CN104873502A - Therapeutic combinations comprising (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid fir treating cancer - Google Patents

Abstract

The present invention discloses methods of treating, preventing or controlling cancer, including certain leukemias. The method involves administering optically pure (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo Generation-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid. Also provided are methods of treatment in which the compounds are combined with chemotherapy, radiation therapy, hormonal therapy, biological therapy or immunotherapy. Pharmaceutical compositions and single unit dosage forms useful in the methods are also disclosed.

Description

Using (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2 -Thiazolyl)-1,8-naphthyridine-3-carboxylic acid Method for treating cancer

The application date is September 05, 2006, the application number is 200680039484.4, and the name is "using (+)-1,4-dihydro-7-[(3s,4s)-3-methoxyl-4- (Methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is a divisional application for the invention of the method for treating cancer.

This application claims U.S. Patent Application Nos. 11/218,387 and 11/218,653 filed September 2, 2005 (and now converted to U.S. Provisional Applications), and U.S. Provisional Application Nos. 60/789,093 and 60 filed April 3, 2006 /788,927 and priority of US provisional application 60/810,285 filed June 1, 2006. All of the above applications are incorporated herein by reference in their entirety.

1. Technical field

The present invention provides optically pure (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4 -Oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, also known as SNS-595 or AG-7352 as a method of treating, preventing or managing cancer including certain leukemias. Dosages, dosing regimens and amounts of SNS-595 and its administration are also provided.

2. Background technology

The chemical name of SNS-595 is (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo Generation-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, which has the following structural formula:

SNS-595 is known for its anticancer activity. The literature mentions that SNS-595 can be used to treat the following cancers: bladder cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, melanoma, myeloma, neuroblastoma ( CNS cancer), ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, sarcoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer and uterine cancer. Various dosing regimens have been reported, see, eg, US Patent Application Publication Nos. 2005-0203120, 2005-0215583, and 2006-0025437, all of which are incorporated herein by reference in their entirety.

There is still a need for a safe and effective dosage and dosage regimen when administering SNS-595 to treat, prevent or control various cancers, including leukemia.

3. Outline of the invention

SNS-595 is a cytotoxic agent with known anticancer potency. The present invention discusses novel therapeutic approaches including the treatment of specific leukemias. Additionally, unique dosage ranges, dosing regimens and drug dosages are described.

This specification describes the treatment, prevention or management of cancer with SNS-595, its pharmaceutical composition and unique dosage. In general, cancer types that can be treated, prevented or controlled using the methods provided by the present invention include, but are not limited to: bladder cancer, breast cancer, cervical cancer, colon cancer (including rectal cancer), esophageal cancer, head and neck cancer, liver cancer , lung cancer (small cell and non-small cell), melanoma, bone marrow cancer, neuroblastoma (i.e., CNS cancer), ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, sarcomas (including osteosarcoma), skin cancer ( Including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer and uterine cancer. These cancers may be relapsed, refractory, or resistant to conventional therapy.

In certain embodiments, the cancer includes hematological malignancies including, but not limited to, leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also known as Hodgkin's lymphoma), and myeloma. Different types of leukemia include, but are not limited to: chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and acute myeloblastic leukemia. The leukemia can be relapsed, refractory or drug resistant. In certain embodiments, the hematological malignancy is promyelocytic leukemia, T-cell leukemia, or lymphocytic leukemia.

The present invention further provides methods of treating, preventing or controlling cancer by administering SNS-595 in a certain manner. In certain embodiments, the method comprises administering to the mammal a dose of about 1 mg/m ² to 150 mg/m ² , about 1 mg/m ² to 100 mg/m ² , 1 mg/m ² to 75 mg/m ² , based on body surface area , 15 mg/m ² to 80 mg/m ² , or about 3 mg/m ² to 24 mg/m ² of SNS-595. In certain embodiments, the method comprises administering to the mammal a dose of SNS-595 of about 15 g/m ² , 25 g/m ² , or 50 mg/m ² based on body surface area. Other dosages and dosing regimens are described in more detail below.

Dosages and regimens for solid tumors are also provided by the invention. The amount of SNS-595 administered can be delivered as a single dose, such as a 10-15 minute IV bolus (e.g., a single bolus injection), or over a period of time, such as a 24-hour period (e.g., as a continuous infusion or in divided doses over time). bolus injection) and repeated as needed, e.g., until the patient stabilizes or recovers, or until the patient progresses or develops unacceptable toxicity.

In some embodiments, SNS-595 can be administered to a patient in circulation. Cycling therapy involves administering the active agent for a period of time followed by a period of rest and repeating the sequence of administration. Cycling therapy can reduce the development of resistance to one or more treatments, avoid or reduce side effects of one treatment and/or improve efficacy.

In another embodiment, SNS-595 is used in combination with another drug ("second active agent") or another conventional therapy for the treatment, prevention or management of cancer, or the SNS-595 described herein. The 595 method of administration may be used in the setting of combination therapy. Second active agents include known small molecules, anti-cancer, anti-tumor or cytotoxic agents and macromolecules such as proteins and antibodies, examples of which are provided herein, as well as stem cells and cord blood. Examples of conventional treatments include, but are not limited to: surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy, immunotherapy, blood transfusion, and combinations thereof.

Thus, in certain embodiments, the present invention provides a combination of treatment, prevention and management of solid tumors. In other embodiments, the present invention provides combinations for the treatment, prevention and management of leukemia and lymphoma.

The invention also provides pharmaceutical compositions, single unit dosage forms and dosing regimens comprising SNS-595, and a second or other active agent. The second active agent includes a specific combination or "cocktail" of drugs or treatments, or both.

4. Description of drawings

Figure 1 depicts the changes in blood drug concentration of SNS-595 over time in different patient groups administered with the qwk×3 regimen;

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

Figure 3 depicts the quantification of lesions by measuring the fluorescence intensity of lesions;

Figure 4 shows the dose- and time-dependent relationship between lesion formation;

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

Figure 6 shows DNA damage induced by SNS-595 and etoposide with and without caffeine, which is an inhibitor of ATM and ATR;

Figure 7 shows DNA damage induced by SNS-595 and etoposide in the presence of DNA-PK (MO59K cells) and without DNA-PK (MO59J cells);

Figure 8a-c shows the synergistic/additive effect of combining SNS-595 and different cytotoxic agents on HCT 116 colon cancer cells;

Figure 8d shows the synergistic/additive effect of combining SNS-595 and different cytotoxic agents on H460 lung cancer cells;

Figure 9 shows the combined use index of SNS-595 with selected DNA damaging agents and antimetabolites in SKOV3 ovarian cancer cell lines expressing p53 (+/+) and not expressing p53 (-/-), respectively in black and gray diamonds represent;

Figure 10a-d shows the effect of combining SNS-595 with different cytotoxic agents on HCT 116 colon cancer cells;

Figure 11 provides the dose linear relationship of three weekly doses (qwk×3; circle = first week; triangle = second week) and once every three weeks (q3wk; diamond) SNS-595 given to patients with advanced solid tumors;

Figure 12 provides a comparison of the antitumor activities of SNS-595, etoposide, doxorubicin and irinotecan in the CCRF-CEM xenograft model;

Figure 13 provides a comparison of the antitumor activity of SNS-595 (20 mg/kg and 25 mg/kg), etoposide, doxorubicin and irinotecan in the LM3-Jck xenograft model;

Figure 14 shows the bone marrow cellularity of female CD-1 mice 6 days after the initial injection of SNS-595. SNS-595 was administered on Day 0 and Day 4. All images are displayed at 10 times magnification;

Figure 15 provides neutrophil responses to SNS-595 doses;

Figure 16 provides neutrophil counts on Day 8 at different SNS-595 doses;

Figure 17 provides WBC counts on day 8 under different SNS-595 doses;

Figure 18 provides platelet counts on day 8 under different SNS-595 doses;

Figure 19 provides the percentage change in body weight at different time intervals after administration of SNS-595; and

Figure 20 shows bone marrow rebound at day 12 following administration of 20 mg/kg of SNS-595.

5. Definition

Unless otherwise specified, the technical terms used in the present invention have the meanings commonly understood by those of ordinary skill in the art. All cited patents, applications, published applications and other publications are hereby incorporated by reference in their entirety. If the terms in this specification have multiple meanings, unless otherwise stated, the definitions in this section shall prevail.

Optically pure (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo Dai-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is substantially free of (-)-1,4-dihydro-7-[(3s,4s)-3-methoxy -4-(Methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid (ie in enantiomeric excess). In other words, the "(+)" form 1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo - 1-(2-Thiazolyl)-1,8-naphthyridine-3-carboxylic acid is substantially free of the "(-)" form of the compound and is thus in enantiomeric excess over the "(-)" form. The term "optically pure" or "pure enantiomer" means containing more than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% by weight % of enantiomers of the compound.

Unless otherwise stated, the term "optically pure (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1- "Pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid" means a compound containing at least about 80% by weight of (+)-1,4-dihydro -7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine -3-carboxylic acid and up to about 20% by weight of (-)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidine Base]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, at least about 90% by weight of (+)-1,4-dihydro-7-[ (3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxy acid and up to about 10% by weight of (-)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4 -Oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, at least about 95% by weight of (+)-1,4-dihydro-7-[(3s,4s )-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and up to about 5% by weight of (-)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo- 1-(2-Thiazolyl)-1,8-naphthyridine-3-carboxylic acid, at least about 97% by weight of (+)-1,4-dihydro-7-[(3s,4s)-3- Methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and up to about 3% by weight The (-)-enantiomer.

As used herein, unless otherwise indicated, the term "treating" means alleviating or reducing the severity of symptoms associated with the disease or condition being treated.

The term "preventing" includes suppressing the symptoms of a particular disease or condition. In some embodiments, patients with a family history of cancer are candidates for preventive regimens. In general, the term "prophylaxis" refers to administration prior to the onset of symptoms, especially in high-risk cancer patients.

As used herein, unless otherwise stated, the term "control" includes preventing the recurrence of a particular disease or disorder in a patient who has suffered from that disease or disorder, prolonging the time that a patient with the disease or disorder is in remission, reducing Patient mortality, and/or maintaining reduced or avoiding the severity of symptoms associated with the disease or condition being treated.

An "individual" as used in the present invention is an animal, usually a mammal, including a human, such as a patient.

The term "cancer" as used in the present invention includes, but is not limited to, solid tumors and blood-borne tumors. The term "cancer" refers to diseases of skin tissue, organs, blood and blood vessels, including but not limited to: bladder cancer, bone or blood cancer, brain cancer, breast cancer, cervical cancer, breast cancer, colon cancer, endometrium cancer (endrometrium) , esophagus, eye, head, kidney, liver, lung, oral cavity, neck, ovary, pancreas, prostate, rectum, stomach, testicles, larynx and uterus.

"Hematological malignancy" as used in the present invention refers to cancers of the body's blood-forming and immune systems-bone marrow and lymphoid tissues. Such cancers include leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also known as Hodgkin's lymphoma), and myeloma.

The term "leukemia" refers to malignant tumors of blood-forming tissues. The leukemia includes, but is not limited to: chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and acute myeloblastic leukemia. The leukemia can be relapsed, refractory, or resistant to conventional therapy.

"Promyelocytic leukemia" or "acute promyelocytic leukemia" as used in the present invention refers to a disease of the bone marrow that lacks mature blood cells in the myeloid lineage but has an excess of immature cells called promyelocytes Malignant tumor. It is usually characterized by an exchange of parts of chromosomes 15 and 17.

"Acute lymphoblastic leukemia (ALL)", also referred to as "acute lymphoblastic leukemia" as used in the present invention refers to a malignant disease caused by abnormal growth and development of early agranular leukocytes or lymphocytes.

"T cell leukemia" as used in the present invention refers to a disease in which certain cells of the lymphatic system called T lymphocytes or T cells are malignant. T cells are white blood cells that normally attack virus-infected cells, foreign cells, cancer cells and produce substances that modulate the immune response.

The term "recurrence" refers to the recurrence of cancer cells in a patient whose cancer has been in remission after treatment.

The term "refractory or resistant" refers to a condition in which cancer cells remain in the patient's body even after intensive treatment.

As used herein, _IC50 refers to the amount, concentration or dose of a particular test compound that achieves 50% of the maximal inhibitory effect in an assay detecting said effect.

Unless otherwise stated, the terms "therapeutically effective amount" and "effective amount" of a compound used in the present invention refer to sufficient therapeutic effects in the treatment, prevention and/or control of diseases, delay or reduction associated with the disease or condition being treated. Amount of associated symptoms. The terms "therapeutically effective amount" and "effective amount" can include an amount that increases the overall therapeutic effect, reduces or eliminates the symptoms or causes of a disease or disorder, or increases the efficacy of another therapeutic agent.

Unless otherwise stated, the term "pharmaceutically acceptable salt" used in the present invention includes, but is not limited to, salts of acidic or basic groups present in the compounds provided by the present invention. Under certain acidic conditions, the compounds can form various salts with various inorganic and organic acids. The acids that can be used to prepare the pharmaceutically acceptable salts of the basic compounds are those acids that form salts containing pharmaceutically acceptable anions, including but not limited to: acetic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, acid Formula tartaric acid, bromide, calcium edetate, dextrocamphorsulfonic acid, carbonic acid, chloride, bromide, iodide, citric acid, dihydrochloride, edetic acid, edetate, etotic acid, analgesic Esylate, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycollylarsanilate, hexylresorcinate, hydrabamine, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, Malic acid, maleic acid, mandelate, methanesulfonic acid, methylsulfuric acid, muscate, naphthalenesulfonic acid, nitric acid, pantothenic acid, phosphoric/diphosphoric acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid , sulfuric acid, tannic acid, tartaric acid, teoclate, triethiodide and pamoic acid. Under certain basic conditions, the compounds can form basic salts with various pharmaceutically acceptable cations. Non-limiting examples of such salts include alkali or alkaline earth metal salts, especially calcium, magnesium, sodium, lithium, zinc, potassium and iron salts.

Unless otherwise stated, the term "hydrate" used in the present invention refers to a compound or a salt thereof provided by the present invention, which also includes stoichiometric or non-stoichiometric amounts of water.

Unless otherwise stated, the term "solvate" used in the present invention refers to a solvate formed by combining one or more solvent molecules with the compounds provided by the present invention. The term "solvate" includes hydrates (eg, monohydrate, dihydrate, trihydrate, tetrahydrate, etc.).

The terms "co-administration" and "combination" include simultaneous, concurrent or sequential administration of two therapeutic agents (eg, SNS-595 and another anticancer agent or a second agent) with no stated time limit. In one embodiment, the two agents are present in the cell or in the patient at the same time, or exert a biological or therapeutic effect at the same time. In one embodiment, the two therapeutic agents are in the same composition or unit dosage form. In another embodiment, the two therapeutic agents are in separate compositions or unit dosage forms.

The term "supportive care agent" refers to any substance that treats, prevents, or manages adverse effects resulting from SNS-595 treatment.

