 2 of a dose of SNS-595 twice weekly (1 st day, 4 th day, 8 th day, 11 days); ii) wait for a period of 28 days without any SNS-595 administration to the mammal; And iii) administering another dose of SNS-595 at about 3 mg / m 2 to 24 mg / m 2 to the mammal for two weeks (week 1, day 4, day 8, and day 11) for two weeks . In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the methods provided herein comprise the steps of i) administering to a mammal SNS-595 at a dose of about 15 mg / m 2 to 80 mg / m 2 per week for 3 weeks; ii) awaiting a period of 14 days without any SNS-595 administration to the mammal; And iii) another dose of SNS-595 at about 15 mg / m 2 to 80 mg / m 2 per week for three weeks to the mammal. In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the methods provided herein comprise i) administering to a mammal about 15 mg / m 2 to 80 mg / m 2 of a dose of SNS-595 per week for 3 weeks (eg, 1 day, 8 days and 15 Primary administration); ii) awaiting a period of at least 28 days without any SNS-595 administration to the mammal; And iii) another dose of SNS-595 at about 15 mg / m 2 to 80 mg / m 2 per week for three weeks to the mammal. In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the methods provided herein comprise the steps of: i) administering to a mammal an amount of about 15 mg / m 2 to 80 mg / m 2 of SNS-595 per week for two weeks (first day, fourth day, 11 days); ii) awaiting a period of at least 28 days without any SNS-595 administration to the mammal; And iii) administering another dose of about 15 mg / m 2 to 80 mg / m 2 of SNS-595 to the mammal for two weeks (week 1, day 4, day 8, and day 11) for two weeks . In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the methods provided herein comprise i) administering to a mammal about 15 mg / m 2 to 80 mg / m 2 of a dose of SNS-595 per week for 3 weeks (eg, 1 day, 8 days and 15 Primary administration); ii) wait for a period of 28 days without any SNS-595 administration to the mammal; And iii) another dosage of SNS-595 at about 15 mg / m 2 to 80 mg / m 2 per week for three weeks in a mammal. In one embodiment, step ii) -iii) is repeated a plurality of times.

In another embodiment, the methods provided herein comprise the steps of: i) administering to a mammal an amount of about 15 mg / m 2 to 80 mg / m 2 of SNS-595 per week for two weeks (first day, fourth day, 11 days); ii) wait for a period of 28 days without any SNS-595 administration to the mammal; And iii) administering another dose of SNS-595 at about 15 mg / m 2 to 80 mg / m 2 to the mammal for two weeks (week 1, day 4, day 8, and day 11) for two weeks . In one embodiment, steps ii) -iii) are repeated a plurality of times.

In another embodiment, the method comprises administering to a patient, once per week, SNS-595 at a dose of from 1 mg / m 2 to 100 mg / m 2, wherein the one week period comprises a treatment period, Repeat this process. In another embodiment, the method comprises administering to the patient, once per week, SNS-595 at a dose of 1 mg / m 2 to 75 mg / m 2, wherein the one week period comprises a treatment period, Repeat 3 times or more. In another embodiment, the method comprises administering to a patient, once per week, SNS-595 at a dose of 1 mg / m 2 to 60 mg / m 2, wherein the one week period comprises a treatment period, Repeat this process. In another embodiment, the method comprises administering to the patient, once per week, SNS-595 at a dose of 1 mg / m 2 to 48 mg / m 2, wherein the one week period comprises a treatment period, Repeat this process. In another embodiment, the method comprises administering to a patient once per week a SNS-595 dosage of from 1 mg / m 2 to 24 mg / m 2, wherein the one week period comprises a treatment period, Repeat 3 times or more. In another embodiment, the dosage is from about 2 mg / m 2 to about 40 mg / m 2 per week, the one week period including a treatment cycle, and the treatment cycle is repeated three or more times. In another embodiment, the dosage is from about 3 mg / m 2 to 24 mg / m 2 per week, and the one week period includes a treatment cycle, wherein the treatment cycle is repeated three or more times. In another embodiment, the dose is about 15 mg / m 2 per week, wherein the one week period includes a treatment period, and the treatment cycle is repeated three or more times.

In another embodiment, the method comprises administering to the patient, once per week, SNS-595 at a dose of 15 mg / m 2 to 80 mg / m 2, wherein the one week period includes a treatment period, Repeat 3 times or more. In another embodiment, the method comprises administering to the patient once per week a SNS-595 dosage of from 15 mg / m 2 to 75 mg / m 2, wherein the one week period comprises a treatment period, Repeat 3 times or more. In another embodiment, the method comprises administering to a patient once per week a dose of SNS-595 from 20 mg / m 2 to 65 mg / m 2, wherein the one week period comprises a treatment period, The cycle repeats more than 3 times. In another embodiment, the method comprises administering to the patient once per week a SNS-595 dosage of 30 mg / m 2 to 50 mg / m 2, wherein the one week period comprises a treatment period, Repeat 3 times or more.

In a particular embodiment, the method comprises administering to the patient one week (e.g., day 1, day 8, and day 15) of SNS-595 at a dose of about 1 mg / m 2 to 40 mg / The one week period includes a treatment period, which includes at least three repetitions followed by a waiting period of at least 28 days. In certain embodiments, the method comprises administration of SNS-595 at a dose of about 1 mg / m 2 to 40 mg / m 2 to the patient two times a week (day 1, day 4, day 8, day 11) The one week period includes a treatment period, and the treatment period includes a waiting period of 28 days or more after repeating three or more times. In a particular embodiment, the method comprises administering to the patient one week (e.g., day 1, day 8, and day 15) of SNS-595 at a dose of about 1 mg / m 2 to 40 mg / The one week period includes a treatment period, which includes a waiting period of 28 days followed by at least 3 repetitions. In a particular embodiment, the method comprises administering to the patient two (week 1, four, eight, and eleven) doses of SNS-595 at a dose of about 1 mg / m 2 to 40 mg / , Wherein the one week period includes a treatment period, wherein the treatment period comprises at least three repetitions followed by a 28 day waiting period.

In a particular embodiment, the method comprises administering to the patient one week (e.g., day 1, day 8 and day 15) of SNS-595 at a dose of about 3 mg / m 2 to 24 mg / The one week period includes a treatment period, which includes a waiting period of 28 days followed by at least 3 repetitions. In a particular embodiment, the method comprises administering to the patient two (week 1, day 4, day 8, and day 11) doses of SNS-595 at a dose of about 3 mg / m 2 to 24 mg / The one-week period includes a treatment period, which includes at least three repetitions followed by a 28-day waiting period. In a particular embodiment, the method comprises administering to a patient once weekly (e.g., day 1, day 8, and day 15) SNS-595 at a dose of about 3 mg / m 2 to 24 mg / The one week period includes a treatment period, which includes a waiting period of 28 days followed by at least 3 repetitions. In a particular embodiment, the method comprises administering to the patient two (week 1, day 4, day 8, and day 11) doses of SNS-595 at a dose of about 3 mg / m 2 to 24 mg / The one-week period includes a treatment period, which includes at least three repetitions followed by a 28-day waiting period.

In certain embodiments, the method comprises administering to a patient once weekly (e.g., day 1, day 8, and day 15) a dose of about 15 mg / m 2 to 80 mg / m 2 of SNS-595, The one week period includes a treatment period, which includes a waiting period of 28 days followed by at least 3 repetitions. In a particular embodiment, the method comprises administration of SNS-595 at a dose of about 15 mg / m 2 to 80 mg / m 2 per week to the patient (week 1, day 4, day 8, day 11) The one-week period includes a treatment period, which includes at least three repetitions followed by a 28-day waiting period. In certain embodiments, the method comprises administering to a patient once weekly (e.g., day 1, day 8, and day 15) a dose of about 15 mg / m 2 to 80 mg / m 2 of SNS-595, The one week period includes a treatment period, which includes a waiting period of 28 days followed by at least 3 repetitions. In a particular embodiment, the method comprises administering to the patient two (week 1, four, eight, and eleven) doses of SNS-595 at a dose of about 15 mg / m 2 to 80 mg / , The one week period includes a treatment period, and the treatment period includes a waiting period of 28 days followed by 3 or more repetitions.

In another embodiment, the method comprises administering to a mammal once per week a SNS-595 dose of about 1 mg / m 2 to 50 mg / m 2, wherein the one week period comprises a treatment period, The treatment cycle is repeated two or more times. In another embodiment, the dosage is about 2 mg / m 2 to 40 mg / m 2. In another embodiment, the dosage is from about 3 mg / m 2 to 24 mg / m 2. In another embodiment, the dosage is about 4 mg / m 2 to 20 mg / m 2.

6.4 Exemplary dosing regimen

Exemplary dosing regimens associated with a particular cancer are provided below. These dosage regimens are for illustrative purposes only and are not exclusive.

In one embodiment, a method of treating a solid tumor is provided. I) administering to a patient a dose of about 1 mg / m2 to 100 mg / m < 2 > of SNS-595; ii) wait at least 6 days for which no SNS-595 is administered to the subject; iii) administering to the patient another dose of SNS-595 of about 1 mg / m 2 to 100 mg / m 2; iv) repeating step ii) -iii a plurality of times.

In another embodiment, the method of treating a solid tumor comprises administering to a patient once per week a dose of about 1 mg / m 2 to 75 mg / m 2 of SNS-595, wherein the one week period includes a treatment period , The treatment cycle is repeated two or more times. In another embodiment, the dosage is about 15 mg / m 2 to 80 mg / m 2. In another embodiment, the dosage is from about 3 mg / m 2 to 24 mg / m 2.

In another embodiment, the method of treating a solid tumor comprises administering to the patient SNS-595 at a dose of about 15 mg / m 2 to 40 mg / m 2 per week for three weeks, and administering to the subject any SNS-595 Wherein the period is repeated a plurality of times. In another embodiment, the dosage is about 15 mg / m 2 to 35 mg / m 2. In another embodiment, the dosage is about 20 mg / m 2 to 30 mg / m 2. In another embodiment, the dosage is about 20 mg / m 2 to 25 mg / m 2.