6. Detailed description of the invention

6.1 SNS-595

The compound used in the therapeutic methods and compositions of this invention is optically pure (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)- 1-Pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, also known as SNS-595 or AG-7352. SNS-595 has the following chemical structure:

In certain embodiments, pharmaceutically acceptable salts, solvates, hydrates or prodrugs of SNS-595 are used in the methods and compositions of the invention.

SNS-595 can be prepared by methods known in the art. For example, the title of "Compounds, processes for the preparation thereof and antitumor agents" published on October 6, 1998 is US Patent No. 5,817,669. The preparation method among the example C-1, and the Japanese patent application Hei 10-173986 of Chikugi etc., these two patents are all incorporated herein as a reference in full. Some examples of pharmaceutical compositions comprising SNS-595 and methods of their use are described in US Patent Application Publication Nos. 2005-0203120, 2005-0215583, and 2006-0025437, which are incorporated herein by reference in their entirety.

6.2 How to use

Proliferating cells go through _four phases of the cell cycle: _G1 , S, G2 and M. These phases are first determined by observing dividing cells as they undergo DNA synthesis (known as the synthetic phase or S phase of the cell cycle) and mitosis (also known as the mitotic phase or M phase or S phase of the cell cycle). The time gaps observed between the completion of DNA synthesis and mitosis and between mitosis and the next DNA synthesis cycle are the _G1 phase and the _G2 phase, respectively. Non-proliferating cells that maintain proliferative capacity under favorable conditions are in a quiescent or G0 state, typically characterized by having _exited the cell cycle.

SNS _- 595 is a cell cycle inhibitor capable of trapping cells in the G2 phase. Without being bound by a particular theory, SNS-595 mediates the activation of the DNA-PK pathway that ultimately leads to apoptotic cell death. These events are S-phase specific, ie they occur only in the S phase of the cell cycle. Without being bound by a particular theory, treatment with SNS-595 resulted in an increase in the number of double-strand DNA breaks formed in S phase, which impede the ability of cells to synthesize DNA and prolong the time that cells remain in S phase. Apoptotic markers emerge rapidly upon detection of DNA damage in cells. The rapid onset of apoptosis appears to be p73-dependent, as the sensitivity of SNS-595 was decreased more than 11-fold in p73-null cells compared to p73-containing cells.

As shown in Figure 7, the formation of double-strand breaks activates DNA-PK-mediated repair and apoptosis cellular mechanisms in a dose-dependent manner, including but not limited to: i) DNA-PK expression; ii) H2AX phosphorylation; iii) c-Abl phosphorylation; iv) p53 phosphorylation; v) p73 phosphorylation; vi) p21 expression; vii) Caspases-9 activation; and viii) Caspases-9 3 activation. If the DNA damage is so severe that the double-strand break cannot be repaired by non-homologous end joining (NHEJ), the cell rapidly enters apoptosis. Some cells are able to reach the _G2 phase, but these cells cannot enter the M phase due to damage and are captured (mediated by cdc2/cyclin B) and eventually undergo apoptosis. Without being bound by a particular theory, due to the S-phase selectivity of SNS-595, doses of SNS-595 that are toxic to proliferating cells (and thus undergoing a cell cycle that includes S phase) are non-lethal to non-proliferating cells.

6.2.1 Solid Tumors

Accordingly, the present invention provides a method of treating, controlling or preventing cancer comprising administering to a mammal in need of such treatment, managing or preventing SNS-595 at a dose of 1 mg/m ² to about 100 mg/m ² . Cancer types include, but are not limited to: bladder cancer, breast cancer, cervical cancer, colon cancer (including rectal cancer), esophageal cancer, head and neck cancer, liver cancer, lung cancer (small cell lung cancer and non-small cell lung cancer), melanoma cancer, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, and uterine cancer. In one embodiment, the method comprises treating, preventing or managing colon cancer, pancreatic cancer, breast cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, melanoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian Carcinoma, kidney cancer, salivary gland cancer, small cell lung cancer, or spindle cell carcinoma.

6.2.2 Leukemia

In one embodiment, the method provided by the present invention comprises treating, preventing or controlling various types of leukemia, such as chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, acute myelogenous leukemia and acute myeloblastic leukemia .

In some embodiments, the method includes treating, preventing or managing acute leukemia, such as AML, including but not limited to undifferentiated AML (M0), myeloblastic leukemia (M1), myeloblastic leukemia (M2), early Myeloid leukemia (M3 or M3 variant [M3V]), myelomonocytic leukemia (M4 or M4 eosinophilic variant [M4E]), monocytic leukemia (M5), erythroleukemia (M6), Acute megakaryoblastic leukemia (M7). In some embodiments, acute lymphoblastic leukemia (ALL) includes leukemias derived from bone marrow blasts (B-cells), thymocytes (T-cells), and lymph nodes. According to the French-American-British (FAB) morphological classification, acute lymphoblastic leukemia can be divided into L1-mature lymphoblastoid (T-cell or pre-B-cell), L2-immature and pleomorphic (polymorphic). shape) lymphoblastoids (T-cells or pre-B-cells) and L3-lymphoblastoids (B-cells; Burkitt cells).

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

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

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

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

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

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

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

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

In one embodiment, acute lymphoblastic leukemia arises from myeloid blasts (B-cells).

In one embodiment, acute lymphoblastic leukemia arises from thymocytes (T-cells).

In one embodiment, acute lymphoblastic leukemia arises from lymph nodes.

In one embodiment, the acute lymphoblastic leukemia is of the L1 type characterized by mature morphological lymphoblastoid cells (T-cells or pre-B-cells).

In one embodiment, acute lymphoblastic leukemia is of the L2 type characterized by immature and pleomorphic (multiple shapes) lymphoblastoid cells (T-cells or pre-B-cells).

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

In certain embodiments, the acute myeloid leukemia is promyelocytic leukemia, or lymphocytic leukemia. In certain embodiments, acute lymphoblastic leukemia refers to T-cell leukemia. In one embodiment, the methods provided herein include methods of treating, preventing or managing promyelocytic leukemia, T-cell leukemia or lymphocytic leukemia. In one embodiment, T-cell leukemia refers to peripheral T-cell leukemia, T-cell lymphocytic leukemia, cutaneous T-cell leukemia, and adult T-cell leukemia.

In some embodiments, SNS-595 is used to treat drug-resistant leukemia, such as chronic myelogenous leukemia (CML). Thus, treatment with SNS-595 may provide an option for patients who have not responded to other treatments. In some embodiments, these other methods of treatment include the use of for treatment. In some embodiments, methods of treating Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) are provided. In some embodiments, there is provided a treatment for A method for drug-resistant Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML).

The methods provided herein include treating patients who have previously received cancer treatment but have not responded to standard therapy, as well as patients who have not previously received treatment. Although some diseases or conditions are more prevalent in certain age groups, the present invention also provides methods of treating patients regardless of the patient's age. Further, methods of treating patients who have undergone surgery to treat a disease or condition of tissue and patients who have not undergone such treatment are also provided. Since cancer patients have different clinical manifestations and produce different clinical effects, the treatment methods given to a patient may vary according to his/her prognosis. Without undue experimentation, an experienced clinician can readily determine the specific secondary agents, types of surgery, types of standard non-drug-based treatments that can be used to effectively treat an individual patient with cancer.

Dosing of SNS-595 can be delivered as a single dose, such as a 10-15 minute IV bolus (e.g., a single bolus injection), or over a period of time, such as a 24-hour period (e.g., as a continuous infusion or in divided doses over time). bolus injection) and repeated as needed, e.g., until the patient stabilizes or recovers, or until the patient progresses or develops unacceptable toxicity. For example, solid tumor stable disease usually means that the vertical diameter of the measurable lesion has not increased by more than 25% from the previous measurement, see, Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3): 205-216 (2000). Stable or unstable disease can be determined by known methods, such as assessment of patient symptoms, physical examination, visualization of tumors using X-ray, CAT, PET, or MRI scan imaging, and other commonly used evaluation methods.

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

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

In other embodiments, SNS-595 is used in combination with another drug ("second active agent") or another method of treating, managing or preventing cancer. Secondary active agents include small and large molecules (ie, proteins and antibodies), examples of which are provided herein, as well as stem cells or cord blood. Methods or treatments that may be used in combination with SNS-595 include, but are not limited to, surgery, immunotherapy, biological therapy, radiation therapy, and other non-drug therapies currently used to treat, prevent, or manage cancer. The present invention discusses different dosing regimens of SNS-595 administered alone and/or in combination therapy.

The invention also provides pharmaceutical compositions (ie, single unit dosage forms) useful in the methods of the invention, especially pharmaceutical compositions comprising SNS-595 and a second active agent.

6.3 Dosage and Administration Regimen

In one embodiment, the method of the present invention for treating, preventing or controlling cancer comprises administering SNS-595 at a dose of about 1 mg/m ² to 150 mg/m ² according to the patient's skin surface area. 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 SNS-595 at a dose of about 1 mg/m ² to 50 mg/m ² . In another embodiment, the method comprises administering SNS-595 at a dose of about 1 mg/m ² to 48 mg/m ² . 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/ ^m2 to 27 mg/m2 based on body surface area. In another embodiment, the method comprises administering SNS-595 at a dose of about ³ mg/ ^m2 to 24 mg/m2 based on body surface area. In another embodiment, the method comprises administering SNS-595 at a dose of about ¹⁰ mg/ ^m2 to 90 mg/m2 based on body surface area. In another embodiment, the method comprises administering SNS-595 at a dose of about 15 ^mg / ^m2 to 80 mg/m2 based on body surface area. Body surface area can be calculated, for example, according to the Mosteller formula:

BSA(m ² ) ^: ＝Square root of [(height (cm)×weight (kg)/3600]

In another embodiment, the dose is 3 mg/m ² to 24 mg/m ² based on body surface area. In another embodiment, the dose is 3 mg/ ^m2 to 18 mg/m2 based ^on body surface area. In another embodiment, the dosage is 3 mg/m ² to 15 mg/m ² . In another embodiment, the dose is 1 mg/m ² , 2 mg/m ² , 3 mg/m ² , 4 mg/m ² , 5 mg/m ² , 6 mg/m ² , 7 mg/m 2 , 8 mg/m ² , 8 mg/m 2 , based on body surface area /m ² , 9mg/m ² , 10mg/m ² , 11mg/m ² , 12mg/m ² , 13mg/m ² , 14mg/m ² , 15mg/m ² , 16mg/m ² , 17mg/m ² , 18mg /m ² , 19mg/m ² , 20mg/m ² , 21mg/m ² , 22mg/m ² , 23mg/m ² , 24mg/m ² , 25mg/m ² , 26mg/m ² , 27mg/m ² , 30mg /m ² , 36 mg/m ² , 42 mg/m ² , 48 mg/m ² , 50 mg/m ² , 55 mg/m ² , 60 mg/m ² or 65 mg/m ² . In another embodiment, the dosage is 3 mg/m ² , 6 mg/m ² , 9 mg/m ² , 12 mg/m ² , 15 mg/m ² , 18 mg/m ² , 21 mg/m ² , 24 mg/m ² , 25 mg/m ² , 27 mg/m ² , 36 mg/m ² , 48 mg/m ² or 50 mg/m ² .

In one embodiment, the dose is 15 mg/m2 based ^on body surface area. In another embodiment, the dosage is 25 mg/m2 based ^on body surface area. In another embodiment, the dosage is 30 mg/m2 based ^on body surface area. In another embodiment, the dose is 50 mg/m2 based ^on body surface area.

In another embodiment, the dose is 15 mg/m ² to 80 mg/m ² based on body surface area. In another embodiment, the dose is 15 mg/ ^m2 to 75 mg/m2 based ^on body surface area. In another embodiment, the dosage is 30 mg/m ² to 50 mg/m ² . In another embodiment, the dose is 15 mg/m ² , 20 mg/m ² , 25 mg/m ² , 30 mg/m ² , 35 mg/m ² , 40 mg/m ² , 45 mg/m ² , 50 mg/m 2 based on body surface area /m ² , 55 mg/m ² , 60 mg/m ² , 65 mg/m ² , 70 mg/m ² , 75 mg/m ² or 80 mg/m ² .

The dosage of SNS-595 can be expressed in units other than mg/m ² . For example, dosages may be expressed in mg/kg. Conversion of mg/ ^m2 to mg/kg can be readily accomplished by one of ordinary skill in the art given the height or weight or height and weight of an individual (see http://www.fda.gov/cder/cancer/animalframe .htm). For example, a dose of 1 mg/m ² to 30 mg/m ² is approximately equivalent to 0.026 mg/kg to 0.79 mg/kg for a human weighing 65 kg. In another example, a dose of ³ mg/m2 is approximately equal to 0.078 mg/kg for a human having a body weight of 65 kg. In another example, a dose of 15 ^mg / ^m2 to 80 mg/m2 is approximately equivalent to 0.39 mg/kg to 2.11 mg/kg for a human having a body weight of 65 kg.

In certain embodiments, SNS-595 can be delivered as a single dose, such as a 10-15 minute IV bolus injection (e.g., a single bolus injection), or over a period of time, such as a 24-hour period (e.g., a continuous infusion or over a period of time). Time-fractionated bolus injections) and repeated as needed, for example, until disease stabilization or recovery, or until the patient progresses or develops unacceptable toxicity. For example, stable or unstable disease is determined by known methods, such as assessment of patient symptoms, physical examination, and other generally accepted assessments.

The amount of the pharmaceutical composition administered in the methods of this invention will depend on the mammal being treated, the severity of the disease or symptoms of the disease, the mode of administration, the frequency of administration, and the judgment of the prescribing physician.

In some embodiments, the frequency of dosing is from about once a day to about once a month. In certain embodiments, the dosing 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 weekly.

In certain embodiments, SNS-595 is administered periodically to the patient. Cyclic administration involves the administration of an active drug for a period of time followed by a period of rest, and repeating the sequence. Cycling therapy can reduce the development of resistance to one or more treatments, avoid or reduce the side effects of a treatment, and/or improve the efficacy of the treatments.

Thus, in one embodiment, SNS-595 is administered weekly in a single dose or in divided doses in a three- to six-week cycle with a rest period of about 1 day to about 30 days. In another embodiment, SNS-595 is administered weekly in a single dose or in divided doses for one, two, three, four, five, or six weeks with 1, 3, 5, 7, 9, 12, 14, 16, 18, 20, 22, 24, 26, 28, 29 or 30 days. In some embodiments, the waiting period is 14 days. In some embodiments, the waiting period is 28 days. In one embodiment, the waiting period is until sufficient bone marrow has recovered. The frequency, number and length of dosing cycles can be increased or decreased. Accordingly, another embodiment includes administering more treatment cycles than typical therapy when SNS-595 is administered alone.

In one embodiment, the method provided by the invention comprises: i) administering SNS-595 to the patient at a dose of 1 mg/m ² to 150 mg/m ² ; ii) waiting at least one day, during which time the mammal is not administered SNS-595; and iii) administering another dose of SNS-595 of 1 mg/m ² to 150 mg/m ² to the patient. In one embodiment, steps ii)-iii) are repeated multiple times. In another embodiment, the method comprises administering a dose of 1 mg/m ² to 100 mg/m ² in steps i) and iii).

For example, in one embodiment, in the method of treating certain leukemia, the method provided by the present invention comprises: i) administering SNS-595 to a mammal at a dose of about 10 mg/m ² -150 mg/m ² ; ii) waiting at least one day during which time SNS-595 is not administered to the mammal; iii) administering another dose of SNS-595 of about 10 mg/m ² -150 mg/m ² to the mammal; and, iv) repeating step ii )-iii) multiple times. In another embodiment, the method comprises administering a dose of 1 mg/m ² to 100 mg/m ² in steps i) and iii).

In one embodiment, the methods provided herein include: i) administering to the patient SNS-595 at a dose of about 1 mg/m ² -75 mg/m ² ; ii) waiting for at least one day, during which time the mammal is not administered SNS-595; and iii) administering another dose of SNS-595 in the range of 1 mg/m ² -75 mg/m ² to the patient. In one embodiment, steps ii)-iii) are repeated multiple times.

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

In one embodiment, the methods provided herein include: i) administering to the patient SNS-595 at a dose of about 1 mg/m ² -24 mg/m ² ; ii) waiting for at least one day, during which time the mammal is not administered SNS-595; and iii) administering to the patient another dose of SNS-595 in the range of about 1 mg/m ² -24 mg/m ² . In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method comprises administering a dose of about 3 mg/m ² to 24 mg/m ² in steps i) and iii). In yet another embodiment, the method comprises administering a dose of about ¹⁵ mg/m2 in steps i) and iii). In another embodiment, the method comprises administering 1 mg/m ² to 40 mg/m ² , about 1.5 mg/m ² to 30 mg/m ² , about 2 mg/m ² to 25 mg/m 2 in steps i) and iii). ² or a dose of about 3 mg/m ² to 24 mg/m ² .

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

In the above method, for example, if the waiting period is 6 days, then the initial dose of SNS-595 is given on day 1 (step i); the waiting period is 6 days (step ii); the next dose is given on day 8 Dosing of SNS-595 (step iii). Other typical periods include 2 days, 3 days, 5 days, 7 days, 10 days, 12 days, 13 days, 14 days, 15 days, 17 days, 20 days, 27 days and 28 days. In another embodiment, the waiting period is at least 2 days and steps ii) to iii) are repeated at least three times. In another embodiment, the waiting period is at least 3 days and steps ii) to iii) are repeated at least five times. In another embodiment, the waiting period is at least 3 days and steps ii) to iii) are repeated at least three times. In another embodiment, the waiting period is at least 3 days and steps ii) to iii) are repeated at least five times. In another embodiment, the waiting period is at least 6 days and steps ii) to iii) are repeated at least three times. In another embodiment, the waiting period is at least 6 days and steps ii) to iii) are repeated at least five times. In another embodiment, the waiting period is at least 14 days and steps ii) to iii) are repeated at least three times. In another embodiment, the waiting period is at least 20 days and steps ii) to iii) are repeated at least three times. In another embodiment, the waiting period is at least 20 days and steps ii) to iii) are repeated at least five times. In another embodiment, the waiting period is at least 28 days and steps ii) to iii) are repeated at least three times. In another embodiment, the waiting period is at least 27 days and steps ii) to iii) are repeated at least five times. In another embodiment, the waiting period is at least 28 days and steps ii) to iii) are repeated at least five times.

In another embodiment, the method of administration comprises administering SNS-595 to the mammal twice weekly (administered on days 1, 4, 8, and 11). In another embodiment, the method of administration comprises administering SNS-595 to the mammal once a week. In another embodiment, the method of administration comprises administering SNS-595 to the mammal every two weeks. In another embodiment, the method of administration comprises administering SNS-595 to the mammal every three weeks. In another embodiment, the method of administration comprises administering SNS-595 to the mammal every four weeks.

In another embodiment, the method of administration comprises a cycle, wherein the cycle comprises administering SNS-595 to the mammal once a week for three weeks, followed by not administering SNS-595 to the mammal for a period of at least 14 days , repeating the cycle multiple times. In another embodiment, the period in which SNS-595 is not administered is 14 days. In another embodiment, the period in which SNS-595 is not administered is 21 days.

In another embodiment, the method provided herein comprises: i) administering SNS-595 to the mammal at a dose of about 1 mg/m ² to 100 mg/m ² once a week for three weeks; ii) waiting for 14 days , not administering any SNS-595 to the mammal during this period; and iii) further administering SNS-595 to the mammal at a dose of about 1 mg/m ² to 100 mg/m ² once a week for three weeks. In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method provided by the present invention comprises: i) administering SNS-595 to the mammal once a week at a dose of about 1 mg/m ² to 75 mg/m ² for three weeks; ii) waiting 14 days , not administering any SNS-595 to the mammal during this period; and iii) further administering SNS-595 to the mammal once a week at a dose of about 1 mg/m ² to 75 mg/m ² for three weeks. In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the provided method comprises: i) administering to the mammal a dose of about 1 mg/m ² to 60 mg/m ² of SNS-595 once a week for three weeks; ii) waiting 14 days, The mammal is not administered any SNS-595 during this period; and iii) the mammal is then administered SNS-595 at a dose of about 1 mg/m ² to 60 mg/m ² once a week for three weeks. In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the provided method comprises: i) administering to the mammal a dose of about 1 mg/m ² to 50 mg/m ² of SNS-595 once a week for three weeks; ii) waiting 14 days, not administering any SNS-595 to the mammal during this period; and iii) additionally administering SNS-595 to the mammal once a week at a dose of about ¹ mg/m to 50 mg/m for ^three weeks; and iv ) Repeat steps ii)-iii) multiple times.

In another embodiment, the method provided by the invention comprises: i) administering SNS-595 at a dose of about 1 mg/m ² to 48 mg/m ² to the mammal once a week for three weeks; ii) waiting 14 days, during which time the mammal is not given any SNS-595; and iii) the mammal is given a dose of SNS-595 of about 1 mg/m ² to 48 mg/m ² once a week for three weeks. In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method provided by the present invention comprises: i) administering SNS-595 to the mammal at a dose of about 1 mg/m ² to 24 mg/m ² once a week; ii) waiting for 14 days, where The mammal is not administered any SNS-595 during this period; and iii) the mammal is then administered SNS-595 at a dose of about 1 mg/m ² to 24 mg/m ² once a week for three weeks. In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method provided by the invention comprises: i) administering SNS-595 at a dose of about 2 mg/m ² to 40 mg/m ² to the mammal once a week for three weeks; ii) waiting 14 days, during which time the mammal is not given any SNS-595; and iii) the mammal is given a dose of SNS-595 of about 2 mg/m ² to 40 mg/m ² once a week for three weeks. In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method provided herein comprises: i) administering SNS-595 to the mammal at a dose of about 3 mg/m ² to 24 mg/m ² once a week for three weeks; ii) waiting 14 days , not administering any SNS-595 to the mammal during this period; and iii) further administering SNS-595 to the mammal once a week at a dose of about 3 mg/m ² to 24 mg/m ² for three weeks. In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method provided by the present invention comprises: i) administering SNS-595 at a dose of about 3 mg/m ² to 24 mg/m ² to the mammal once a week for three weeks (i.e. 8 and 15 days); ii) wait for at least 28 days, during which time no SNS-595 is administered to the mammal; and iii) re-administer the mammal once a week at a dose of approximately 3 mg/m ² to 24mg/m ² of SNS-595 for three weeks. In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method provided by the invention comprises: i) administering SNS-595 of about 3 mg/m ² to 24 mg/m ² to the mammal twice a week for two weeks (in the first, 4, 8, and 11 days); ii) wait at least 28 days without administering any SNS-595 to the mammal during this period; and iii) re-administer the mammal twice weekly at a dose of approximately 3 mg/ m ² to 24 mg/m ² of SNS-595 for two weeks (dose on days 1, 4, 8 and 11). In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method provided by the present invention comprises: i) administering SNS-595 to the mammal at a dose of about 3 mg/m ² to 24 mg/m ² once a week for three weeks (i.e. at 1 , 4, and 15 days); ii) wait at least 28 days, during which time no SNS-595 is administered to the mammal; and iii) re-administer the mammal once a week at a dose of approximately 3 mg/m ² to 24mg/m ² of SNS-595 for three weeks. In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method provided by the present invention comprises: i) administering SNS-595 at a dose of about 3 mg/m ² to 24 mg/m ² twice a week to the mammal for 2 weeks (in 1, 4, 8, and 11 days); ii) wait 28 days, during which time the mammal is not administered any SNS-595; and iii) then dose the mammal twice weekly at approximately 3 mg/m ² to 24 mg/m of SNS-595 for ² weeks (dose on days 1, 4, 8 and 11). In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method provided by the invention comprises: i) administering SNS-595 at a dose of about 15 mg/m ² to 80 mg/m ² to the mammal once a week for 3 weeks; ii) waiting 14 days, during which the mammal is not given any SNS-595; and iii) the mammal is given a dose of SNS-595 of about 15 mg/m ² to 80 mg/m ² once a week for 3 weeks. In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method provided by the invention comprises: i) administering to the mammal a dose of about 15 mg/m ² to 80 mg/m ² of SNS-595 once a week (i.e., on days 1, 8 and 15 2 days); ii) wait at least 28 days, during which time no SNS-595 is administered to the mammal; and iii) re-administer the mammal once a week at a dose of about 15 mg/m ² to 80 mg/m ² doses of SNS-595 for 3 weeks. In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method provided by the present invention comprises: i) administering SNS-595 of about 15 mg/m ² to 80 mg/m ² twice a week to the mammal for 2 weeks (in 1, 4, 8, and 11 days); ii) wait at least 28 days without administering any SNS-595 to the mammal during this period; and iii) re-administer the mammal twice weekly at a dose of approximately 15 mg/ m ² to 80 mg/m ² of SNS-595 for 2 weeks (dose on days 1, 4, 8 and 11). In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the methods provided herein include: i) administering to the mammal a dose of about 15 mg/m ² to 80 mg/m ² of SNS-595 once a week for three weeks (eg, at 1, 8, and 15 days); ii) wait 28 days, during which time the mammal is not administered any SNS-595; and iii) re-administer the mammal once a week at a dose of approximately 15 ^mg /m Up to 80mg/m ² of SNS-595 for three weeks. In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method provided by the invention comprises: i) administering SNS-595 at a dose of about 15 mg/m ² to 80 mg/m ² twice a week to the mammal for two weeks (in 1, 4, 8, and 11 days); ii) wait 28 days, during which time the mammal is not administered any SNS-595; and iii) then dose the mammal twice weekly at approximately 15 mg/m ² to 80 mg/ ^m2 of SNS-595 for two weeks (dose on days 1, 4, 8 and 11). In one embodiment, steps ii)-iii) are repeated multiple times.

In another embodiment, the method comprises administering to the patient a dose of about 1 mg/ ^m2 to 100 mg/ ^m2 of SNS-595 once a week, wherein the period of one week includes a treatment cycle and the treatment cycle is repeated at least three times. In another embodiment, the method comprises administering to the patient a dose of about 1 mg/ ^m2 to 75 mg/ ^m2 of SNS-595 once a week, wherein the period of one week includes a treatment cycle and the treatment cycle is repeated at least three times. In another embodiment, the method comprises administering to the patient a dose of about 1 mg/ ^m2 to 60 mg/ ^m2 of SNS-595 once a week, wherein the period of one week includes a treatment cycle and the treatment cycle is repeated at least three times. In another embodiment, the method comprises administering SNS-595 to the patient at a dose of about 1 mg/m ² to 48 mg/m ² once weekly, wherein the period of one week includes a treatment cycle and the treatment cycle is repeated at least three times. In another embodiment, the method comprises administering SNS-595 to the patient at a dose of about 1 mg/m ² to 24 mg/m ² once weekly, wherein the period of one week includes a treatment cycle and the treatment cycle is repeated at least three times. In another embodiment, the dosage is about ² mg/m2 to 40 ^mg /m2 once a week, wherein the period of one week includes a treatment cycle and the treatment cycle is repeated at least three times. In another embodiment, the dosage is about 3 mg/ ^m2 to ²⁴ mg/m2 once a week, wherein the period of one week includes a treatment cycle and the treatment cycle is repeated at least three times. In another embodiment, the dosage is about 15 mg/ ^m2 once a week, wherein the week includes a treatment cycle and the treatment cycle is repeated at least three times.

In another embodiment, the method comprises administering to the patient a dose of SNS-595 of 15 ^mg / ^m2 to 80 mg/m2 once a week, wherein the period of one week comprises a treatment cycle and the cycle is repeated at least three times. In another embodiment, the method comprises administering to the patient a dose of SNS-595 of 15 mg/m ² to 75 mg/m ² once weekly, wherein the period of the week comprises a treatment cycle and the cycle is repeated at least three times. In another embodiment, the method comprises administering SNS-595 to the patient at a dose of 20 mg/m ² to 65 mg/m ² once weekly, wherein the period of the week comprises a treatment cycle and the cycle is repeated at least three times. In another embodiment, the method comprises administering to the patient a dose of SNS-595 of 30 mg/m ² to 50 mg/m ² once weekly, wherein the period of the week comprises a treatment cycle and the cycle is repeated at least three times.

In some embodiments, the method comprises administering to the patient a dose of about 1 mg/m ² to 40 mg/m ² of SNS-595 once a week (i.e., on days 1, 8, and 15), wherein during the week A treatment cycle is included and repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering to the patient a dose of about 1 mg/m ² to 40 mg/m ² of SNS-595 (administered on days 1, 4, 8, and 11) twice weekly, wherein the week A period consists of a treatment cycle that is repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering to the patient a dose of about 1 mg/m ² to 40 mg/m ² of SNS-595 once a week (i.e., on days 1, 8, and 15), wherein the period of the week includes The treatment cycle was repeated at least three times, followed by a waiting period of 28 days. In some embodiments, the method comprises administering to the patient a dose of about 1 mg/m ² to 40 mg/m ² of SNS-595 (administered on days 1, 4, 8, and 11) twice weekly, wherein the week The period consisted of a treatment cycle that was repeated at least three times, followed by a 28-day waiting period.

In some embodiments, the method comprises administering to the patient a dose of about 3 mg/m ² to 24 mg/m ² of SNS-595 once a week (i.e., on days 1, 8, and 15), wherein during the week A treatment cycle is included and repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering to the patient a dose of about 3 mg/m ² to 24 mg/m ² of SNS-595 (administered on days 1, 4, 8, and 11) twice weekly, wherein the week A period consists of a treatment cycle that is repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering to the patient a dose of about 3 mg/m ² to 24 mg/m ² of SNS-595 once a week (i.e., on days 1, 8, and 15), wherein the period of the week includes The treatment cycle was repeated at least three times, followed by a waiting period of 28 days. In some embodiments, the method comprises administering to the patient a dose of about 3 mg/m ² to 24 mg/m ² of SNS-595 (administered on days 1, 4, 8, and 11) twice weekly, wherein the week The period consisted of a treatment cycle that was repeated at least three times, followed by a 28-day waiting period.