In another embodiment, the method of treating a solid tumor comprises administering to the patient, once per three-week period, a SNS-595 dose of about 35 mg / m 2 to 80 mg / m 2, Cycle, and the treatment cycle is repeated two or more times.

In another embodiment, a method of treating blood cancer is provided. The method comprises administering to a patient a SNS-595 dose of from about 20 mg / m 2 to 60 mg / m 2 in a particular embodiment.

In a patient who is considered to have received pre-intensive therapy ("Pre-Intensive Care Patient"), the method involves administering SNS-595 at a dose of 35 mg / m 2 to 60 mg / Wherein the three-week period includes a treatment period, and the treatment period is repeated two or more times. In another embodiment, the method of treatment of a patient who has received pre-intensive therapy administers a dose of 40 mg / m 2 to 50 mg / m 2. In another embodiment, the method of treatment of a subject who has received pre-intensive therapy comprises administering a dose of 45 mg / m 2 to 50 mg / m 2. Patients receiving pre-intensive therapy are described in Tolcher et al., J. Clin . Oncol . 19: 2937-2947 (2001), which includes an alkylating agent containing chemotherapeutic regimen of more than 6 courses, carboplatin or mitomycin C of more than 2 courses, any conventional nitroso urea containing therapy, , 25% of the area containing the hematopoietic stem cell transplantation, or receiving pre-treatment with high-dose chemotherapy requiring hematopoietic stem cell re-transfusion or a wide spread to the bone.

Patients who have not received prior treatment for these solid tumors or who have been treated but who are not considered to receive pre-intensive therapy receive minimal pre-treatment ("minimal pre-treatment"). In order to treat patients with minimal pre-treatment, the method comprises administering to the patient a single dose of SNS-595 at a dose of 45 mg / m 2 to 80 mg / m 2 for a period of 3 weeks, Includes a treatment cycle, and the treatment cycle is repeated two or more times. In another embodiment, the method of treatment of a patient who has undergone minimal prior treatment comprises administering a dose of 50 mg / m 2 to 75 mg / m 2. In another embodiment, the method of treatment of a patient with minimal pre-treatment comprises administering a dosage of 55 mg / m 2 to 70 mg / m 2. In another embodiment, the method of treatment of a patient with minimal prior treatment comprises administering a dose of 55 mg / m 2 to 65 mg / m 2.

In another embodiment, a method of treating blood cancer, such as leukemia and lymphoma, is provided. This method comprises i) administering to the patient SNS-595 at a dose of 10 mg / m 2 to 50 mg / m 2; ii) awaiting a period of two or more days without administering any SNS-595 to the subject; iii) administering to the patient another dose of SNS-595 from 10 mg / m 2 to 50 mg / m 2; iv) repeating step ii) -iii a plurality of times.

In one embodiment, the waiting period is six days. In another embodiment, the waiting period is two days. In another embodiment, the waiting period is three days.

In one embodiment, the method for treating blood cancer comprises administering to a patient once a week a dose of SNS-595 at a dose of about 20 mg / m 2, 22 mg / m 2, 25 mg / m 2, 27 mg / m 2 or 30 mg / Wherein the one week period includes a treatment period, and the treatment period is repeated two or more times. In one embodiment, the method for treating blood cancer comprises administering to a patient once per week a dose of about 25 mg / m < 2 > of SNS-595, wherein the one week period comprises a treatment period, Repeat for more times.

Other administration schedules useful for the treatment of patients with blood cancer may include from about 25 mg / m 2 to about 50 mg / m 2 administered twice weekly for two weeks. In another embodiment, the use of an administration schedule in blood cancer treatment may comprise about 30 mg / m 2 to about 45 mg / m 2 administered twice weekly for two weeks. In another embodiment, the dosing schedule for blood cancer treatment comprises 30, 35, 40 or 45 mg / m < 2 > administered twice weekly for two weeks.

In one embodiment, the method for treating blood cancer comprises administering a dose of SNS-595 at a dose of about 40 mg / m 2, 45 mg / m 2, 50 mg / m 2, 55 mg / m 2 or 60 mg / , Wherein said two week period comprises a treatment period. In one embodiment, the method for treating blood cancer comprises administering to a patient, once every two weeks, about 50 mg / m < 2 > dose of SNS-595, wherein said two week period comprises a treatment period.

6.5 Concurrent Therapy

In the methods and compositions provided herein, SNS-595 can be used with or in combination with other pharmacologically active compounds ("second active agent"). Certain combinations have been shown to exhibit synergy in the treatment of certain types of cancer. In addition, SNS-595 may act to relieve 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 The second active agent

One or more second active ingredients or agents may be used in the methods and compositions provided herein with SNS-595. The second active agent can be a macromolecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic, organometallic or organic molecule).

Examples of macromolecular active agents include, but are not limited to, hematopoietic growth factors, cytokines and monoclonal and polyclonal antibodies, particularly therapeutic antibodies against cancer antigens. Typical macromolecular active agents are biological molecules, such as natural or artificially produced proteins. Proteins particularly useful in the methods and compositions provided herein include proteins that stimulate the survival and / or proliferation of in vitro or in vivo hematopoietic precursor cells and immune activity-producing cells. Others stimulate the division and differentiation of ordered erythrocyte stroma in vitro or in vivo. Certain proteins include interleukins such as IL-2 (including recombinant IL-II ("rIL2") and canola oscillator IL-2), IL-10, IL-12 and IL-18; Interferons such as interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-I a and interferon gamma- GM-CF and GM-CSF; And EPO, but are not limited thereto.

Particular proteins that may be used in the methods and compositions include, but are not limited to, peggillus team, including the brand name Neupogen (TM) (Amgen, Thousand Oaks, CA) Tim, and derivatives thereof; The Sarkramos team, available from the United States under the trade name Leukine (registered trademark) (Immunex, Seattle, Washington, USA); Recombinant EPO marketed in the United States under the trade name Epogen TM (Amgen, Thousand Oaks, CA); Epoetin alfa; And dovepoethin alpha.

Recombinant and mutant forms of GM-CSF can be produced as described in U.S. Patent Nos. 5,391,485, 5,393,870 and 5,229,496, the patents of which are incorporated herein by reference. Recombinant and mutant forms of G-CSF can be produced as described in U.S. Patent Nos. 4,810,643, 4,999,291, 5,528,823 and 5,580,755, the patents of which are incorporated herein by reference.

In addition, for use in conjunction with SNS-595, native, native and recombinant proteins are provided. In addition, it includes mutations and derivatives (e.g., modified forms) of the native protein that exhibit at least part of the pharmacological activity on which the protein is based in vivo. Examples of mutations include, but are not limited to, proteins having at least one amino acid residue that is a natural form of the protein and that is different from the corresponding residue. In addition, the term "mutation" includes proteins deficient in carbohydrate moieties normally present in its natural form (e.g., non-glycosylated form). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins such as proteins formed by fusing IgGl or IgG3 to a protein or an active portion of the protein. See, e.g., Penichet, ML and Morrison, SL, J. Immunol . Methods 248: 91-101 (2001).

Examples of antibodies that can be used in parallel with SNS-595 include monoclonal and polyclonal antibodies. Examples of antibodies include, but are not limited to, Herceptin (R), Rituxan (R), Avastin (TM), Omnitarg (TM), Bexxar ), Edrecolomab (Panorex (R)), and G250, but are not limited thereto. In addition, SNS-595 can be used with or in combination with an anti-TNF-a antibody and / or an anti-EGFR antibody such as Erbitux (R) or panitumum.

Macromolecular activators may be administered in the form of anti-cancer vaccines. For example, vaccines that secrete cytokines, such as IL-2, G-CSF and GM-CSF, or cause secretion thereof, can be used in the methods and pharmaceutical compositions provided. See, e.g., Emen, LA, et al, Curr . Opinion Mol Ther . 3 (l): 77-84 (2001).

R. and Takimoto, C, "Principles of Chemotherapy," Cancer Management: A New Approach to Chemotherapy, in contrast to the general rule that drugs with various mechanisms of action should be selected to maximize the potential for activity or synergy [ A Multidisciplinary Approach (2001), p. 23], a second agent that interferes with DNA synthesis, and a composition comprising SNS-595 have been found to have a synergistic or synergistic effect.

As used herein, the agent interferes with DNA synthesis when it directly or indirectly affects the ability of the cell to synthesize or repair DNA damage. The agent can directly interact with (e.g., bind to, or intervene) DNA, or it can bind to a DNA-binding protein that is involved in DNA synthesis or DNA repair. Generally, agents that inhibit DNA synthesis are active during S phase, but need not be S phase specific.

Since SNS-595 affects the DNA-PK pathway, the second agent may be an agent that mediates its cytotoxicity through the DNA-PK pathway. Examples are agents that inhibit non-homologous end binding recovery, such as DNA-PK inhibitors. As used herein and unless otherwise indicated, the term "DNA-PK inhibitor" refers to an agent that inhibits or prevents the signaling pathway mediated by DNA-PK. Inhibition of the activity of DNA-PK can be direct (for example, a catalyst inhibitor of DNA-PK itself) or indirectly (for example, an agent that interferes with the formation of active DNA-PK complexes (DNA-PK, Ku70 and Ku80) have. Other examples include, but are not limited to, ligase IV inhibitors and apoptosis enhancers such as caspase-9 activator, caspase-3 activator and Hsp90 inhibitor.

In addition, the second active agent, which is a small molecule, can be used to alleviate side effects associated with administration of SNS-595. However, as with some macromolecules, many have been found to be able to provide a synergistic effect when administered with SNS-595 (e.g., before, after or concurrently). Small molecule second active agents include, but are not limited to, anticancer agents, antibiotics, immunosuppressants, and steroids.

Examples of anticancer agents include alkylating agents, antineoplastic agents, metabolic inhibitors (e.g., folic acid analogs, purine analogs, adenosine analogs, pyrimidine analogs and substituted ureas), platinum coordination complexes, topoisomerase II inhibitors, But is not limited to.