In some embodiments, the method comprises administering to the patient a dose of about 15 mg/m ² to 80 mg/m ² of SNS-595 once a week (i.e., on days 1, 8, and 15), wherein during the week A treatment cycle is included and repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering to the patient a dose of about 15 mg/m ² to 80 mg/m ² of SNS-595 twice weekly (i.e., on days 1, 4, 8, and 11), wherein the The one-week period includes a treatment cycle and the cycle is repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method comprises administering to the patient a dose of about 15 mg/m ² to 80 mg/m ² of SNS-595 once a week (i.e., on days 1, 8, and 15), wherein the period of the week includes The treatment cycle was repeated at least three times, followed by a waiting period of 28 days. In some embodiments, the method comprises administering to the patient a dose of about 15 mg/m ² to 80 mg/m ² of SNS-595 (administered on days 1, 4, 8, and 11) twice weekly, wherein the week The period consisted of a treatment cycle that was repeated at least three times, followed by a 28-day waiting period.

In another embodiment, the method comprises administering to the mammal a dose of SNS-595 from about ^{1 mg} /m2 to 50 mg/m2 once a week, wherein the weekly period includes a treatment cycle and the cycle is repeated at least twice. In another embodiment, the dose is about 2 mg/m ² -40 mg/m ² . In another embodiment, the dose is about 3 mg/m ² -24 mg/m ² . In another embodiment, the dose is about 4 mg/m ² -20 mg/m ² .

6.4 Typical dosing regimen

Typical dosing regimens associated with specific cancers are provided below. These dosing regimens are intended to be illustrative, not exclusive.

In one aspect, methods of treating solid tumors are provided. The method includes:

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

ii) Wait at least 6 days, during which time the individual is not administered any SNS-595;

iii) Administer another dose of SNS-595 from 1 mg/m ² to 100 mg/m ² to the patient; and

iv) iv) Repeat steps ii)-iii) multiple times.

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

In another aspect, a method of treating a solid tumor comprises administering to a patient SNS-595 at a dose of about 15 mg/m ² to 40 mg/m ² once weekly for three weeks, followed by at least two weeks without administering SNS-595 to said individual. 595, and wherein the treatment cycle is repeated multiple times. In another embodiment, the dose is about 15 mg/m ² to 35 mg/m ² . In another embodiment, the dose is about 20 mg/m ² to 30 mg/m ² . In another embodiment, the dose is about 20 mg/m ² to 25 mg/m ² .

In another aspect, a method of treating a solid tumor comprises administering to a patient SNS-595 at a dose of 35 ^mg /m to 80 ^mg /m once over a three-week period, wherein the three-week period includes a treatment cycle and the cycle is repeated for at least two Second-rate.

In another aspect, the invention provides methods of treating hematological malignancies. In certain embodiments, the method comprises administering to the patient SNS-595 at a dose of about 20 mg/m ² to 60 mg/m ² .

For those patients who are considered heavily pretreated ("heavily pretreated patients"), the method involves administering SNS-595 at a dose of 35 mg/m ² to 60 mg/m ² once over a three-week period, wherein the three Periods include a treatment period and the treatment period is repeated at least twice. In another embodiment, the method of treatment of heavily pretreated patients comprises administering a dose of 40 mg/m ² to 50 mg/m ² . In another embodiment, the method of treatment of heavily pretreated patients comprises administering a dose of 45 mg/m ² to 50 mg/m ² . The definition of severe pretreatment patients is as described by Tolcher et al. in J.Clin.Oncol.19: 2937-2947 (2001), which means that they have received more than six courses of chemotherapy containing alkylating agents, more than two courses Carboplatin or mitomycin C, any upfront nitrosourea regimen, radiation therapy to 25% bone marrow area, high-dose chemotherapy requiring reinfusion of hematopoietic stem cells, or patients with extensive bone metastases.

Those patients who have not been treated for solid tumors or who have received treatment but are not considered heavily pretreated are considered lightly pretreated patients ("mildly pretreated patients"). For lightly pretreated patients, the method comprises administering to the patient a dose of SNS-595 of 45 ^mg / ^m2 to 80 mg/m2 once over a three-week period, wherein the three-week period includes a treatment cycle and the treatment cycle is repeated at least twice . In another embodiment, the method of treatment of a lightly pretreated patient comprises administering a dose of 50 mg/m ² to 75 mg/m ² . In another embodiment, the method of treatment in a lightly pretreated patient comprises administering a dose of 55 mg/m ² to 70 mg/m ² . In another embodiment, the method of treatment in a lightly pretreated patient comprises administering a dose of 55 mg/m ² to 65 mg/m ² .

In another aspect, methods of treating hematological malignancies such as leukemias and lymphomas are provided. The method includes:

i) Administer SNS-595 at a dose of 10mg/m ² -50mg/m ² to the patient;

ii) Wait at least two days, during which time no SNS-595 is administered to the individual;

iii) Administer another dose of SNS-595 in the range of 10 mg/m ² -50 mg/m ² to the patient; and

iv) Repeat steps ii)-iii) multiple 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 of treating a hematologic malignancy comprises administering to a patient once weekly 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/m ² , wherein This week included a treatment cycle and the treatment cycle was repeated at least twice. In one embodiment, a method of treating a hematological malignancy comprises administering to a patient a dose of about 25 mg/m of SNS ^- 595 once a week, wherein the week comprises a treatment cycle and the treatment cycle is repeated at least twice.

Other useful dosage regimens for treating patients with hematological malignancies include administration of about 25 mg/ ^m2 to 50 mg/m2 twice weekly for ^two weeks. In another embodiment, the dosage regimen for the treatment of hematological malignancies comprises administration of about 30 mg/ ^m2 to about 45 mg/m2 twice weekly for ^two weeks. In another embodiment, the dosing regimen for the treatment of a hematological malignancy comprises administration of 30, 35, 40, or 45 mg/m2 twice weekly for ^two weeks.

In one embodiment, the method of treating a hematological malignancy comprises administering to a patient a dose of about 40 mg/m ² , 45 mg/m ² , 50 mg/m ² , 55 mg/m ² or 60 mg/m ² of SNS- 595, where the two-week period includes the treatment cycle. In one embodiment, a method of treating a hematologic malignancy comprises administering to a patient a dose of SNS-595 of about 50 mg/m2 every ^two weeks, wherein the two-week period includes the treatment cycle.

6.5 Combination therapy

In the methods and compositions provided herein, SNS-595 may be used in combination with other pharmacologically active compounds ("second active agents"). Certain combinations are believed to be synergistic in the treatment of certain types of cancer. Moreover, SNS-595 can alleviate the adverse effects caused by some second active agents, and some second active agents can also alleviate the adverse effects caused by SNS-595.

6.5.1 Second active agent

In the methods and compositions provided by the present invention, one or more second active components or second active agents can be used together with SNS-595. The second active agent can be a large molecule (such as a protein) or a small molecule (such as a synthetic inorganic, organometallic, or organic molecule).

Examples of macromolecularly active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, especially therapeutic antibodies to cancer antigens. Typical macromolecular active agents are biomolecules such as natural or man-made proteins. Proteins that are particularly useful in the methods and compositions of the present invention include those that stimulate the survival and/or proliferation of hematopoietic progenitor cells and immunogenic poietic cells in vitro or in vivo. Other proteins stimulate committed erythroid progenitor cell division and differentiation in vitro or in vivo. Specific proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II ("rIL2") and canarypox IL-2), IL-10, IL-12, and IL-2 -18; interferons, such as interferon α-2a, interferon α-2b, interferon α-n1, interferon α-n3, interferon β-I a and interferon γ-I b; GM-CF and GM-CSF; and EPO.

Specific proteins that may be used in the methods and compositions of the invention include, but are not limited to: available in the U.S. under the trade name Filgrastim (Amgen, Thousand Oaks, CA) and its derivatives, including but not limited to pegfilgrastim, are sold in the U.S. under the trade name Sagragrastim ((Immunex, Seattle, WA); sold in the United States under the trade name Recombinant EPO sold (Amgen, Thousand Oaks, CA); Epoetin alfa and Darbetine alfa.

Recombinant and mutated forms of GM-CSF can be prepared as described in US Patent Nos. 5,391,485, 5,393,870 and 5,229,496, all of which are incorporated herein by reference. Recombinant and mutated forms of G-CSF can be prepared as described in US Patent Nos. 4,810,643, 4,999,291, 5,528,823, and 5,580,755, all of which are incorporated herein by reference.

The present invention also provides natural and recombinant proteins used in combination with SNS-595. The invention further encompasses mutants and derivatives (eg modified forms) of the native protein which exhibit in vivo at least a portion of the pharmacological activity of the protein on which it is based. Examples of mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding residues in the native protein. The term "mutant" also includes proteins lacking carbohydrate groups normally found in native proteins (ie, non-glycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgG1 or IgG3 to a protein or active portion of a protein of interest. See, Penichet, M.L. and Morrison, S.L., J. Immunol. Methods 248:91-101 (2001).

Antibodies that can be used in combination with SNS-595 include monoclonal and polyclonal antibodies. Examples of antibodies include, but are not limited to: Trastuzumab ( ), MabThera ( ), bevacizumab (Avastin ^TM ), pertuzumab (Omnitarg ^TM ), tositumomab ( ), edrolizumab ( ) and G250. SNS-595 can also be combined with anti-TNF-α antibody, and/or anti-EGFR antibody such as Or combination or joint use of panitumumab.

Macromolecular active agents can be used as anticancer vaccines. For example, vaccines that secrete or cause the secretion of cytokines such as IL-2, G-CSF, and GM-CSF can be used in the methods and pharmaceutical compositions provided herein. See, L.A., et al., Curr. Opinion Mol Ther. 3(1):77-84 (2001).

Contrary to the general rule that selection of drugs with different mechanisms of action maximizes additive or synergistic properties (see Page, R. and Takimoto, C, "Principles of Chemotherapy", Cancer Management: A Multidisciplinary Approach (2001), p.23) , a combination comprising SNS-595 and a second active agent that also prevents DNA synthesis was found to have an additive or synergistic effect.

In the present invention, an agent prevents DNA synthesis when it directly or indirectly affects the ability of a cell to synthesize DNA or repair DNA damage. The agent can directly interact with DNA (eg, bind or intercalate) or bind to a DNA-binding protein involved in DNA synthesis or DNA repair. In general, agents that prevent DNA synthesis are active in S phase but need not be S phase specific.

Since SNS-595 affects the DNA-PK pathway, the second agent may be an agent capable of mediating its cytotoxicity through the DNA-PK pathway. An example is an agent that inhibits non-homologous end joining repair such as a DNA-PK inhibitor. As used herein, unless otherwise stated, "DNA-PK inhibitor" refers to an agent that inhibits or interferes with DNA-PK-mediated signaling pathways. Inhibition of DNA-PK activity can be direct (eg, catalytic inhibitors of DNA-PK itself) or indirect (eg, agents that interfere with the formation of active DNA-PK complexes (DNA-PK, Ku70, and Ku80)). Other examples include, but are not limited to: ligase IV inhibitors and apoptosis enhancing agents such as but not limited to caspase-9 activators, caspase-3 activators and Hsp90 inhibitors .

Small molecule second active agents can also be used to mitigate adverse effects caused by SNS-595. However, like some large molecules, it is believed that many small molecule second active agents may also have a synergistic effect when administered together (before, after, or simultaneously) with SNS-595. Examples of small molecule second active agents include, but are not limited to, anticancer agents, antibiotics, immunosuppressants, and steroids.

Examples of anticancer agents include, but are not limited to: alkylating agents, antineoplastic agents, antimetabolites (e.g., folic acid analogs, purine analogs, adenosine analogs, pyrimidine analogs, and substituted ureas), platinum coordination complexes drugs, topoisomerase II inhibitors, and radiation.

Specific anticancer agents include, but are not limited to: acivecin, arubicin, alcodazole hydrochloride, acronine, adolaisine, adesleukin, hexamethylmelamine, dimycin, aramex acetate Anthraquinone, amsacrine, anastrozole, antramycin, asparaginase, trilindactin, azacitidine, azathepa, azothycin, batimastat, benzotepa , bicalutamide, bisantrene hydrochloride, dinephrine dimesylate, bizellexine, bleomycin sulfate, buquina sodium, bropirimine, busulfan, actinomycetes C, Captestosterone, capecitabline (capecitabine capecitabine), carbamide, carbetim, carboplatin, carmustine, carrubicin hydrochloride, cazellexine, cedifenagore, celecoxib (COX-2 inhibitor), chlorambucil, siromycin, cisplatin, cladribine, clinatosulfonate, cyclophosphamide, cytarabine, dacarbazine, actinomyces D , daunorubicin hydrochloride, decitabine, dextromethorplastin, dezaguanine, dezaguanine mesylate, diacriquinone, docetaxel, doxorubicin, doxorubicin hydrochloride, dr Loxifen, droloxifen citrate, drostansterone propionate, dazolone, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, eprabamate, Piperidine, Epirubicin Hydrochloride, Ebrozole, Erlotinib, Esorubicin Hydrochloride, Estramustine, Estramustine Phosphate Sodium, Etanidazole, Etoposide, Etoposide Phosphate Glycosides, chlorpheniramine, fadrozole hydrochloride, fazarabine, fenretinide, azauridine, fludarabine phosphate, fluorouracil, flucitabine, phosphoquinone, fostrixin sodium, gemini Fitinib, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, imofosin, isoproplatin, irinotecan, irinotecan hydrochloride, lanreotide acetate, letrozole, Leuprolide Acetate, Liarazole Hydrochloride, Lometrexol Sodium, Lomustine, Loxoanthraquinone Hydrochloride, Masoprofen, Maytansine, Dichloromethyldiethylamine Hydrochloride, Metepregne Acetate Ketone, melengestrol acetate, melphalan, menoril, mercaptopurine, methotrexate, methotrexate sodium, chlorpheniramine, metutepa, mibudomide, mitoxacin, silk Cleave red body, mitoxetine, mitomacin, mitomycin, mitosperm, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, noramycin, Omar Platinum, Oxysulam, Paclitaxel, Pegaspargase, Pelithromycin, Pemetrexed, Penetrazine, Pelomycin Sulfate, Pefosfamide, Piperbromide, Piposulfan, Pimidyl Hydrochloride Roxanthraquinone, plicamycin, pprometane, porfimer sodium, phenomycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazole furans Safingol, Riboadenosine, Safingol, Safingol Hydrochloride, Semustine, Singtrazine, Sparfosate Sodium, Spamycin, Germanospiramine Hydrochloride, Spiromustine, Spiroplatinum, Streptigrin , streptozocin, sulfochlorfenurea, talithromycin, tecogalan sodium, taxotere, fluridine, tiloxantrone hydrochloride, temoporfin, teniposide, tiroxiron, testosterone , thiamiprine, thioguanidine, thioguanine, plug Tepa, carboxamide thiazole, tirapazamine, toremifene citrate, tritorolone acetate, tricitribine phosphate, trimetrexate, trimethyltrimethyl glucuronate, triptorelin, trimethyridine hydrochloride Buclozole, uracil mustard, uretipa, vapretide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinblastine sulfate, vinblastine sulfate, Vinblastin sulfate, vinorelbine tartrate, vinblastine sulfate, vinblastine sulfate, vorozole, zeniplatin, netastatin, and zorubicin hydrochloride.