Specific anticancer agents include acibicin; Aclarubicin; Acodazole hydrochloride; Acronine; Adozelesin; Aldethsky; Altretamine; Ambomycin; Amethanthrone acetate; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Aspirin; Azacytidine; Azeta; Azothomaine; Batimastat; Benzodepa; Bicalutamide; Bicarbonate hydrochloride; Bisnipid dimesylate; Bezelesin; Bleomycin sulfate; Sodium brexanal; Bropyrimine; Layout; Cactinomycin; Callus teron; Caffeitabine; Caracameide; Carbethimere; Carboplatin; Carmustine; Carbaric acid hydrochloride; Carzelesin; Sedefin; Celecoxib (COX-2 inhibitor); Chlorambucil; Sirolamine; Cisplatin; Cladribine; Chinatol mesylate; Cyclophosphamide; Cytarabine; Dakar Basin; Dactinomycin; Daunorubicin hydrochloride; Decitabine; Dexormaplatin; Not dejected; Mesylate; Diazquinone; Docetaxel; Doxorubicin; Doxorubicin hydrochloride; Droloxifene; Droloxifen citrate; Dlromotranolone propionate; Doadomycin; Etrexate; In flunitin hydrochloride; Elasmitruscin; Enloflatatin; Enpromeate; Epipropidine; Epirubicin hydrochloride; Erburosol; Erlotinib; Esorubicin hydrochloride; Estra mestin; Estramustine phosphate sodium; Ethanedisole; Etoposide; Etoposide phosphate; Etopren; Hydrazone hydrochloride; Fazarabine; Fenretinide; Floc repairin; Fludarabine phosphate; Fluorouracil; Fluorochloride; Phosquidone; Postriasin sodium; Gepetinib; Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Rubicin hydrochloride; Iospasmide; Ilmofosin; Iuproplatin; Irinotecan; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate; Liarasol hydrochloride; Lometrexol sodium; Rosemastin; Rosantan hydrochloride; MASO PROCOL; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Menogaryl; Mercaptopurine; Methotrexate; Methotrexate sodium; Methoprene; Metourethamine; Mitomodide; Mitocarcin; Mitochromin; Mitogyline; Mitochondria; Mitomycin; Mitosper; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Nogalamycin; Ormaflatin; Oxysulane; Paclitaxel; Pegasper; Peliomycin; Femetrexed; Pentamustine; Perfromycin sulfate; Perphosphamide; Pipobroman; Chopped sulp; Pyrroxanthrone hydrochloride; Plicamycin; Flomestane; Sodium formate; Porphyromycin; Fred Nimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazopurine; Riboprene; Sapphine; Sapphine bone marrow hydrochloride; Taxostin; SimTragen; Sparsosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiromustine; Spiroplatin; Streptonigreen; Streptozocin; Sulpheur; Talisomycin; Tetogalan sodium; Taxotere; Tegapur; Tellosan hydrochloride; Temoporphine; Tenifocide; Tetracyclone; Testol lactone; Thiamipine; Thioguanidine; Thioguanine; Thiotepa; Thiazopurine; Tyrapazamin; Teremiphen citrate; Tristolone acetate; Tricyribine phosphate; Trimetrexate; Trimetrexate glucuronate; Tryptophan; Tetrazole hydrochloride; Uracil mustard; Uredepa; Bafreotide; Vertefopin; Vinblastine sulfate; Vincristine sulfate; Bindeseo; Vindesine sulphate; Vinepidine sulfate; Vin glycinate sulfate; Binalourosine sulfate; Vinorelvin tartrate; Vincrosidine sulfate; Bin zolyidine sulfate; Borosal; Nipple latin; Zinostatin, and glucocorticoid hydrochloride, but are not limited thereto.

Other anti-cancer drugs include 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; Aviratorone; Acclubicin; Acylphenol; Adhephenol; Adozelesin; Aldethsky; ALL-TK antagonists; Altretamine; Amvamustine; Amidox; Amipostin; Aminolevulinic acid; Amrubicin; Amsacrine; Anagrelide; Anastrozole; Andrographolide; Angiogenesis inhibitors; Antagonist D; Antagonist G; Antaralicious; Anti-isodendimulant morphogenesis protein-1; Antiandrogen, prostate carcinoma; Antiestrogen; Anti neoprene stone; Antisense oligonucleotides; Ampicillin glycinate; Apoptosis gene regulators; Apoptotic regulators; Apurinic acid; ARA-CDP-DL-PTBA; Arginine deaminase; Asulacrine; Atamestane; Artimustine; Acycinastatin 1; Acuminastatin 2; Acuminastatin 3; Azacetone; Azotoxin; Azathiocin; A baccatin III derivative; Valanol; Batimastat; BCR / ABL antagonists; Benzochlorine; Benzoylstaurosporine; Betalactam derivatives; Beta-alletin; Betaclomycin B; Betulinic acid; bFGF inhibitors; Bicalutamide; Arsenate; Bisaziridinyl spermine; Bisnaphid; Bistatten A; Bezelesin; Brake plate; Bropyrimine; Subordinate titanium; Butthionine sulfoximine; Calcipotriol; Calpostatin C; Camptothecin derivatives; Capecitabine; Carboxamide-amino-triazole; Carboxyamidotriazole; CaRest M3; CARN 700; Cartilage induction inhibitors; Carzelesin; Casein kinase inhibitor (ICOS); Carnano-spermine; Secropin B; Set Laurelrix; Chlorine; Chloroquinoxaline sulfonamide; Sika Frost; cis-porphyrin; Cladribine; Clomiphene analogs; Clotrimazole; Colistin A; Collymycin B; Combretastatin A4; Combretastatin analogs; Congenin; Krambescidin 816; Chinatol; Cryptophycin 8; Cryptophycin A derivatives; Kurasin A; Cyclopentanthraquinone; Cyclophotam; Cephemycin; Cytarabine octosperate; Cell lysis factors; Cytostatin; Docicimab; Decitabine; Dehydrodimnin B; Deslorin; Dexamethasone; Dexiposphamide; Dexlazoic acid; Dex verapamil; Diaziquone; Dimedinin B; Dodox; Diethylnorpheumine; Dihydro-5-azacytidine; Dihydrotaxol, 9-; Dioxamycin; Diphenyl spiromustine; Docetaxel; Dococanol; Dolasitron; Doxifluridine; Doxorubicin; Droloxifene; Dronabinol; Duo Karmaisin SA; Ebselene; Ecomustine; Edelosine; Adrecolomab; Eflornithine; Elements; Emitepur; Epirubicin; Episteide; Estra mestin analog; Estrogen agonists; Estrogen antagonists; Ethanedisole; Etoposide phosphate; Exemestane; Fadrosol; Fazarabine; Fenretinide; Phil Grass Team; Pinastellite; Flavopyridone; Flaselastine; Fluastarone; Fludarabine; Fluorodurnornin hydrochloride; Porphnimex; Formestane; Post lysine; Potemustine; Gadolinium tetrapyrin; Gallium nitrate; Galoshita bin; Ganilelix; Gelatinase inhibitors; Gemcitabine; Glutathione inhibitors; Hept sulfam; Herlegolin; Hexamethylene bisacetamide; Hiperidine; Ibandronic acid; Rubicin; This doxifene; Idraemantone; Ilmofosin; Daymastat; Imatinib (e.g., Gleevec (R)); Imiquimode; Immunostimulatory peptides; Insulin-like growth factor-1 receptor inhibitors; Interferon agonists; Interferon; Interleukin; Iobengan; Iododoxirubicine; I-propanol, 4-; Iroplast; Irgoglidine; Isobenzazole; Isomerized halocondrine B; Itacetone; Jas flucinolide; Carbhalide F; Lamellarin-N triacetate; Lanthanide; Reinamycin; Reno Grass Team; Lentan sulfate; Leptolastatin; Letrozole; Leukemia inhibitory factor; Leukocyte alpha interferon; Leuprolide + estrogen + progesterone; Leuprorelin; Levamisole; Riazolone; Linear polyamine analogs; Lipophilic disaccharide peptides; A lipophilic platinum compound; Lithoclinamide 7; Roba flatin; Rhombicin; Lometrex sol; Ronidamin; Rosantanone; Rosovirus; Rutotethene; Rutethium texapyrin; Lysophylline; Lytic peptide; Mytansine; Manostatin A; Marimastat; MASO PROCOL; Town spin; Matrilysin inhibitors; Substrate metalloproteinase inhibitors; Menogaryl; Merbaron; Methelin; Methionine; Methocloframide; MIF inhibitors; Mepp lithotone; Miltefosine; Premoist team; Mitoguazone; Mitolactol; Mitomycin analogs; Mitomapride; Mitotoxin fibroblast growth factor-serine; Mitoxantrone; Mofarotene; Morgol Ramos Team; Erbitux, human chorionic gonadotropin; Monophosphoryl lipid A + myobacterium cell wall sk; Fur damol; Mustard anticancer agent; Mica peroxide B; Mycobacterial cell wall extract; Pre-apron; N-acetyl dinalin; N-substituted benzamides; Napalelin; Nagres tips; Naloxone + pentazocine; Napa bin; Naphterpine; Nartograss Team; Your dapplatin; Nemorubicin; Neridronic acid; Nilutamide; Nisamycin; Nitrogen oxides regulators; Nitroxides antioxidants; Nitrulline; ≪ / RTI > Oblomerchen (Genasense (R)); O ⁶ -benzylguanine; Octreotide; Oxycenone; Oligonucleotides; Onafristone; Ondansetron; Ondansetron; Oracle; Oral cytokine inducer; Ormaflatin; Osaterone; Oxaliplatin; Oxanomycin; Paclitaxel; Papyrus texel analog; Papyrus texel derivatives; Palauamine; Palmi Taylor Josin; Pamidronic acid; Paraxyltriol; Panomimpen; Paramartin; Pascel liptin; Gaspard; Peledin; Sodium pentosan polysulfate; Pentostatin; Pentrozole; Perfluorobutane; Perpospamide; Peryl alcohol; Phenazinomycin; Phenylacetate; Phosphatase inhibitors; Fish barnil; Pilocarpine hydrochloride; Pyra rubicin; Pyrite tree core; Plasetin A; Plasetin B; Plasminogen activator inhibitors; Platinum complex; Platinum compounds; Platinum-triamine complex; Sodium formate; Polypyramycin; Prednisone; Propyl bis-acridone; Prostaglandin J2; Proteasome inhibitors; Protein A immunomodulators; Protein kinase C inhibitors; Protein kinase C inhibitors, microalgae; Protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Furfurin; Pyrazoloacridine; A pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; Ralitic trecks; Ramosetron; rasparnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; Retelipitin demethylation; Rhenium Re 186 etidronate; Ricosyn; Ribozyme; RII retinamide; Lohitkin; Rosemutide; Quinimex; Ruby Guinea B1; Leuco; Sapphine; Tosin; SarCNU; Sarcopitol A; Sarragramos Team; Sdi 1 mimetic; Taxostin; Cenenseense induction inhibitor 1; Sense oligonucleotides; Signal transduction inhibitors; Xanthopyran; Bovine acid; Sodium borocapthalate; Sodium phenylacetate; Sorbrole; Somatomedin binding protein; Sonermin; Sparfosan; Spicamycin D; Spiromustine; Splenopentin; Sponge statin 1; Squalamine; Stipiamide; Stromelysin inhibitors; Sulfinosine; Super-active vasoactive intestinal peptide antagonists; Suradistar; Suramin; Swishonin; Talimustine; Tamoxifen methiodide; Tauromustine; Tazaroten; Tetogalan sodium; Tegapur; Telulapyrilium; Telomerase inhibitors; Temoporphine; Tenifocide; Tetrachlorodecaoxide; Tetrazomine; Talli blastin; Thiocolrine; Thrombopoietin; Thrombopoietin mimetic; Thalam fascin; Thymopoietin receptor agonists; Timothyran; Thyroid stimulating hormone; Tin ethyl thiopurfurin; Tyrapazamin; Titanocene chloride; Topcentin; Toremie pen; Translational inhibitors; Tretinoin; Triacetylidene; Trishyribine; Trimetrexate; Tryptophan; Trophis set ron; Trosstile; Tyrosine kinase inhibitors; Tyrphostin; UBC inhibitors; Ubenimex; Urogenital oyster-induced growth inhibitory factor; Urokinase receptor antagonists; Bafreotide; Barrydin B; Belalethol; Veramin; Berdins; Vertefopin; Vinorelbine; Empty saline; Non-thaxin; Borosal; Zanoterone; Nipple latin; Zilas corv; And zinostatin stimamer, but are not limited thereto.