Other anticancer agents include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, arrubicin, acylfulvenes, adenol, adrol Laixin, aldesleukin, ALL-TK antagonist, hexamethylmelamine, amustine, amidox (2,4-Dichlorophenoxyacetic acid 2,4-dichlorophenoxyacetic acid), amifostine, aminolevulinic acid, amroxine Bixing, Amsacrine, Anagrelide, Anastrozole, Andrographolide, Angiogenesis Inhibitors, Antagonist D, Antagonist G, Anrelix, Anti-dorsification Morphogenetic Protein-1, Antiandrogen, Prostate cancer, anti-estrogens, anti-tumor substances, antisense oligonucleotides, aphidicolin glycine, apoptotic gene modulators, apoptotic regulators, apurine nucleic acid, ara-CDP-DL-PTBA, Arginine deaminase, asulacrine, atamestane, amustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, diazotyrosine, baccatin III derivatives , balanol, batimastat, BCR/ABL antagonists, benzochlorins, benzoylstaurosporine, beta-lactam derivatives, beta-alethine, betaclamycinB, betulinic acid, bFGF inhibitors, bicalutamide, bisantrene, bisaziridinylspermine, dinat French and German, bistratene A, bizolexin, breflate, brompirimin, Budotitanium, butyrsulfinimide, calcipotriol, calphostin C, camptothecin derivatives, capecitabine, amides -Aminotriazole, carboxyaminoimidazole, CaRest M3, CARN 700, cartilage-derived inhibitors, kazolexin, casein kinase inhibitor (ICOS), castanospermine, cecropin B, cetrorelix, chlorlns, Sulfachloroquine, cicaprostin, cis porphyrin, cladribine, clomiphene analogues, clotrimazole, collismycin A, collismycin B, combretastatin A4, combretastatin analogues, conagenin, crambescidin 816, Clinato, cryptophycin 8, cryptophycin A derivatives, curacin A, cyclopentanthraquinones, cycloplatam, cypemycin, cytarabine ocfosfate, cytolytic factor, cytostatin, dalcimab, decitabine, dehydromembranin B, desloride Lin, dexamethasone, dexifosfamide, dexrazoxane, dexverapamil, diacriquinone, anescidin B, didox, diethylnorsper mine, dihydro-5-azacytidine, dihydropaclitaxel, 9-, dioxymycin, diphenylspiromustine, docetaxel, docosanol, dolasetron, deoxofluor Uridine, doxorubicin, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edefoxine, edrecolumab, eflornithine, elemene , etaziridine, epirubicin, eristamide, estramustine analogues, estrogen agonists, estrogen antagonists, etanidazole, etoposide phosphate, exemestane, fadrozole , Fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, fludlastine, fluasterone, fludarabine, fluorodaunorunicin hydrochloride, fofenamex, formestane, forstrixine, Formustine, gadolinium texaphyrin, gallium nitrate, gallitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, heregulin, hexamethylenediethylamide, hypericum Su, ibandronic acid, idarubicin, edoxifene, ijumenone, imofosine, ilomastat, imatinib (such as ), imiquimod, peptide immunostimulant, insulin-like growth factor-1 individual inhibitor, interferon agonist, interferon, interleukin, iodobenzidine, iodorubicin, sweet potato alcohol, 4-, i Ropra, Isoladine, isobengazole, isohomohalicondrin B, itasetron, jasplakinolide, kahalalide F, spirulina triacetate-N, lanreotide, leinamycin, legrastim, mushroom polysaccharide sulfate, leptolstatin, letroxine Azole, leukemia inhibitory factor, interferon-alpha, leuprolide acetate + estrogen + progesterone, leuprolide, levamisole, liarazole, linear polyamine analogs, lipophilic diglycopeptide, lipophilic platinum compound, lissoclinamide 7, lobaplatin, phospholipid, lometrexol, lonidamine, loxoanthraquinone, loxoribine, letotecan, lutetium texaphyrin, lysofylline, lytic peptide, maytansine, mannostatin A. Malimastat, Masorol, maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors, menoril, merbarone, metyrelin, methioninase, metoclopramide, MIF inhibitors, rice Fepristone, Miltefosine, Milistim, Mitoguanidine Hydrazone, Dibromodulcitol, Mitomycin Analogues, Mitonaphthamide, Mitotoxin Fibroblast Growth Factor-Saporin, Mitoxin Anthraquinone, mofarotine, molastim, Erbitux, human chorionic gonadotropin, monophosphate lipid A+myobacterium cell wall sk, mopedalol, mustard anticancer agent, Indian ocean sponge B, branch Bacillus cell wall extract, myriaporone, N-acetyldinaline, N-substituted benzamide, nafarelin, nagrestip, naloxone + pentazocine, napavin, naphterpin, nartograstim, nedaplatin, namorubicin Star, neridronic acid, nilutamide, nisamycin, nitric oxide conditioning, nitroxide antioxidants, nitrullyn, olimerson ( ), O ⁶ -benzylguanine, octreotide, okicenone, oligonucleotides, onapristone, ondansetron, ondansetron, oracin, oral cytokine inducers, omaplatin, oxatimerone, Saliplatin, oxaunomycin, paclitaxel, paclitaxel analogues, paclitaxel derivatives, palauamine, palmitoylrhizoxin, pamidronate, panaxatriol, panomiphene, parabactin, paceptin, pegaspargase, pedexin, Sodium wood polysulfide, pentostatin, pentrozole, perfluorobromane, pefosfamide, perillyl alcohol, phenazinomycin, phenyl acetate, phosphatase inhibitors, bisibanib, pilocarpine hydrochloride, pirarubicin, Trixine, placetin A, placetin B, plasminogen activator inhibitors, platinum complexes, platinum compounds, platinum triamine complexes, porfimer sodium, morphomycin, prednisone, propyldiacril pyridone, prostaglandin J2, proteasome inhibitor, protein A-based immunomodulator, protein kinase C inhibitor, protein kinase C inhibitors, microalgae, protein tyrosine phosphatase inhibitor, purine nucleoside phosphorylase Inhibitors, purpurin, pyrazolinacridine, pyridoxylated hemoglobin polyoxyethylene conjugates, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein transferase inhibitors, ras inhibitors, ras -GAP inhibitors, desmethylreteprotine, rhenium Re 186 bisphosphonate, rhizomycin, ribozyme, RII retinamide, roxitine, romotide, roquinex, rubiginone B1, ruboxyl, safingol, saintopin, SarCNU, sarcophytol A, sargragrastim, Sdi 1 mimetic, semustine, senescence derivative inhibitor 1, sense oligonucleotide, signal transduction inhibitor, xezol Phosphate, sobuzoxan, borcasin, sodium phenylacetate, solverol, growth factor binding protein, sonamin, phosphonaspartate, spicamycin D, spiromustine, spleen pentapeptide, spongistatin 1, squalamine, stipiamide, stromelysin inhibitors, sulfinosine, potent vasoactive intestinal peptide antagonists, suradista, suramin, swainsonine, tamustine, tamoxifen meridian, taurustine, taza Rotene, tecogalan sodium, fluridine, tellurapyrylium, terminal enzyme inhibitors, temoporfin, teniposide, tetrachlorodecaoxide, tetrazomine, thaliblastine, tiacolaline, thrombopoietin, thrombopoietin mimic Thymofasin, Thymopoietin individual agonist, Thymustrinan, Thyroid-stimulating hormone, Ethylpurpurin, Tirapazamine, Titanocene dichloride, topsentin, Toremifene, Translation inhibitors, Retinoic Acid, Triethyl Acyluridine, tricitribine, trimetrexate, triptorelin, tropisetron, torosterure, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, genitourinary sinus derivatives Growth inhibitors, urokinase receptor antagonists, vapreotide, variolin B, viraresol, veratramine, verdins, verteporfin, vinorelbine, vinxaltine, vitaxin, vorozole, zanotron , geniplatin, benzyl vitamin C, and net statins ester.

Specific second active agents include, but are not limited to: Rituximab, Olimerson ( ), remicade, docetaxel, celecoxib, melphalan, dexamethasone ( ), steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temozolomide (temodar), carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Paclitaxel, taxotere, fluorouracil, leucovorin, irinotecan, Xeloda, CPT-11, interferon alfa, pegylated interferon alfa (eg, PEG INTRON-A), capecitabine, Cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, paclitaxel, vinblastine, IL-2, GM- CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonates, arsenic trioxide, vincristine, doxorubicin ( ), paclitaxel, ganciclovir, doxorubicin, estramustine phosphate sodium ( ), sulindac, and etoposide.

In certain embodiments, the second active agent is etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin, carboplatin, pemetrexed, methotrexate , Ara-C, 5-FU, wortmannin, gemcitabine, geldanamycin, or a combination thereof.

In other embodiments, the second active agent is a supportive care agent. Examples of supportive care agents are antiemetics. Specific antiemetics include, but are not limited to, phenothiazines, butyrophenones, benzodiazepines, corticosteroids, serotonin antagonists, cannabinoids, and _NK1 receptor antagonists. Examples of phenothiazine antiemetics include, but are not limited to: prochlorperazine and trimebenzine. Examples of butyrophenone antiemetics include, but are not limited to, haloperidol. Examples of benzodiazepine antiemetics include, but are not limited to, lorazepam. Examples of corticosteroid antiemetics include, but are not limited to, dexamethasone. Examples of serotonin antagonist antiemetics include, but are not limited to, ondansetron, granisetron, and dolasetron. Examples of cannabinoid antiemetics include, but are not limited to, dronabinol. Examples _of NK1 receptor antagonists include, but are not limited to, aprepitant. The dosage and dosing regimen of the antiemetic will depend on the particular indication being treated, the age and condition of the patient, and the severity of adverse effects, and can be adjusted accordingly by those skilled in the art. For example, see The Physician's Desk Reference for dosages and regimens.

6.5.2 Typical approaches to combination therapy

In certain embodiments, the methods provided herein comprise the use of SNS-595 in combination with one or more second active agents, and/or in combination with radiation therapy or surgery. Administration of SNS-595 and the second active agent to the patient may be by the same or different routes of administration simultaneously or sequentially. The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (eg, can it be administered orally and not break down before entering the bloodstream) and the disease being treated. Recommended routes of administration for the second active agent are well known in the art, see Physicians' Desk Reference (60th Edition, 2006).

In one embodiment, the second active agent is administered intravenously or subcutaneously once or twice a day at a dose of about 1 mg to about 1,000 mg, about 5 mg to about 500 mg, about 10 mg to about 375 mg, or about 50 mg to about 200mg. In one embodiment, the second active agent is rituximab, oblimersen ( ), GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, retinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, multi Ruubicin, COX-2 inhibitors, IL2, IL8, IL18, IFN, Ara-C, vinorelbine, or combinations thereof. In certain embodiments, the second active agent is etoposide, daunorubicin, actinomycin D, mitomycin C, cisplatin, carboplatin, pemetrexed, methotrexate, Ara -C, 5-FU, wortmannin, geldanamycin, gemcitabine, or combinations thereof.

In another embodiment, the present invention provides a method for treating, preventing and/or controlling hematologic malignancies, the method comprising using SNS-595 in combination with conventional treatment methods (for example, before, during or after), conventional treatment methods Including but not limited to surgery, immunotherapy, biological therapy, radiation therapy or their non-drug therapies currently used to treat, prevent or manage cancer. Without being bound by a particular theory, SNS-595 may provide additive or synergistic effects when used concurrently with conventional treatments.

In certain embodiments, the second active agent is administered concurrently with or delayed from 1 to 50 hours with SNS-595. In certain embodiments, SNS-595 is administered first, followed by a second active agent after a delay of 1-50 hours. In other embodiments, the second active agent is administered first, followed by SNS-595 after a 1-50 hour delay. In some embodiments, the delay time is 24 hours.

In one embodiment, SNS-595 may be used alone or in combination with the second active agent disclosed herein before, during or after conventional therapy 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/m ² , 1 to about 50 mg/m ² , 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 .

In another embodiment, the method provided herein comprises: a) administering SNS-595 to a patient in need thereof at a dose of about 1 mg/m ² to 75 mg/m ² , and b) administering to the patient a therapeutically effective amount of support Sexual care reagents.

In one embodiment, the second reagent is an alkylating reagent. In another embodiment, the alkylating agent is an alkylsulfonate and the cancer treated is leukemia or lymphoma. In another embodiment, the alkylsulfonate is busulfan. In another embodiment, the alkylsulfonate is busulfan and the therapeutically effective amount is at least 1 mg per day. In another embodiment, the alkylsulfonate is busulfan and the therapeutically effective amount is an oral dose of about 2 mg to 8 mg per day. In another embodiment, the alkylsulfonate is busulfan and the therapeutically effective amount is about 1 mg to 3 mg per day in oral doses.

In another embodiment, the alkylating agent is a nitrogen mustard and the cancer 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 an oral dose of about 0.1 mg/kg to about 0.2 mg/kg per day for three to six weeks. In another embodiment, the nitrogen mustard is chlorambucil and the therapeutically effective amount is a dose of 0.4 mg/kg every three to four weeks. In another embodiment, the nitrogen mustard is cyclophosphamide. In another embodiment, the nitrogen mustard is cyclophosphamide and the therapeutically effective amount is an intravenous dose of at least 10 mg/kg. In another embodiment, the nitrogen mustard is cyclophosphamide and the therapeutically effective amount is an intravenous dose of about 10 mg/kg to about 15 mg/kg every seven to ten days. In another embodiment, the nitrogen mustard is cyclophosphamide and the therapeutically effective amount is an oral dose of about 1 mg/kg to 5 mg/kg per day. In another embodiment, the nitrogen mustard is melphalan. In another embodiment, the nitrogen mustard is melphalan and the therapeutically effective amount is an oral dose of at least 2 mg per day. In another embodiment, the nitrogen mustard is melphalan and the therapeutically effective amount is an oral dose of 6 mg per day for two to three weeks, followed by an oral dose of about 2 mg to about 4 mg per day after cessation of melphalan for two to four weeks. In another embodiment, the nitrogen mustard is melphalan and the therapeutically effective amount is an oral dose of ¹⁰ mg/m2 per day four days out of every four to six weeks.

In another embodiment, the alkylating agent is a nitrosourea and the cancer treated is brain tumor, rectal cancer, Hodgkin's disease, liver cancer, lung cancer, lymphoma, or melanoma. In another embodiment, the nitrosourea is carmustine. In another embodiment, the nitrosourea is carmustine and the therapeutically effective amount is at least 150 mg/ ^m2 . In another embodiment, the nitrosourea is carmustine and the therapeutically effective amount is an intravenous dose of about 150 mg/m ² to 200 mg/m ² every six to eight weeks.