Examples of specific second active agents include, but are not limited to, rituximab, oblomerchen (Genasense TM), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron TM), steroids, But are not limited to, tamavastatin, tamavillin, cisplatin, tamoxifide, cyclophosphamide, tamoxifen, tamavir, tamavir, tamavir, tamavir, , Interferon alpha, pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, vialin, bisulfan, prednisone, , Bisphosphonate, arsenic trioxide, vincristine, toxin ruby But are not limited to, Doxil (R), paclitaxel, riverclovir, adriamycin, estramustine sodium phosphate (Emcyt (R)), sulindac and etoposide.

In a particular embodiment, the second active agent is selected from the group consisting of etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin, carboline, femetrexed, methotrexate, Ara-C, 5-FU, Mannin, gemcitabine, geladinamycin, or a combination thereof.

In other embodiments, the second active agent is a patient care agent. An example of a patient care formulation is a pesticide. Examples of particular anti-infective agents include, but are not limited to, phenothiazine, butyrophenone, benzodiazapine, corticosteroids, serotonin antagonists, cannabinoids, and NK ₁ receptor antagonists. Examples of phenothiazine antagonists include, but are not limited to, prochlorperazine and trimethobenzamide. Examples of butyrophenone antagonists include, but are not limited to, haloperidol. Examples of benzodiazapine antagonists include, but are not limited to, lorazepam. Examples of corticosteroid antagonists include, but are not limited to, dexamethasone. Examples of serotonin antagonist antagonists include, but are not limited to, ondansetron, granisetron, and dolasetron. Examples of cannabinoid antagonists include, but are not limited to, doronivanol. Examples of NK ₁ receptor antagonists include, but are not limited to, aprepitant. The dosage and the dosage regimen of the antiepileptic agent should be determined by the particular indication to be treated, the age and condition of the patient and the severity of the side effect, and may be adjusted by those skilled in the art. Dosages and administration regimens can be found, for example, in The Physician's Desk Reference .

6.5.2 Examples of Concurrent Therapy

In certain embodiments, the methods provided herein include administering SNS-595 in combination with one or more second active agents and / or in conjunction with radiation therapy or surgery. SNS-595 and the second active agent may be administered to a patient either simultaneously or sequentially by administration of the same or different routes. The suitability of the particular route of administration for the particular active agent will depend on the active agent itself (e.g., whether it can be orally administered without degradation prior to entry into the bloodstream) and the disease to be treated. Administration of the referral route of the second active agent is well known to those skilled in the art. See Physicians' Desk Reference (60 ^th ed., 2006).

In one embodiment, the second active agent is administered intravenously once or twice a day in an amount of about 1 to about 1,000 mg, about 5 to about 500 mg, about 10 to about 375 mg, or about 50 to about 200 mg Or subcutaneously. In one embodiment, the second active agent is selected from the group consisting of rituximab, oblomerchen (Genasense TM), GM-CSF, G-CSF, EPO, taxotere, irinotecan, TNX, IL8, IL18, IFN, Ara-C, vinorelbine or a combination thereof. In a particular embodiment, the second active agent is selected from the group consisting of etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin, carboline, femetrexed, methotrexate, Ara-C, 5-FU, Mannin, geldanamycin, gemcitabine, or a combination thereof.

In another embodiment, conventional treatments, including but not limited to surgery, immunotherapy, biotherapy, radiation therapy or other non-drug based therapies currently used to treat, prevent or manage cancer, Prevention and / or management of blood cancer, comprising administering SNS-595 together (eg, before, during, or after treatment). While not intending to be limited to any particular theory, it has been found that SNS-595 can provide a synergistic or synergistic effect when presented concurrently with conventional therapy.

In certain embodiments, the second active agent is administered concurrently with SNS-595 or with a delay of 1 to 50 hours. In certain embodiments, the SNS-595 is first administered followed by the second active agent for a delay of 1 to 50 hours. In another embodiment, the second active agent is administered first, followed by SNS-595 for 1 to 50 hours. In certain embodiments, the delay time is 24 hours.

In one embodiment, SNS-595 is administered at a dose of about 1 to about 75 mg / m 2, 1 to about 60 mg / m 2, 1 to about 48 mg / m 2, 1 to about 24 mg / At a concentration of about 1 to about 40 mg / m 2, about 1 to about 30 mg / m 2, about 3 to about 30 mg / m 2, about 3 to about 24 mg / m 2, alone or in combination with a second active agent Or before, during, or after the use of the conventional treatment.

In another embodiment, the methods provided herein comprise a) administering to a patient in need of treatment from about 1 mg / m 2 to about 75 mg / m 2 of a dose of SNS-595, and b) administering a therapeutically effective amount of a patient- ≪ / RTI >

In one embodiment, the second agent is an alkylating agent. In another embodiment, the alkylating agent is an alkyl sulphonate and the cancer to be treated is leukemia or lymphoma. In another embodiment, the alkyl sulfonate is a laid panel. In another embodiment, the alkyl sulfonate is a laid panel, and the therapeutically effective amount is 1 mg or more per day. In another embodiment, the alkyl sulphonate is a laid panel and the therapeutically effective amount is about 2 mg to 8 mg per day. In another embodiment, the alkyl sulfonate is a laid panel, and the therapeutically effective amount is from about 1 mg to about 3 mg per oral daily dose.

In another embodiment, the alkylating agent is a nitrogen mustard and the cancer to be 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 to about 0.2 mg / kg for 3 to 6 weeks. In another embodiment, the nitrogen mustard is chlorambucil and the therapeutically effective amount is 0.4 mg / kg dose per 3 to 4 weeks. In another embodiment, the nitrogen mustard is a cyclophosphamide. In another embodiment, the nitrogen mustard is a cyclophosphamide and the therapeutically effective amount is an intravenous dose of greater than or equal to 10 mg / kg. In another embodiment, the nitrogen mustard is a cyclophosphamide and the therapeutically effective amount is an intravenous dose of about 10 mg / kg to about 15 mg / kg per 7-10 days. In another embodiment, the nitrogen mustard is a cyclophosphamide and the therapeutically effective amount is a daily oral 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 2 mg or more. In another embodiment, the nitrogen mustard is melphalan and the therapeutically effective amount is an oral daily dose of 6 mg for 2 to 3 weeks, no melphalan administered for 2 to 4 weeks, then about 2 mg to about It is an oral dose of 4 mg per day. 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 per 4 to 6 weeks.

In another embodiment, the alkylating agent is nitroso urea, and the cancer to be treated is a brain tumor, rectal cancer, hodgkin's disease, liver cancer, lung cancer, lymphoma or melanoma. In another embodiment, the nitroisourea is a carmustine. In another embodiment, the nitroisourea is Carmustine and the therapeutically effective amount is at least 150 mg / m 2. In another embodiment, the nitroisourea is carmustine and the therapeutically effective amount is an intravenous dose of about 150 mg / m 2 to 200 mg / m 2 per 6 to 8 weeks.

In another embodiment, the alkylating agent is triazine, and the cancer to be treated is a hodgkin's disease, melanoma, neuroblastoma or soft tissue sarcoma. In another embodiment, the triazene is Dakar Vazine. In another embodiment, the triazene is Dakar Vazine and the therapeutically effective amount is a daily intravenous dose of about 2.0 mg / kg to about 4.5 mg / kg for 10 days per 4 weeks. In another embodiment, the triazene is Dakar Vazine and the therapeutically effective amount is a daily intravenous dose of 250 mg / m < 2 > for 5 days per 3 weeks. In another embodiment, the triazine is saccharin and the therapeutically effective amount is an intravenous dose of 375 mg / m 2 per 16 days. In another embodiment, the triazene is Dakar Vazine and the therapeutically effective amount is an intravenous dose of 150 mg / m < 2 > for 5 days per 4 weeks.

In another embodiment, the second agent is an antitumor antibiotic and the cancer to be treated is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, head and neck cancer, hodgkin's disease, leukemia, multiple myeloma, neuroblastoma, ovarian cancer, sarcoma, 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 about 10 units / m2 to about 20 units / m2 once or twice per 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 about 0.010 mg / kg to about 0.015 mg / kg for 5 days per 3 weeks. In another embodiment, the antibiotic is dactinomycin and the therapeutically effective amount is an intravenous dose of 2 mg / m 2 per 3 or 4 weeks. In another embodiment, the antibiotic is daunorubicin. In another embodiment, the antibiotic is daunorubicin and the therapeutically effective amount is 30 mg / m 2 or greater. In another embodiment, the antibiotic is daunorubicin and the therapeutically effective amount is a daily intravenous dose of about 30 mg / m 2 to about 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 per 2 weeks. In another embodiment, the antibiotic is doxorubicin. 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 from about 60 mg / m 2 to about 90 mg / m 2 intravenous dose per 3 weeks. In another embodiment, the antibiotic is doxorubicin and the therapeutically effective amount is an intravenous dose per week of 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 an intravenous dose of 30 mg / m 2 per week for 2 weeks followed by no administration of doxorubicin for 2 weeks.

In another embodiment, the second agent is a metabolic inhibitor. In another embodiment, the metabolic inhibitor is a folic acid analog and the cancer to be treated is breast cancer, head and neck cancer, leukemia, lung cancer, non-Hodgkin's lymphoma or osteosarcoma. In another embodiment, the folic acid analog is methotrexate. In another embodiment, the folic acid analog is methotrexate and the therapeutically effective amount is at least 2.5 mg. In another embodiment, the folic acid analog is methotrexate and the therapeutically effective amount is from about 2.5 mg to about 5 mg per day. In another embodiment, the folic acid analog is methotrexate, and the therapeutically effective amount is from about 5 mg / m 2 to about 25 mg / m 2 twice a week. In another embodiment, the folic acid analog is methotrexate and the therapeutically effective amount is an intravenous dose per week of 50 mg / m 2 / week. In another embodiment, the folic acid analog is femetrexed. In another embodiment, the folic acid analog is pemetrexed and the therapeutically effective amount is at least 300 mg / m 2. In another embodiment, the folic acid analog is pemetrexed and the therapeutically effective amount is an intravenous dose of about 300 mg / m 2 to about 600 mg / m 2 per 2 or 3 weeks. In another embodiment, the folic acid analog is pemetrexed and the therapeutically effective amount is an intravenous dose of 500 mg / m 2 per 3 weeks.

In another embodiment, the metabolic inhibitor is a purine analog and the cancer to be treated is rectal cancer, leukemia or myeloma. In another embodiment, the purine analog is mercaptopurine. In another embodiment, the purine analog is mercaptopurine and the therapeutically effective amount is at least 1.5 mg / kg. In another embodiment, the purine analog is mercapurine and the therapeutically effective amount is a daily oral dose of 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 2 mg / kg or more. 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 metabolic inhibitor is an adenosine analog and the cancer to be 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 greater than or equal to 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 > every other week. In another embodiment, the adenosine analog is pentostatin and the therapeutically effective amount is an intravenous dose of 4 mg / m 2 per 3 weeks.

In another embodiment, the metabolic inhibitor is a pyrimidine analogue and the cancer to be treated is bladder cancer, breast cancer, rectal cancer, esophageal cancer, head and neck cancer, leukemia, liver 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 greater than or equal to 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 a daily dose of at least 2,000 mg / m < 2 >. In another embodiment, the pyrimidine analog is capecitabine and the therapeutically effective amount is an oral dose of about 1,200 mg / m 2 to about 1,300 mg / m 2 twice daily for 14 days. In another embodiment, the pyrimidine analog is capecitabine, and the therapeutically effective amount is a three week cycle, wherein no dosage is administered for about 14 days followed by a dose of about 1,250 mg / m 2 for one week. In another embodiment, the pyrimidine analog is fluorouracil. In another embodiment, the pyrimidine analog is fluorouracil and the therapeutically effective amount is greater than or equal to 10 mg / kg. In another example, the pyrimidine analog is fluorouracil, and the therapeutically effective amount is a daily intravenous dose of about 300 mg / m 2 to about 500 mg / m 2 for more than 3 days. In another example, the pyrimidine analog is fluorouracil and the therapeutically effective dose is a daily intravenous dose of 12 mg / kg for 3 to 5 days. In another embodiment, the pyrimidine analog is fluorouracil and the therapeutically effective amount is an intravenous dose per week of from about 10 mg / kg to about 15 mg / kg.

In another embodiment, the metabolic inhibitor is a substituted urea, and the cancer to be 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 20 mg / kg or more. In another embodiment, the substituted urea is hydroxyurea and the therapeutically effective dose is an oral dose of 80 mg / kg / day. 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 to be 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 300 mg / m 2 or more. In another embodiment, the platinum coordination complex is carboplatin and the therapeutically effective amount is 300 mg / m < 2 > or more per 4 weeks. In another embodiment, the platinum coordination complex is carboplatin and the therapeutically effective amount is 300 mg / m2 per 4 weeks. In another embodiment, the platinum coordination complex is carboplatin and the therapeutically effective amount is 360 mg / m < 2 > or more per 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 20 mg / m 2 or more. 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 per 3-4 weeks. In another embodiment, the platinum coordination complex is cisplatin and the therapeutically effective amount is 50 mg / m2 intravenous dose per 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 or more. In another embodiment, the platinum coordination complex is oxaliplatin and the therapeutically effective amount is IV infusion of about 50 mg / m 2 to about 100 mg / m 2 per 2 weeks. In another embodiment, the platinum coordination complex is oxaliplatin and the therapeutically effective amount is an IV infusion of about 80 mg / m 2 to about 90 mg / m 2 per 2 weeks. In another embodiment, the platinum coordination complex is oxaliplatin and the therapeutically effective amount is a 2 hour IV infusion of 85 mg / m 2 per two weeks.

In another embodiment, the second agent is a topoisomerase II inhibitor and the cancer to be treated is Hodgkin's disease, leukemia, small cell lung cancer, sarcoma or testicular cancer. In another embodiment, the topoisomerase II inhibitor is an etoposide. In another embodiment, the topoisomerase II inhibitor is an etoposide and the therapeutically effective amount is at least 35 mg / m 2. In another embodiment, the topoisomerase II inhibitor is an 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 an etoposide, and the therapeutically effective amount is from about 35 mg / m 2 to about 50 mg / m 2 intravenously administered three times per day for five days every three or four weeks . In another embodiment, the topoisomerase II inhibitor is an etoposide, and the therapeutically effective amount is an intravenous dose of about 50 mg / m 2 to about 100 mg / m 2 three or more times a day for 5 days every three or four weeks . In another embodiment, the topoisomerase II inhibitor is an etoposide and the therapeutically effective amount is an oral dose of 100 mg / m < 2 > more than 3 times daily for 5 days every 3 or 4 weeks. In another embodiment, the topoisomerase II inhibitor is a teniposide. In another embodiment, the topoisomerase II inhibitor is a teniposide and the therapeutically effective amount is at least 20 mg / m 2. In another embodiment, the topoisomerase II inhibitor is a teniposide and the therapeutically effective amount is a dose of 100 mg / m 2 per week. In another embodiment, the topoisomerase II inhibitor is a teniposide and the therapeutically effective dose is a dose of 100 mg / m 2 twice per week. In another embodiment, the topoisomerase II inhibitor is a teniposide and the therapeutically effective amount is a daily dosage of about 20 mg / m 2 to about 60 mg / m 2 for 5 days. In another embodiment, the topoisomerase II inhibitor is a teniposide and the therapeutically effective amount is a daily dosage of about 80 mg / m 2 to about 90 mg / m 2 for 5 days.

6.6 Pharmaceutical composition and dosage form

The methods provided herein use pharmaceutical compositions comprising SNS-595 and a pharmaceutically acceptable carrier, such as a diluent or ezburt, in combination with another active ingredient, such as another anti-cancer agent. In clinical practice, SNS-595 may be administered by any conventional route including oral, parenteral, rectal or inhaled (e.g., in the form of an aerosol). In certain embodiments, the composition provided herein is an acidic composition (e.g., pH < 4). While not wishing to be bound by any particular theory, acidic compositions provide increased solubility and desirable pharmaceutical properties of SNS-595 (e. G., Reduce irritation at the delivery site thereby increasing comfort to the patient).

In one embodiment, SNS-595 is administered as an IV injection. The composition for parenteral administration may be an emulsion or a sterile liquid preparation. As the solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oil, especially olive oil or injectable organic ester such as ethyl oleate may be used. In addition, such compositions may also comprise very bunts, especially wetting agents, isotonic agents, emulsifying agents, dispersing agents and stabilizers. The sterilization can be carried out in various ways, for example using a bacterial filter, by radiation or by heating. They can also be produced in the form of sterile solid compositions which can be dissolved in the use of sterile water or any other injectable sterile medium.

In addition, the composition may be an aerosol. For use in the form of a liquid aerosol, the composition may be a stable sterile liquid or solid composition dissolved in non-pyrogen-free sterile water, in saline, or in any other pharmaceutically acceptable vehicle when used. For use in the form of a dry aerosol intended to be inhaled directly, the active ingredient is made into a finely divided powder and mixed with a water soluble solid diluent or vehicle, such as dextran, mannitol or lactose.