In another embodiment, the alkylating agent is a triazene and the cancer treated is Hodgkin's disease, melanoma, neuroblastoma, or soft tissue sarcoma. In another embodiment, the triazene is dacarbazine. In another embodiment, the triazene is dacarbazine and the therapeutically effective amount is an intravenous dose of about 2.0 mg/kg to about 4.5 mg/kg per day for ten days out of four weeks. In another embodiment, the triazene is dacarbazine and the therapeutically effective amount is an intravenous dose of ²⁵⁰ mg/m2 per day for five days every three weeks. In another embodiment, the triazene is dacarbazine and the therapeutically effective amount is an intravenous dose of 375 ^mg /m2 every sixteen days. In another embodiment, the triazene is dacarbazine and the therapeutically effective amount is an intravenous dose of 150 ^mg /m2 per day for five days every four weeks.

In another embodiment, the second agent is an antineoplastic antibiotic and the cancer treated is bladder cancer, breast cancer, cervical cancer, head and neck cancer, Hodgkin's disease, leukemia, multiple myeloma, Neuroblastoma, ovarian cancer, sarcoma, skin cancer, testicular cancer, or thyroid cancer. In another embodiment, the antibiotic is bleomycin. In another embodiment, the antibiotic is bleomycin and the therapeutically effective amount is at least 10 units/ ^m2 . In another embodiment, the antibiotic is bleomycin and the therapeutically effective amount is an intravenous, subcutaneous or intramuscular injection dose of ¹⁰ to ²⁰ units/m2 once or twice a week. In another embodiment, the antibiotic is actinomycin D. In another embodiment, the antibiotic is actinomycin D and the therapeutically effective amount is at least 0.01 mg/kg. In another embodiment, the antibiotic is actinomycin D and the therapeutically effective amount is an intravenous dose of about 0.010 mg/kg to about 0.015 mg/kg per day for five days every three weeks. In another embodiment, the antibiotic is actinomycin D and the therapeutically effective amount is an intravenous dose of ² mg/m2 every three or four weeks. In another embodiment, the antibiotic is daunorubicin. In another embodiment, the antibiotic is daunorubicin and the therapeutically effective amount is at least 30 mg/ ^m2 . In another embodiment, the antibiotic is daunorubicin and the therapeutically effective amount is an intravenous dose of about 30 ^mg / ^m2 to about 45 mg/m2 per day for three days. In another embodiment, the antibiotic is liposomal daunorubicin and the therapeutically effective amount is an intravenous dose of 40 mg/m2 every ^two 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/ ^m2 . In another embodiment, the antibiotic is doxorubicin and the therapeutically effective amount is an intravenous dose of about 60 ^mg / ^m2 to about 90 mg/m2 every three weeks. In another embodiment, the antibiotic is doxorubicin and the therapeutically effective amount is a weekly intravenous dose of about 15 mg/ ^m2 to about ²⁰ mg/m2. In another embodiment, the antibiotic is doxorubicin and the therapeutically effective amount is for a cycle comprising weekly intravenous doses of 30 mg/m2 for ^two weeks followed by doxorubicin withdrawal for two weeks.

In another embodiment, the second agent is an antimetabolite. In another embodiment, the antimetabolite is a folic acid analog and the cancer treated is breast cancer, head and neck cancer, leukemia, lung cancer, non-Hodgkin's lymphoma or osteosarcoma. In another embodiment, the folate analog is methotrexate. In another embodiment, the folate analog is methotrexate and the therapeutically effective amount is at least 2.5 mg. In another embodiment, the folate analog is methotrexate and the therapeutically effective amount is an oral dose of 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 a twice weekly dose of about 5 mg/ ^m2 to about ²⁵ mg/m2. In another embodiment, the folic acid analog is methotrexate and the therapeutically effective amount is a weekly intravenous dose of 50 mg/m2 every ^two to three weeks. In another embodiment, the folate analog is pemetrexed. In another embodiment, the folate analog is pemetrexed, and the therapeutically effective amount is at least 300 mg/ ^m2 . 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 every two or three weeks. In another embodiment, the folic acid analog is pemetrexed and the therapeutically effective amount is an intravenous dose of 500 mg/m2 every ^three weeks.

In another embodiment, the antimetabolite is a purine analog and the cancer treated is rectal cancer, leukemia or myeloid cancer. 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 mercaptopurine, and the therapeutically effective amount is an oral dose of about 1.5 mg/kg to about 5 mg/kg per day. In another embodiment, the purine analog is thioguanidine. In another embodiment, the purine analog is thioguanidine, and the therapeutically effective amount is at least 2 mg/kg. In another embodiment, the purine analog is thioguanidine, and the therapeutically effective dose is an oral dose of about 2 mg/kg to 3 mg/kg per day.

In another embodiment, the antimetabolite is an adenosine analog and the cancer treated is leukemia or lymphoma. In another embodiment, the adenosine analog is cladribine. In another embodiment, the adenosine analog is cladribine and the therapeutically effective amount is at least 0.09 mg/kg. In another embodiment, the adenosine analog is cladribine and the therapeutically effective amount is an intravenous dose of 0.09 mg/kg per day for seven days. In another embodiment, the adenosine analog is cladribine and the therapeutically effective amount is an intravenous dose of ⁴ mg/m2 per day for seven 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/m2 every other week. In another embodiment, the adenosine analog is pentostatin, and the therapeutically effective amount is a dose of 4 mg/m ² administered intravenously every three weeks.

In another embodiment, the antimetabolite is a pyrimidine analog and the cancer treated is bladder cancer, breast cancer, rectal cancer, esophageal cancer, head and neck cancer, leukemia, liver cancer, lymphoma, ovarian cancer , pancreatic, skin or stomach cancer. In another embodiment, the pyrimidine analog is cytarabine. In another embodiment, the pyrimidine analog is cytarabine and the therapeutically effective amount is at least 100 mg/m ² . In another embodiment, the pyrimidine analog is cytarabine and the therapeutically effective amount is an intravenous dose of 100 ^mg /m2 per day for seven 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 2000 ^mg /m2. In another embodiment, the pyrimidine analog is capecitabine and the therapeutically effective amount is an oral dose of about 1200 ^mg / ^m2 to about 1300 mg/m2 twice daily for 14 days. In another embodiment, the pyrimidine analog is capecitabine and the therapeutically effective amount is a three-week cycle in which 1250 mg/ ^m2 is dosed twice daily for 14 days followed by a one-week rest. In another embodiment, the pyrimidine analog is fluorouracil. In another embodiment, the pyrimidine analog is fluorouracil and the therapeutically effective amount is at least 10 mg/kg. In another embodiment, the pyrimidine analog is fluorouracil and the therapeutically effective amount is an intravenous dose of about 300 ^mg / ^m2 to about 500 mg/m2 per day for at least three days. In another example, the pyrimidine analog is fluorouracil, and the therapeutically effective amount is an intravenous dose of about 12 mg/kg per day for 3 to 5 days. In another embodiment, the pyrimidine analog is fluorouracil and the therapeutically effective amount is a weekly intravenous dose of about 10 mg/kg to about 15 mg/kg.

In another embodiment, the antimetabolite is a substituted urea and the cancer treated is head and neck cancer, leukemia, melanoma or ovarian cancer. In another embodiment, the substituted urea is hydroxyurea. In another embodiment, the substituted urea is hydroxyurea and the therapeutically effective amount is at least 20 mg/kg. In another embodiment, the substituted urea is hydroxyurea and the therapeutically effective amount is an oral dose of 80 mg/kg every three days. In another embodiment, the substituted urea is hydroxyurea and the therapeutically effective amount is an oral dose of about 20 mg/kg to about 30 mg/kg per day.

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, sarcoma, testicular, or uterine cancer. In another embodiment, the platinum coordination complex is carboplatin. In another embodiment, the platinum coordination complex is carboplatin and the therapeutically effective amount is at least 300 mg/ ^m2 . In another embodiment, the platinum coordination complex is carboplatin and the therapeutically effective amount is a dose of at least 300 ^mg /m2 every four weeks. In another embodiment, the platinum coordination complex is carboplatin, and the therapeutically effective amount is a dose of 300 mg/m ² every four weeks. In another embodiment, the platinum coordination complex is carboplatin and the therapeutically effective amount is a dose of at least 360 ^mg /m2 every four weeks. In another embodiment, the platinum coordination complex is cisplatin. In another embodiment, the platinum coordination complex is cisplatin and the therapeutically effective amount is at least 20 mg/ ^m2 . In another embodiment, the platinum coordination complex is cisplatin and the therapeutically effective amount is an intravenous dose of ²⁰ mg/m2 per day for four to five days out of every three to four weeks. In another embodiment, the platinum coordination complex is cisplatin and the therapeutically effective amount is an intravenous dose of 50 mg/m2 every ^three weeks. In another embodiment, the platinum coordination complex is oxaliplatin. In another embodiment, the platinum coordination complex is oxaliplatin and the therapeutically effective amount is at least 75 mg/ ^m2 . In another embodiment, the platinum coordination complex is oxaliplatin and the therapeutically effective amount is from about 50 mg/m ² to about 100 mg/m ² . In another embodiment, the platinum coordination complex is oxaliplatin and the therapeutically effective amount is about 50 mg/ ^m2 to about 100 mg/m2 as an IV infusion every ^two weeks. In another embodiment, the platinum coordination complex is oxaliplatin and the therapeutically effective amount is an IV infusion of about 80 ^mg /m2 to about 90 mg/m2 every ^two weeks. In another embodiment, the platinum coordination complex is oxaliplatin and the therapeutically effective amount is 85 mg/m2 IV infusion over ^two hours every two weeks.

In another embodiment, the second agent is a topoisomerase II inhibitor and the cancer being treated is Hodgkin's disease, leukemia, small cell lung cancer, sarcoma, or testicular cancer. In another embodiment, the topoisomerase II inhibitor is etoposide. In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is at least 35 mg/ ^m2 . In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is from about 50 mg/m ² to about 100 mg/m ² . In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is about 35 mg/m ² to about 50 mg/m ² intravenously per day at least three times every three weeks or five days out of four weeks Administration dose. In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is about 50 mg/m to about 100 ^mg /m intravenously every ^three weeks or five days out of four at least three times per day. Administration dose. In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is an oral dose of about 100 ^mg /m2 per day at least three times every three weeks or five days out of four weeks. In another embodiment, the topoisomerase II inhibitor is teniposide. In another embodiment, the topoisomerase II inhibitor is teniposide, and the therapeutically effective amount is at least 20 mg/ ^m2 . In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is 100 ^mg /m2 per week. In another embodiment, the topoisomerase II inhibitor is teniposide, and the therapeutically effective amount is 100 mg/m ² administered twice a week. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is from about 20 mg/m ² to about 60 mg/m ² per day for five days. In another embodiment, the topoisomerase II inhibitor is teniposide, and the therapeutically effective amount is about 80 mg/m ² to about 90 mg/m ² per day for five days.

6.6 Pharmaceutical composition and dosage form

The methods provided by the present invention use a pharmaceutical composition containing SNS-595 and a pharmaceutically acceptable carrier, such as a diluent or adjuvant, or SNS in combination with other active ingredients such as another anticancer agent -595. In clinical practice, SNS-595 can be administered by any conventional route, including but not limited to oral, parenteral, rectal or by inhalation (eg, in aerosol form) route. In some embodiments, the compositions of the invention are acidic compositions (eg, pH<4). Without being bound by a particular theory, the acidic composition may provide the right balance between increasing the solubility of SNS-595 and desirable drug properties such as improving patient comfort by reducing irritation at the site of delivery.

In one embodiment, SNS-595 is administered by IV injection. Compositions for parenteral administration may be emulsions or sterile solutions. Propylene glycol, polyethylene glycol, vegetable oil (especially olive oil), or injectable organic ester (such as ethyl oleate) can be used as a solvent or carrier when used. These compositions may also comprise adjuvants, especially wetting agents, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be performed in various ways, such as using bacteriological filters, radiation or heat. They can also be prepared in the form of sterile solid compositions which can be dissolved in sterile water or any other injectable sterile medium for use.

The composition can also be an aerosol. For use in liquid aerosol form, the composition may be a stable sterile solution or a solid composition soluble in pyrogen-free sterile water, physiological saline or any other pharmaceutical carrier at the time of use. For direct inhalation in dry aerosol form, the active ingredient is finely divided and combined with a water-soluble solid diluent or carrier (eg dextran, mannitol, lactose).

The pharmaceutical compositions can be prepared in discrete, single unit dosage forms. Pharmaceutical compositions and dosage forms comprise SNS-595 and one or more excipients.

Pharmaceutical compositions and dosage forms can also contain one or more additional active ingredients. Examples of optional second or additional 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 contain a prophylactically or therapeutically effective amount of SNS-595, and one or more typical pharmaceutically acceptable carriers or excipients. The term "carrier" refers to a diluent, adjuvant (ie, Freund's adjuvant (complete and incomplete)), excipient or vehicle with which a drug is used. Such pharmaceutical carriers can be sterile liquids, including, for example, water or oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. In certain embodiments, water serves as a carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose solutions, as well as glycerol, can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.

Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the pharmaceutical arts, non-limiting examples of which include: starch, dextrose, lactose, sucrose, gelatin, maltose, rice, flour, chalk, silica gel, sodium stearate, glycerol monohard Fatty acid esters, talc, sodium chloride, dry skim milk powder, glycerin, propylene, glycol, water, ethanol, etc. Whether a particular excipient is suitable for combination with a pharmaceutical composition or dosage form depends on various factors well known in the art including, but not limited to, the manner in which the dosage form will be administered to an individual and the particular active ingredients in the dosage form. The composition or single unit dosage form, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

The invention further provides pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate of decomposition of the active ingredient. Such compounds are referred to herein as "stabilizers" and 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 be in the form of solutions, suspensions, emulsions, powders and the like. Such compositions and dosage forms contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, and an appropriate amount of carrier to provide a form suitable for administration to an individual. The dosage form should match the mode of administration. In one embodiment, the pharmaceutical composition or single unit dosage form is sterile and in a form suitable for administration to an individual, such as an animal individual or a mammalian individual and a human individual.

The pharmaceutical compositions provided herein are formulated to be compatible with the desired mode of administration. Examples of modes of administration include, but are not limited to, parenteral, such as intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, topical, mucosal, intratumoral, synovial administration, and rectal administration . In particular embodiments, the compositions are formulated in a conventional manner suitable for intravenous, subcutaneous, intramuscular, intranasal or topical administration to humans. In embodiments, the pharmaceutical compositions are formulated in a conventional manner suitable for subcutaneous administration to humans. Typically, compositions for intravenous administration are sterile isotonic aqueous buffered solutions. The composition, if desired, may also contain a solubilizer and a local anesthetic such as lidocaine to relieve pain at the site of injection.

Examples of dosage forms include, but are not limited to: liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (such as crystalline or amorphous solids) that can be reconstituted into liquid dosage forms suitable for parenteral administration to a subject .