The pharmaceutical compositions may be used in the preparation of individual single unit dosage forms. The pharmaceutical compositions and dosage forms comprise SNS-595 and one or more excipients.

In addition, the pharmaceutical compositions and dosage forms may comprise one or more additional active ingredients. Examples of optional second or further active ingredients are disclosed herein.

In certain embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of SNS-595 and typically one or more pharmaceutically acceptable carriers or excipients. The term "carrier" refers to a diluent to which a therapeutic agent has been administered, such as a zufin (e.g., Freudian zebrand (complete and incomplete)), an excipient or a vehicle. Such pharmaceutical carriers may be sterile solutions such as water and oils, including petrolatum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. In certain embodiments, when the pharmaceutical composition is administered intravenously, the water becomes a carrier. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly as injectable solutions. Suitable pharmaceutical carriers are described in Remington &apos; s Pharmaceutical Sciences , EW Martin.

Conventional pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the pharmaceutical arts and suitable non-limiting examples of excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat, lime, silica gel, sodium stearate, glycerol monostearate , Talc, sodium chloride, skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is appropriate for incorporation into a pharmaceutical composition or dosage form will depend on a number of factors known in the art including the manner in which the dosage form is administered to the individual and the particular active ingredient in the dosage form, But is not limited thereto. In addition, the composition or single unit dosage formulation may contain, if desired, a minimal amount of wetting or emulsifying agent or pH buffering agent.

Pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate at which the active ingredient is degraded are further provided herein. Such compounds are referred to herein as "stabilizers ", examples of which include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers.

The pharmaceutical compositions and single unit dosage forms may take the form of solutions, suspensions, emulsions, powders, and the like. Such compositions and dosage forms comprise a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in purified form, together with an amount of the carrier, to provide a formulation for proper administration to a subject in a particular embodiment. The formulation should be compatible with the mode of administration. In one embodiment, the pharmaceutical composition or single unit dosage form is sterile and is a formulation suitable for administration to an individual, such as an animal or mammalian individual, and a human subject, for example.

The pharmaceutical compositions provided herein are formulated to be compatible with the intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, such as intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, inhaled, intranasal, transdermal, topical, intratumoral, intratumoral, . In certain embodiments, the composition is formulated by routine procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, intranasal, or topical administration to a human. In an embodiment, the pharmaceutical composition is formulated by routine procedures for human subcutaneous administration. Typically, the composition for intravenous administration is a solution in a sterile isotonic aqueous buffer. If desired, the compositions may also contain stabilizers and local anesthetics such as lignocam to relieve pain at the injection site.

Examples of dosage forms include liquid dosage forms suitable for parenteral administration to a subject; Sterile solid (e.g., crystalline or amorphous solids) that can be reconstituted to provide a liquid dosage formulation suitable for parenteral administration to an individual, and the like.

The composition, shape, and type of dosage formulations provided herein typically vary depending on their use. For example, the dosage form used for the initial treatment of the disease may comprise a larger amount of one or more active ingredients than the dosage form used for maintenance treatment of the same infection. Similarly, parenteral dosage forms may contain a smaller amount of one or more active ingredients than the oral dosage forms used to treat the same disease or disorder. The methods and other methods in which the particular dosage formulations included herein are altered will be apparent to those skilled in the art. See, for example, Remington ' s Pharmaceutical Sciences , 20th ed., Mack Publishing, Easton PA (2000).

In general, the components of the compositions provided herein are provided separately or mixed in unit dosage form, for example, as a lyophilized powder or anhydrous concentrate in an enclosed container, such as an ampoule or shasher indicating the content of active agent. If the composition is to be administered by infusion, it may be dispensed into an infusion bottle containing sterile pharmaceutical grade water or saline. When the composition is administered by injection, an ampoule of injectable sterile water or saline can be provided so that it can be mixed with the ingredient prior to administration.

The usual dosage formulations provided herein may be formulated to be in the range of about 1 mg / m 2 to about 75 mg / m 2 per day or week as a single daily dose in the morning or as divided doses during the day taken with the food SNS-595. The particular dosage formulations provided herein comprise SNS-595 at about 1, 3, 6, 9, 12, 15, 18, 21, 24, 27 or 30 mg / m 2.

6.6.1 Parenteral dosage form

Parenteral dosage forms may be administered to a patient by various routes including, but not limited to, subcutaneous, intravenous (including temporary injection), intramuscular, and intraarterial. It is preferred that the parenteral dosage form be in a sterile condition or sterilized prior to administration to the patient, since administration usually neglects the patient's natural defense against contamination. Examples of parenteral administration formulations include, but are not limited to, injectable solutions, dry products for dissolving or suspending in injectable pharmaceutically acceptable vehicles, injectable suspensions and emulsions, and the like.

Suitable vehicles that can be used to provide parenteral dosage formulations are well known to those skilled in the art. Examples thereof include water for injection USP; But are not limited to, aqueous vehicles such as, but not limited to, sodium chloride injection, Ringer's injection, glucose injection, glucose and sodium chloride injection, and lactated Ringer's injection, water-miscible vehicles such as ethyl alcohol, polyethylene glycol and polypropylene glycol Not); Non-aqueous vehicles such as corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

In addition, compounds that increase the solubility of the active ingredient 1 or higher disclosed herein can be incorporated into parenteral dosage forms. For example, cyclodextrins and derivatives thereof can be used to increase the solubility of the active ingredient. See, for example, U.S. Patent No. 5,134,127, which is incorporated herein by reference.

6.6.2 Topical and mucosal dosage formulations

In certain embodiments, transdermal, topical and mucosal dosage forms are provided herein. Examples of transdermal, topical and mucosal dosage forms provided herein include, but are not limited to ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions or other formulations known to those skilled in the art . See, for example, Remington 's Pharmaceutical Sciences , 20th ed., Mack Publishing, Easton PA (2000); And Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating oral mucosal tissues may be formulated as either toothpastes or oral gels. In addition, transdermal dosage forms include "reservoir-shaped" or "matrix-like" patches that can be applied to the skin and worn for a certain amount of time to allow penetration of a certain amount of the active ingredient.

Suitable excipients (e. G., Carriers and diluents) and other materials that may be used to provide the topical and mucosal dosage forms included herein are well known to those skilled in the pharmaceutical arts and may be formulated as pharmaceutical compositions, It depends on the specific organization. Given this fact, examples of conventional excipients include water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1, 3-diol, isopropyl (meth) acrylate to form a non-toxic and pharmaceutically acceptable liquid, emulsion or gel. But are not limited to, starch, isopropyl palmitate, mineral oil, and mixtures thereof. In addition, a water or moisturizing agent can be added to the pharmaceutical composition and the dosage form, if necessary. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences , 20th ed., Mack Publishing, Easton PA (2000).

In addition, the pH of the pharmaceutical composition or dosage form can be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of the solvent carrier, its ionic strength or its tension can be controlled to improve delivery. A compound, such as a stearate, may be added to a pharmaceutical composition or dosage form to modify the hydrophilicity or lipophilicity of the one or more active ingredients to improve delivery. In this regard, the stearate may serve as a lipid vehicle for formulation, as an emulsifier or surfactant, and as a delivery improvement or permeation enhancer. Various salts, hydrates or solvates of the active ingredient may be used to further control the properties of the resulting composition.

7. Example

The specific embodiments provided herein are illustrated by the following non-limiting examples.

Example 1: Pharmaceutical compositions suitable for injection or intravenous infusion

The acidic composition (<pH 4) provides an adequate balance of the increased solubility and desirable pharmacological properties of SNS-595 (eg, less irritation at the delivery site to increase patient comfort). An example of a suitable composition includes 10 mg SNS-595 per ml of an aqueous solution of 4.5% sorbitol adjusted to pH 2.5 with methanesulfonic acid. The protocol for generating such a solution was to add 100 mg of SNS-595 and 450 mg of D-sorbitol to distilled water to make a volume of 10 ml or less to produce a 100 mg / 10 ml formulation, The pH of the solution was adjusted to 2.5 with methanesulfonic acid. The resulting composition is therefore suitable for lyophilization. The lyophilized form was then reconstituted with sterile water to an appropriate concentration before use.

Example 2: Clinical trial data of SNS-595 in advanced solid tumor cancer patients

The safety and efficacy of SNS-595 was studied by two dose escalation trials. As illustrated below, SNS-595 provides an excellent safety profile and evidence of anti-tumor activity in non-responding solid tumor patients.

SNS-595 was administered to patients with solid tumors advanced as IV infusion over 10 minutes on two schedules. In the first schedule (A), the dose of SNS-595 per week is administered for three weeks and then not more than seven days (qwk x 3). In a second schedule (B), a given dose of SNS-595 was administered once every three weeks (q3wk).

In both schedules, the starting SNS-595 dose was 3 mg / m &lt; 2 &gt;, and the dose was increased to 3 sequential cohorts. The dose was doubled from Grade 2 or higher to first-order associated adverse events, or until the first abnormal test value. The dose was then increased by the modified Fibonacci sequence.

Other treatments, such as mitomycin-C, BCNU, nitroso urea drug or MAb treatment, were not administered during the 42-day trial.

In experiment A, 21 patients (9 males, 12 females) were treated with 6 cohorts (dosage range 3 to 24 mg / m 2 / wk). In experiment B, 42 patients (25 males, 16 females) were treated with 9 cohorts (dosage range 3 to 75 mg / m 2 / wk). The median age was 61 years (Experiment A) and 59 years (Experiment B), sex 12F / 9M (Experiment A) and 16F / 25M (Experiment B) -2. Patient eligibility includes an unresponsive solid tumor and appropriate organ function. Table 1 below shows the patient demographics in both experiments.

Table 2 below lists the types of tumors treated in both tests.

For patients dosed by Schedule A, PK samples were collected on days 1 and 15 of treatment and analyzed using non-compartmental analysis. Plasma SNS-595 concentrations were determined using an identified LC-MS / MS assay. The AUC (area under the curve) increases in proportion to the dose and mean AUC _inf, and is 1.7 to 15 μg · hr / ml for the 3 to 24 mg / m 2 dose level, respectively. The terminal half-life is about 19 hours. No evidence of drug-dependent deformation in pharmacokinetic parameters was observed after three weekly dosing. Figure 1 shows plasma concentrations of SNS-595 over time in various patient cohorts. Table 3 below provides pharmacokinetic parameters for patients administered according to Schedule A.