The composition, shape and type of dosage forms provided by the invention will vary according to their use. For example, a dosage form used for the first treatment of a disease may contain higher doses of one or more active ingredients contained in the dosage form than a dosage form used for the maintenance treatment of the same disease. Likewise, a parenteral dosage form may contain smaller doses of one or more of the active ingredients contained in the dosage form than an oral dosage form used to treat the same disease or condition. Differences in these and other aspects among particular dosage forms of the invention will be apparent to those skilled in the art. See: Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000).

The ingredients of the compositions provided herein are typically provided alone or in combination in unit dosage form, for example, lyophilized powders or dry concentrates in hermetically sealed containers such as ampoules or sachets showing the quantity of active agent. When the composition is administered by infusion, it can be dispensed with an infusion bottle containing sterile medicinal water or physiological saline. When the composition is administered by injection, an ampoule of sterile water or saline for injection can be provided to allow the ingredients to be mixed prior to administration.

Typical dosage forms provided by this invention contain a daily or weekly amount of about 1 mg/ ^m2 to about 75 mg/ ^m2 of SNS-595, taken as a single daily morning dose or in divided doses with food. Particular dosage forms provided by the invention contain about 1, 3, 6, 9, 12, 15, 18, ²¹ , 24, 27 or 30 mg/m2 of SNS-595.

6.6.1 Parenteral dosage forms

Parenteral dosage forms can be administered to patients by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration will usually circumvent patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or can be sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions for injection, dry products that can be dissolved or suspended in pharmaceutically acceptable carriers for injection, suspensions and emulsions for injection.

Carriers suitable for parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: USP Water for Injection; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; Miscible vehicles such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, such as but not limited to: corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate esters and benzyl benzoate.

Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms. For example, cyclodextrins and their derivatives can be used to increase the solubility of active ingredients. See US Patent No. 5,134,127, which is incorporated herein by reference.

6.6.2 Topical and mucosal dosage forms

In certain embodiments, the present invention provides dermal, topical and mucosal dosage forms. The dosage forms for skin administration, topical administration and mucosal administration in the present invention include, but are not limited to: ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions or other Any dosage form known in the art. See, 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 the treatment of mucosal tissues within the oral cavity are available as mouthwashes or oral gels. Further, transdermal dosage forms include "reservoir" or "matrix" patches, which are applied to the skin and remain in place for a period of time to allow penetration of the desired dose of active ingredient.

Excipients (such as carriers and diluents) and other materials suitable for use in topical and mucosal dosage forms of the invention are well known to those skilled in the pharmaceutical art and depend on the particular pharmaceutical composition or dosage form being administered. organize. In fact, typical excipients include, but are not limited to: water, acetone, ethanol, ethylene glycol, propylene glycol, 1,3-butanediol, isopropyl myristate, isopropyl palmitate, mineral oil, and Mixtures thereof for use in forming sterile pharmaceutically acceptable solutions, emulsions or gels. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms, if desired. Examples of the above additional ingredients are known in the art, see Remington's Pharmaceutical Sciences, 20th Edition, Mack Publishing, Easton PA (2000).

The pH of a pharmaceutical composition or dosage form can also be adjusted to increase delivery of one or more active ingredients. Likewise, the polarity, ionic strength, or tonicity of solvent carriers can be adjusted to enhance delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle, emulsifying agent or surfactant for the formulations and as delivery-enhancing or penetration-enhancing agents. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the final composition.

7. Example

Certain embodiments provided by the present invention are illustrated by the following non-limiting examples.

Embodiment 1: The pharmaceutical composition that is suitable for injection or intravenous infusion

The acidic composition (<pH 4) can provide the right balance between increasing the solubility of SNS-595 and desirable drug properties such as increased patient comfort through less irritation to the site of administration. An illustrative example of a suitable composition includes: 10 mg SNS-595 per mL of 4.5% aqueous sorbitol solution adjusted to pH 2.5 with methanesulfonic acid. A scheme for preparing the above solution is as follows to prepare 100mg/10mL as an example: add 100mg of SNS-595 and 450mg of D-sorbitol to distilled water; make the volume to 10mL; adjust the pH of the final solution to 2.5 with methanesulfonic acid. The resulting composition can also be freeze-dried. The freeze-dried dosage form can be dissolved in sterile water to obtain a suitable concentration before use.

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

The safety and efficacy of SNS-595 were investigated in two dose-escalating studies. As described below, SNS-595 has demonstrated favorable safety and anticancer activity in patients with refractory solid tumors.

SNS-595 was administered as an IV infusion over 10 minutes to patients with advanced solid tumors using 2 regimens. In the first regimen (A), SNS-595 was administered weekly for three weeks followed by at least 7 days of rest (qwkx3). In the second regimen (B), SNS-595 was administered every three weeks (q3wk).

In both regimens, the initial dose of SNS-595 was 3 mg/m ² , and the dose was gradually increased in sequential cohorts of 3. The dose was doubled until the first relevant adverse event reached or exceeded grade 2 or the first abnormal laboratory value, and then the dose was gradually increased in a modified Fibonacci sequence mode.

No other treatment, such as mitomycin-C, BCNU, nitrosourea drugs, or MAb therapy, was used within 42 days of the study.

In Study A, 21 patients (9 males, 12 females) were divided into 6 groups for treatment (dose range 3-24 mg/ ^m2 /wk). In Study B, 41 patients (25 males, 16 females) were divided into 9 groups for treatment (dose range 3-75 mg/ ^m2 /wk). Median age 61 years (Study A) and 59 years (Study B), sex 12 female/9 male (Study A), 16 female/25 male (Study B), all patients had European Cooperative Oncology functional status score (ECOG PS) 0-2 level. Selected patients had refractory solid tumors and good organ function. Table 1 provides the demographics of the patients in the two study groups. Table 1: Patient Demographics

Table 2 is a list of the tumor types treated in the two studies.

Table 2: Tumor Types Treated

qwk×3 wxya total N (#treatment) twenty one 41 62 ovarian cancer 1 9 10 colon cancer 3 6 9 NSCLC 0 6 6 pancreatic cancer 3 2 5 kidney cancer 1 4 5 melanoma 1 3 4 Adenocarcinoma (of unknown etiology) 0 3 3 breast cancer 2 0 2 sarcoma 0 3 3 Cholangiocarcinoma 1 1 2 Mesothelioma 2 0 2 neuroendocrine carcinoma 1 1 2 Bladder Cancer 0 1 1 Leiomyosarcoma 1 1 2 Liposarcoma 1 0 1 Müllerian carcinoma 0 1 1

nasopharyngeal carcinoma 1 0 1 salivary gland cancer 1 0 1 Small Cell Lung Cancer 1 0 1 spindle cell carcinoma 1 0 1

For patients dosed on schedule A, PK samples were collected on treatment days 1 and 15 and analyzed by noncompartmental assays. SNS-595 plasma concentrations were determined by confirmatory LC-MS/MS analysis. AUC (area under the curve) increased proportionally with dose and the mean AUC _inf ranged from 1.7 to 15 μg*hr/ml correspondingly at dose levels of ³ to 24 mg/m2. The terminal half-life is approximately 19 hours. No drug-dependent changes in pharmacokinetic parameters were observed after three weeks of administration. Figure 1 depicts the change in plasma concentration of SNS-595 over time in different patient groups. Table 3 provides the pharmacokinetic parameters for patients dosed according to schedule A.

Table 3: Mean Pharmacokinetic Parameters at Weeks 1 and 3

Kinetic parameters were evaluated in 36 patients (21 heavily pretreated patients and 15 lightly pretreated patients) following single dose administration of ³ to 75 mg/m2 of patients treated according to regimen B. Clearance (CL), volume of distribution, and terminal half-life (T _1/2 ) remained unchanged in all patients up to 48 mg/m ² . In lightly pretreated patients, the PK parameters remained unchanged up to 75 mg/m ² . CL was 2.2 L/hr/m ² (range 1.0-3.8 L/hr/m ² ), volume of distribution was 53 L/m ² (range 31-76 L/m ² ), and T _1/2 was about 21 hours (range 13-49 hours). Drug exposures were similar in heavily pretreated and lightly pretreated patients and increased linearly with dose up to dose escalation to 48 mg/m ² . Mildly pretreated patients exhibited greater drug exposure than dose-linear AUC (area under the curve) at doses up to the 60 mg/ ^m2 dose level. Table 4 shows the pharmacokinetic parameters for patients dosed according to schedule B.

Table 4: Pharmacokinetic parameters at week 3

In Study A, pharmacokinetic assessments were performed on Days 1 and 15 (after the first and third dose), as shown in Table 5, SNS-595 showed highly reproducible pharmacokinetics and low interpatient variability. No accumulation or changes in pharmacokinetic parameters were observed after repeated dosing. In the 8-fold dose range (1.6-15μg-hr/mL), the drug exposure increased linearly, and the mean values of clearance (CL), volume of distribution (Vss) and T _1/2 were 2L/hr/m ² and 48L, respectively /m ² , 19 hours, and no change from day 1 to day 15.

In Study B, pharmacokinetic parameters were assessed on the first day after the first dose; drug exposure increased linearly (1.1-46 μg hr/mL) over a 24-fold dose range, CL, Vss, and T ₁ The average values for _/2 were 2 L/hr/m ² , 53 L/m ² , and 21 hours, respectively.

Table 5 provides the mean pharmacokinetic parameters of the two study groups

Table 5: Mean values of pharmacokinetic parameters for wk 1 and wk 3

Figure 11 shows the dose linearity in Studies A and B.

Table 6 provides data on the hematological effects observed in the study.

Table 6: Hematological Effects

n = number of patients in the cohort

*Absolute neutrophil count (cells/μL) ≤ 500 for more than 7 days

As used herein, the term "maximum tolerated dose" or "MTD" refers to the dose level of SNS-595 below which dose-limiting toxicity (DLT) occurs in ≥ 2 out of 6 patients. The term "severely pretreated" or "HP" refers to patients who have previously received >6 courses of alkylating agents, chemotherapy, or >2 courses of platinum, mitomycin-C, or any nitrosourea, or >25% XRT of bone in patients. The term "mildly pretreated" or "MP" patients refers to patients who do not meet the definition of HP (see Tolcher et al., JCO 2001; 19:2937-2947).

Here, dose-limiting toxicity (DLT) refers to absolute neutrophil count (ANC) ≤ 500 for more than 7 days or febrile neutropenia or platelet nadir < 25000 or bleeding or non-hematological adverse reactions (AE) ≥ Grade 3 (as described in Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE v3.0)), where adverse reactions require >14 days of dose delay.

Tables 7-9 provide the safety data of the two groups of studies.

Table 7: Common (>10% of Patients) Adverse Reactions

*Number of patients with score grade ≥3/Number of patients with all grades

Table 8: Hematological Effects

Table 9: Serious Adverse Events (SAEs) Possibly Related to Study Drug

As can be seen from the data, neutropenia was the dose-limiting toxicity (DLT) in both studies. In Study ^A , the first patient experienced a dose-limiting toxicity (DLT) of neutropenia at a dose level of 24 mg/m2. Five patients were then treated with a dose of 18 mg/m2, ^two of whom developed neutropenic DLTs. In Study B, dose-limiting toxicity (DLT) of grade 4 neutropenia over ⁷ days was observed at a dose of 60 mg/m2 in heavily pretreated patients. In lightly pretreated patients, dose-limiting toxicity occurred at a dose of 75 mg/ ^m2 .

In Study A, the MTD was 15mg/m ² ; in Study B, the MTD was 48mg/m ² for heavily pretreated patients (HP) and 60mg/m ² for mildly pretreated patients (MP).

Two patients in each study had grade 4 thrombocytopenia; nonhematologic toxicities were mostly grade 1/2, and there were no dose-limiting gastrointestinal or neurotoxicities.

Table 10 provides the clinical activity of SNS-595 in the two groups of studies. For Study A, the best response included a partial response (PR) in one patient and stable SD in six patients (range 16-24 weeks). For Study B, the best response included one PR and 11 SD (range 18-58 weeks). Table 11 provides detailed data on partial responses/minimal responses in the two groups of studies.

Table 10: Clinical Activity

Table 11: Partial/Minor Reaction (PR/MR) Detailed Data

Significantly, SNS-595 demonstrated clinical activity in patients with advanced solid tumors, including partial responses in two patients and stable disease in seventeen patients over a 16-week period.

As can be seen from the data, SNS-595 was well tolerated, with both once-weekly and three-weekly dosing regimens showing clinical activity. The dose-limiting toxicity was nonaccumulative neutropenia. SNS-595 exhibited predictable pharmacokinetics with low intra-patient and inter-patient variability. No changes in pharmacokinetic parameters were observed after repeated dosing.

According to the description of this embodiment, the effective therapeutic dosage for patients with solid tumors includes 48 mg/m ^{2 every three weeks and 15 mg/m 2 every} week.

Example 3: High Content Screening and Microscopy Methods

Cells were plated in a near confluent colony and grown for 36 hours. Cells are then treated with a given concentration of compound for a given time. Cells were fixed with 4% formaldehyde and permeabilized with 0.1% triton. Cells were exposed to a 1:100 dilution of the primary antibody in 10% FBS/PBS for 1 hour at 25°C (anti-pATM-Chemicon, anti-gH2AX-Cell Signaling Technology). Cells were exposed to a 1:100 dilution of the secondary antibody in 10% FBS/PBS for 1 hour at 25°C. Hoechst staining was performed in 10% FBS/PBS at a concentration of 500 ng/ml. High-content screening was analyzed with a Cellomics Arrayscan instrument using a point detection algorithm.

Figure 2 shows HCT116 cells administered with various compounds for 6 hours. Cells were then fixed and analyzed for protein phosphorylation status (gH2AX images by fluorescence microscopy, pATM images by ArrayScan VTi). As can be seen from the figure, SNS-595 treatment resulted in the formation of nuclear foci.

Figures 3-5 illustrate the dose and time dependence of nuclear foci formation. Cells were then fixed for phospho-ATM analysis. Cellomics Arrayscan software was used to identify lesions (Figure 3, orange dots). Quantification of lesions can be carried out by measuring the fluorescence intensity of lesions (Figure 4) or the functional relationship between cells with more than 2 lesions, time and SNS-595 concentration (Figure 5).

Embodiment 4: MTT colorimetry and sensitization treatment

Cells were plated in 96-well plates at 4000 cells/well, cultured for 24 hours and then treated with compounds for 72 hours. Cells were then incubated with 5% MTT for 1-2 hours and lysed. MTT colorimetric analysis was performed at a wavelength of 570nm and _EC50 was determined by linear regression analysis.

Sensitization is performed by various chemical treatments. Cells were pretreated with chemosensitizers for 16 hours, and then drugs were added (concentrations as follows: caffeine, 2 mM; DNAPK inhibitor II (homemade), 10 uM; and wortmannin, 100 nM). Data are provided in Table 12. Sensitization was determined by the fold reduction in _EC50 cytotoxicity determined by MTT colorimetry.

The data suggest that SNS-595 displays a unique PIKK dependence. Although both ATM/ATR and DNAPK were activated after treatment with SNS-595, only DNAPK was required for DNA repair and cells were sensitive to SNS-595 only when DNAPKcs activity was reduced. ATM/ATR mediates G2-gate capture. Loss of the G2-checkpoint does not sensitize cells to SNS-595. In contrast to SNS-595, all other DSB inducers tested utilized ATM/ATR for repair and showed sensitivity when either ATM or DNAPK activity was inhibited.