For patients administered by Schedule B, the pharmacokinetic parameters were assessed in 36 patients (21 pre-intensive and 15 minimal pre-treatment) after a single dose of 3 to 75 mg / . Clearance (CL), volume of distribution and the end half-life (T _1/2) was constant for all the patients in less than 48 ㎎ / ㎡. In patients with minimal pre - treatment, the PK variable was unchanged below 75 ㎎ / ㎡. CL is 2.2 ℓ / hr / ㎡ (1.0 to 3.8 ℓ / hr / ㎡ range), and the distribution volume of 53 ℓ / ㎡ (31 to 76 ℓ / ㎡ range), and T _1/2 is about 21 hours ( 13 to 49 hours). Exposure was similar for both intensive and minimally pretreated patients, with a primary increase at a dose of 48 mg / m2 or less. Exposure to patients with minimal pre-treatment was greater than the primary AUC (area under the curve) at the 60 mg / m2 dose level. Table 4 below shows the pharmacokinetic parameters of the patients administered by Schedule B.

In Experiment A, pharmacokinetics were evaluated at day 1 and day 15 (after the first dose and after the third dose). As can be seen in Table 5 below, SNS-595 exhibits high reproducible pharmacokinetics and low patient-to-patient variability. No accumulation or alteration was observed in the pharmacokinetic parameters after repeated administration. Exposure dose range of 8-fold (1.6 to 15 ㎍ · hr / ㎖) increased primary and with respect to, the removal rate (CL), the distribution volume (Vss) and T _1/2 is the average 2 ℓ / hr / ㎡ respectively, 48 ℓ / ㎡, 19 hr, and it was not changed from day 1 to day 15.

In experiment B, the pharmacokinetics are first evaluated at Day 1 after administration, the exposure, and increase the primary with respect to the dose range (1.1 to 46 ㎍ · hr / ㎖) of 24 times, CL, Vss, and T _1/2 is And the average was 2 L / hr / m 2, 53 L / m 2 and 21 hr, respectively.

The mean pharmacokinetic parameters for both experiments are presented in Table 5 below.

Figure 11 shows the dose linearity in Experiments A and B;

Table 6 below provides data on the hematological effects observed in the experiment.

As used herein, the term "maximum tolerated dose" or "MTD" refers to a dose level below a certain dose of SNS-595 in which ≥2 out of 6 patients experienced dose limiting toxicity (DLT) do. Patients with the term "pre-intensive therapy" or "HP" have previously> 6 courses of alkylating agents, chemotherapy or> 25% of courses or bones of> 2 platinum, mitomycin-C or any nitroso urea Of patients who received XRT in advance. The term, "minimal pre-treatment" or "MP" patient refers to a patient who does not meet HP definition. Tolcher et al, JCO 2001; 19: 2937-2947.

As used herein, Dose Limit Toxicity (DLT) is defined as an absolute neutrophil count (ANC) <500 or febrile neutropenia or platelet low point <25,000 or non-hematological adverse event (AE) ≥ grade 3 (as described in the Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE v3.0)), where adverse side effects require> 14 days of delayed administration.

Tables 7 to 9 below provide safety data for both experiments.

As can be seen from the data, neutropenia was dose-limiting toxicity (DLT) for both experiments. In Experiment A, dose - limiting toxicity (DLT) of neutropenic leukopenia was seen in the first patient at the level of 24 mg / m 2. Thereafter, 5 patients were treated with 18 mg / ㎡, and DLT of neutropenic leukopenia was formed in 2 patients. In Experiment B, a dose - limiting toxicity (DLT) of grade 4 neutropenia for more than 7 days was observed at 60 mg / m 2 in patients receiving pre - intensive therapy. For patients with minimal pre-treatment, one dose-limiting toxicity appeared at a dose of 75 mg / m2.

The MTD for Experiment A is 15 mg / m 2; MTD for Experiment B was 48 ㎎ / ㎡ for pre - intensive (HP) patients and 60 ㎎ / ㎡ for patients with minimal pre - treatment (MP).

In both experiments, two patients were grade 4 hypoplasia; Non-hematologic toxicity was usually a grade of 1/2 without dose limiting gastrointestinal toxicity or neurotoxicity.

Table 10 below provides evidence of the clinical activity of SNS-595 for both experiments. For Experiment A, the best response included one patient who achieved a partial response (PR) and six patients who achieved a stable disease SD (range 16 to 24 weeks). For experiment B, the best response includes 1 PR and 11 SDs (range 18 to 58 weeks). Table 11 below provides details of the partial / minimal response (PR / MR) in both experiments.

Significantly, SNS-595 represents evidence of clinical activity in advanced solid cancer patients, including two patients who have reached partial response for more than 16 weeks and 17 patients who have reached stable disease.

As can be seen from the data, SNS-595 is well regulated and shows clinical activity in both once-weekly and once-three-weekly doses. Dose limiting toxicity is non-cumulative neutropenia. SNS-595 represents predictable pharmacokinetics with low patient and intra-patient variability. Changes in pharmacokinetic parameters were not observed after repeated dosing.

Doses useful for the treatment of solid tumors in patients requiring treatment are 48 mg / m 2 once per 3 weeks and 15 mg / m 2 per week, as described in this Example.

Example 3 High Screening and Microscopy

The cells were seeded as a sub-fusion population and allowed to grow for 36 hours. The cells are then treated with the compound at a predetermined concentration for a predetermined period of time. Cells were fixed with 4% formaldehyde and permeabilized with 0.1% Triton. Cells were exposed to primary antibodies at 25 [deg.] C for 1 hour at 1: 100 dilution in 10% FBS / PBS (anti-pATM-chemicon, anti-gH2AX-cell signaling technology). Cells were exposed to secondary antibodies in 10% FBS / PBS at a dilution of 1: 100 at 25 &lt; 0 &gt; C for 1 hour. 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 a Spot Detector algorithm.

Figure 2 shows HCT116 cells administered with various compounds over a period of 6 hours. Cells were then fixed and analyzed for protein phosphorylation status (pATM images obtained using a gH2AX image obtained using a fluorescence microscope, ArrayScan VTi). As can be seen in the figure, SNS-595 treatment results in nuclear lesion formation.

Figures 3-5 illustrate the dependence of lesion formation on dose and time. Cells were fixed and analyzed for phospho-AT. Cellomics Arrayscan software was used to identify lesions (Fig. 3, orange dot). The lesion quantification was performed by measuring the lesion fluorescence intensity (FIG. 4) or cells with lesions greater than 2 (FIG. 5) as a function of time and SNS-595 concentration.

Example 4: MTT assay and sensitization treatment

Cells were seeded at 4,000 cells per well on a 96-well plate, cultured for 24 hours, and then treated with compound for 72 hours. The cells were then incubated with 5% MTT for 1 to 2 hours and lysed. MTT was colorimetric read at 570 nm and EC ₅₀ was measured using linear regression analysis.

The sensitization was carried out using various chemical treatments. Cells were pretreated with a chemical sensitizing agent for 16 hours prior to drug addition (concentrations were as follows: caffeine 2 mM, DNAPK inhibitor II (make 10 μM and wortmannin 100 nM). The data are presented in Table 12 below. Sensitization was measured as fold reduction in EC ₅₀ for cytotoxicity as measured by MTT assay.

This data indicates that SNS-595 represents a unique PIKK dependency. Both ATM / ATR and DNAPK are activated after treatment with SNS-595, DNAPK alone is required for DNA repair, and cells are only sensitized to SNS-595 when DNAPKcs activity is reduced. ATM / ATR mediates G2-checkpoint stop. The loss of G2-checkpoint does not sensitize the cells to SNS-595. In contrast to SNS-595, all other DSB-derived agents tested use ATM / ATR for recovery and exhibit sensitization when ATM or DNAPK activity is inhibited.

Example 5: DNA damage sensitizing kinase ATM and ATR-Repair of DNA damage in the absence of damage

HCT-116 cells were treated with 10 mM SNS-595 or 10 mM ethopocide for 6 hours with or without 2 mM caffeine. The compound was then removed and the cells allowed to recover for 16 hours. Cells were analyzed for gH2AX lesions before and after drug efflux of the drug. As can be seen in FIG. 6, DNA damage induced by SNS-595 is easily restored in the absence of ATM and ATR. Conversely, other drugs (eg, etoposide) use ATM and ATR for DNA repair. Caffeine treatment inhibits the activity of ATM and ATR, which results in defects in homologous recombination, nucleotide ablation repair, and mismatch repair.

Example 6: DNA-sensitizing kinase DNA-PK - Repair of DNA damage in the absence of damage

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

Example 7: Concurrent experiment using SNS-595

Cell lines and cell cultures: HCT116 and NCI-H460 cell lines were obtained from ATCC. SKOV3 (p53 - / -) and SKOV3 (p53 + / +) were obtained from Dr. George Stark's laboratory at the Lerner Institute of 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 seeded at 4,000 cells per well in 96 well plates (except SKOV3 (p53 - / -) seeded at 8,000 cells per well) and cultured for 24 hours before treatment with compounds. Compound treatment lasted for 72 hours. The cells were then incubated with 5% MTT for 1 to 2 hours and lysed. MTT was read in color at 570 ㎚. The fraction of dead cells was determined by the following equation:

The percentage of dead cells = 1- [abs-Avg of sample well (Abs without cell control)] / [Avg (Abs of DMSO single control) -Avg (abs without cell control)

Schedule Experiment: When the compound was administered on a schedule including medicinal cleansing, the cells were washed with 100 μl of fresh warm medium for 30 minutes, then washed again after 90 minutes.

Statistical analysis: The data (fraction of dead cells) was analyzed using Calculusyn.V2 (BioSoft) and expressed as the value at compound index of infected fraction Fa = 0.5. All data are presented as error bars representing the 95% confidence interval of the mean value.

When calculating the compound index of 0.85 to 1.2, the parallelism is assumed to be additive. If a composite index of less than 0.85 is calculated, the parallelism is assumed to be ascending, and if the composite index is calculated above 1.2, the parallelism is assumed to be antagonistic. 8 to 10.

As can be seen from Figures 8a-8d, SNS-595 co-administered HCT116 colon carcinoma cell lines (Figures 8a, 8b and 8c) and various cytotoxic agents in H460 lung cancer cell line 8 (d) It represents at least a complex composite index. As can be seen in FIG. 9, SNS-595 administered concurrently with the selection of the DNA damaging agent and the metabolic inhibitor did not show any significant change in the composite index between p53-expressing or nonexpressed SKOV3 ovarian cancer cell lines.

As can be seen in Figures 10a to 10d, SNS-595 co-administered SNS-595 with HCT116 colon carcinoma cells with docetaxel (see Figures 10a and 10c) and gemcitabine (see Figures 10b and 10d) If administered at a delay of 24 hours, it may be antagonistic. Antagonism can be reduced by the first administration of SNS-595 (Figs. 10c and 10d, concurrent administration and 24 hours) and the first administration of other agents (Figs. 10a and 10b, concurrent administration and 24 hours) have. When the cells were treated with the first agent and the agent was washed and then treated with the second agent, a synergistic effect or possibly a synergistic effect was achieved (Figs. 10A to 10D, 2 hour potency wash and 24 hour potency wash).

Example 8: MTT cell bioassay analysis - Leukemia cells:

The following cell lines were used for this analysis: HL-60 (pre-mucosal leukemia); Jurkat (T cell leukemia); CCRF-CEM (lymphocyte leukemia); CEM / C2 (a camptothecin-resistant derivative of CCRF-CEM).

Cells were seeded on 96-well plates at 3,000 cells per well and cultured for 16 hours. Compound dilutions were performed in 10 mM DMSO at 3-fold dilution. Titration was diluted 1: 100 in media to achieve final compound concentration. A 96 well plate was aspirated and the compound dilutions in media were added (100 mL / well). MTT assays were performed after incubation at 37 ° C for 72 hours. Briefly, 20 ml of MTT solution was added to each well. The cells were incubated at 37 ° C for 1 to 2 hours. Cells were lysed by adding 100 ml / well cell lysis buffer, and MTT was solubilized at 37 [deg.] C overnight. Plates were read on a metal analyzer by absorbance measurements at 570 nm. IC ₅₀ was calculated using a regression analysis in GraphPad Prism (data are presented in Table 13 below). As shown in Table 13 below, SNS-595 shows an effective antiproliferative activity against tested hematological cell lines.

Example 9: Xenotransplantation model

LM3-Jck human malignant lymphoma tumor lobes (2-3 mm2) were subcutaneously transplanted into nude mice. The tumors were allowed to grow to a diameter of about 7 to 14 mm. Mice were treated with no treatment, irinotecan (100 mg / kg, IV, q4d x 3), doxorubicin (12 mg / kg, IV, single shot), etoposide (12 mg / kg, IV, qld x 5) 595 (25 and 20 mg / kg, IV, q7d x 5). Tolerable toxicity is defined as an average mass loss of less than 30%, or as less than 1 toxic death in 6 treated animals. The anti-tumor activity of the drug was evaluated at 21 days after initiation of administration.

CCRF-CEM acute lymphoblastic leukemia tumor lobes of 2-3 mm &lt; 2 &gt; were subcutaneously transplanted into nude mice. The tumors were allowed to grow to a diameter of about 8 to 20 mm. (12 mg / kg, IV, q1d x 5), irinotecan (100 mg / kg, IV, q4d x 3), doxorubicin (12 mg / kg, IV, q7d x 3), etoposide And SNS-595 (25 and 20 mg / kg, IV, q7d x 5) treatment groups. Acceptable toxicity is defined as an average group weight loss of less than 30%, or as less than 1 toxic death in 6 treated animals. The anti-tumor activity of the drug was evaluated at 20 days or 21 days after initiation of administration. Table 14 below provides data on tumor suppression (TI) and survival in the CCRF-CEM and LM3-Jck xenograft models.

As can be seen in Table 14, SNS-595 administered at 20 and 25 mg / kg exhibits potent anti-tumor activity with complete tumor regression for LM-3 Jck malignant lymphoma. The tumor suppression rate (IR) of SNS-595 is similar to irinotecan and is superior to etoposide and doxorubicin in both CCRF-CEM and LM3-Jck xenograft models.

Example 10: Bone marrow / cytology analysis

CD-1 mouse females were administered intravenously 5, 10, 15 or 20 mg / kg SNS-595 at day 0 and day 4. For hematological analysis, blood was collected from the 6th, 8th, and 12th post - initial injections. The femur was fixed on Streck at day 6 and stained with H & E before analysis of bone marrow cell integrity. Two days after the second administration of SNS-595, bone marrow separated from the femur showed a dose-dependent decrease in cell fidelity. At 20 mg / kg, cell integrity was reduced to 7.5%, and circulating neutrophils were reduced from the pre-dose level of 1,244 + 55 cells / ml at day 8 to nadir of 51 + 24 cells / ml blood. After that, the absolute neutrophil counts recovered and soon returned to normal levels. Also, the total WBC reached nadir on day 8, but returned to normal level. The dose-dependent reduction in hematopoietic bone marrow cell integrity is shown in FIG. The figure shows cell fidelity at initial doses after 6 days of bone marrow SNS-595 at various doses.

Figure 15 shows the neutrophil counts from blood samples at 4 days, 6 days, 8 days and 12 days post-initial injections. As can be seen in FIG. 16, all SNS-595 treated groups show significant reduction in peripheral neutrophils up to day 8. As can be seen in FIG. 17, animals receiving SNS-595 20 mg / kg injection were less than 50 cells / ml on day 8.

Figure 18 shows that there is a minimal platelet response at day 8 for SNS-595 injection. Figure 19 shows the percent body weight loss (%) at various times after administration of SNS-595. Figure 20 shows recovered bone marrow at day 12 post-injection of 20 mg / kg SNS-595.

Example 11: Clinical trial data of SNS-595 in patients with blood cancer

SNS-595 was administered to patients with advanced or unresponsive acute leukemia as a slow IV push. Diagnosis includes AML (19 patients) and ALL (2 patients). All patients are unresponsive to previous treatments or have recurrent disease from treatment (median pre-treatment 3 (range 1 to 6)).

A total of 21 patients (9 women and 12 men; median age = 64 years, range 21 to 80 years) were treated with 5 cohorts using 2 schedules. In the first schedule (A), the dose of SNS-595 per week was administered for 3 weeks and not for 7 days (qwk x 3). In a second schedule (B), a given dose of SNS-595 was administered twice weekly for two weeks (biwk x 2). The cycle duration including delay days was 28 days for both schedules. Schedule A is a total of 3 doses per cycle and Schedule B is a total of 4 doses per cycle. Additional cycles are allowed when the patient has reached a stable disease or has improved. Starting dose was 18 mg / m 2 in schedule A and 9 mg / m 2 in schedule B, and the dose was gradually increased by cohort. The cohort of 3 to 6 patients was increased to a dose using the modified Fibonacci sequence.

Pharmacokinetic analysis for SNS-595 was performed on plasma samples collected during cycle 1. Table 15 below provides specific pharmacokinetic parameters derived from the experiment.

Plasma SNS-595 concentrations were determined using an identified LC-MS / MS assay. Plasma exposure at the first two dose levels for each schedule is linearly increased to produce an AUC of 4.3 to 17.8 占 퐂 / hr / ml for the 9 to 27 mg / m2 dose. CL, Vss and terminal half - life are similar to those of solid tumors, and mean values are about 2 ℓ / hr / ㎡, 58 ℓ / ㎡ and 23 hr, respectively. Six patients in all the treatment groups presented in Table 15 experienced an over 50% reduction in peripheral B cells after cycle 1.

No dose - limiting toxicity (DLT) was observed below 27 ㎎ / ㎡ in the qwk × 3 schedule or below 13.5 ㎎ / ㎡ in the biwk × 2 schedule. Non-dose limiting toxicity includes nausea / vomiting, diarrhea and mucositis. Grade 4 neutropenic fever fever was observed in only one patient.

Other patient cohorts are given doses of 38 mg / m2 and 50 mg / m2, respectively, according to Schedule A (qwk x 3). Still other patient cohorts are administered at doses of 19 mg / m2 and 25 mg / m2, respectively, according to Schedule B (biwk × 2). Safety data are presented in Table 16 below.

A dosing schedule useful for the treatment of blood cancer may include about 50 mg / m 2 to about 80 mg / m 2 administered once per week for 3 weeks. Another dose found to be of use in the treatment of blood cancer is about 55 mg / m 2 to about 75 mg / m 2 administered once per week for 3 weeks. Other doses for which use in blood cancer treatment has been found are 60, 65, 70 or 75 mg / m 2 administered once per week for 3 weeks.

Other administration schedules useful for the treatment of patients with hematological malignancies can include from about 25 mg / m 2 to about 50 mg / m 2 administered twice a week for two weeks. Another dose found to be of use in the treatment of blood cancer is about 30 mg / m 2 to about 45 mg / m 2 administered twice per week for two weeks. Other doses for which use in blood cancer treatment has been found are 30, 35, 40 or 45 mg / m 2 administered twice per week for 2 weeks.

The embodiments of the invention described above are presented for illustrative purposes only, and those of ordinary skill in the art will be able to ascertain using the ordinary experimentation to various equivalent examples of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the present invention and are intended to be included within the scope of the following claims.

Claims (1)

(+) - 1,4-dihydro-7 - [(3S, 4S) -3-methoxy-4- (methylamino) -pyridazinone in an amount suitable for administering a dose of 10 mg / ) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid for the treatment of acute myelogenous leukemia in humans Use of.

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