Example 5: Repair of DNA damage in the absence of the DNA-damage sensitive kinases ATM and ATR

HCT-116 cells were treated with 10 mM SNS-595 or 10 mM etoposide in the presence or absence of caffeine for 6 hours. Compounds were then removed and cells were allowed to recover for 16 hours. Cells were analyzed for gH2AX foci before and after drug washout. As shown in Figure 6, DNA damage induced by SNS-595 can be easily repaired in the absence of ATM and ATR. In contrast, other drugs, such as etoposide, require the use of ATM and ATR for DNA repair. Caffeine treatment inhibits the activity of ATM and ATR, resulting in defects in homologous recombination, nucleotide excision repair, and mismatch repair.

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

MO59K (wt) and MO59J (DNAPKcs(-/-)) cells were treated with 10 mM SNS-595 or 10 mM etoposide for 6 hours. Compounds were then removed and cells were allowed to recover for 16 hours. Cells were analyzed for gH2AX foci before and after drug washout. As shown in Figure 7, SNS-595 damage was not effectively repaired in the absence of DNA-PK. In contrast, damage induced by other drugs, such as etoposide, can be easily repaired.

Example 7: Combination studies of SNS-595

Cell lines and cell culture: HCT1116 and NCI-H460 cell lines were obtained through ATCC. SKOV3(p53-/-) and SKOV3(p53+/+) were obtained from the laboratory of Dr. George Stark, Lerner Institute of the Cleveland Clinic. All cell lines were cultured in RPMI medium supplemented with 10% FBS, 1% sodium bicarbonate solution and 1% antibiotic solution (Cellgro).

MTT colorimetric assay: Cells were plated in 96-well plates at 4000 cells/well (except for SKOV3(p53-/-), which were plated at 8000 cells/well), incubated for 24 hours and then treated with compounds. Compound treatment was continued for 72 hours. The cells were then treated with 5% MTT for 1-2 hours and the cells were lysed. Colorimetric analysis was performed at a wavelength of 570 nm. The specific gravity of dead cells is determined by the following formula:

Proportion of dead cells=1-[absolute value of sample well-absolute value of control group without cells

mean of ]/[mean of absolute values of DMSO-only control group - no fine

mean of the absolute value of the control group]

Protocol studies: When compounds were administered in a protocol that included a wash step, cells were washed with 100 μl of fresh warm medium for 30 minutes, followed by another round of washes 90 minutes later.

Statistical Analysis: The data (dead cell fraction) were analyzed with Calculsyn.V2 (Biosoft) and expressed here as the combined index value at fraction affected (Fa) = 0.5. All data are indicated with 95% confidence intervals for the mean with error bars.

A combination was considered additive if a combination index of 0.85-1.2 was obtained. The combination was considered synergistic if a combination index of less than 0.85 was obtained. The combination was considered antagonistic if a combination index greater than 1.2 was obtained. See Figures 8-10.

As can be seen in Figures 8a-8d, simultaneous administration of SNS-595 and various cytotoxins to the HCT116 colon cancer cell line (8a, 8b and 8c) and the H460 lung cancer cell line 8(d) showed a clear synergy or at least an additive effect. Composite index. As can be seen in Figure 9, co-administration of SNS-595 with some DNA damaging agents and antimetabolites, no significant change in combination index was seen in SKOV3 ovarian cancer cell lines with or without p53 expression.

As shown in Figures 10a-10d, when SNS-595 was coadministered with docetaxel (see Figures 10a and 10c) and gemcitabine (see Figures 10b and 10d) to HCT116 colon cancer cells, or SNS-595 was delayed for 24 hours When administered, SNS-595 may be antagonistic. Administration of SNS-595 first (see 10c and 10d, co-administration and 24 hours) may have reduced antagonism relative to other agents administered first (see Figures 10a and 10b, co-administration and 24 hours). Additivity, or possibly synergy, was obtained when cells were treated with the first agent, washed and then treated with the second agent (see Figures 10a-d, 2 hour wash and 24 hour wash).

Example 8: Detection of MTT cell viability—leukemia cells:

The following cell lines were used for this assay: HL-60 (promyelocytic leukemia); Jurkat (T-cell leukemia); CCRF-CEM (lymphoblastic leukemia); CEM/C2 (camptothecin-resistant derivative of CCRF-CEM things).

Cells were plated in 96-well plates at 3000 cells/well and cultured for 16 hours. Compound dilutions were made from 10 mM in 3-fold dilutions in DMSO. A 1:100 dilution titration was performed in culture medium to obtain final compound concentrations. The 96-well plate was aerated and compound dilutions in culture medium (100 ml/well) were added. MTT assays were performed after 72 hours of incubation at 37°C. Briefly, 20 ml of MTT solution was added to each well. Cells were incubated at 37°C for 1-2 hours. Cell lysis was performed by adding 100 ml/well of cell lysis buffer and MTT was solubilized overnight at 37°C. Plates were read using the absorbance method at 570 nm with a spectromax instrument. _IC50s were calculated using regression analysis in GraphPad Prism (data are provided in Table 13). As shown in Table 13, SNS-595 exhibited potent antiproliferative activity against the tested blood cell lines.

Table 13: _IC50 values of different cell lines

Example 9: Xenograft Model

LM3-Jck human malignant lymphoma tumor parietal lobe (2-3 mm2) was subcutaneously transplanted into nude mice. Tumors were allowed to grow to approximately 7-14 mm in diameter. Mice were paired and divided into no treatment group, irinotecan treatment group (100mg/kg, IV, q4d×3), doxorubicin treatment group (12mg/kg, IV, single administration), etoposide treatment group ((12 mg/kg, IV, q1d×5)), and SNS-595 treatment groups (25 and 20 mg/kg, IV, q7d×5). A mean group body weight loss of 30% or less and no more than 1 death in 6 treated animals was defined as acceptable toxicity. The anticancer activity of the drugs was assessed on day 21 from the initial administration.

The parietal lobe of acute lymphoblastic leukemia tumor of 2-3 mm2 was subcutaneously transplanted into nude mice. Tumors were allowed to grow to approximately 8-20 mm in diameter. Mice were paired and divided into no treatment group, irinotecan treatment group (100mg/kg, IV, q4d×3), doxorubicin treatment group (12mg/kg, IV, q7d×3), etoposide treatment group ( (12mg/kg, IV _, q1d×5)), and SNS-595 treatment groups (25 and 20mg/kg, IV, q7d×5). A mean group body weight loss of 30% or less and no more than 1 death in 6 treated animals was defined as acceptable toxicity. The anticancer activity of the drugs was assessed on day 20 or 21 from initial dosing. Table 14 provides tumor inhibition (TI) and survival data in CCRF-CEM and LM3-Jck xenograft models.

Table 14: Comparison of anticancer activity between SNS-595 and other anticancer drugs

As can be seen from the data in Table 14, the tumor completely regressed when administered at a dose of 20 and 25 mg/kg, and SNS-595 showed strong anticancer activity against LM-3Jck malignant lymphoma. In CCRF-CEM and LM3-Jck xenograft models, SNS-595 showed tumor inhibition rate (IR) comparable to irinotecan but better than etoposide and doxorubicin.

Example 10: Bone Marrow/Cytology Analysis

SNS-595 was administered intravenously at doses of 5, 10, 15 or 20 mg/kg to female CD-1 mice on days 0 and 4. Blood was drawn for hematology analysis on days 6, 8 and 12 after the initial injection. Femurs were harvested on day 6 and mounted on Streck and H&E stained prior to analysis of bone marrow cells. Bone marrow isolated from femurs showed a dose-dependent decrease in cellularity two days after re-administration of SNS-595. When the dose was 20mg/kg, the cellular structure decreased to 7.5%, and the circulating neutrophils decreased from 1244±55 cells/mL blood before administration to the nadir 51±24cells/mL blood on the 8th day. Absolute neutrophil counts subsequently rebounded and quickly returned to normal levels. Total WBCs also nadir on day 8 but also returned to normal levels. The dose-dependent reduction in hematopoietic myeloid cellularity is shown in FIG. 14 . The figure shows the cellular structure in the bone marrow at day six after the initial injection of different doses of SNS-595.

Figure 15 shows neutrophil numbers on days 4, 6, 8 and 12 after the initial injection. As can be seen from Figure 16, peripheral neutrophils decreased significantly on day 8 in all SNS-595 dose groups. As can be seen in Figure 17, animals receiving 20 mg/kg SNS-595 injection had less than 50 cells/ml on day 8.

Figure 18 shows a mild platelet response at day 8 to SNS-595 injection. Figure 19 shows the percent change in body weight at different times after administration of SNS-595. Figure 20 shows bone marrow rebound on day 12 after injection of 20 mg/kg of SNS-595.

Example 11: Clinical trial data of SNS-595 in patients with malignant hematological diseases

Slow IV bolus injection of SNS-595 in patients with advanced or refractory acute leukemia. Diagnoses included AML (19 patients) and ALL (2 patients). All patients had disease that was resistant to previous therapy or relapsed after previous therapy (pre-protocol median 3 (range 1-6)).

A total of 21 patients (9 males and 12 females; median age = 64 years, range 21-80 years) were divided into five groups and treated with the two regimens. In the first regimen (A), SNS-595 was administered once a week for three weeks, followed by a 7-day rest (qwk×3). In the second regimen (B), SNS-595 was administered twice a week for two weeks (biwk x 2). The cycle duration for both regimens including the drug-free period was 28 days. A total of 3 doses per cycle were administered in program A, and a total of 4 doses per cycle were administered in program B. If the patient's condition is stable or better, the treatment cycle can be increased. The initial dose was 18 mg/m ^{2 in regimen A and 9 mg/m 2 in} regimen B, and the dose was gradually increased according to the group. Groups of 3-6 patients had their doses escalated by a modified Fibonacci sequence pattern.

Pharmacokinetic analysis was performed on plasma samples collected in Cycle 1. Table 15 provides some pharmacokinetic parameters from the study.

Table 15: Pharmacokinetic parameters

*Similar PK after dosing on days 4, 8 and 11

SNS-595 plasma concentrations were determined by confirmatory LC-MS/MS analysis. Blood exposure increased linearly for the first ^two dose levels in each regimen, with an AUC of 4.3-17.8 μghr/mL at doses of 9-27 mg/m2. CL, Vss, and terminal half-life were similar to solid tumor patients with mean values of ~2L/hr/ ^m2 , 58L/ ^m2 , and 23 hours, respectively. Table 15 shows that six patients across all dose groups had greater than 50% reduction in peripheral blasts after treatment cycle 1 .

No dose-limiting toxicity (DLT) was observed up to 27 mg/m ² in the qwk×3 regimen or up to 13.5 mg/m ² in the biwk×2 regimen. Non-dose-limiting toxicities included nausea/vomiting, diarrhea, and mucositis. Only one case of grade 4 febrile leukopenia was observed.

In scheme A (qwk×3), the dosages of other patient groups were 38 mg/m ² and 50 mg/m ² respectively. In plan B (biwk×2), the doses of other patient groups were 19 mg/m ² and 25 mg/m ² respectively. The safety data are shown in Table 16.

Table 16: Serious Adverse Events (SAEs) Possibly Related to Study Drug

An effective dosage regimen for the treatment of hematological malignancies may be about 50 mg/m ² to about 80 mg/m ² per week for three weeks, and another effective dosage regimen for the treatment of hematological malignancies is about 55 mg/m ² to about 80 mg/m 2 per week. About 75mg/m ² for three weeks. Other effective dosing regimens for the treatment of hematological malignancies include weekly administration of 60 mg/m ² , 65 mg/m ² , 70 mg/m ² or 75 mg/m ² for three weeks.

Other effective dosing regimens for the treatment of hematological malignancies may include administration of about 25 mg/ ^m2 to about 50 mg/m2 twice weekly for ^two weeks. Another effective dose for the treatment of hematologic malignancies is about 30 mg/ ^m2 to about 45 mg/m2 administered twice weekly for ^two weeks. Other effective doses for the treatment of hematological malignancies include 30, 35, 40 or 45 mg/m2 administered twice weekly for ^two weeks.

The above-mentioned embodiments in the present invention are only exemplary, and those skilled in the art will know or can determine many equivalents of specific compounds, materials and steps through routine experiments. All such equivalents are considered to be within the scope of this invention and are covered by the claims.

Claims (24)

1. A method for the treatment of acute myeloid leukemia comprising administering to a human with acute myeloid leukemia a dose of 50-90 mg/m Optically pure ( ⁺ )-1,4-dihydro-7-[(3S ,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid. 2. The method of claim 1, wherein the acute myeloid leukemia is myeloblastic leukemia or promyelocytic leukemia. 3. The method of claim 1, wherein the leukemia is relapsed, refractory, or resistant to a therapy selected from surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy, immunotherapy, transfusion, and combinations thereof Receptivity. 4. The method of claim 1, wherein the dose is 50 mg/ ^m2 to 80 mg/m2 administered once a week for at least ^two weeks. 5. The method of claim 4, wherein the dose is 55 mg/ ^m2 to 75 mg/ ^m2 . 6. The method of claim 5, wherein the dose is 60 mg/ ^m2 . 7. The method of claim 5, wherein the dose is 65 mg/ ^m2 . 8. The method 5 of claim 5, wherein the dose is 70 mg/ ^m2 . 9. The method 5 of claim 5, wherein the dose is 75 mg/ ^m2 . 10. The method of claim 1, wherein said dose is administered weekly for at least three weeks. 11. The method of claim 1, wherein said dose is administered twice weekly. 12. The method of claim 11, wherein the dose is 80 mg/ ^m2 to 90 mg/ ^m2 . 13. The method of claim 11, wherein the dose is 65 mg/ ^m2 to 75 mg/ ^m2 . 14. The method of claim 11, wherein said dose is administered for two weeks. 15. The method of claim 1, wherein the optically pure (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrole Alkyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid was administered as IV injection. 16. The method of claim 1, wherein said dose is administered as a 10-15 minute IV bolus. 17. A method for treating acute myeloid leukemia, comprising administering optically pure ( ⁺ )-l,4-dihydro-7-[(3S ,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid. 18. A method for treating acute myeloid leukemia comprising administering optically pure ( ⁺ )-l,4-dihydro-7-[(3S ,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid. 19. The method of claim 17 or 18, wherein the acute myeloid leukemia is myeloblastic leukemia or promyelocytic leukemia. 20. The method of claim 17 or 18, wherein the leukemia is relapsed, refractory or to a therapy selected from surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy, immunotherapy, blood transfusion, and combinations thereof Tolerated. 21. The method of claim 17 or 18, wherein the dose is administered weekly for three weeks. 22. The method of claim 17 or 18, wherein the dose is administered twice a week. 23. The method of claim 17 or 18, wherein the optically pure (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1 - Pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid administered as IV injection. 24. The method of claim 17 or 18, wherein the dose is administered as a 10-15 minute IV bolus.